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To determine prevalence of probable polypoidal choroidal vasculopathy (PCV) among White patients with neovascular age-related macular degeneration (nAMD) using non-indocyanine green angiography (ICGA) criteria DESIGN: Multicenter, multinational, retrospective, cross-sectional study.A total of 208 treatment-naive eyes from Hispanic and non-Hispanic White individuals diagnosed with nAMD were included. All underwent color fundus photography (CFP), optical coherence tomography (OCT), and fluorescein angiography (FFA). De-identified images of study eyes were sent to 2 groups of graders. Group 1 reviewed CFP, OCT, and FFA to confirm nAMD diagnosis. Group 2 reviewed CFP and OCT to determine highly suggestive features for PCV. Probable PCV diagnosis defined as the presence of ≥2 of 4 highly suggestive features for PCV: notched or fibrovascular pigment epithelial detachment (PED) on CFP, sharply-peaked PED, notched PED, and hyperreflective ring on OCT.Eleven eyes were excluded because of poor image quality (6) or non-nAMD diagnosis (5). Of 197 eligible eyes (197 patients), the mean age (SD) was 78.8 years (8.9), 44.2% were men, 26.4% were Hispanic, and 73.6% were non-Hispanic White individuals; 41.1%, 23.4%, 9.1%, and 2.5% had ≥1, ≥2, ≥3, and 4 highly suggestive features. Results showed that 23.4% (95% CI, 17.6%-29.9%) had probable PCV diagnosis. Predominantly occult CNV was more frequently found in probable PCV than nAMD subgroup (84.8% vs 64.9%, P = .01). Hispanic White individuals had a lower prevalence of probable PCV than non-Hispanic White individuals (9.6% vs 28.2%, P = .006) CONCLUSIONS: These findings suggest that probable PCV occurs between 17.6% and 29.9% in White individuals with nAMD, and more commonly in non-Hispanic than in Hispanic White individuals.

To develop a classification system of visual field (VF) abnormalities in highly myopic eyes with and without glaucoma.Secondary analysis of VF data from a longitudinal cohort study.One thousand eight hundred ninety-three VF tests from 1302 eyes (825 individuals).All participants underwent VF testing (Humphrey 24-2 Swedish interactive threshold algorithm standard program; Carl Zeiss Meditec) and detailed ophthalmic examination. A comprehensive set of VF defect patterns was defined via observation of the 1893 VF reports, literature review, and consensus meetings. The classification system comprised 4 major types of VF patterns, including normal type, glaucoma-like defects (paracentral defect, nasal step, partial arcuate defect, arcuate defect), high myopia-related defects (enlarged blind spot, vertical step, partial peripheral rim, nonspecific defect), and combined defects (nasal step with enlarged blind spot). A subset (n = 1000) of the VFs was used to evaluate the interobserver and intraobserver agreement and weighted κ values of the classification system by 2 trained readers. The prevalence of various VF patterns and their associated factors were determined.The classification of VF in highly myopic eyes and its associated risk factors.We found that normal type, glaucoma-like defects, high myopia-related defects, and combined defects accounted for 74.1%, 10.8%, 15.0%, and 0.1% of all unique VF tests, respectively. The interobserver and intraobserver agreements were89%, and the corresponding κ values were 0.86 or more between readers. Both glaucoma-like and high myopia-related VF defects were associated with older age (odds ratios [ORs], 1.07 [95% confidence interval (CI), 1.04-1.10; P0.001] and 1.06 [95% CI, 1.04-1.10; P0.001]) and longer axial length (ORs, 1.65 [95% CI, 1.32-2.07; P0.001] and 1.37 [95% CI, 1.11-1.68; P = 0.003]). Longer axial length showed a stronger effect on the prevalence of glaucoma-like VF defects than on the prevalence of high myopia-related VF defects (P = 0.036).We propose a new and reproducible classification system of VF abnormalities for nonpathologic high myopia. Applying a comprehensive classification system will facilitate communication and comparison of findings among studies.

PURPOSE: Since eyes with center-involved diabetic macular edema (CI-DME) and good baseline visual acuity (VA) showed no difference in VA loss when managed initially with observation, laser, or aflibercept, understanding the estimated costs of these strategies to the US population is relevant for health care planning. METHODS, SETTING, AND PARTICIPANTS: Total costs for managing participants with CI-DME and good baseline VA assigned to aflibercept (n= 236), laser (n=240), or observation (n = 236) during the 2-year trial were calculated. Using epidemiological data and extrapolating costs, 10-year costs for caring for persons with CI-DME and good baseline VA throughout the US was estimated. INTERVENTIONS: Observation or laser groups initiated aflibercept if VA decreased. Aflibercept group received injections up to every 4 weeks. MAIN OUTCOMES AND MEASURES: Estimated 10-year U.S. population costs to manage CI-DME with good VA. RESULTS: Assuming all patients in the US with CI-DME and good baseline VA received aflibercept initially, 10-year costs were projected to be $28.80 billion compared with $14.42 billion if initially receiving laser treatment or $15.70 billion if initially observed, with aflibercept added if VA worsened in the laser or observation arms. CONCLUSIONS AND RELEVANCE: Similar VA outcomes on average are obtained by initially managing CI-DME and good baseline VA with laser or observation strategies instead of immediately using aflibercept. While any one of these three strategies might be warranted depending on an individual’s specific circumstances, on a societal level, cost savings might be achieved with these first two approaches. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01909791

Purpose To investigate the natural history and genetic associations of drusenoid pigment epithelial detachment (DPED) associated with age-related macular degeneration (AMD). Design Retrospective analysis of a prospective cohort study. Participants Of the 4203 Age-Related Eye Disease Study 2 (AREDS2) participants, 391 eyes (325 participants) had DPED without late AMD at the time of DPED detection. Genetic analyses included 120 white AREDS2 participants and 145 Age-Related Eye Disease Study (AREDS) participants with DPED. Methods Baseline and annual stereoscopic fundus photographs were graded centrally to detect DPED, a well-defined yellow elevated mound of confluent drusen ≥433 μm in diameter, and to evaluate progression rates to late AMD: geographic atrophy (GA) and neovascular (NV)-AMD. Five single nucleotide polymorphisms (CFH [rs10611670], C3 [rs2230199], CFI [rs10033900], C2/CFB [rs114254831], ARMS2 [rs10490924]) and genetic risk score (GRS) group were investigated for association with DPED development. Kaplan–Meier analyses and multivariable proportional hazard regressions were performed. Main Outcome Measures Progression rates to late AMD and decrease of ≥3 lines in visual acuity (VA) from the time of DPED detection; association of rate of DPED development with genotype. Results Mean (standard deviation [SD]) follow-up time from DPED detection was 4.7 (0.9) years. DPED was associated with increased risk of progression to late AMD (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.98–2.82; P Conclusions This study replicates the results of previous natural history studies of eyes with DPED including the high rates of progression to late AMD and vision loss (regardless of progression to late AMD). The genetic associations are consistent with genes associated with AMD progression.

Purpose To analyze the prevalence, incidence, and clinical characteristics of eyes with geographic atrophy (GA) in age-related macular degeneration (AMD), including clinical and genetic factors affecting enlargement. Design Prospective cohort study within a controlled clinical trial. Participants Age-Related Eye Disease Study 2 (AREDS2) participants, aged 50–85 years. Methods Baseline and annual stereoscopic color fundus photographs were evaluated for GA presence and area. Analyses included GA prevalence and incidence rates, Kaplan-Meier rates, mixed-model regression, and multivariable analysis of the square root of GA, area adjusted for covariates, including clinical/imaging characteristics and genotype. Main Outcome Measures (1) Presence or development of GA; (2) change in the square root of GA area over time. Results At baseline, 517 eyes (6.2%) of 411 participants (9.8%) had pre-existing GA (without neovascular AMD), with the following characteristics: 33% central, 67% noncentral; and the following configurations: 36% small, 26% solid/unifocal, 24% multifocal, 9% horseshoe/ring, and 6% indeterminate. Of the remaining 6530 eyes at risk, 1099 eyes (17.3%) of 883 participants developed incident GA without prior neovascular disease during mean follow-up of 4.4 years. The Kaplan-Meier rate of incident GA was 19% of eyes at 5 years. In eyes with incident GA, 4-year risk of subsequent neovascular AMD was 29%. In eyes with incident noncentral GA, 4-year risk of central involvement was 57%. GA enlargement rate (following square root transformation) was similar in eyes with pre-existing GA (0.29 mm/year; 95% confidence interval 0.27–0.30) and incident GA (0.28 mm/year; 0.27–0.30). In the combined group, GA enlargement was significantly faster with noncentrality, multifocality, intermediate baseline size, and bilateral GA (P Conclusions Analyses of AREDS2 data on natural history of GA provide representative data on GA evolution and enlargement. GA enlargement, which was influenced by lesion features, was relentless, resulting in rapid central vision loss. The genetic variants associated with faster enlargement were partially distinct from those associated with risk of incident GA. These findings are relevant to further investigations of GA pathogenesis and clinical trial planning.

