Ronald Danis

Ophthalmol Retina. 2021 Jan;5(1):41-48. doi: 10.1016/j.oret.2020.07.006. Epub 2020 Jul 15.

ABSTRACT

PURPOSE: To compare geographic atrophy (GA) area and enlargement rate measured with spectral domain OCT (SD-OCT) with fundus autofluorescence (FAF), color fundus photography (CFP), and infrared reflectance (IR) imaging.

DESIGN: Retrospective, multicenter, natural history case series.

PARTICIPANTS: A total of 70 eyes with GA from 48 participants were included.

METHODS: Participants underwent SD-OCT, FAF, CFP, and IR imaging at baseline and 12 months in the study eye. Spectral domain OCT images were graded for GA area using 2 distinct criteria: (1) complete retinal pigment epithelium and outer retinal atrophy (cRORA) and (2) hypertransmission through Bruch's membrane. Areas were measured with SD-OCT using a custom-developed tool that allows for mapping areas of retinal layer loss on SD-OCT cross-sectional scans with co-registered IR images. Circularity index was calculated from area and perimeter. Spectral domain OCT images were also assessed for presence of reticular pseudodrusen, outer-retinal tubules, and hyporeflective wedge-shaped bands. Area of GA was measured in millimeters squared from FAF, CFP, and IR images.

MAIN OUTCOME MEASURES: Geographic atrophy mean baseline area and enlargement rate measured with 2 SD-OCT criteria, FAF, CFP, and IR.

RESULTS: At baseline, the mean GA area was 6.9 (standard deviation [SD], 4.7) mm² using the SD-OCT cRORA criteria and 7.3 (SD, 4.7) mm² using the SD-OCT hypertransmission criteria. The mean annual enlargement rate of GA was 1.6 (SD, 1.1) mm² using the SD-OCT cRORA criteria and 1.5 (SD, 1.0) mm² using the SD-OCT hypertransmission criteria. When comparing both SD-OCT grading criteria with FAF, CFP, and IR, there were no statistically significant differences in baseline area or annual enlargement rate of GA. Circularity index was identified as the risk factor for increased annual enlargement rate.

CONCLUSIONS: Measuring GA using retinal layer morphology provides a novel means of obtaining area measurements. Area measurements tend to vary based on criteria used and are comparable to other imaging modalities.

PMID:32679202 | DOI:10.1016/j.oret.2020.07.006

JAMA Ophthalmol. 2020 Jun 1;138(6):610-617. doi: 10.1001/jamaophthalmol.2020.0824.

ABSTRACT

IMPORTANCE: The Age-Related Eye Disease Study age-related macular degeneration (AREDS AMD) scale is designed to classify AMD severity. The present cohort study explored whether 2-year progression along this scale was useful for estimating the risk of future progression to late AMD or best-corrected visual acuity (BCVA) loss.

OBJECTIVE: To assess whether 2-year progression along the AREDS AMD scale can be used to estimate the probability of long-term clinically meaningful outcome measures for clinical trials or epidemiologic studies.

DESIGN, SETTING, AND PARTICIPANTS: Age-Related Eye Disease Study participants enrolled in a clinical trial of oral micronutrient supplements had annual color fundus photographs graded centrally using the AREDS AMD scale. Two-year progression (≥2-step and ≥3-step increases in AMD score between baseline and the 2-year study visit) was evaluated as a method of estimating the risk of long-term progression to late AMD or BCVA loss. The AREDS (1992-2001) was a randomized, placebo-controlled clinical trial based at 11 retinal specialty clinics in the United States. The dates of analysis in the present cohort study were November 1992 through November 2005.

MAIN OUTCOMES AND MEASURES: Development of neovascular (NV) AMD, central geographic atrophy (CGA), any geographic atrophy (GA), or BCVA loss of at least 2 lines or at least 3 lines.

RESULTS: Among 3868 participants in the AREDS free of late AMD at baseline, the mean (SD) age was 68.3 (5.0) years, and 2180 of 3868 (56.4%) were women. In the first 2 years after randomization to the AREDS, 669 of 7458 (9.0%) of eyes had at least 2-step 2-year progression, and 275 of 7458 (3.7%) of eyes had at least 3-step 2-year progression. In the 5-year follow-up period (years 2-7), 486 of 7223 (6.7%) of eyes developed NV AMD, 339 of 7253 (4.7%) developed CGA, 726 of 7246 (10.0%) developed any GA, 2622 of 7095 (37.0%) had at least 2-line BCVA loss, and 1494 of 7155 (20.9%) had at least 3-line BCVA loss. After adjusting for demographic and clinical confounders and stratifying by baseline AMD score, statistically significant associations were observed between at least 2-step and at least 3-step 2-year progression of AMD score and subsequent 5-year development of NV AMD: hazard ratios (HRs) ranged from 3.6 (99% CI, 2.4-5.2) to 19.4 (99% CI, 7.7-48.9). For CGA, HRs ranged from 2.6 (99% CI, 1.7-4.0) to 4.7 (99% CI, 2.5-8.9); the results were similar for any GA. For at least 2-line and at least 3-line BCVA loss, HRs ranged from 1.3 (99% CI, 1.0-1.7) to 2.8 (99% CI, 1.8-4.3). For all outcomes, at least 3-step 2-year progression had stronger associations than at least 2-step 2-year progression. These findings were also validated in the AREDS2 cohort.

CONCLUSIONS AND RELEVANCE: Two-year progression of AMD score was associated with progression to clinically meaningful anatomic (late AMD) and vision (≥2-line or ≥3-line loss) outcomes, suggesting that this scale may be useful for future clinical trials designed to slow the progression of AMD.

PMID:32271358 | PMC:PMC7146539 | DOI:10.1001/jamaophthalmol.2020.0824

Invest Ophthalmol Vis Sci. 2019 May 1;60(6):2218-2225. doi: 10.1167/iovs.18-26070.

ABSTRACT

PURPOSE: To evaluate relationships among retinal vascular caliber and biomarkers of systemic inflammation in patients with AIDS.

METHODS: A total of 454 participants with AIDS had retinal vascular caliber (central retinal artery equivalent and central retinal vein equivalent) determined from enrollment retinal photographs by reading center graders masked to clinical and biomarker information. Cryopreserved plasma specimens were assayed for inflammatory biomarkers, including C-reactive protein (CRP), IL-6, interferon-γ inducible protein (IP)-10, kynurenine/tryptophan (KT) ratio, and intestinal fatty acid binding protein (I-FABP).

RESULTS: In the simple linear regression of retinal vascular caliber on plasma biomarkers, elevated CRP, IL-6, and IP-10 were associated with retinal venular dilation, and elevated KT ratio with retinal arteriolar narrowing. In the multiple linear regression, including baseline characteristics and plasma biomarkers, AMD was associated with dilation of retinal arterioles (mean difference: 9.1 μm; 95% confidence interval [CI] 5.2, 12.9; P < 0.001) and venules (mean difference, 10.9 μm; 95% CI, 5.3, 16.6; P < 0.001), as was black race (P < 0.001). Hyperlipidemia was associated with retinal venular narrowing (mean difference, -7.5 μm; 95% CI, -13.7, -1.2; P = 0.02); cardiovascular disease with arteriolar narrowing (mean difference, -5.2 μm; 95% CI, -10.3, -0.1; P = 0.05); age with arteriolar narrowing (slope, -0.26 μm/year; 95% CI, -0.46, -0.06; P = 0.009); and IL-6 with venular dilation (slope, 5.3 μm/standard deviation log10[plasma IL-6 concentration]; 95% CI, 2.7, 8.0; P < 0.001).

CONCLUSIONS: These data suggest that retinal vascular caliber is associated with age, race, AMD, hyperlipidemia, cardiovascular disease, and selected biomarkers of systemic inflammation.

PMID:31108552 | PMC:PMC6528842 | DOI:10.1167/iovs.18-26070

Ophthalmol Retina. 2018 Oct;2(10):1028-1040. doi: 10.1016/j.oret.2018.03.001. Epub 2018 Apr 17.

ABSTRACT

PURPOSE: To investigate the efficacy of intravenous GSK933776, a humanized monoclonal antibody directed against the N-terminal amino acids of amyloid β, for the treatment of geographic atrophy (GA) in age-related macular degeneration (AMD).

DESIGN: Prospective, randomized, placebo-controlled, double-masked, multicenter phase 2 clinical trial.

PARTICIPANTS: Patients with GA secondary to AMD, a visual acuity score of at least 35 letters, and GA with a total area of 1.9 to 17 mm² were enrolled.

METHODS: Participants were monitored monthly for 4 months during an observation period to determine the rate of GA enlargement in the study eye. After the observation period, randomization was performed into 1 of 4 treatment arms (GSK933776 at 3, 6, and 15 mg/kg/month and placebo). At each monthly visit over 18 months, participants underwent visual acuity testing under normal luminance and low-luminance conditions. Ocular imaging included color fundus photography, fundus autofluorescence, fluorescein angiography, and spectral-domain OCT.

MAIN OUTCOME MEASURE: Enlargement in the area of GA measured from color fundus photographs with reference to fundus autofluorescence images.

RESULTS: A total of 191 participants were randomized into the study, with 139 (73%) fulfilling the efficacy population criteria. Over 18 months, GSK933776 did not reduce the rate of GA enlargement relative to placebo. Overall, there were no consistent meaningful differences relative to placebo in any of the visual function measures. There was a correlation between the low-luminance visual acuity (LLVA) deficit at baseline and the rate of GA enlargement. Genetic variations in complement factor I (CFI) gene did not correlate with GA progression. No ocular serious adverse events considered related to the GSK933776 treatment were identified, and a similar number of nonocular serious adverse events were reported across all treatment groups.

CONCLUSIONS: Intravenous amyloid β inhibition with GSK933776 did not slow the rate of GA enlargement compared with placebo, and no clinically meaningful differences relative to placebo were observed in visual function testing over 18 months. The LLVA deficit was associated with faster GA enlargement; however, no correlation was shown between genetic variations in the CFI gene and the rate of GA enlargement.

PMID:31047490 | DOI:10.1016/j.oret.2018.03.001

Invest Ophthalmol Vis Sci. 2019 May 1;60(6):1853-1862. doi: 10.1167/iovs.18-26517.

ABSTRACT

PURPOSE: To evaluate risk factors for severity of cytomegalovirus (CMV) retinitis lesion whitening (opacity), using a standardized scoring system.

METHODS: We performed a cross-sectional, observational investigation of all individuals with newly diagnosed AIDS-related CMV retinitis in three randomized clinical trials and one prospective observational study. Opacity was scored by masked readers, using a prospectively defined ordinal 6-point scale. Demographic factors, laboratory data (CD4+, CD8+ T-lymphocyte counts, human immunodeficiency virus [HIV] blood levels), and lesion characteristics (location, size) were compared to the highest opacity score assigned to either eye. Among eyes with active lesions (scores ≥3), factors associated with severe opacity (scores 5, 6) were identified.