PURPOSE: Assess systemic vascular endothelial growth factor-A (VEGF) levels after treatment with intravitreous aflibercept, bevacizumab or ranibizumab. DESIGN: Comparative-effectiveness trial with participants randomly assigned to 2-mg aflibercept, 1.25-mg bevacizumab, or 0.3-mg ranibizumab following a retreatment algorithm. PARTICIPANTS: Participants with available plasma samples (N=436) METHODS: Plasma samples were collected before injections at baseline, 4-week, 52-week and 104-week visits. In a pre-planned secondary analysis, systemic free-VEGF levels from an ELISA immunoassay were compared across anti-VEGF agents and correlated with systemic side effects. MAIN OUTCOME MEASURES: Changes in the natural log (ln) of plasma VEGF levels. RESULTS: Baseline free-VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were −0.30±0.61, −0.31±0.54, −0.02±0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted CI; P-value) were −0.01 (−0.12, +0.10; P=0.89), −0.31 (−0.44, −0.18; P

Geographic atrophy (GA) is an advanced form of age-related macular degeneration characterized by progressive, irreversible visual function loss. This analysis evaluates the psychometric properties of the 25-Item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) composite, near activity, and distance activity scores in patients with GA.Reliability and validity study.Reliability and validity were tested with NEI VFQ-25 data collected from 100 subjects with GA from United States' sites of the phase 2 Mahalo study of lampalizumab (ClinicalTrials.gov identifier: NCT01229215).Strong internal consistency and reproducibility were demonstrated for the NEI VFQ-25 composite (Cronbach's α, 0.95; intraclass correlation coefficient [ICC], 0.86), near activity (Cronbach's α, 0.84; ICC, 0.80), and distance activity (Cronbach's α, 0.84; ICC, 0.84) scores. Convergent validity with the binocular measures, Minnesota Low-Vision Reading Test (MNRead) reading speed and Functional Reading Independence (FRI) index score, was demonstrated for baseline NEI VFQ-25 composite (Pearson correlation [r] = 0.61 and 0.69, respectively), near activities (r = 0.69 and 0.73), and distance activities (r = 0.57 and 0.64) scores. Known-group validity testing for baseline mean NEI VFQ-25 scores (composite, near activities, and distance activities) showed differences between patients with mean maximum MNRead reading speed ≥ 80 vs80 words per minute, and between mean FRI index score ≥ 2.5 vs2.5 (all P.0001).Psychometric evidence supports the NEI VFQ-25 as a reliable and valid cross-sectional measure of the impact of GA on patient visual function and vision-related quality of life.

The purpose of this study was to examine the influence of students' seating location in a large, lecture-style university course on student engagement, attention, classroom learning experience, and course performance. Participants (N = 407) were students in two cohorts of an undergraduate financial accounting course at a large university in the United States. They participated in the Experience Sampling Method measuring their self-reported seating location, engagement, attention, and other experiential dimensions throughout the one-semester course. Results showed that students reported lower engagement, attention, and quality of classroom experience when sitting in the back of the classroom than when sitting in the middle or front. Those sitting in the back of the classroom most of the time also received lower course grades. Engagement, attention, and other experiential factors mediated the influence of seating location on course grade. Multilevel models revealed both within-student and between-student effects of seating on classroom experience.

Purpose To compare patient-centered outcomes in patients with proliferative diabetic retinopathy (PDR) treated with ranibizumab vs panretinal photocoagulation (PRP). Design Randomized clinical trial. Methods Setting: Multicenter (55 U.S. sites). Patient Population: Total of 216 adults with 1 study eye out of 305 adults (excluding participants with 2 study eyes, because each eye received a different treatment) with PDR, visual acuity 20/320 or better, no history of PRP. Intervention: Ranibizumab (0.5 mg/0.05 mL) vs PRP. Main Outcome Measures: Change from baseline to 2 years in composite and prespecified subscale scores from the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25), University of Alabama Low Luminance Questionnaire (UAB-LLQ), and Work Productivity and Activity Impairment Questionnaire (WPAIQ). Results For the NEI VFQ-25 and UAB-LLQ composite scores, ranibizumab–PRP treatment group differences (95% CI) were +4.0 (-0.2, +8.3, P = .06) and +1.8 (-3.5, +7.1, P = 0.51) at 1 year, and +2.9 (-1.5, +7.2, P = .20) and +2.3 (-2.9, +7.5, P = .37) at 2 years, respectively. Work productivity loss measured with the WPAIQ was 15.6% less with ranibizumab (-26.3%, −4.8%, P = .005) at 1 year and 2.9% (-12.2%, +6.4%, P = .54) at 2 years. Eighty-three ranibizumab participants (97%) were 20/40 or better in at least 1 eye (visual acuity requirement to qualify for an unrestricted driver's license in many states) at 2 years compared with 82 PRP participants (87%, adjusted risk ratio = 1.1, 95% CI: 1.0, 1.2, P = .005). Conclusions Though differences in some work productivity and driving-related outcomes favored ranibizumab over PRP, no differences between treatment regimens for PDR were identified for most of the other patient-centered outcomes considered.

Purpose To provide 2-year results comparing anti–vascular endothelial growth factor (VEGF) agents for center-involved diabetic macular edema (DME) using a standardized follow-up and retreatment regimen. Design Randomized clinical trial. Participants Six hundred sixty participants with visual acuity (VA) impairment from DME. Methods Randomization to 2.0-mg aflibercept, 1.25-mg repackaged (compounded) bevacizumab, or 0.3-mg ranibizumab intravitreous injections performed up to monthly using a protocol-specific follow-up and retreatment regimen. Focal/grid laser photocoagulation was added after 6 months if DME persisted. Visits occurred every 4 weeks during year 1 and were extended up to every 4 months thereafter when VA and macular thickness were stable. Main Outcome Measures Change in VA, adverse events, and retreatment frequency. Results Median numbers of injections were 5, 6, and 6 in year 2 and 15, 16, and 15 over 2 years in the aflibercept, bevacizumab, and ranibizumab groups, respectively (global P = 0.08). Focal/grid laser photocoagulation was administered in 41%, 64%, and 52%, respectively (aflibercept vs. bevacizumab, P P = 0.04; bevacizumab vs. ranibizumab, P = 0.01). At 2 years, mean VA improved by 12.8, 10.0, and 12.3 letters, respectively. Treatment group differences varied by baseline VA ( P = 0.02 for interaction). With worse baseline VA (20/50 to 20/320), mean improvement was 18.1, 13.3, and 16.1 letters, respectively (aflibercept vs. bevacizumab, P = 0.02; aflibercept vs. ranibizumab, P = 0.18; ranibizumab vs. bevacizumab, P = 0.18). With better baseline VA (20/32 to 20/40), mean improvement was 7.8, 6.8, and 8.6 letters, respectively ( P > 0.10, for pairwise comparisons). Anti-Platelet Trialists' Collaboration (APTC) events occurred in 5% with aflibercept, 8% with bevacizumab, and 12% with ranibizumab (global P = 0.047; aflibercept vs. bevacizumab, P = 0.34; aflibercept vs. ranibizumab, P = 0.047; ranibizumab vs. bevacizumab, P = 0.20; global P = 0.09 adjusted for potential confounders). Conclusions All 3 anti-VEGF groups showed VA improvement from baseline to 2 years with a decreased number of injections in year 2. Visual acuity outcomes were similar for eyes with better baseline VA. Among eyes with worse baseline VA, aflibercept had superior 2-year VA outcomes compared with bevacizumab, but superiority of aflibercept over ranibizumab, noted at 1 year, was no longer identified. Higher APTC event rates with ranibizumab over 2 years warrants continued evaluation in future trials.

Objective To report the 3-year follow-up results within a previously reported randomized trial evaluating prompt versus deferred (for ≥24 weeks) focal/grid laser treatment in eyes treated with intravitreal 0.5 mg ranibizumab for diabetic macular edema (DME). Design Multicenter, randomized clinical trial. Participants Three hundred sixty-one participants with visual acuity of 20/32 to 20/320 (approximate Snellen equivalent) and DME involving the fovea. Methods Ranibizumab every 4 weeks until no longer improving (with resumption if worsening) and random assignment to prompt or deferred (≥24 weeks) focal/grid laser treatment. Main Outcome Measures Best-corrected visual acuity and safety at the 156-week (3-year) visit. Results The estimated mean change in visual acuity letter score from baseline through the 3-year visit was 2.9 letters more (9.7 vs. 6.8 letters; mean difference, 2.9 letters; 95% confidence interval, 0.4–5.4 letters; P = 0.02) in the deferral group compared with the prompt laser treatment group. In the prompt laser treatment group and deferral group, respectively, the percentage of eyes with a ≥10-letter gain/loss was 42% and 56% ( P = 0.02), whereas the respective percentage of eyes with a ≥10-letter gain/loss was 10% and 5% ( P = 0.12). Up to the 3-year visit, the median numbers of injections were 12 and 15 in the prompt and deferral groups, respectively ( P = 0.007), including 1 and 2 injections, respectively, from the 2-year up to the 3-year visit. At the 3-year visit, the percentages of eyes with central subfield thickness of 250 μm or more on time-domain optical coherence tomography were 36% in both groups ( P = 0.90). In the deferral group, 54% did not receive laser treatment during the trial. Systemic adverse events seemed to be similar in the 2 groups. Conclusions These 3-year results suggest that focal/grid laser treatment at the initiation of intravitreal ranibizumab is no better, and possibly worse, for vision outcomes than deferring laser treatment for 24 weeks or more in eyes with DME involving the fovea and with vision impairment. Some of the observed differences in visual acuity at 3 years may be related to fewer cumulative ranibizumab injections during follow-up in the prompt laser treatment group. Follow-up through 5 years continues. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

Purpose To assess the development of vision-threatening lesions at least 3.5 years after initiating anti-vascular endothelial growth factor (VEGF) for choroidal neovascularization (CNV) in eyes with age-related macular degeneration (AMD). Design Retrospective cohort study. Participants A total of 75 patients (81 eyes) with CNV secondary to AMD who received intravitreous anti-VEGF treatment and were followed for at least 3.5 years after initiating treatment. Methods Retrospective record review of patients initiating anti-VEGF treatment between November 2005 and June 2008 at a university-based institution for whom at least 3.5 years of follow-up was available at the same institution. Main Outcome Measures Predominantly hemorrhagic lesions or geographic atrophy (GA). Results Among 75 patients (81 eyes; 59% were women; median age, 78 years), mean follow-up was 4.9 years and at least 6 years for 40%. Median visual acuity (VA) was 20/80 (interquartile range [IQR], 20/50–20/100) initially, 20/63 (IQR, 20/40–20/160) at 2 years, 20/80 (IQR, 20/40–20/200) at 3.5 years, and 20/63 (IQR 20/32–20/200) at 6 years. Six eyes (7%) had predominantly hemorrhagic lesions initially, whereas this developed in an additional 3 eyes (4%, 95% confidence interval [CI], 1% to 10%) in 3.5 years and in 1 additional eye (1%, 95% CI, 0.03% to 7%) at more than 3.5 years of follow-up. Initially, GA within or overlapping the boundary of the entire CNV was present in 4 eyes (5%) and outside this boundary in 8 eyes (10%). Geographic atrophy enlarged in each eye over time. The only eyes that developed GA outside the CNV boundary were those that had GA outside the lesion at baseline. Additional atrophy within the boundary of CNV defined at baseline, termed "atrophic disciform scars," developed in 5 eyes (6%), all within 4 years of treatment initiation. Conclusions Longer-term follow-up of neovascular AMD managed with anti-VEGF therapy suggests that predominantly hemorrhagic lesions may develop within 3.5 years of initiating therapy and more than 3.5 years after initiating therapy. In contrast, new areas of GA beyond the boundaries of the CNV lesion as defined at initiation of anti-VEGF therapy seem unlikely to develop if there is no GA outside of the CNV lesion initially.

Objective To examine the effects of intravitreal ranibizumab (Lucentis; Genentech, Inc., South San Francisco, CA) treatment on patient-reported vision-related function, as assessed by 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) scores, in patients with visual impairment secondary to center-involved diabetic macular edema (DME). Design Within 2 randomized, double-masked, phase 3 clinical trials (RIDE [A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema {ME} With Center Involvement Secondary to Diabetes Mellitus; NCT00473382] and RISE [A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema {ME} With Center Involvement Secondary to Diabetes Mellitus; NCT00473330]), the NEI VFQ-25 was administered at baseline and at the 6-, 12-, 18-, and 24-month follow-up visits. Participants Three hundred eighty-two (100%) RIDE patients and 377 (100%) RISE patients. Intervention Patients were randomized 1:1:1 to monthly injections of intravitreal ranibizumab 0.3 or 0.5 mg or sham. Study participants could receive macular laser for DME from month 3 onward if specific criteria were met. Main Outcome Measures Exploratory post hoc analysis of mean change from baseline in NEI VFQ-25 scores at 12 and 24 months. Results Across all treatment arms, 13% to 28% of enrolled eyes were the better-seeing eye. For all eyes in RIDE and RISE, the mean change in NEI VFQ-25 composite score improved more in ranibizumab-treated eyes at both the 12- and 24-month visits compared with sham treatment. For the better-seeing eyes at baseline, the mean change in composite score with 0.3 mg ranibizumab at the 24-month visit was 10.9 more (95% confidence interval [CI], 2.5–19.2) than sham for RIDE patients and 1.3 more (95% CI, −10.5 to 13.0) than sham for RISE patients. For the worse-seeing eyes at baseline, the mean change in composite score with 0.3 mg ranibizumab at the 24-month visit was 1.0 more (95% CI, −4.7 to 6.7) than sham for RIDE patients and 1.8 more (95% CI, −2.7 to 6.2) than sham for RISE patients. Similar results for most of these outcomes were seen with 0.5 mg ranibizumab. Conclusions These phase 3 trials demonstrated that ranibizumab treatment for DME likely improves patient-reported vision-related function outcomes compared with sham, further supporting treatment of DME with ranibizumab.

Purpose Guidelines recommend daptomycin combination therapy as an option for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia after vancomycin failure. Recent data suggest that combining daptomycin with a β-lactam may have unique benefits; however, there are very limited clinical data regarding the use of ceftaroline with daptomycin. Methods All 26 cases from the 10 medical centers in which ceftaroline plus daptomycin was used for treatment of documented refractory staphylococcal bacteremia from March 2011 to November 2012 were included. In vitro (synergy studies, binding assays, cathelicidin LL-37 killing assays), and in vivo (virulence assays using a murine subcutaneous infection model) studies examining the effects of ceftaroline with daptomycin were also performed. Findings Daptomycin plus ceftaroline was used in 26 cases of staphylococcal bacteremia (20 MRSA, 2 vancomycin-intermediate S aureus , 2 methicillin-susceptible S aureus [MSSA], 2 methicillin-resistant S epidermidis ). Bacteremia persisted for a median of 10 days (range, 3–23 days) on previous antimicrobial therapy. After daptomycin plus ceftaroline was started, the median time to bacteremia clearance was 2 days (range, 1–6 days). In vitro studies showed ceftaroline synergy against MRSA and enhanced MRSA killing by cathelicidin LL-37 and neutrophils. Ceftaroline also induced daptomycin binding in MSSA and MRSA to a comparable degree as nafcillin. MRSA grown in subinhibitory concentrations of ceftaroline showed attenuated virulence in a murine subcutaneous infection model. Implications Ceftaroline plus daptomycin may be an option to hasten clearance of refractory staphylococcal bacteremia. Ceftaroline offers dual benefit via synergy with both daptomycin and sensitization to innate host defense peptide cathelicidin LL37, which could attenuate virulence of the pathogen.