RESULTS: There were 299 participants (401 eyes with CMV retinitis). In one or more comparisons, increased opacity was associated with lower CD4+ and lower CD8+ T-lymphocyte counts, higher HIV blood level, lack of antiretroviral therapy, male sex, race/ethnicity, and bilateral disease. In eyes with active disease, severe opacity was associated with lower CD4+ T-lymphocyte count, higher HIV blood level, older age, Karnofsky score, lesion size, and bilateral disease. No relationship was identified between opacity and lesion location.

CONCLUSIONS: Lesion border opacity (resulting from CMV activity) reflects level of immune function; as immunodeficiency becomes worse, CMV activity (and opacity) increases. The positive relationship between opacity and HIV blood level may reflect both immunodeficiency and increased CMV activity caused by transactivation of CMV by HIV. Scoring of opacity may be a useful, standard measure for continued study of CMV retinitis across different settings and populations. (Clinicaltrials.gov number for the HPMPC CMV Retinitis Trial: NCT00000142; Clinicaltrials.gov number for the Monoclonal Antibody CMV Retinitis Trial: NCT00000135; Clinicaltrials.gov number for the Ganciclovir-Cidofovir CMV Retinitis Trial: NCT0000014; Clinicaltrials.gov number for the Longitudinal Study of the Ocular Complications of AIDS: NCT00000168.).

PMID:31042791 | PMC:PMC6890425 | DOI:10.1167/iovs.18-26517

Ophthalmol Retina. 2019 Apr;3(4):326-335. doi: 10.1016/j.oret.2019.01.004. Epub 2019 Jan 11.

ABSTRACT

PURPOSE: To characterize choroidal neovascular (CNV) lesions and the corresponding change in visual acuity (VA) in eyes that converted to neovascular age-related macular degeneration (AMD) in the Age-Related Eye Disease Study 2-HOme Monitoring of the Eye Study. (AREDS2-HOME Study).

DESIGN: Cohort study.

PARTICIPANTS: A total of 1520 participants at risk of developing CNV were enrolled, each of whom contributed 1 or both study eye(s) that had a best-corrected VA letter score of ≥54 letters (Snellen equivalent 20/60) and ≥1 large (≥125 μm) macular druse in the absence of neovascular AMD or central geographic atrophy.

METHODS: A multicenter clinical trial comparing standard care (SC) versus SC plus ForeseeHome (FH; Notal Vision, Manassas, VA) monitoring strategy in the detection of neovascular AMD. Fluorescein angiograms (FA) and OCT were evaluated by an independent reading center (RC) from the visit in which the ophthalmologist identified progression to CNV (n = 82 eyes).

MAIN OUTCOME MEASURES: Development of CNV on OCT, FA, or both.

RESULTS: The RC confirmed CNV in 67 of 82 eyes (82%); lesions were confirmed in 42 of 70 eyes (60%) with FA, 59 of 72 eyes (82%) with OCT, and on both images in 34 of 67 eyes (51%). Among the FA-confirmed cases, the median lesion size was 0.82 disc area (DA); lesions were subfoveal in 40.5%, occult CNV composition was present in 54.8%, and associated hemorrhage in 50%. Median (interquartile range [IQR]) lesion size on FA was 0.23 (0.0-0.91) DA versus 0.70 (0.0-1.50) DA, P = 0.051) in the FH and SC eyes, respectively. Among the OCT-confirmed cases median (IQR) center point thickness was 209 (175-274) μm, retinal pigment epithelial lesion complex was present in 86.4%, and subretinal fluid (SRF) was present in 76.3%. The median change in VA from baseline was -4.0 letters and -10.0 letters in the FH and SC eyes (P = 0.008) confirmed as CNV at the RC.

CONCLUSIONS: Incident CNV lesions were more prevalent on OCT images than on FA; however, the use of both OCT and FA enhanced detection of incident lesions. Lesions were smaller and associated with less vision loss among eyes in the FH group.

PMID:31014685 | DOI:10.1016/j.oret.2019.01.004

Diabetes Care. 2019 May;42(5):875-882. doi: 10.2337/dc18-2308. Epub 2019 Mar 4.

ABSTRACT

OBJECTIVE: The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy reduced the development and progression of retinopathy in type 1 diabetes (T1D) compared with conventional therapy. The Epidemiology of Diabetes Interventions and Complications (EDIC) study observational follow-up showed persistent benefits. In addition to glycemia, we now examine other potential retinopathy risk factors (modifiable and nonmodifiable) over more than 30 years of follow-up in DCCT/EDIC.

RESEARCH DESIGN AND METHODS: The retinopathy outcomes were proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), and ocular surgery. The survival (event-free) probability was estimated using the Kaplan-Meier method. Cox proportional hazards models assessed the association between risk factors and subsequent risk of retinopathy. Both forward- and backward-selection approaches determined the multivariable models.

RESULTS: Rate of ocular events per 1,000 person-years was 12 for PDR, 14.5 for CSME, and 7.6 for ocular surgeries. Approximately 65%, 60%, and 70% of participants remained free of PDR, CSME, and ocular surgery, respectively. The greatest risk factors for PDR in descending order were higher mean HbA_1c, longer duration of T1D, elevated albumin excretion rate (AER), and higher mean diastolic blood pressure (DBP). For CSME, risk factors, in descending order, were higher mean HbA_1c, longer duration of T1D, and greater age and DBP and, for ocular surgeries, were higher mean HbA_1c, older age, and longer duration of T1D.

CONCLUSIONS: Mean HbA_1c was the strongest risk factor for the progression of retinopathy. Although glycemic control is important, elevated AER and DBP were other modifiable risk factors associated with the progression of retinopathy.

PMID:30833368 | PMC:PMC6489114 | DOI:10.2337/dc18-2308

Am J Ophthalmol. 2019 Mar;199:230-237. doi: 10.1016/j.ajo.2018.12.002. Epub 2018 Dec 12.

ABSTRACT

PURPOSE: To evaluate the relationships among age-related macular degeneration (AMD), mortality, and biomarkers of systemic inflammation in patients with acquired immunodeficiency syndrome (AIDS).

DESIGN: Case-control study.

METHODS: In participants with intermediate-stage AMD at enrollment in the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) and 2:1 controls matched for age and sex, cryopreserved baseline plasma specimens were assayed for biomarkers of inflammation, including high-sensitivity C-reactive protein (CRP), interleukin (IL)-6, interferon-γ inducible protein (IP)-10, soluble CD14 (sCD14), soluble CD163 (sCD163), kynurenine/tryptophan (KT) ratio, and intestinal fatty acid binding protein (I-FABP). Main outcome measure was mortality.

RESULTS: The study included 189 patients with AMD and 385 controls. In the unadjusted analysis, AMD was associated with mortality (hazard ratio [HR] 1.48; 95% confidence interval [CI] 1.02, 2.15; P = .04). In an adjusted analysis, CRP (HR 1.36; 95% CI 1.08, 1.71; P = .009), IL-6 (HR 1.45; 95% CI 1.11, 1.90; P = .006), and IP-10 (HR 1.41; 95% CI 1.08, 1.84; P = .01) were associated with mortality. In a Cox regression analysis adjusted for human immunodeficiency virus load, blood CD4+ T cell level, CRP, IL-6, and IP-10, the association of AMD with mortality was attenuated (HR 1.08; 95% CI 0.73, 1.59; P = .70), primarily by the addition of the inflammatory biomarkers.

CONCLUSIONS: These data suggest that the increased mortality observed in patients with AIDS with AMD is, at least in part, a result of systemic inflammation.

PMID:30552890 | PMC:PMC6639058 | DOI:10.1016/j.ajo.2018.12.002

Retina. 2018 Oct;38(10):1896-1904. doi: 10.1097/IAE.0000000000002302.

ABSTRACT

PURPOSE: To explore 5-year changes from baseline in diabetic retinopathy severity among eyes treated with ranibizumab for diabetic macular edema.

METHODS: Diabetic retinopathy severity was assessed from study visits and annual fundus photographs among participants in Protocol I (DRCR.net). The proportion of eyes that improved at annual examinations and the cumulative probability of worsening through 5 years were estimated.

RESULTS: Among 235 participants with nonproliferative diabetic retinopathy at baseline, there were 29%, 28%, and 32% of eyes with retinopathy improvement at 1, 3, and 5 years, respectively. Among 111 participants with proliferative diabetic retinopathy, corresponding improvement percentages were 38%, 35%, and 23%. The 5-year cumulative probability of worsening was 18% (95% CI: 14%-25%) among nonproliferative diabetic retinopathy eyes and 31% (95% CI: 23%-42%) among proliferative diabetic retinopathy eyes (P = 0.01). In Years 1, 3, and 5, the mean (SD) number of ranibizumab injections was 8.1 (2.5), 2.2 (2.6), and 1.8 (2.6) for nonproliferative diabetic retinopathy eyes, and 9.0 (2.8), 2.3 (2.9), and 1.7 (2.6) for proliferative diabetic retinopathy eyes, respectively. Proportions with improvement or rates of worsening did not change with time.

CONCLUSION: Individuals receiving ranibizumab therapy for diabetic macular edema may have favorable changes in DR severity throughout a 5-year period concomitant with sequential reduction in anti-vascular endothelial growth factor therapy.

PMID:30234859 | PMC:PMC6547828 | DOI:10.1097/IAE.0000000000002302

Ophthalmology. 2018 Dec;125(12):1913-1928. doi: 10.1016/j.ophtha.2018.05.028. Epub 2018 Jul 27.

ABSTRACT

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 < 0.0001 for interaction in each case) but not with AREDS2 treatment assignment (P = 0.33) or smoking status (P = 0.05). Enlargement was significantly faster with ARMS2 risk (P < 0.0001), C3 non-risk (P = 0.0002), and APOE non-risk (P = 0.001) genotypes.

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.

PMID:30060980 | PMC:PMC6246813 | DOI:10.1016/j.ophtha.2018.05.028

Ophthalmol Retina. 2018 May;2(5):441-450. doi: 10.1016/j.oret.2017.08.015.

ABSTRACT

OBJECTIVE/PURPOSE: To evaluate efficacy and safety of monthly intravitreal injections of sirolimus, an immunosuppressive drug, for the treatment of age-related macular degeneration associated geographic atrophy (GA).

DESIGN: Randomized, controlled, single-masked multi-center phase 2 clinical trial of intravitreal sirolimus vs. sham therapy in AREDS2 clinical centers.

SUBJECTS: Participants with GA.

METHODS: Participants eligible in one eye were randomly assigned to a monthly intravitreal injection of sirolimus (20 µL [440 µg]) or sham treatment while participants with two study eyes were assigned to a monthly intravitreal injection in a randomly-selected eye. Best-corrected visual acuities (BVCA), spectral domain optical coherence tomography (OCT), fundus color photography and fundus autofluorescence (FAF) images were obtained at baseline and every 6 months until visit month 24.

MAIN OUTCOME MEASURES: Rate of progression of GA (mm²/year) measured on color fundus photograph from baseline to 24 months. Secondary outcome measures include change in BVCA, worsening of vision by ≥3 lines, and changes in area of GA measured on FAF and OCT.

RESULTS: 52 participants (mean age 79 years) were enrolled with 27 study eyes assigned to sirolimus from May 2012 to March 2014. The baseline median area of GA was 4.73 DA (12.01 mm²). The mean (standard deviation) growth rates of GA detected on color fundus photographs were 2.27 (2.17) mm² and 1.91 (2.27) mm² at month 12, and 4.94 (2.96) mm² and 5.72 (3.97) mm² at month 24, for the sirolimus and sham groups, respectively. There was no statistically significant difference in the GA growth rates between the two treatment groups (P=0.33). Median visual acuity changes and incidence of 15-letter loss from baseline were not different between the 2 treatment groups (p=0.19). The intervention was stopped early because of sterile endophthalmitis that occurred in 3 participants in the sirolimus group. Participants were followed for safety until the study was closed in May 2015 due to lack of efficacy.

CONCLUSION: Sirolimus did not result in different rates of GA growth in this phase 2 study. Immunosuppression may be important for some stages of the AMD process but may not necessarily be the main pathway for the development of GA.

PMID:29806044 | PMC:PMC5967618 | DOI:10.1016/j.oret.2017.08.015

Am J Ophthalmol. 2018 May;189:178. doi: 10.1016/j.ajo.2018.03.002. Epub 2018 Mar 22.

NO ABSTRACT

PMID:29576184 | DOI:10.1016/j.ajo.2018.03.002

Invest Ophthalmol Vis Sci. 2018 Feb 1;59(2):904-908. doi: 10.1167/iovs.17-23334.

ABSTRACT

PURPOSE: To evaluate the relationship between retinal vascular caliber and AMD in patients with AIDS.

METHODS: Participants enrolled in the Longitudinal Study of the Ocular Complications of AIDS had retinal photographs taken at enrollment. Retinal vascular caliber (central retinal artery equivalent [CRAE] and central retinal vein equivalent [CRVE]) and intermediate-stage AMD were determined from these retinal photographs. Photographs were evaluated by graders at a centralized reading center, using the Age-Related Eye Disease Study grading system for AMD and semiautomated techniques for evaluating retinal vascular caliber.

RESULTS: Of the 1171 participants evaluated, 110 (9.4%) had AMD and 1061 (90.6%) did not. Compared with participants without AMD, participants with AMD had larger mean CRAEs (151 ± 16 μm versus 147 ± 16 μm; P = 0.009) and mean CRVEs (228 ± 24 μm versus 223 ± 25 μm; P = 0.02). The unadjusted differences were: CRAE, 4.3 μm (95% confidence interval [CI] 1.1-7.5; P = 0.009) and CRVE, 5.5 μm (95% CI 0.7-10.3; P = 0.02). After adjustment for age, race/ethnicity, sex, human immunodeficiency syndrome (HIV) transmission category, smoking, enrollment and nadir CD4+ T cells, and enrollment and maximum HIV load, the differences between patients with and without AMD were as follows: CRAE, 5.4 μm (95% CI 2.3-8.5; P = 0.001) and CRVE, 6.0 μm (95% CI 1.4-10.6; P = 0.01).

CONCLUSIONS: In patients with AIDS, AMD is associated with greater retinal arteriolar and venular calibers, suggesting a role for shared pathogenic mechanisms, such as persistent systemic inflammation.

PMID:29435590 | PMC:PMC5812413 | DOI:10.1167/iovs.17-23334

Am J Ophthalmol. 2018 Mar;187:138-147. doi: 10.1016/j.ajo.2017.12.007. Epub 2017 Dec 22.

ABSTRACT

PURPOSE: To report the longitudinal association between use of thiazolidinediones (TZDs), visual acuity (VA) change, and diabetic eye disease incidence and progression.

DESIGN: Cohort study ancillary to a randomized clinical trial.

METHODS: We analyzed baseline and 4-year follow-up data of 2856 ACCORD trial participants with no history of proliferative diabetic retinopathy. Based on stereoscopic fundus photographs, we evaluated diabetic macular edema (DME) progression and DR progression. We also evaluated 10- and 15-letter change on the ETDRS visual acuity chart. Main outcome measures were incidence or progression of DME or DR and change in visual acuity.

RESULTS: TZD use was not associated with DME incidence in either the analysis of any use (adjusted odds ratio [aOR] [95% CI]: 1.22 [0.72-2.05]) or duration of use (aOR: 1.02 [0.99-1.04]). Diabetic retinopathy (DR) incidence/progression was more common in patients with no or mild DR at baseline who were ever treated with TZDs (aOR: 1.68 [1.11-2.55]), but this association disappeared when adjusting for the time on TZD (aOR: 1.02 [1.00-1.04]). DR progression among those with moderate or worse DR at baseline was no different between TZD users and non-users. TZD usage had no effect on the ultimate visual acuity outcome.

CONCLUSION: In this longitudinal study of patients with type 2 diabetes, we found no association between TZD use and visual acuity outcomes or DME progression, and no consistent evidence of increased DR progression in patients ever treated with TZDs vs those never treated with TZDs.

PMID:29275147 | PMC:PMC6381823 | DOI:10.1016/j.ajo.2017.12.007

Am J Ophthalmol. 2018 Feb;186:144-151. doi: 10.1016/j.ajo.2017.11.020. Epub 2017 Dec 2.

ABSTRACT

PURPOSE: To evaluate choroidal and suprachoroidal changes following suprachoroidal injection of triamcinolone acetonide injectable suspension (CLS-TA), in eyes with macular edema due to retinal vein occlusion (RVO).

DESIGN: Prospective cohort study within a randomized, controlled phase 2 clinical trial.

METHODS: Enhanced depth imaging optical coherence tomography (EDI-OCT) images were analyzed from 38 eyes of 38 treatment-naïve patients with macular edema due to RVO, enrolled in the prospective Suprachoroidal Injection of Triamcinolone Acetonide with Intravitreal Aflibercept in Subjects with Macular Edema Due to Retinal Vein Occlusion (TANZANITE) study who received either a suprachoroidal injection of CLS-TA with an intravitreal injection of aflibercept (combination arm) or only an intravitreal injection of aflibercept (monotherapy arm), followed by monthly intravitreal aflibercept injections in both arms based on pro re nata criteria.

RESULTS: Macular choroidal thickness measured to the outer choroidal vessel lumen (vascular choroidal thickness, VCT), outer choroid stroma (stromal choroidal thickness, SCT), or inner scleral border (total choroidal thickness, TCT) showed no significant changes over 3 months in both study arms (P = .231-.342). Eyes that received combination therapy showed a trend toward thickening of the suprachoroidal space (SCS) compared with monotherapy alone (13.4 μm vs 5.3 μm at 3 months; P = .077). In the 15 eyes that demonstrated a visible SCS at baseline, the SCS expanded significantly after suprachoroidal CLS-TA injection (16.2 μm to 27.8 μm at 3 months; P = .033).

CONCLUSIONS: Suprachoroidal injection of CLS-TA does not alter choroidal thickness in eyes with macular edema due to RVO, but may result in expansion of the SCS.

PMID:29199012 | PMC:PMC5805638 | DOI:10.1016/j.ajo.2017.11.020

Ophthalmology. 2018 Apr;125(4):537-548. doi: 10.1016/j.ophtha.2017.09.028. Epub 2017 Nov 2.

ABSTRACT

PURPOSE: To develop consensus terminology and criteria for defining atrophy based on OCT findings in the setting of age-related macular degeneration (AMD).

DESIGN: Consensus meeting.

PARTICIPANTS: Panel of retina specialists, image reading center experts, retinal histologists, and optics engineers.

METHODS: As part of the Classification of Atrophy Meetings (CAM) program, an international group of experts surveyed the existing literature, performed a masked analysis of longitudinal multimodal imaging for a series of eyes with AMD, and reviewed the results of this analysis to define areas of agreement and disagreement. Through consensus discussions at 3 meetings over 12 months, a classification system based on OCT was proposed for atrophy secondary to AMD. Specific criteria were defined to establish the presence of atrophy.

MAIN OUTCOME MEASURES: A consensus classification system for atrophy and OCT-based criteria to identify atrophy.

RESULTS: OCT was proposed as the reference standard or base imaging method to diagnose and stage atrophy. Other methods, including fundus autofluorescence, near-infrared reflectance, and color imaging, provided complementary and confirmatory information. Recognizing that photoreceptor atrophy can occur without retinal pigment epithelium (RPE) atrophy and that atrophy can undergo an evolution of different stages, 4 terms and histologic candidates were proposed: complete RPE and outer retinal atrophy (cRORA), incomplete RPE and outer retinal atrophy, complete outer retinal atrophy, and incomplete outer retinal atrophy. Specific OCT criteria to diagnose cRORA were proposed: (1) a region of hypertransmission of at least 250 μm in diameter, (2) a zone of attenuation or disruption of the RPE of at least 250 μm in diameter, (3) evidence of overlying photoreceptor degeneration, and (4) absence of scrolled RPE or other signs of an RPE tear.

CONCLUSIONS: A classification system and criteria for OCT-defined atrophy in the setting of AMD has been proposed based on an international consensus. This classification is a more complete representation of changes that occur in AMD than can be detected using color fundus photography alone. Longitudinal information is required to validate the implied risk of vision loss associated with these terms. This system will enable such future studies to be undertaken using consistent definitions.

PMID:29103793 | PMC:PMC11366072 | DOI:10.1016/j.ophtha.2017.09.028

Am J Ophthalmol. 2017 Jul;179:151-158. doi: 10.1016/j.ajo.2017.05.004. Epub 2017 May 10.

ABSTRACT

PURPOSE: To evaluate the incidence of intermediate-stage age-related macular degeneration (AMD) in patients with acquired immunodeficiency syndrome (AIDS).

DESIGN: Cohort study.