Objective To report the 3-year follow-up results within a previously reported randomized trial evaluating prompt versus deferred (for ≥24 weeks) focal/grid laser treatment in eyes treated with intravitreal 0.5 mg ranibizumab for diabetic macular edema (DME). Design Multicenter, randomized clinical trial. Participants Three hundred sixty-one participants with visual acuity of 20/32 to 20/320 (approximate Snellen equivalent) and DME involving the fovea. Methods Ranibizumab every 4 weeks until no longer improving (with resumption if worsening) and random assignment to prompt or deferred (≥24 weeks) focal/grid laser treatment. Main Outcome Measures Best-corrected visual acuity and safety at the 156-week (3-year) visit. Results The estimated mean change in visual acuity letter score from baseline through the 3-year visit was 2.9 letters more (9.7 vs. 6.8 letters; mean difference, 2.9 letters; 95% confidence interval, 0.4–5.4 letters; P = 0.02) in the deferral group compared with the prompt laser treatment group. In the prompt laser treatment group and deferral group, respectively, the percentage of eyes with a ≥10-letter gain/loss was 42% and 56% ( P = 0.02), whereas the respective percentage of eyes with a ≥10-letter gain/loss was 10% and 5% ( P = 0.12). Up to the 3-year visit, the median numbers of injections were 12 and 15 in the prompt and deferral groups, respectively ( P = 0.007), including 1 and 2 injections, respectively, from the 2-year up to the 3-year visit. At the 3-year visit, the percentages of eyes with central subfield thickness of 250 μm or more on time-domain optical coherence tomography were 36% in both groups ( P = 0.90). In the deferral group, 54% did not receive laser treatment during the trial. Systemic adverse events seemed to be similar in the 2 groups. Conclusions These 3-year results suggest that focal/grid laser treatment at the initiation of intravitreal ranibizumab is no better, and possibly worse, for vision outcomes than deferring laser treatment for 24 weeks or more in eyes with DME involving the fovea and with vision impairment. Some of the observed differences in visual acuity at 3 years may be related to fewer cumulative ranibizumab injections during follow-up in the prompt laser treatment group. Follow-up through 5 years continues. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

Purpose To examine the impact of intravitreal ranibizumab on patient-reported visual function using the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) through 6 months in patients with macular edema (ME) secondary to branch or central retinal vein occlusion (RVO). Design Two multicenter, double-masked trials, which enrolled participants with ME secondary to branch or central RVO: the RanibizumaB for the Treatment of Macular Edema following BRAnch Retinal Vein Occlusion: Evaluation of Efficacy and Safety (BRAVO) trial or the Central Retinal Vein OcclUsIon Study: Evaluation of Efficacy and Safety (CRUISE) trial. Participants Three hundred ninety-seven BRAVO and 392 CRUISE patients. Methods Patients were randomized 1:1:1 to monthly sham, 0.3-mg, or 0.5-mg injections of ranibizumab for 6 months. Main Outcome Measures Although visual acuity was the main outcome measure for the trials, mean change from baseline in NEI VFQ-25 scores at month 6 was a secondary outcome measure. Results In BRAVO, among the 132, 134, and 131 patients randomized, respectively, to sham, 0.3 mg ranibizumab, or 0.5 mg ranibizumab, the study eye was the worse-seeing eye in 121 (91.7%), 118 (88.1%), and 125 (95.4%) patients and 123 (93.2%), 128 (95.5%), and 125 (95.4%), respectively, had a 6-month follow-up visit. In CRUISE, among the 130, 132, and 130 patients randomized, respectively, to sham, 0.3 mg ranibizumab, and 0.5 mg ranibizumab, the study eye was the worse-seeing eye in 117 (90.0%), 123 (93.2%), and 120 (92.3%) patients and 115 (88.5%), 129 (97.7%), and 119 (91.5%), respectively, had a 6-month follow-up visit. In both trials, patients treated with ranibizumab reported greater mean improvements in visual function, with substantial differences observed as early as month 1, including the NEI VFQ-25 composite score and near and distance activities subscales, compared with sham patients. P values for comparisons with sham for the composite score and these 2 subscales were Conclusions These results from the BRAVO and CRUISE trials indicate that patients with ME from RVOs treated with monthly ranibizumab report greater improvements in vision-related function compared with sham-treated patients through 6 months, even when a majority of patients present with RVOs in the worse-seeing eye. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

Purpose To determine the sensitivity of time domain optical coherence tomography (OCT) in detecting conversion to neovascular age-related macular degeneration (AMD) in eyes at high risk for choroidal neovascularization (CNV), compared with detection using fluorescein angiography (FA) as the gold standard. Design Prospective, multicenter, observational study. Participants Individuals aged ≥50 years with nonneovascular AMD at high risk of progressing to CNV in the study eye and evidence of neovascular AMD in the fellow eye. Methods At study entry and every 3 months through 2 years, participants underwent best-corrected visual acuity, supervised Amsler grid testing, preferential hyperacuity perimetry (PHP) testing, stereoscopic digital fundus photographs with FA, and OCT imaging. A central Reading Center graded all images. Main Outcomes Measures The sensitivity of OCT in detecting conversion to neovascular AMD by 2 years, using FA as the reference standard. Secondary outcomes included comparison of sensitivity, specificity, positive predictive value, and negative predictive value of OCT, PHP, and supervised Amsler grid relative to FA for detecting incident CNV. Results A total of 98 participants were enrolled; 87 (89%) of these individuals either completed the 24-month visit or exited the study after developing CNV. Fifteen (17%) study eyes had incident CNV confirmed on FA by the Reading Center. The sensitivity of each modality for detecting CNV was: OCT 0.40 (95% confidence interval [CI], 0.16–0.68), supervised Amsler grid 0.42 (95% CI, 0.15–0.72), and PHP 0.50 (95% CI, 0.23–0.77). Treatment for incident CNV was recommended by the study investigator in 13 study eyes. Sensitivity of the testing modalities for detection of CNV in these 13 eyes was 0.69 (95% CI, 0.39–0.91) for OCT, 0.50 (95% CI, 0.19–0.81) for supervised Amsler grid, and 0.70 (95% CI, 0.35–0.93) for PHP. Specificity of the OCT was higher than that of the Amsler grid and PHP. Conclusions Time-domain OCT, supervised Amsler grid, and PHP have low to moderate sensitivity for detection of new-onset CNV compared with FA. Optical coherence tomography has greater specificity than Amsler grid or PHP. Among fellow eyes of individuals with unilateral CNV, FA remains the best method to detect new-onset CNV. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

Objective To describe the underlying principles used to develop a web-based algorithm that incorporated intravitreal anti–vascular endothelial growth factor (anti-VEGF) treatment for diabetic macular edema (DME) in a Diabetic Retinopathy Clinical Research Network ( DRCR.net ) randomized clinical trial. Design Discussion of treatment protocol for DME. Participants Subjects with vision loss resulting from DME involving the center of the macula. Methods The DRCR.net created an algorithm incorporating anti-VEGF injections in a comparative effectiveness randomized clinical trial evaluating intravitreal ranibizumab with prompt or deferred (≥24 weeks) focal/grid laser treatment in eyes with vision loss resulting from center-involved DME. Results confirmed that intravitreal ranibizumab with prompt or deferred laser provides superior visual acuity outcomes compared with prompt laser alone through at least 2 years. Duplication of this algorithm may not be practical for clinical practice. To share their opinion on how ophthalmologists might emulate the study protocol, participating DRCR.net investigators developed guidelines based on the algorithm's underlying rationale. Main Outcome Measures Clinical guidelines based on a DRCR.net protocol. Results The treatment protocol required real-time feedback from a web-based data entry system for intravitreal injections, focal/grid laser treatment, and follow-up intervals. Guidance from this system indicated whether treatment was required or given at investigator discretion and when follow-up should be scheduled. Clinical treatment guidelines, based on the underlying clinical rationale of the DRCR.net protocol, include repeating treatment monthly as long as there is improvement in edema compared with the previous month or until the retina is no longer thickened. If thickening recurs or worsens after discontinuing treatment, treatment is resumed. Conclusions Duplication of the approach used in the DRCR.net randomized clinical trial to treat DME involving the center of the macula with intravitreal ranibizumab may not be practical in clinical practice, but likely can be emulated based on an understanding of the underlying rationale for the study protocol. Inherent differences between a web-based treatment algorithm and a clinical approach may lead to differences in outcomes that are impossible to predict. The closer the clinical approach is to the algorithm used in the study, the more likely the outcomes will be similar to those published. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