METHODS: Patients enrolled in the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) underwent 5- and 10-year follow-up retinal photographs. Intermediate-stage AMD (AREDS stage 3) was determined from these photographs by graders at a centralized Reading Center, using the Age-Related Eye Disease Study-2 grading system. The incidence of AMD in LSOCA was compared with that in the Multi-Ethnic Study of Atherosclerosis (MESA), a Human Immunodeficiency Virus (HIV)-uninfected cohort, which used a similar photographic methodology.

RESULTS: The incidence of AMD in LSOCA was 0.65/100 person-years (PY). In a multivariate analysis the only significant risk factor for AMD in LSOCA was smoking; the relative risk vs never-smokers was 3.4 for former smokers (95% confidence interval [CI] 1.3, 9.5; P = .02) and 3.3 for current smokers (95% CI 1.1, 9.7; P = .03). Compared with the MESA cohort, the race/ethnicity- and sex-adjusted risk of AMD in LSOCA was 1.75 (95% CI 1.16, 2.64; P = .008), despite the fact that the mean age of the MESA cohort was 17 years greater than the LSOCA cohort (61 ± 9 years vs 44 ± 8 years).

CONCLUSIONS: Patients with AIDS have a 1.75-fold increased race- and sex-adjusted incidence of intermediate-stage AMD compared with that found in an HIV-uninfected cohort. This increased incidence is consistent with the increased incidence of other age-related diseases in antiretroviral-treated, immune-restored, HIV-infected persons when compared with HIV-uninfected persons.

PMID:28499708 | PMC:PMC5523452 | DOI:10.1016/j.ajo.2017.05.004

Ophthalmology. 2017 Apr;124(4):479-487. doi: 10.1016/j.ophtha.2016.12.004. Epub 2017 Jan 12.

ABSTRACT

PURPOSE: To compare rates of peripheral retinal changes in Age-Related Eye Disease Study 2 (AREDS2) participants with at least intermediate age-related macular degeneration (AMD) with control subjects without intermediate age-related changes (large drusen).

DESIGN: Cross-sectional evaluation of clinic-based patients enrolled in AREDS2 and a prospective study.

PARTICIPANTS: Participants from prospective studies.

METHODS: The 200° pseudocolor and fundus autofluorescence (FAF) images were captured on the Optos 200 Tx Ultrawide-field device (Optos, Dunfermline, Scotland) by centering on the fovea and then steering superiorly and inferiorly. The montaged images were graded at a reading center with the images divided into 3 zones (zone 1 [posterior pole], zone 2 [midperiphery], and zone 3 [far periphery]) to document the presence of peripheral lesions.

MAIN OUTCOME MEASURES: Peripheral retinal lesions: drusen, hypopigmentary/hyperpigmentary changes, reticular pseudodrusen, senile reticular pigmentary changes, cobblestone degeneration, and FAF abnormalities.

RESULTS: A total of 484 (951 eyes) AREDS2 participants with AMD (cases) and 89 (163 eyes) controls without AMD had gradable color and FAF images. In zones 2 and 3, neovascularization and geographic atrophy (GA) were present, ranging from 0.4% to 6% in eyes of cases, respectively, and GA was present in 1% of eyes of controls. Drusen were detected in 97%, 78%, and 64% of eyes of cases and 48%, 21%, and 9% of eyes of controls in zones 2 and 3 superior and 3 inferior, respectively (P < 0.001 for all). Peripheral reticular pseudodrusen were seen in 15%. Senile reticular pigmentary change was the predominant peripheral change seen in 48% of cases and 16% of controls in zone 2 (P < 0.001). Nonreticular pigment changes were less frequent in the periphery than in the posterior pole (46% vs. 76%) and negligible in controls.

CONCLUSIONS: Peripheral retinal changes are more prevalent in eyes with AMD than in control eyes. Drusen are seen in a majority of eyes with AMD in both the mid and far periphery, whereas pigment changes and features of advanced AMD are less frequent. Age-related macular degeneration may be more than a "macular" condition but one that involves the entire retina. Future longitudinal studies of peripheral changes in AMD and their impact on visual function may contribute to understanding AMD pathogenesis.

PMID:28089680 | DOI:10.1016/j.ophtha.2016.12.004

Am J Ophthalmol. 2017 Feb;174:23-32. doi: 10.1016/j.ajo.2016.10.011. Epub 2016 Oct 27.

ABSTRACT

PURPOSE: To evaluate the rates of new-onset cytomegalovirus (CMV) retinitis and worsening existing CMV retinitis in patients with AIDS after initiating combination antiretroviral therapy (cART) and the role of an immune recovery inflammatory syndrome (IRIS).

DESIGN: Cohort study.

METHODS: Immune recovery was defined as an increase in CD4⁺ T cells to ≥100 cells/μL; rates of new-onset CMV retinitis and of worsening of CMV retinitis (either increasing border activity or retinitis progression) were compared between those with and without immune recovery.

RESULTS: Among patients without CMV retinitis, 1 of 75 patients with immune recovery developed CMV retinitis in the first 6 months after initiating cART vs 1 of 31 without immune recovery (P = .14). Among patients with CMV retinitis, the rates of retinitis progression and increasing retinitis border activity among patients during the first 6 months after initiating cART in those with immune recovery were 0.11 per person-year (PY; 95% confidence interval [CI] 0-0.62) and 0.11 per PY (95% CI 0-0.62), respectively, vs 0.67 per PY (95% CI 0.22-1.56) and 0.40 per PY (95% CI 0.08-1.17), respectively, for those without immune recovery (P = .11 and .47).

CONCLUSIONS: Among persons with AIDS who experience immune recovery, there was neither an increased rate of new-onset CMV retinitis nor worsening of existing CMV retinitis in the first 6 months after initiating cART vs those without immune recovery. These data are consistent with the known 3- to 6-month lag in recovery of specific immunity to CMV after initiating cART and suggest that "immune recovery retinitis," a proposed immune recovery inflammatory syndrome phenomenon, is rare.

PMID:27984023 | PMC:PMC5253245 | DOI:10.1016/j.ajo.2016.10.011

Ophthalmology. 2016 Nov;123(11):2401-2407. doi: 10.1016/j.ophtha.2016.06.025. Epub 2016 Jul 19.

ABSTRACT

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.

PMID:27448832 | PMC:PMC5077673 | DOI:10.1016/j.ophtha.2016.06.025

JAMA Ophthalmol. 2016 Sep 1;134(9):1041-7. doi: 10.1001/jamaophthalmol.2016.2383.

ABSTRACT

IMPORTANCE: To test potential treatments for age-related macular degeneration (AMD), clinical trials need standardized outcome measures that are valid for predicting AMD progression in different study populations.

OBJECTIVE: To evaluate the validity of the Age-Related Eye Disease Study (AREDS) detailed and simple AMD severity scales by comparing rates of development of late AMD (neovascular AMD and/or central geographic atrophy) between AREDS and AREDS2 participants.

DESIGN, SETTING, AND PARTICIPANTS: Both AREDS (1992-2001) and AREDS2 (2006-2012) enrolled patients from academic and community-based retinal practices across the United States. In AREDS (n = 4519), participants with varying severity of AMD-from no AMD to late AMD in 1 eye-were enrolled. In AREDS2 (n = 4203), participants with bilateral large drusen or large drusen in the study eye and late AMD in the fellow eye were enrolled.

MAIN OUTCOMES AND MEASURES: Five-year incidence of late AMD, assessed by annual masked centralized fundus photograph grading.

RESULTS: In AREDS, the mean (SD) age of the patients was 69.3 (5.7) years, and 2519 (55.7%) were female. In AREDS2, the mean (SD) age of the patients was 73.1 (7.7) years, and 2388 (56.8%) were female. The 5-year rates of late AMD did not differ between AREDS2 and AREDS participants within nearly all baseline AMD detailed severity scale levels: levels 1 to 3: 2.4% vs 0.5% (difference, 1.9%; 95% CI, -0.2% to 4.0%; P < .001); level 4: 6.5% vs 4.9% (difference, 1.6%; 95% CI, -1.7% to 4.8%; P = .34); level 5: 8.0% vs 5.6% (difference, 2.4%; 95% CI, -1.2% to 5.9%; P = .22); level 6: 12.8% vs 13.7% (difference, -0.9%; 95% CI, -4.8% to 3.1%; P = .66); level 7: 26.2% vs 27.8% (difference, -1.5%; 95% CI, -6.6% to 3.5%; P = .54); and level 8: 46.4% vs 44.7% (difference, 1.7%; 95% CI, -7.5% to 10.9%; P = .72). Within simple scale levels, AREDS2 and AREDS 5-year rates did not differ significantly except for level 1 (9.4% vs 3.1%, P = .02; level 2: 12.8% vs 11.8%, P = .65; level 3: 26.3% vs 25.9%, P = .90; and level 4: 45.6% vs 47.3%, P = .57).

CONCLUSIONS AND RELEVANCE: The AREDS detailed and simple AMD severity scales were useful measures for assessing the risk of developing late AMD in the AREDS2 population; these data suggest that they should be useful tools for clinical trials of AMD treatments.

PMID:27442263 | PMC:PMC8371745 | DOI:10.1001/jamaophthalmol.2016.2383

Ophthalmic Surg Lasers Imaging Retina. 2016 May 1;47(5):418-25. doi: 10.3928/23258160-20160419-04.

ABSTRACT

BACKGROUND AND OBJECTIVE: To evaluate glaucomatous changes in patients with diabetic macular edema (DME) treated with intravitreal implants releasing 0.2 µg/day or 0.5 µg/day fluocinolone acetonide (FAc) (Iluvien 0.2 µg/day; Alimera Sciences, Alpharetta, GA) or sham control.

PATIENTS AND METHODS: Fundus photographs were assessed to determine clinically significant changes in glaucomatous indicators.

RESULTS: The mean cup-to-disc ratio (CDR) change was similar with all three treatments. Compared with sham control, a significantly greater proportion of patients treated with 0.5 µg/day but not 0.2 µg/day FAc experienced a CDR increase of greater than 0.1. There was no significant increase in the proportion of patients experiencing a CDR increase of greater than 0.2 with either dose of implant versus sham control. Other indicators of glaucomatous change did not differ significantly with treatment. Subgroup analyses showed no differences in cupping based on ocular or baseline characteristics.

CONCLUSION: Treatment with FAc for 36 months was not associated with significant glaucomatous optic nerve head changes in patients with DME with or without increased intraocular pressure. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:418-425.].

PMID:27183545 | DOI:10.3928/23258160-20160419-04

Ophthalmic Epidemiol. 2016 Jun;23(3):193-201. doi: 10.3109/09286586.2015.1119285. Epub 2016 Apr 29.

ABSTRACT

PURPOSE: To quantify variation in spectral-domain optical coherence tomography (SD-OCT) measures of total retinal thickness (top of inner limiting membrane to top of retinal pigment epithelium, RPE) and RPE thickness measures over a 4-week period and by age.

METHODS: A total of 76 volunteers aged 40-85 years were seen at three visits over 4 weeks. Two Topcon SD-OCT scans were taken at each visit. Following grid re-centration, total retinal and RPE thickness were determined in nine subfields. Multilevel modeling was used to quantify variance between scans and by age.

RESULTS: In the central circle, mean total retinal thickness was 237.9 µm (standard deviation, SD, 23.5 µm) and RPE thickness was 46.0 µm (SD 5.3 µm). Intraclass correlation coefficient in the central circle was 0.988 for total retinal thickness and 0.714 for RPE thickness. Pairwise measures taken within 4 weeks were strongly correlated (p > 0.95). Within-subject variation of total retinal thickness increased significantly with age. Subjects in the oldest age group had significantly increased among- and within-subject variability in measures of RPE thickness.

CONCLUSIONS: Correlation between retinal thickness measures was very high (>0.95) over a period of 4 weeks with small changes likely due to variation in measurement. Increasing variability in total retinal and RPE thickness measures with age suggest that the use of more and/or higher quality images to calculate mean thickness to reduce variability may benefit the study of these measures in older persons. This may also impact sample size calculations for future studies of SD-OCT measures in older adults.

PMID:27128499 | PMC:PMC4950942 | DOI:10.3109/09286586.2015.1119285

Int J Ophthalmol. 2016 Jan 18;9(1):111-8. doi: 10.18240/ijo.2016.01.19. eCollection 2016.

ABSTRACT

AIM: To investigate the relationship between C-reactive protein (CRP) and diabetic retinopathy (DR) in a cohort of Chinese patients with type 2 diabetes mellitus (T2DM).

METHODS: Community-based observational cohort study. There were 1131 participants recruited from November 2009 to September 2011 in Desheng community in urban Beijing. Patients diagnosed T2DM were recruited and underwent a standardized evaluation consisting of a questionnaire, ocular and anthropometric examinations and laboratory investigation. The presence and severity of DR were assessed by seven fields 30° color fundus photographs. Subjects were then classified into groups with no DR, any DR, or vision-threatening DR. CRP was analyzed from serum of study subjects.

RESULTS: A total of 1007 patients with T2DM were included for analysis, including 408 (40.5%) men and 599 (59.5%) women. The median CRP level was 1.5 mg/L for women and 1.1 mg/L for men (P=0.004, OR 0.37, 95% CI 0.18-0.74). After adjusting for possible covariates, higher levels of CRP were associated with lower prevalence of any DR (P=0.02, OR 0.55, 95% CI 0.35-0.89), but not associated with vision-threatening DR (P=0.62, OR 0.78, 95% CI 0.28-2.14). After stratification by sex, the inverse association between CRP and DR was found to be statistically significant in men (P=0.006, OR 0.35, 95% CI 0.16-0.73), but not in women (P=0.58, OR 0.88, 95% CI 0.29-1.16).

CONCLUSION: The data drawn from a Chinese population with T2DM suggest that increasing CRP levels may be inversely associated with development of DR.

PMID:26949620 | PMC:PMC4768512 | DOI:10.18240/ijo.2016.01.19

Br J Ophthalmol. 2016 Oct;100(10):1359-65. doi: 10.1136/bjophthalmol-2014-306078. Epub 2016 Jan 28.

ABSTRACT

AIMS: To describe the relationship of retinal arteriolar and venular calibre with diabetic retinopathy (DR) and related risk factors, including glucose levels and other biomarkers in a Chinese population with type 2 diabetes mellitus (T2DM).

METHODS: A cross-sectional study. Patients with T2DM were recruited from a local community in urban Beijing. Seven fields 30° colour fundus photographs were taken and examined for the presence and severity of DR using a standardised grading system. Retinal vascular calibres were measured and expressed as average central retinal arteriolar and venular equivalent using a computer-based program.

RESULTS: A total of 1340 patients with T2DM were included for analysis. Of these, 472 (35.22%) had DR. Wider retinal venular calibre, but not arteriolar calibre, was associated with increasing glucose and glycosylated haemoglobin A1c levels (p<0.006) and dyslipidaemia (p for trend <0.05). After adjusting for possible covariates, the higher quartile of retinal venular calibre was associated with higher prevalence of any DR (OR 2, 95% CI 1.36 to 2.95). Venular calibre increased from 224.33 μm in those without retinopathy to 231.21 μm in those with mild, 241.01 μm in those with moderate and 235.65 μm in those with severe retinopathy (p for trend <0.001). Arteriolar calibre was not associated with DR.

CONCLUSIONS: In the current study, wider venular calibre, but not arteriolar calibre, was shown to be associated with development and increased severity of DR independently from other risk factors in a Chinese diabetic population.

PMID:26823397 | DOI:10.1136/bjophthalmol-2014-306078

Retina. 2016 Jun;36(6):1170-6. doi: 10.1097/IAE.0000000000000851.

ABSTRACT

PURPOSE: To evaluate the relationship between changes in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) in eyes from two clinical trials of dexamethasone intravitreal implant 0.7 mg for macular edema after branch or central retinal vein occlusion.

METHODS: Patients with vision loss as a result of macular edema (≥6-week duration) after branch retinal vein occlusion or central retinal vein occlusion were treated with a single dexamethasone intravitreal implant or sham. Prospectively defined outcomes included BCVA and CRT (as assessed by optical coherence tomography).

RESULTS: There was a modest but statistically significant negative linear correlation between changes in CRT and changes in BCVA in both treatment groups at Days 90 and 180 (correlation coefficient: -0.23 to -0.34; P < 0.001). Improvements in BCVA at Day 180 were significantly greater (P < 0.001) in eyes that achieved and maintained CRT ≤250 μm from Day 90 to 180 (mean BCVA improvement: 14 letters; 49% of eyes with ≥15-letter gain) than in eyes that never achieved CRT ≤250 μm (mean BCVA improvement: 2 letters; 13% of eyes with ≥15-letter gain).

CONCLUSION: The greatest improvements in BCVA were seen in eyes that achieved and maintained the greatest improvements in CRT.

PMID:26655606 | DOI:10.1097/IAE.0000000000000851

Clin Ophthalmol. 2015 Nov 20;9:2159-74. doi: 10.2147/OPTH.S92359. eCollection 2015.

ABSTRACT

Geographic atrophy (GA) of the retinal pigment epithelium (RPE) is a devastating complication of age-related macular degeneration (AMD). GA may be classified as drusen-related (drusen-associated GA) or neovascularization-related (neovascular-associated GA). Drusen-related GA remains a large public health concern due to the burden of blindness it produces, but pathophysiology of the condition is obscure and there are no proven treatment options. Genotyping, cell biology, and clinical imaging point to upregulation of parainflammatory pathways, oxidative stress, and choroidal sclerosis as contributors, among other factors. Onset and monitoring of progression is accomplished through clinical imaging instrumentation such as optical coherence tomography, photography, and autofluorescence, which are the tools most helpful in determining end points for clinical trials at present. A number of treatment approaches with diverse targets are in development at this time, some of which are in human clinical trials. Neovascular-associated GA is a consequence of RPE loss after development of neovascular AMD. The neovascular process leads to a plethora of cellular stresses such as ischemia, inflammation, and dramatic changes in cell environment that further taxes RPE cells already dysfunctional from drusen-associated changes. GA may therefore develop secondary to the neovascular process de novo or preexisting drusen-associated GA may continue to worsen with the development of neovascular AMD. Neovascular-associated GA is a prominent cause of continued vision loss in patients with otherwise successfully treated neovascular AMD. Clearly, treatment with vascular endothelial growth factor (VEGF) inhibitors early in the course of the neovascular disease is of great clinical benefit. However, there is a rationale and some suggestive evidence that anti-VEGF agents themselves could be toxic to RPE and enhance neovascular-associated GA. The increasing prevalence of legal blindness from this condition due to the aging of the general population lends urgency to the search for a therapy to ameliorate GA.

PMID:26640366 | PMC:PMC4662367 | DOI:10.2147/OPTH.S92359

Br J Ophthalmol. 2016 Jun;100(6):796-801. doi: 10.1136/bjophthalmol-2015-306823. Epub 2015 Nov 18.

ABSTRACT

BACKGROUND/AIM: To assess long-term effects of dexamethasone intravitreal implant (DEX implant) monotherapy on retinal morphology in diabetic macular oedema (DME).

METHODS: Two multicentre, masked, phase III studies with identical protocols randomised patients with DME, best-corrected visual acuity of 34-68 Early Treatment Diabetic Retinopathy Study letters and central subfield retinal thickness (CSRT) ≥300 µm to DEX implant 0.7, 0.35 mg or sham procedure. Patients were followed up for 3 years (39 months if treated at month 36), with retreatment allowed at ≥6-month intervals. Patients needing other macular oedema (ME) therapy exited the study. Changes from baseline in CSRT, macular volume and ME grade, area of retinal thickening, macular leakage, macular capillary loss and diabetic retinopathy severity were assessed.

RESULTS: After 3 years, more eyes treated with DEX implant 0.7 and 0.35 mg than sham showed improvement (although small) in ME grade (p<0.05 vs sham). DEX implant 0.7 mg delayed time to onset of two-step progression in diabetic retinopathy severity by ∼12 months. DEX implant 0.7 and 0.35 mg produced small, non-sustained reductions in macular leakage but had no significant effect on macular capillary loss.

CONCLUSIONS: DEX implant 0.7 or 0.35 mg, administered at ≥6-month intervals over 3 years, produced sustained retinal structural improvement in DME.

TRIAL REGISTRATION NUMBER: NCT00168337 and NCT00168389.

PMID:26581718 | PMC:PMC4893085 | DOI:10.1136/bjophthalmol-2015-306823

Ophthalmology. 2016 Feb;123(2):361-368. doi: 10.1016/j.ophtha.2015.09.036. Epub 2015 Nov 3.

ABSTRACT

PURPOSE: The Geographic Atrophy Progression (GAP) study was designed to assess the rate of geographic atrophy (GA) progression and to identify prognostic factors by measuring the enlargement of the atrophic lesions using fundus autofluorescence (FAF) and color fundus photography (CFP).

DESIGN: Prospective, multicenter, noninterventional natural history study.

PARTICIPANTS: A total of 603 participants were enrolled in the study; 413 of those had gradable lesion data from FAF or CFP, and 321 had gradable lesion data from both FAF and CFP.

METHODS: Atrophic lesion areas were measured by FAF and CFP to assess lesion progression over time. Lesion size assessments and best-corrected visual acuity (BCVA) were conducted at screening/baseline (day 0) and at 3 follow-up visits: month 6, month 12, and month 18 (or early exit).