Objective To report expanded 2-year follow-up of a previously reported randomized trial evaluating intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid laser compared with focal/grid laser alone for treatment of diabetic macular edema (DME). Design Multicenter, randomized clinical trial. Participants A total of 854 study eyes of 691 participants with visual acuity of 20/32 to 20/320 (approximate Snellen equivalent) and DME involving the fovea. Methods Continuation of procedures previously reported for the randomized trial. Main Outcome Measures Best-corrected visual acuity and safety at the 2-year visit. Results At the 2-year visit, compared with the sham + prompt laser group, the mean change in the visual acuity letter score from baseline was 3.7 letters greater in the ranibizumab + prompt laser group (95% confidence interval adjusted for multiple comparisons [aCI], −0.4 to +7.7), 5.8 letters greater in the ranibizumab + deferred laser group (95% aCI, +1.9 to +9.8), and 1.5 letters worse in the triamcinolone + prompt laser group (95% aCI, −5.5 to +2.4). After the 1- to 2-year visit in the ranibizumab + prompt or deferred laser groups, the median numbers of injections were 2 and 3 (potential maximum of 13), respectively. At the 2-year visit, the percentages of eyes with central subfield thickness ≥250 μm were 59% in the sham + prompt laser group, 43% in the ranibizumab + prompt laser group, 42% in the ranibizumab + deferred laser group, and 52% in the triamcinolone + prompt laser group. No systemic events attributable to study treatment were apparent. Three eyes in 3 (0.8%) of 375 participants had injection-related endophthalmitis in the ranibizumab groups, whereas elevated intraocular pressure and cataract surgery were more frequent in the triamcinolone + prompt laser group. Conclusions The expanded 2-year results reported are similar to results published previously and reinforce the conclusions originally reported: Ranibizumab should be considered for patients with DME and characteristics similar to those of the cohort in this clinical trial, including vision impairment with DME involving the center of the macula. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

Purpose Visual acuity (VA) is the primary outcome measure in many studies involving eye diseases. A standard statistical approach for comparing a continuous measurement such as a VA letter score between 2 treatment groups is to perform a t test comparing the means. However, frequently a binary variable is created from the continuous VA letter score based on whether or not there has been a worsening (or gain) of ≥15 letters (equivalent to ≥3 lines), and a chi square or similar statistical test is performed to compare the proportions of success (or failure) between groups. The purpose of this article is to contrast these 2 approaches. Methods Clinical trial reports of retinal disorders were used to compare results using mean change in the VA letter score versus binary proportions created from the VA letter score. Additionally, analyses were performed using generated data to gain a perspective on the magnitude of differences that might be expected between the 2 methods. Results Studies from the literature showed that differences of 6% to 15% in ≥15-letter worsening corresponded to mean differences in letter scores between groups of 3.0 to 7.0 (approximately 0.6 to 1.4 lines). Analyses using generated data demonstrated that a mean improvement in the VA letter score of 5 corresponded to a doubling of the proportion of eyes with ≥15-letter improvement and a 28% relative reduction in the proportion of eyes with ≥15-letter worsening. Conclusions How VA data should be analyzed in a clinical trial depends to large extent on the research question. The frequently used outcome of ≥15-letter change has several drawbacks, including loss of efficiency (need for a larger sample), misclassification of the outcome, and potential for a ceiling or floor effect. Therefore, for most clinical trials we believe that the primary outcome analysis should be a comparison of changes in the VA letter score, and created binary variables should be reported as secondary outcomes. This approach maximizes the information gained from the data and accommodates both improvement and worsening of acuity.

To evaluate optical coherence tomography (OCT) reproducibility in patients with diabetic macular edema (DME).Prospective 1-day observational study.Two hundred twelve eyes of 107 patients with DME involving the macular center by clinical examination and OCT central subfield thickness ofor =225 microm.Retinal thickness was measured with the OCT3 system, and scans were evaluated by a reading center. Reproducibility of retinal thickness measurements was assessed, and 95% confidence intervals (CIs) for a change in thickness were estimated.Reproducibility of OCT-measured central subfield thickness.Reproducibility was better for central subfield thickness than for center point thickness (half-width of the 95% CI for absolute change, 38 microm vs. 50 microm, and for relative change, 11% vs. 17%, respectively; P0.001). The median absolute difference between replicate measurements of the central subfield was 7 microm (2%). Half-widths of the 95% CI for a change in central subfield thickness were 22, 23, 33, and 56 microm for scans with central subfield thicknesses of200, 200 to250, 250 to400, andor =400 microm, respectively. When expressed as percentage differences between 2 measurements, half-widths of the 95% CI for a change in central subfield thickness were 10%, 10%, 10%, and 13% for scans with central subfield thicknesses of200, 200 to250, 250 to400, andor =400 microm, respectively. We were unable to identify an effect on reproducibility of central subfield measurements with respect to the presence of cystoid abnormalities, subretinal fluid, vitreomacular traction, or reduced visual acuity. Reproducibility was better when both scans had a standard deviation (SD) of the center point of10.0% (half-width of the 95% CI for change, 33 microm vs. 56 microm; P0.001).Reproducibility is better for central subfield thickness measurements than for center point measurements, and variability is less with retinal thickness when expressed as a percent change than when expressed as an absolute change. A change in central subfield thickness exceeding 11% is likely to be real. Scans with an SD of the center point ofor =10.0% are less reproducible and should be viewed with caution when assessing the validity of an observed change in retinal thickness in patients with DME.

To assess the incidence or progression of macular edema (ME) after cataract surgery in diabetic patients using optical coherence tomography (OCT) and correlating this with degree of diabetic retinopathy or other risk factors.Prospective cohort study.Fifty diabetic eyes undergoing cataract surgery.Each eye underwent 7-field fundus photography no more than 3 months before surgery. Optical coherence tomography testing was performed within 4 weeks before surgery and at 1- and 3-month postoperative visits. Best-corrected visual acuity (BCVA) was recorded at each visit. Macular edema was defined as an increase of center point thickness on OCT30% from preoperative baseline.Changes in foveal thickness and BCVA.The incidence of ME on OCT was 22% (95% confidence interval, 13%-35%). The average increase in center point thickness at 1 month for eyes with ME was 202 microm, which resulted in a nearly 1-line loss of vision (0.07 logarithm of the minimum angle of resolution [logMAR] units) compared with eyes without ME gaining2 lines of vision (0.24 logMAR units) (P0.001). Eyes with no diabetic retinopathy developed minimal thickening of 18 mum and 14 mum at 1 and 3 months, respectively, associated with approximately 2 and 3 lines of improved vision, respectively (0.22 and 0.26 logMAR units). Eyes with moderate or severe nonproliferative diabetic retinopathy or proliferative diabetic retinopathy developed thickening of 145 mum and 131 mum at 1 and 3 months, respectively, associated with1 and 2 lines of improved visual acuity, respectively (0.08 and 0.17 logMAR units). This difference (P = 0.05) in thickening (127 microm and 117 mum at 1 and 3 months, respectively) was correlated inversely with visual improvement (r = -0.662). Both duration of diabetesor = 10 years (P = 0.04) and insulin dependence (P = 0.007) were associated with reduced visual improvement.Diabetic eyes have a high incidence of increased center point thickness on OCT after cataract surgery, associated with a loss of vision at 1 month, with limited visual recovery at 3 months. Treatment to prevent this might improve outcomes in similar individuals after surgery.

Purpose To report the enlargement rate of geographic atrophy (GA) over time, its relationship to size of atrophy at baseline and to prior enlargement rate, and the implications for designing future treatment trials for GA. Design Prospective natural history study of GA resulting from age-related macular degeneration. Participants Two hundred twelve eyes of 131 patients were included in the analysis. Methods Annual follow-up included stereo color fundus photographs. The areas of GA were identified and measured, and the rate of enlargement of the atrophy was assessed. Sample sizes for clinical trials using systemic treatment and uniocular treatment were determined. Main Outcome Measure Rate of enlargement of the atrophy. Results The median overall enlargement rate was 2.1 mm 2 /year (mean, 2.6 mm 2 /year). Eyes with larger areas of atrophy at baseline tended to have larger enlargement rates, but knowledge of prior rates of enlargement was the most significant factor in predicting subsequent enlargement rates. There was high concordance between the enlargement rates in the 2 eyes of patients with bilateral GA (correlation coefficient, 0.76). To detect a 25% reduction in enlargement rate for a systemic treatment (α, 0.05; power, 0.80; losses to follow-up, 15%), 153 patients each in a control and treatment group would be required for a trial with a 2-year follow-up period for each patient. For a uniocular treatment, 38 patients with bilateral GA would be required, with the untreated eye serving as a control for the treated eye. Conclusions Treatment trials for GA with an outcome variable of change in enlargement rate are feasible.