MAIN OUTCOME MEASURES: The GA lesion progression rate in disease subgroups and mean change from baseline visual acuity.

RESULTS: Mean (standard error) lesion size changes from baseline, determined by FAF and CFP, respectively, were 0.88 (0.1) and 0.78 (0.1) mm(2) at 6 months, 1.85 (0.1) and 1.57 (0.1) mm(2) at 12 months, and 3.14 (0.4) and 3.17 (0.5) mm(2) at 18 months. The mean change in lesion size from baseline to month 12 was significantly greater in participants who had eyes with multifocal atrophic spots compared with those with unifocal spots (P < 0.001) and those with extrafoveal lesions compared with those with foveal lesions (P = 0.001). The mean (standard deviation) decrease in visual acuity was 6.2 ± 15.6 letters for patients with image data available. Atrophic lesions with a diffuse (mean 0.95 mm(2)) or banded (mean 1.01 mm(2)) FAF pattern grew more rapidly by month 6 compared with those with the "none" (mean, 0.13 mm(2)) and focal (mean, 0.36 mm(2)) FAF patterns.

CONCLUSIONS: Although differences were observed in mean lesion size measurements using FAF imaging compared with CFP, the measurements were highly correlated with one another. Significant differences were found in lesion progression rates in participants stratified by hyperfluorescence pattern subtype. This large GA natural history study provides a strong foundation for future clinical trials.

PMID:26545317 | DOI:10.1016/j.ophtha.2015.09.036

PLoS One. 2015 Nov 3;10(11):e0141286. doi: 10.1371/journal.pone.0141286. eCollection 2015.

ABSTRACT

Implementation of multicenter and/or longitudinal studies requires an effective quality assurance program to identify trends, data inconsistencies and process variability of results over time. The Diabetes Control and Complications Trial (DCCT) and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study represent over 30 years of data collection among a cohort of participants across 27 clinical centers. The quality assurance plan is overseen by the Data Coordinating Center and is implemented across the clinical centers and central reading units. Each central unit incorporates specific DCCT/EDIC quality monitoring activities into their routine quality assurance plan. The results are reviewed by a data quality assurance committee whose function is to identify variances in quality that may impact study results from the central units as well as within and across clinical centers, and to recommend implementation of corrective procedures when necessary. Over the 30-year period, changes to the methods, equipment, or clinical procedures have been required to keep procedures current and ensure continued collection of scientifically valid and clinically relevant results. Pilot testing to compare historic processes with contemporary alternatives is performed and comparability is validated prior to incorporation of new procedures into the study. Details of the quality assurance plan across and within the clinical and central reading units are described, and quality outcomes for core measures analyzed by the central reading units (e.g. biochemical samples, fundus photographs, ECGs) are presented.

PMID:26529311 | PMC:PMC4631458 | DOI:10.1371/journal.pone.0141286

Ophthalmology. 2015 Jul;122(7):1452-63. doi: 10.1016/j.ophtha.2015.02.033. Epub 2015 Apr 17.

ABSTRACT

PURPOSE: To describe the long-term outcomes of patients with cytomegalovirus (CMV) retinitis and AIDS in the modern era of combination antiretroviral therapy.

DESIGN: Prospective, observational cohort study.

PARTICIPANTS: Patients with AIDS and CMV retinitis.

METHODS: Immune recovery, defined as a CD4+ T-cell count >100 cells/μl for ≥3 months.

MAIN OUTCOME MEASURES: Mortality, visual impairment (visual acuity <20/40), and blindness (visual acuity ≤20/200) on logarithmic visual acuity charts and loss of visual field on quantitative Goldmann perimetry.

RESULTS: Patients without immune recovery had a mortality of 44.4/100 person-years (PYs) and a median survival of 13.5 months after the diagnosis of CMV retinitis, whereas those with immune recovery had a mortality of 2.7/100 PYs (P < 0.001) and an estimated median survival of 27.0 years after the diagnosis of CMV retinitis. The rates of bilateral visual impairment and blindness were 0.9 and 0.4/100 PYs, respectively, and were similar between those with and without immune recovery. Among those with immune recovery, the rate of visual field loss was approximately 1% of the normal field per year, whereas among those without immune recovery it was approximately 7% of the normal field per year.

CONCLUSIONS: Among persons with CMV retinitis and AIDS, if there is immune recovery, long-term survival is likely, whereas if there is no immune recovery, the mortality rate is substantial. Although higher than the rates in the population not infected by human immunodeficiency virus, the rates of bilateral visual impairment and blindness are low, especially when compared with rates in the era before modern antiretroviral therapy.

PMID:25892019 | PMC:PMC4485590 | DOI:10.1016/j.ophtha.2015.02.033

Am J Ophthalmol. 2015 Jun;159(6):1115-1122.e1. doi: 10.1016/j.ajo.2015.01.037. Epub 2015 Mar 11.

ABSTRACT

PURPOSE: To evaluate the prevalence of intermediate-stage age-related macular degeneration (AMD) in patients with acquired immunodeficiency syndrome (AIDS).

DESIGN: Cross-sectional study of patients with AIDS enrolled in the Longitudinal Study of the Ocular Complications of AIDS.

METHODS: Intermediate-stage AMD was determined from enrollment retinal photographs by graders at a centralized Reading Center, using the Age-Related Eye Disease Study grading system. Graders were masked as to clinical data.

RESULTS: Of 1825 participants with AIDS and no ocular opportunistic infections, 9.9% had intermediate-stage AMD. Risk factors included age, with an odds ratio (OR) of 1.9 (95% confidence interval [CI] 1.6, 2.3, P < .001) for every decade of age; the prevalence of AMD ranged from 4.0% for participants 30-39 years old to 24.3% for participants ≥60 years old. Other risk factors included the human immunodeficiency virus (HIV) risk groups of injection drug use (OR = 2.4, 95% CI 1.5, 3.9, P < .001) or heterosexual contact (OR = 1.9, 95% CI 1.3, 2.8, P = .001). Compared with the HIV-uninfected population in the Beaver Dam Offspring Study, there was an approximate 4-fold increased age-adjusted prevalence of intermediate-stage AMD.

CONCLUSIONS: Patients with AIDS have an increased age-adjusted prevalence of intermediate-stage AMD compared with that found in a non-HIV-infected cohort evaluated with similar methods. This increased prevalence is consistent with the increased prevalence of other age-related diseases in antiretroviral-treated, immune-restored, HIV-infected persons when compared to non-HIV-infected persons.

PMID:25769246 | PMC:PMC6126535 | DOI:10.1016/j.ajo.2015.01.037

Ophthalmology. 2015 May;122(5):990-6. doi: 10.1016/j.ophtha.2014.12.014. Epub 2015 Mar 5.

ABSTRACT

PURPOSE: To investigate the potential of lipoprotein-associated phospholipase A2 inhibition as a novel mechanism to reduce edema and improve vision in center-involved diabetic macular edema (DME).

DESIGN: Prospective, multicenter, randomized, double-masked, placebo-controlled phase IIa study.

PARTICIPANTS: Fifty-four center-involved DME patients randomized 2:1 to receive darapladib (n = 36) or placebo (n = 18).

METHODS: Darapladib 160 mg or placebo monotherapy was administered orally once daily for 3 months, and patients were followed up monthly for 4 months.

MAIN OUTCOME MEASURES: Mean change from baseline in best-corrected visual acuity (BCVA) and the center subfield and center point of the study eye at month 3 as determined by spectral-domain optical coherence tomography.

RESULTS: Five patients in the study received intravitreal anti-vascular endothelial growth factor rescue therapy before the day 90 assessment, 2 of 36 (6%) in the darapladib arm and 3 of 18 (17%) in the placebo arm. Administration of 160 mg darapladib for 3 months resulted in statistically significant mean improvements, from baseline to month 3, in BCVA of 4.1 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (95% confidence interval [CI], 2.3-5.8) and of 57 μm in central subfield thickness (95% CI, -84 to -30) in the study eyes. An increase in BCVA of 1.7 ETDRS letters (95% CI, -1.0 to 4.4) and a decrease in center subfield thickness of 34 μm (95% CI, -75 to 6.8) for the placebo group were not significant. No ocular severe adverse events (SAEs) or SAEs considered related to darapladib were reported. One SAE of myocardial infarction, not considered related to darapladib, was reported, and 1 SAE of severe diarrhea was reported in a placebo patient, subsequently withdrawn from the study. Study eye ocular adverse events (AEs) and nonocular AEs were similar between treatment groups.

CONCLUSIONS: Once-daily oral darapladib administered for 3 months demonstrated modest improvements in vision and macular edema that warrant additional investigation of this novel lipoprotein-associated phospholipase A2 inhibitory mechanism for the treatment of DME.

PMID:25749297 | DOI:10.1016/j.ophtha.2014.12.014

Ophthalmology. 2015 Apr;122(4):787-95. doi: 10.1016/j.ophtha.2014.10.014. Epub 2014 Dec 31.

ABSTRACT

PURPOSE: To describe the prevalence and interrelationships of epiretinal membranes (ERMs), vitreomacular traction (VMT), macular cysts, paravascular cysts (PVCs), lamellar macular holes (LMHs), full-thickness macular holes (FTMHs), and visual impairment in a population-based study of older adults.

DESIGN: Cross-sectional study.

PARTICIPANTS: There were 1913 participants aged 63 to 102 years at the 20-year Beaver Dam Eye Study follow-up examination in 2008-2010, of whom 1540 (2980 eyes) had gradable spectral-domain optical coherence tomography (SD OCT) scans of the macula in at least 1 eye.

METHODS: The presence of ERMs and other retinal lesions was determined by standardized grading of macular SD OCT scans and photographs of 3 standard fields.

MAIN OUTCOME MEASURES: Epiretinal membranes, VMT, macular cysts, PVCs, LMHs, FTMHs, and visual impairment.

RESULTS: By using SD OCT, the prevalence of ERMs (34.1%), VMT (1.6%), macular cysts (5.6%), PVCs (20.0%), LMHs (3.6%), and FTMHs (0.4%) was estimated. The prevalence of macular cysts (P < 0.001), ERMs (P < 0.001), and VMT (P = 0.005) increased with age; the prevalence of PVCs (P = 0.05) decreased with age; and the prevalence of LMHs was not associated with age (P = 0.70). The prevalence of macular cysts, LMHs, and ERMs was higher in eyes with a history of cataract surgery. Macular cysts and ERMs were more common in eyes with retinal diseases, such as proliferative diabetic retinopathy, retinal vein occlusion, and retinal detachment, than in eyes without these conditions. Macular cysts, ERMs, and FTMHs were associated with visual impairment. While adjusting for age and sex, macular cysts (odds ratio [OR], 3.96; P < 0.0001), PVCs (OR, 1.45, P = 0.007), LMHs (OR, 10.62; P < 0.001), VMT (OR, 2.72, P = 0.01), and visual impairment (OR, 3.23; P < 0.001) were more frequent in eyes with ERMs compared with eyes without ERMs.

CONCLUSIONS: Epiretinal membranes are associated with macular cysts, PVCs, LMHs, VMT, and visual impairment. Further follow-up will allow better understanding of the natural history of ERMs and VMT and their relationships to the development of macular cysts and LMHs in the aging population.

PMID:25556116 | PMC:PMC4372472 | DOI:10.1016/j.ophtha.2014.10.014

Am J Ophthalmol. 2015 Mar;159(3):445-56.e1. doi: 10.1016/j.ajo.2014.11.025. Epub 2014 Nov 25.

ABSTRACT

PURPOSE: To examine relationships of age, sex, and systemic and ocular conditions with retinal thickness measured by spectral-domain ocular coherence tomography (SD OCT) in participants without retinal disease.

DESIGN: Longitudinal study.

METHODS: setting: Population-based cohort. study population: Persons aged 43-86 years living in Beaver Dam, Wisconsin in 1988-1990. observation procedures: Retinal thickness was measured via SD OCT at the Beaver Dam Eye Study examination in 2008-2010. Retinal disease was determined by ophthalmoscopy, fundus photography, or SD OCT. main outcome measures: Retinal thickness from the inner limiting membrane to the Bruch membrane.

RESULTS: The retina was thickest in the inner circle (mean 334.5 μm) and thinnest in the center subfield (285.4 μm). Mean retinal thickness decreased with age in the inner circle (P < .0001) and outer circle (P < .0001). Adjusting for age, eyes in men had thicker retinas than eyes in women in the center subfield (P < .001) and inner circle (P < .001). Sex, axial length/corneal curvature ratio, and peak expiratory flow rate were associated with center subfield thickness. Sex and peak expiratory flow rate were associated with retinal thickness in the inner circle. Alcohol consumption, age, axial length/corneal curvature ratio, cataract surgery, ocular perfusion pressure, and peak expiratory flow rate were associated with retinal thickness in the outer circle.

CONCLUSIONS: This study provides data for retinal thickness measures in eyes of individuals aged 63 years and older without retinal disease. This information may be useful for clinical trials involving the effects of interventions on retinal thickness and for comparisons with specific retinal diseases affecting the macula.

PMID:25461295 | PMC:PMC4329258 | DOI:10.1016/j.ajo.2014.11.025

Ophthalmology. 2015 Mar;122(3):579-88. doi: 10.1016/j.ophtha.2014.09.036. Epub 2014 Nov 26.

ABSTRACT

PURPOSE: To evaluate pazopanib eye drops in subjects with active subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD).

DESIGN: Multicountry, randomized, parallel-group, double-masked, active and placebo-controlled, dose-ranging study of eye drops.

PARTICIPANTS: A total of 510 subjects (93% white; 58% female; mean age, 75.3 years) whose AMD was previously managed by anti-vascular endothelial growth factor intravitreal injections.

METHODS: Treatments administered for 52 weeks included placebo eye drops instilled 4 times daily (n=73); pazopanib 5 mg/ml instilled 3 (n=72) or 4 times daily (n=74); pazopanib 10 mg/ml instilled 2 (n=73), 3 (n=73), or 4 times daily (n=72); or ranibizumab injection administered once every 4 weeks (n=73). In addition, for all eye drop treatment groups, open-label ranibizumab was administered as needed.

MAIN OUTCOME MEASURES: The main outcome measures were best-corrected visual acuity (BCVA) and injection frequency assessed at week 52. Safety was assessed every 4 weeks and pazopanib plasma concentrations were determined at weeks 4 and 24.

RESULTS: At week 52, pazopanib, with allowance for as-needed ranibizumab injections, was noninferior to monthly ranibizumab as well as to as-needed ranibizumab administered with placebo eye drops in maintaining BCVA (estimated BCVA gains of 0.3-1.8 vs. 1.4 vs. 0.2 letters, respectively). Pazopanib treatment did not reduce as-needed ranibizumab injections by ≥50% (prespecified efficacy criterion). At week 52, there were no clinically meaningful changes from baseline in retinal thickness or morphology, CNV size, or lesion characteristics on optical coherence tomography or fluorescein angiography. Complement factor H genotype had no effect on the responses to pazopanib and/or ranibizumab (BCVA, injection rate, or optical coherence tomography/fluorescein angiography changes). Steady-state concentrations of pazopanib in plasma seemed to be reached by week 4. The most common ocular adverse events related to pazopanib and ranibizumab were application site pain (3%) and injection site hemorrhage (1%), respectively. No treatment-related serious adverse events were reported.

CONCLUSIONS: Pazopanib was well tolerated. Daily pazopanib eye drops in neovascular AMD subjects did not result in therapeutic benefit beyond that obtained with ranibizumab alone.

PMID:25432081 | DOI:10.1016/j.ophtha.2014.09.036

Ophthalmic Surg Lasers Imaging Retina. 2014 Sep-Oct;45(5):394-7. doi: 10.3928/23258160-20140909-03.

ABSTRACT

BACKGROUND AND OBJECTIVE: This study examines the clinical response of patients transitioned to aflibercept, the newest anti-VEGF medication, due to persistent evidence of exudation on optical coherence tomography (OCT) despite regular treatment with bevacizumab and/or ranibizumab.

PATIENTS AND METHODS: Aflibercept was administered to 111 patients considered for study inclusion. Eyes were included if they were transitioned to aflibercept for treatment of persistent exudation on OCT despite regular treatment with at least three injections of ranibizumab or bevacizumab. Retrospective data were collected from medical records.

RESULTS: Complete resolution of exudation was seen in 34% of eyes at final follow-up. Clear improvement in exudation amount or severity without complete resolution was seen in 25%. No improvement was seen in 34%, and 6% demonstrated worsening of exudation. Snellen visual acuity at the time of transition versus final follow-up after aflibercept injection did not appreciably change (logMAR 0.494 to 0.505, Snellen equivalent 20/62 to 20/64; P = .84). The mean center point neurosensory retina thickness decreased from 228.6 to 176.9 µm (P = .001).

CONCLUSION: Aflibercept may decrease the amount of exudation in a significant number of patients. However, this reduction did not result in an improvement in Snellen visual acuity.

PMID:25230402 | DOI:10.3928/23258160-20140909-03

Diabetes Care. 2014 Dec;37(12):3244-52. doi: 10.2337/dc14-0502. Epub 2014 Sep 5.

ABSTRACT

OBJECTIVE: Longitudinal evidence linking diabetic retinopathy with changes in brain structure and cognition is sparse. We used data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial to determine whether diabetic retinopathy at baseline predicted changes in brain structure or cognition 40 months later.

RESEARCH DESIGN AND METHODS: Participants from the ACCORD-MIND and ACCORD-Eye substudies were included in analyses of cognition (n = 1,862) and MRI-derived brain variables (n = 432). Retinopathy was categorized as none, mild nonproliferative, or moderate/severe. Tests of cognition included the Mini-Mental State Examination (MMSE), Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Test, and Stroop test. Primary brain outcomes were gray matter and abnormal white matter volumes.

RESULTS: Baseline retinopathy was associated with lower gray matter volume (adjusted means of 470, 466, and 461 cm(3) for none, mild, and moderate/severe retinopathy, respectively; P = 0.03). Baseline retinopathy also predicted a greater change in MMSE and DSST scores at 40 months in each retinopathy category (MMSE: -0.20, -0.57, and -0.42, respectively [P = 0.04]; DSST: -1.30, -1.84, and -2.89, respectively [P = 0.01]).

CONCLUSIONS: Diabetic retinopathy is associated with future cognitive decline in people with type 2 diabetes. Although diabetic retinopathy is not a perfect proxy for diabetes-related brain and cognitive decline, patients with type 2 diabetes and retinopathy represent a subgroup at higher risk for future cognitive decline.

PMID:25193529 | PMC:PMC4237980 | DOI:10.2337/dc14-0502

Ophthalmology. 2014 Dec;121(12):2443-51. doi: 10.1016/j.ophtha.2014.07.019. Epub 2014 Aug 29.

ABSTRACT

PURPOSE: To report additional ocular outcomes of intensive treatment of hyperglycemia, blood pressure, and dyslipidemia in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study.

DESIGN: Double 2×2 factorial, multicenter, randomized clinical trials in people with type 2 diabetes who had cardiovascular disease or cardiovascular risk factors. In the glycemia trial, targets of intensive and standard treatment were: hemoglobin A1c <6.0% and 7.0% to 7.9%, respectively, and in the blood pressure trial: systolic blood pressures of <120 and <140 mmHg, respectively. The dyslipidemia trial compared fenofibrate plus simvastatin with placebo plus simvastatin.

PARTICIPANTS: Of the 3472 ACCORD Eye Study participants enrolled, 2856 had 4-year data (85% of survivors).

METHODS: Eye examinations and fundus photographs were taken at baseline and year 4. Photographs were graded centrally for retinopathy severity and macular edema using the Early Treatment Diabetic Retinopathy Study (ETDRS) methods.

MAIN OUTCOME MEASURES: Three or more steps of progression on the ETDRS person scale or treatment of retinopathy with photocoagulation or vitrectomy.

RESULTS: As previously reported, there were significant reductions in the primary outcome in the glycemia and dyslipidemia trials, but no significant effect in the blood pressure trial. Results were similar for retinopathy progression by 1, 2, and 4 or more steps on the person scale and for ≥ 2 steps on the eye scale. In the subgroup of patients with mild retinopathy at baseline, effect estimates were large (odds ratios, ∼0.30; P < 0.001), but did not reach nominal significance for participants with no retinopathy or for those with moderate to severe retinopathy at baseline.

CONCLUSIONS: Slowing of progression of retinopathy by intensive treatment of glycemia was observed in ACCORD participants, whose average age and diabetes duration were 62 and 10 years, respectively, and who had cardiovascular disease or cardiovascular risk factors. The effect seemed stronger in patients with mild retinopathy. Similar slowing of progression was observed in patients treated with fenofibrate, with no effect observed with intensive blood pressure treatment. This is the second study to confirm the benefits of fenofibrate in reducing diabetic retinopathy progression, and fenofibrate should be considered for treatment of diabetic retinopathy.

PMID:25172198 | PMC:PMC4252767 | DOI:10.1016/j.ophtha.2014.07.019

PLoS One. 2014 Jun 18;9(6):e98587. doi: 10.1371/journal.pone.0098587. eCollection 2014.