Objective To study effects of intravitreal pegaptanib (Macugen) on retinal neovascularization. Design Retrospective analysis of a randomized clinical trial. PARTICIPANTS, INTERVENTION, AND MAIN OUTCOME MEASURES: Individuals with retinal neovascularization identified from a multicenter, randomized, controlled trial evaluating pegaptanib for treatment of diabetic macular edema, with a best-corrected visual acuity letter score between 68 and 25 (approximate Snellen equivalent between 20/50 and 20/320) and receiving a sham injection or intravitreal pegaptanib (0.3 mg, 1 mg, 3 mg) administered at study entry, week 6, and week 12, with additional injections and/or focal photocoagulation as needed during the ensuing 18 weeks, up to a maximum of 6 pegaptanib/sham therapies, were evaluated. Scatter panretinal photocoagulation before study enrollment was permitted, but not within 6 months of randomization and study entry. Changes in retinal neovascularization were assessed on fundus photographs and fluorescein angiograms graded at a reading center in a masked fashion. Results Of 172 participants, 19 had retinal neovascularization in the study eye at baseline. Excluding 1 who had scatter photocoagulation 13 days before randomization and 2 with no follow-up photographs, 1 of the remaining 16 subjects had panretinal photocoagulation during study follow-up. Of these 16 subjects, 8 of 13 (62%) in a pegaptanib treatment group (including the one receiving panretinal photocoagulation), 0 of 3 in the sham group, and 0 of 4 fellow (nonstudy) eyes showed either regression of neovascularization on fundus photographs or regression or absence of fluorescein leakage from neovascularization (or both) at 36 weeks. In 3 of 8 with regression, neovascularization progressed at week 52 after cessation of pegaptanib at week 30. Conclusions Most subjects with retinal neovascularization at baseline assigned to pegaptanib showed regression of neovascularization by week 36. These findings suggest a direct effect of pegaptanib upon retinal neovascularization in patients with diabetes mellitus.

PURPOSE To present visual acuity (VA) and related findings from patients enrolled in one of the Submacular Surgery Trials (SST) evaluating surgical removal versus observation of subfoveal choroidal neovascularization secondary to age-related macular degeneration (SST Group N Trial). DESIGN Randomized clinical trial. PARTICIPANTS Eligible patients had age-related macular degeneration with subfoveal choroidal neovascularization, some with a classic pattern on fluorescein angiography, and best-corrected VA (BCVA) of 20/100 to 20/800 in one eye (study eye) that had received no treatment in the macula. Any contiguous blood had to account for

Purpose To compare grading of cytomegalovirus retinitis progression by two different fundus photograph reading centers (FPRCs). Design Patients with AIDS followed in an ophthalmology service were enrolled in a prospective epidemiologic study of the prevalence and incidence of resistant cytomegalovirus in vitro. Methods We compared masked replicate gradings by two different FPRCs of monthly fundus photographs for retinitis progression (onset of a separate new lesion or expansion of an existing lesion by ≥one-half disk diameter). Results For 77 patients, Kaplan-Meier plots of progression over time were similar between FPRCs (median time to progression, 65 vs 69 days). Agreement between FPRCs was 51% (kappa [κ] = .37, “fair”) on exact visit of progression (28 patients) or on absence of progression through follow-up (11 patients) and 62% (κ = .38) on progression visit ± 1 month. Eight of 12 patients with progression graded as more than 1 month apart were only 2 months apart. Considering each monthly visit as a choice point, overall agreement on progression was 78% (κ = .55, “moderate”). Baseline evaluation of retinitis showed 95% agreement on presence/absence and a concordance correlation coefficient of .75 for extent in combined zones 1 and 2. Rates of retinal loss over follow-up were estimated as 2.8%/month vs 2.0%/month (P = .015). Conclusions By adopting similar protocols and procedures, different FPRCs can achieve good agreement on presence and extent of cytomegalovirus retinitis. Further efforts to harmonize evaluation through ongoing comparison of gradings would likely improve agreement on retinitis progression.

Purpose To report 24-month vision and fluorescein angiographic outcomes from trials evaluating photodynamic therapy with verteporfin in patients with subfoveal choroidal neovascularization (CNV) caused by pathologic myopia. Design and setting Multicenter, double-masked, placebo-controlled, randomized clinical trial at 28 ophthalmology practices in Europe and North America. Participants Patients with subfoveal choroidal neovascular lesions caused by pathologic myopia measuring no more than 5400 micro m and best-corrected visual acuity (approximate Snellen equivalent) of 20/100 or better. Methods Similar to methods described for 1-year results with follow-up examinations beyond 1 year, continuing every 3 months (except Photograph Reading Center evaluations only at the month 24 examination). During the second year, the same regimen (with verteporfin or placebo as applied at baseline) was used if angiography showed fluorescein leakage from CNV. Main outcome measures The primary outcome was the proportion of eyes with fewer than 8 letters (approximately 1.5 lines) of visual acuity loss at the month 24 examination, adhering to an intent-to-treat analysis and using the last observation carried forward method to impute for any missing data. Results Seventy-seven of 81 patients (95%) in the verteporfin group, compared with 36 of 39 patients (92%) in the placebo group, completed the month 24 examination. At this time point, 29 of 81 verteporfin-treated patients (36%) compared with 20 of 39 placebo-treated patients (51%) lost at least 8 letters (P = 0.11). The distribution of change in visual acuity at the month 24 examination was in favor of a benefit for the cases assigned to verteporfin (P = 0.05). This included improvement by at least 5 letters (equivalent to at least 1 line) in 32 verteporfin-treated cases [40%] vs. five placebo-treated cases (13%) and improvement by at least 15 letters (equivalent to at least 3 lines) in 10 verteporfin-treated cases (12%) vs. zero placebo-treated cases. No additional photosensitivity adverse reactions or injection site adverse events were associated with verteporfin therapy in the second year of follow-up. Conclusions Verteporfin therapy for subfoveal CNV caused by pathologic myopia safely maintained a visual benefit compared with a placebo therapy through 2 years of follow-up. Although the primary outcome was not statistically significantly in favor of verteporfin therapy at 2 years as it had been at 1 year of follow-up, the distribution of change in visual acuity at the month 24 examination was in favor of the verteporfin-treated group and showed that this group was more likely to have improved visual acuity through the month 24 examination. The VIP Study Group recommends verteporfin therapy for subfoveal CNV resulting from pathologic myopia based on both the 1- and 2-year results of this randomized clinical trial.

Objective To evaluate the safety and effect on visual acuity of photodynamic therapy with verteporfin (Visudyne, Novartis AG) in patients with subfoveal choroidal neovascularization (CNV) secondary to the ocular histoplasmosis syndrome (OHS). Design Open-label, three-center, noncomparative prospective case series. Participants OHS patients with subfoveal CNV lesions no larger than 5400 μm in greatest linear dimension (GLD) with classic or occult CNV extending under the geometric center of the foveal avascular zone and best-corrected visual acuity letter score of 73 to 34 (approximate Snellen equivalent 20/40–20/200). Methods Twenty-six patients received verteporfin (6 mg/m 2 ) infused IV over 10 minutes. Fifteen minutes after the start of infusion, a laser light at 689 nm delivered 50 J/cm 2 at an intensity of 600 mW/cm 2 over 83 seconds using a spot size with a diameter 1000 μm larger than the GLD of the lesion. At 3-month follow-up examinations, retreatment with the same regimen was applied if angiography showed fluorescein leakage. Safety assessments were also made. Main outcome measures Visual function measurements were the changes from baseline in visual acuity and contrast sensitivity scores and the proportion of patients who, based on best-corrected visual acuity scores, (1) gained 7 or more letters, (2) lost 8 or more letters, and (3) lost 15 or more letters. Results One patient was omitted from the study at the month 3 examination for not meeting the visual acuity eligibility requirements at baseline. By the month 12 examination, but excluding any retreatment at that visit, patients had received an average of 2.9 treatments of a maximum of 4 possible treatments. The month 12 median improvement from baseline in visual acuity of the remaining 25 patients was 7 letters, and median contrast sensitivity improved by 2 letters. Median visual acuity improvement was also 7 letters when three patients, who failed to meet all photographic eligibility requirements at baseline, were excluded. At the month 12 examination, 14 (56%) patients gained 7 or more letters of visual acuity from baseline, whereas 4 (16%) patients lost 8 or more letters, of which 2 (8%) lost 15 or more letters. No serious systemic or ocular adverse events were reported. Conclusions Median visual acuity improved after verteporfin therapy for at least 1 year in a small uncontrolled prospective case series of patients with subfoveal CNV caused by OHS. Verteporfin therapy seemed to be safe and well tolerated in these patients. Two-year data from this study will provide important, additional information on the safety and effect of verteporfin therapy for the treatment of subfoveal CNV secondary to OHS.

Keywords: Photomedicine group Reference LPAS-ARTICLE-2001-009 Record created on 2007-07-20, modified on 2016-08-08

PURPOSE: To report complications and changes in vision during 2 years of follow-up of patients with age-related macular degeneration assigned randomly to surgical removal or to laser photocoagulation of subfoveal recurrent neovascular lesions in a pilot trial designed to test methods, to refine estimates of outcome rates, and to project patient accrual rates for a larger multicenter randomized trial to evaluate submacular surgery. PATIENTS AND METHODS: Eligible patients with previous laser photocoagulation of extrafoveal or juxtafoveal choroidal neovascularization secondary to age-related macular degeneration were enrolled at 15 collaborating clinical centers. Assignments to treatment arm were made by personnel at a central coordinating center. Adherence to eligibility criteria and treatment assignment was assessed centrally at a photograph reading center. Patients were examined at 3, 6, 12, and 24 months after treatment for data collection purposes. Outcome measures reported include treatment complications, adverse events, requirements for additional treatment, and 2-year changes in visual acuity from baseline. RESULTS: Of 70 patients enrolled, 36 were assigned to laser photocoagulation and 34 to submacular surgery; all were treated as assigned. One patient in each group died before the 2-year examination. Visual acuity was measured at the 2-year examination for 31 of the surviving patients (89%) in the laser arm and for 28 of the surviving patients (85%) in the surgery arm. The 2-year measurements for 36 of the 59 patients (61%) were made by an examiner masked to treatment assignment and to the identity of the study eye. Improvements and losses of visual acuity were observed in both treatment arms; 20 of 31 study eyes (65%) in the laser arm and 14 of 28 study eyes (50%) in the surgery arm had visual acuity 2 years after enrollment that was better than or no more than 1 line worse than the baseline level. Changes in visual acuity and the size of the central macular lesions from baseline to the 2-year examination were similar in the treatment arms. Few serious complications were observed in either arm at the time of initial treatment; serious adverse events were rare. During follow-up, 11 laser-treated eyes and 18 surgically treated eyes had additional intraocular procedures. CONCLUSIONS: The data from this pilot trial suggest no reason to prefer submacular surgery over laser photocoagulation for treatment of patients with age-related macular degeneration who have lesions similar to those studied in this pilot trial. Any clinical trial designed to compare submacular surgery with laser photocoagulation in eyes with age-related macular degeneration and subfoveal recurrent neovascular lesions must enroll several hundred patients in order to reach a statistically valid conclusion regarding differences between these two methods of treatment with respect to either changes in visual acuity or complication rates.

The Age-Related Eye Disease Study (AREDS) was initially conceived as a long-term multicenter, prospective study of the clinical course of age-related macular degeneration (AMD) and age-related cataract. Data on progression rates and risk factors from the study will increase understanding of the clinical course of both conditions, generate hypotheses about etiology, and aid in the design of clinical trials of potential interventions. In addition to collecting natural history data, AREDS includes a clinical trial of high-dose vitamin and mineral supplements for AMD and a clinical trial of high-dose vitamin supplements for cataract. The clinical trials were initiated largely because of the widespread public use in the United States of commercially available pharmacologic doses of vitamins and minerals to treat these two eye conditions and the absence of definitive studies on the safety and efficacy of their use. Important design issues for the clinical trials include: defining cataract and AMD, estimating event rates, determining the type and dosage of vitamins and minerals to be tested for each condition, and identifying the parameters necessary for monitoring safety and efficacy. This paper describes the AREDS design, including the study rationale and operational structure, and the approach adopted to combine, for two diseases, clinical trials with a natural history study. Control Clin Trials 1999;20:573–600

Objective To describe the progression of geographic atrophy (GA) from age-related macular degeneration (AMD) with respect to visual acuity (VA) loss and enlargement of atrophy. Design A prospectively observed case series. Setting Tertiary retinal referral center. Participants One hundred twenty-three patients with GA due to AMD who completed at least 1 year of follow-up (median follow-up, 3 years) were examined annually. Methods At each examination, a protocol best-corrected VA of each eye was measured, a clinical examination was performed, and color fundus photographs were taken. The areas of atrophy were drawn and measured. Main outcome measures Visual acuity loss and enlargement of total and central atrophy. Results At baseline, median VA was poorer with larger areas of atrophy, but there was wide variation related to sparing of the fovea. Thirty-one percent of all study eyes suffered a three-line VA loss from baseline by 2 years, and 53% had a three-line loss by 4 years. Those eyes with VA better than 20/50 had the highest rate of acuity loss; 27% of these eyes had acuities of 20/200 or worse at 4 years. Visual acuity loss in the GA study eye was similar in patients with bilateral GA and in those with choroidal neovascularization in the fellow eye. Total atrophy enlarged a median of 1.8 Macular Photocoagulation Study disc areas (DA) at 2 years; atrophy within a 4-DA circle centered on the fovea enlarged a median of 0.9 DA. Two (22%) of nine patients with GA in one eye and only drusen without advanced AMD in the fellow eye developed GA in the fellow eye at 2 years. Conclusions Geographic atrophy is associated with a significant decline in VA over time in many eyes. Areas of atrophy continue to enlarge over time, even when already large at baseline. The combination of reduced VA with enlargement of atrophy, occurring bilaterally in most patients, can lead to significant impairment of visual function.

Objective To determine the prevalence of age-related macular degeneration (AMD) and signs of age-related maculopathy in a population-based sample of blacks and whites 40 years of age or older from East Baltimore. Design Cross-sectional population-based study. Participants A total of 5308 black and white subjects received a screening eye examination that included fundus photography. Main outcome measures Stereoscopic color fundus photographs were graded for the presence and severity of drusen, pigmentary abnormalities, geographic atrophy, and choroidal neovascularization in the macula. Results Drusen ≥ 64μm were identified in about 20% of individuals in both groups, but large drusen (>125μm) were more common among older whites (15% for whites versus 9% for blacks over 70). Pigmentary abnormalities were also more common among older whites (7.9% for whites versus 0.4% for blacks over 70). Age-related macular degeneration was more prevalent among whites than blacks. The prevalence of AMD was 2.1% among whites over 70 years of age. No cases of AMD were detected among 243 black subjects in this age group. Logistic regression adjusting for age, sex and smoking (current, former, or never) detected an odds ratio of 4.4 (95% confidence interval: 1.5–12.4) for whites with AMD compared with blacks. Conclusion Although drusen are common in both blacks and whites over the age of 40, more severe forms of age-related maculopathy and late AMD are more prevalent in older whites.

Objective To determine the rate of developing choroidal neovascularization (CNV) in eyes with geographic atrophy (GA) from age-related macular degeneration (AMD) and the characteristics of the CNV in these eyes. Design Prospective natural history study with cohort analysis. Participants One hundred fifty-two patients with GA and no CNV by fluorescein angiography in at least 1 eye, with annual follow-up. Main outcome measures The development of CNV. Results Thirteen eyes with GA developed CNV. For patients with bilateral GA and no CNV at baseline, 2% developed CNV by 2 years and 11% by 4 years. For patients with CNV in the fellow eye, 18% developed CNV in the study eye with GA by 2 years and 34% by 4 years. The eyes that developed CNV experienced more acuity loss than did the eyes with only GA. Within the fellow eye CNV group, those study eyes with GA that had less central atrophy (and better acuity) at baseline were more likely to develop CNV. The CNV developed at a peripheral border of GA in nine eyes, in the spared foveal region in two eyes, and in both center and border in one eye. No eye developed CNV in the area of atrophy itself. The appearance of CNV was evanescent in some cases and had a final appearance of an enlarged area of GA. Twelve other eyes had hemorrhages without definite evidence of CNV; three were thought to be suspicious for CNV and the remainder were thought to be hemorrhages that may be seen in elderly patients. Conclusion An eye with GA whose fellow eye has CNV is at significant risk for the development of CNV in the GA eye. A patient with bilateral GA and no evidence of CNV is at relatively low risk for developing CNV. The CNV may be evanescent and may not be detected. Intraretinal hemorrhages unrelated to CNV are relatively common in this older population.

Objective To describe a cohort of patients with pars planitis followed at a single tertiary care institution, determine the frequency of multiple sclerosis and/or optic neuritis in patients with this disorder, and calculate gene frequencies of human leukocyte antigen (HLA) class II alleles in these patients. Design Fifty-three patients with the diagnosis of pars planitis underwent clinical record review or telephone interview for follow-up or both; 32 of these underwent phlebotomy for analysis of HLA class II alleles. Main outcome measures Outcomes included visual acuity, occurrence of multiple sclerosis and/or optic neuritis, and HLA class II gene frequencies. Results With a mean follow-up of 2 years, approximately 90% of patients maintained a visual acuity better than 20/40 in at least one eye. The most frequently encountered ophthalmic complications included cystoid macular edema, cataract, and epiretinal membrane formation. Of 37 patients with pars planitis who had medical or neurologic follow-up evaluations, 6 (16.2%) developed multiple sclerosis. The HLA-DR15 allele, coding for one of the two HLA-DR2 subtypes, was associated with pars planitis (odds ratio=2.86, 95% confidence interval=1.42–5.78, P = 0.004). Conclusions A common immunogenetic predisposition to multiple sclerosis and pars planitis may be associated with the HLA-DR15 allele. This association may represent genetic linkage to the HLA-DR locus or a role for the HLA-DR15 gene product in the pathogenesis of both of these diseases.

Purpose: To report a surgical method for translocation of the foveal retina in eyes with subfoveal choroidal neovascularization. Methods: In three eyes of three patients, a crescent-shaped, partial-thickness scleral resection was performed near the equator at either the superotemporal or the inferotemporal quadrant. A near-total retinal detachment was created; then the edges of the resected sclera were sutured, causing shortening of the sclera with subsequent reattachment of the retina, resulting in translocation of the fovea to an area overlying nonfoveal retinal pigment epithelium and choroid. Results: In three eyes of three patients, the fovea was surgically translocated to overlie retinal pigment epithelium that preoperatively was not underlying the fovea. In two patients, laser photocoagulation was applied to the choroidal neovascularization that, after translocation of the fovea, was no longer subfoveal, so that the photocoagulation was not associated with immediate visual loss. After a follow-up of 4 to 6 months, the visual acuity had improved in all patients (from 20/126 preoperatively to 20/70 in one patient, from 20/200 preoperatively to 20/70 in the second, and from 20/160 to 20/30 in the third). The patients noted distortion or tilting of the images, which improved over time. Conclusions: Limited foveal translocation may offer a therapeutic modality to preserve or improve vision in cases of subfoveal choroidal neovascularization. Additional follow-up is needed to assess the impact of potential complications associated with the surgical procedure, such as retinal detachment, proliferative vitreoretinopathy, and cataract, as well as the possibility of recurrent choroidal neovascularization.

Purpose To assess the use of the Nidek 3Dx simultaneous stereophotography camera in diabetic patients, comparing the detection of clinically significant macular edema by fundus biomicroscopy to detection by the Nidek 3Dx simultaneous fundus stereophotograph. Methods Two hundred eight eyes of 123 diabetic patients at the Wilmer Retinal Vascular Center were examined for this prospective study between August 1993 and October 1993. Each patient was examined by one of three retina specialists by contact lens biomicroscopy for clinically significant macular edema and foveal center thickening. Nidek 3Dx fundus stereophotographs were obtained and graded independently for clinically significant macular edema and foveal center thickening by a fourth ophthalmologist masked from the clinical examination findings. Percent agreement, kappa statistic, and weighted kappa statistic were determined for the two diagnostic methods. Results One hundred eighty-four (88%) of the 208 stereophotographs were of sufficient quality to detect clinically significant macular edema; 175 (84%) of the 208 stereophotographs detected foveal center thickening. The agreement between the clinician and the photographic grading, measured by weighted kappa, was 0.52 for clinically significant macular edema and 0.58 for foveal center thickening, representing fair to good agreement beyond chance. Agreement was improved when normal fundus Nidek stereophotographs were available as standards for comparison. Conclusions The Nidek 3Dx camera is suitable for photographic detection of clinically significant macular edema and may have a potential advantage over conventional cameras by achieving good-quality, gradable stereophotographs in a large proportion of photographed eyes.

Purpose We sought to identify specific fluorescein angiographic patterns that may have led to the diagnosis of questionable recurrent choroidal neovascularization. We evaluated follow-up information to determine whether any specific angiographic patterns could be used to identify patients at high risk for definite recurrence. Methods We identified fluorescein angiograms graded as questionable for recurrent choroidal neovascularization that were taken from a previous prospective study involving 401 consecutive follow-up visits of patients treated with photocoagulation for choroidal neovascularization. We reviewed these angiograms to identify specific angiographic patterns that might have led to the classification of questionable recurrent choroidal neovascularization. Angiograms from visits subsequent to a questionable recurrence were reviewed to determine which patterns, if any, were associated with an increased risk for a definite recurrence to develop later. Results Forty-four eyes (44 patients) with questionable recurrences (of which 40 had at least four months of follow-up) were categorized into six angiographic patterns. The three most common patterns included the following: (1) focal staining along the edge of the laser lesion (20 cases, 15 subsequently recurred); (2) blocked fluorescence from subretinal hemorrhage not documented at the previous visit (eight cases, five subsequently recurred); (3) speckled hyperfluorescence noted beyond the edge of the laser lesion (eight cases, six subsequently recurred). Conclusions Questionable recurrent choroidal neovascularization may be identified by specific angiographic patterns. Focal staining along the edge of the laser lesion and speckled hyperfluorescence were the patterns that were most likely to progress to definite recurrence.

Purpose: This report was designed to review the current knowledge about preventing the development or progression of age-related macular degeneration (AMD) and visual loss associated with this entity in practical terms for the comprehensive ophthalmologist. Methods: Animal studies, epidemiologic studies, and clinical trials identified through the use of MEDLINE, a reference list of articles reviewed, and personal contact with experts in this area provided information reviewed for this report. Results: Reports concerning ultraviolet and visible light provide limited, inconsistent, and conflicting data to support the theory that light exposure leads to AMD. Micronutrient supplementation is a provocative but largely unproven hypothesis. Positive associations of cigarette smoking and cardiovascular disease or certain risk factors for cardiovascular disease with AMD provide potential clues as to the underlying pathogenesis of AMD and are yet another reason to treat these health problems. Drusen may disappear after laser to the macula; however, this intervention will require careful, randomized, prospective trials to determine if this therapy can reduce the risk of choroidal neovascularization and visual loss developing in patients with AMD. Conclusions: It is reasonable to have individuals wear sunglasses for comfort and possible protection from ultraviolet light exposure to all ocular structures (especially the lens) at little or no risk to the patient. Physicians probably should be reluctant to prescribe micronutrients or suggest other interventions (such as laser to drusen) until their health claims have been substantiated and their long-term safety soundly established.

A common detection and classification system is needed for epidemiologic studies of age-related maculopathy (ARM). Such a grading scheme for ARM is described in this paper. ARM is defined as a degenerative disorder in persons > or = 50 years of age characterized on grading of color fundus transparencies by the presence of the following abnormalities in the macular area: soft drusen > or = 63 microns, hyperpigmentation and/or hypopigmentation of the retinal pigment epithelium (RPE), RPE and associated neurosensory detachment, (peri)retinal hemorrhages, geographic atrophy of the RPE, or (peri)retinal fibrous scarring in the absence of other retinal (vascular) disorders. Visual acuity is not used to define the presence of ARM. Early ARM is defined as the presence of drusen and RPE pigmentary abnormalities described above; late ARM is similar to age-related macular degeneration (AMD) and includes dry AMD (geographic atrophy of the RPE in the absence of neovascular AMD) or neovascular AMD (RPE detachment, hemorrhages, and/or scars as described above). Methods to take and grade fundus transparencies are described.

Cataract operations may be recommended when retinal disease is suspected but cannot be adequately diagnosed or treated because of lens opacity. We evaluated the outcome of cataract operations performed under those circumstances. We reviewed the records of 119 patients who were examined at the Wilmer Retinal Vascular Center and within three months underwent a cataract operation. We identified 17 patients (20 eyes) who underwent a cataract operation at the recommendation of a retinal specialist, to permit diagnosis, to determine eligibility for laser therapy, or to perform laser therapy. After the cataract operation, eight (40%) of the 20 eyes were found to have a retinal disease for which laser therapy was recommended, and six (30%) of the 20 eyes underwent laser therapy that, before the cataract operation, had been impossible. These results indicate that a cataract operation may be useful when lenticular opacity prevents diagnosis or treatment in a patient with a suspected retinal disorder.

Intravenous fluorescein angiography is a commonly performed and extraordinarily valuable diagnostic procedure. The frequency of adverse reactions after angiography has varied considerably in previous reports. In a prospective study of 2789 angiographic procedures in 2025 patients, the authors found that the percentage of adverse reactions depended strongly on the patient's angiographic history. Overall, adverse reactions followed 4.8% of the angiographic procedures. These reactions included nausea (2.9%), vomiting (1.2%), flushing/itching/hives (0.5%), and other reactions (dyspnea, syncope, excessive sneezing) (0.2%). No cases of anaphylaxis, myocardial infarction, pulmonary edema, or seizures occurred. The percentage of reactions was 1.8% for patients who had had previous angiography without ever having had an adverse reaction. In contrast, the percentage of reactions was 48.6% for patients who had had an adverse reaction to angiography previously.