ABSTRACT

BACKGROUND: Diabetic retinopathy (DR) is one of the leading causes of blindness in the United States and world-wide. DR is a silent disease that may go unnoticed until it is too late for effective treatment. Therefore, early detection could improve the chances of therapeutic interventions that would alleviate its effects.

METHODOLOGY: Graded fundus photography and systemic data from 3443 ACCORD-Eye Study participants were used to estimate Random Forest (RF) and logistic regression classifiers. We studied the impact of sample size on classifier performance and the possibility of using RF generated class conditional probabilities as metrics describing DR risk. RF measures of variable importance are used to detect factors that affect classification performance.

PRINCIPAL FINDINGS: Both types of data were informative when discriminating participants with or without DR. RF based models produced much higher classification accuracy than those based on logistic regression. Combining both types of data did not increase accuracy but did increase statistical discrimination of healthy participants who subsequently did or did not have DR events during four years of follow-up. RF variable importance criteria revealed that microaneurysms counts in both eyes seemed to play the most important role in discrimination among the graded fundus variables, while the number of medicines and diabetes duration were the most relevant among the systemic variables.

CONCLUSIONS AND SIGNIFICANCE: We have introduced RF methods to DR classification analyses based on fundus photography data. In addition, we propose an approach to DR risk assessment based on metrics derived from graded fundus photography and systemic data. Our results suggest that RF methods could be a valuable tool to diagnose DR diagnosis and evaluate its progression.

PMID:24940623 | PMC:PMC4062420 | DOI:10.1371/journal.pone.0098587

Ophthalmology. 2014 Oct;121(10):1892-903. doi: 10.1016/j.ophtha.2014.04.019. Epub 2014 Jun 14.

ABSTRACT

PURPOSE: To present the safety and efficacy of intravitreal implants releasing 0.2 μg/day fluocinolone acetonide (FAc) in patients with chronic versus nonchronic diabetic macular edema (DME). To assess ocular characteristics, anatomic changes, and re-treatment and ancillary therapies that may explain the differential treatment effect seen with intravitreal implants releasing FAc 0.2 μg/day in patients with chronic and nonchronic DME. An overall benefit-to-risk assessment for the FAc 0.2-μg/day and FAc 0.5-μg/day doses has been reported previously.

DESIGN: Preplanned subgroup analysis of chronic (duration of diagnosis, ≥3 years) and nonchronic (duration of diagnosis, <3 years) DME in patients from 2 randomized, sham injection-controlled, double-masked, multicenter clinical trials.

PARTICIPANTS: Patients with persistent DME despite 1 or more macular laser treatment were randomized 1:2:2 to sham injection (n = 185), FAc 0.2 μg/day (n = 375), or FAc 0.5 μg/day (n = 393).

METHODS: Patients received study drug or sham injection and after 6 weeks were eligible for rescue laser. Based on re-treatment criteria, additional masked study drug could be given after 1 year.

MAIN OUTCOME MEASURES: Percentage of patients with improvement of 15 letters or more from baseline. Secondary outcomes included other parameters of visual function and foveal thickness.

RESULTS: At month 36, the difference between FAc 0.2 μg/day and sham control in the percentage of patients who gained 15 letters or more was significantly greater in chronic DME patients (FAc 0.2 μg/day, 34.0% vs. sham, 13.4%; P<0.001), compared with patients with nonchronic DME (FAc 0.2 μg/day, 22.3% vs. sham, 27.8%; P = 0.275). The greater response in patients with chronic DME was not associated with baseline ocular characteristics, changes in anatomic features, or differences in re-treatment or ancillary therapies. The ocular adverse event profile for FAc 0.2 μg/day was similar regardless of DME duration.

CONCLUSIONS: This is the first published analysis correlating duration of diagnosis of DME with treatment effect. In patients with chronic DME, FAc 0.2 μg/day provides substantial visual benefit for up to 3 years and would provide an option for patients who do not respond to other therapy.

PMID:24935282 | DOI:10.1016/j.ophtha.2014.04.019

Contemp Clin Trials. 2014 Mar;37(2):294-300. doi: 10.1016/j.cct.2014.02.003. Epub 2014 Feb 13.

ABSTRACT

OBJECTIVE: To evaluate the effects of a home-monitoring device with tele-monitoring compared with standard care in detection of progression to choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD), the leading cause of blindness in the US.

PATIENTS AND METHODS: Participants, aged 55 to 90 years, at high risk of developing CNV associated with AMD were recruited to the HOme Monitoring of Eye (HOME) Study, an unmasked, multi-center, randomized trial of the ForeseeHome (FH) device plus standard care vs. standard care alone. The FH device utilizes preferential hyperacuity perimetry and tele-monitoring to detect changes in vision function associated with development of CNV, potentially prior to symptom and visual acuity loss. After establishing baseline measurements, subsequent changes on follow-up are detected by the device, causing the monitoring center to alert the clinical center to recall participants for an exam. Standard care consists of instructions for self-monitoring visual changes with subsequent self-report to the clinical center. The primary objective of this study is to determine whether home monitoring plus standard care in comparison with standard care alone, results in earlier detection of incident CNV with better present visual acuity. The primary outcome is the decline in visual acuity at CNV diagnosis from baseline. Detection of CNV prior to substantial vision loss is critical as vision outcome following anti-angiogenic therapy is dependent on the visual acuity at initiation of treatment.

DISCUSSION: HOME Study is the first large scale study to test the use of home tele-monitoring system in the management of AMD patients.

PMID:24530651 | PMC:PMC11554420 | DOI:10.1016/j.cct.2014.02.003

PLoS One. 2013 Dec 26;8(12):e82922. doi: 10.1371/journal.pone.0082922. eCollection 2013.

ABSTRACT

PURPOSE: To develop EdgeSelect, a semi-automatic method for the segmentation of retinal layers in spectral domain optical coherence tomography images, and to compare the segmentation results with a manual method.

METHODS: SD-OCT (Heidelberg Spectralis) scans of 28 eyes (24 patients with diabetic macular edema and 4 normal subjects) were imported into a customized MATLAB application, and were manually segmented by three graders at the layers corresponding to the inner limiting membrane (ILM), the inner segment/ellipsoid interface (ISe), the retinal/retinal pigment epithelium interface (RPE), and the Bruch's membrane (BM). The scans were then segmented independently by the same graders using EdgeSelect, a semi-automated method allowing the graders to guide/correct the layer segmentation interactively. The inter-grader reproducibility and agreement in locating the layer positions between the manual and EdgeSelect methods were assessed and compared using the Wilcoxon signed rank test.

RESULTS: The inter-grader reproducibility using the EdgeSelect method for retinal layers varied from 0.15 to 1.21 µm, smaller than those using the manual method (3.36-6.43 µm). The Wilcoxon test indicated the EdgeSelect method had significantly better reproducibility than the manual method. The agreement between the manual and EdgeSelect methods in locating retinal layers ranged from 0.08 to 1.32 µm. There were small differences between the two methods in locating the ILM (p = 0.012) and BM layers (p<0.001), but these were statistically indistinguishable in locating the ISe (p = 0.896) and RPE layers (p = 0.771).

CONCLUSIONS: The EdgeSelect method resulted in better reproducibility and good agreement with a manual method in a set of eyes of normal subjects and with retinal disease, suggesting that this approach is feasible for OCT image analysis in clinical trials.

PMID:24386127 | PMC:PMC3873283 | DOI:10.1371/journal.pone.0082922

JAMA Ophthalmol. 2014 Feb;132(2):142-9. doi: 10.1001/jamaophthalmol.2013.7376.

ABSTRACT

IMPORTANCE: The Age-Related Eye Disease Study (AREDS) formulation for the treatment of age-related macular degeneration (AMD) contains vitamin C, vitamin E, beta carotene, and zinc with copper. The Age-Related Eye Disease Study 2 (AREDS2) assessed the value of substituting lutein/zeaxanthin in the AREDS formulation because of the demonstrated risk for lung cancer from beta carotene in smokers and former smokers and because lutein and zeaxanthin are important components in the retina.

OBJECTIVE: To further examine the effect of lutein/zeaxanthin supplementation on progression to late AMD.

DESIGN, SETTING, PARTICIPANTS: The Age-Related Eye Disease Study 2 is a multicenter, double-masked randomized trial of 4203 participants, aged 50 to 85 years, at risk for developing late AMD; 66% of patients had bilateral large drusen and 34% had large drusen and late AMD in 1 eye.

INTERVENTIONS: In addition to taking the original or a variation of the AREDS supplement, participants were randomly assigned in a factorial design to 1 of the following 4 groups: placebo; lutein/zeaxanthin, 10 mg/2 mg; omega-3 long-chain polyunsaturated fatty 3 acids, 1.0 g; or the combination.

MAIN OUTCOMES AND MEASURE: S Documented development of late AMD by central, masked grading of annual retinal photographs or by treatment history. RESULTS In exploratory analysis of lutein/zeaxanthin vs no lutein/zeaxanthin, the hazard ratio of the development of late AMD was 0.90 (95% CI, 0.82-0.99; P = .04). Exploratory analyses of direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.82 (95% CI, 0.69-0.96; P = .02) for development of late AMD, 0.78 (95% CI, 0.64-0.94; P = .01) for development of neovascular AMD, and 0.94 (95% CI, 0.70-1.26; P = .67) for development of central geographic atrophy. In analyses restricted to eyes with bilateral large drusen at baseline, the direct comparison of lutein/zeaxanthin vs beta carotene showed hazard ratios of 0.76 (95% CI, 0.61-0.96; P = .02) for progression to late AMD, 0.65 (95% CI, 0.49-0.85; P = .002) for neovascular AMD, and 0.98 (95% CI, 0.69-1.39; P = .91) for central geographic atrophy.

CONCLUSION AND RELEVANCE: The totality of evidence on beneficial and adverse effects from AREDS2 and other studies suggests that lutein/zeaxanthin could be more appropriate than beta carotene in the AREDS-type supplements.

TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00345176.

PMID:24310343 | PMC:PMC4636082 | DOI:10.1001/jamaophthalmol.2013.7376

Br J Ophthalmol. 2014 Feb;98(2):172-8. doi: 10.1136/bjophthalmol-2013-303117. Epub 2013 Nov 13.

ABSTRACT

AIMS: To evaluate pazopanib eye drops in patients with subfoveal choroidal neovascularisation secondary to age-related macular degeneration.

METHODS: 70 patients with minimally classic or occult subfoveal choroidal neovascularisation were randomly assigned to 5 mg/mL TID, 2 mg/mL TID, and 5 mg/mL QD pazopanib eye drops for 28 days in a multicentre, double-masked trial with an optional safety extension for up to 5 additional months. The primary outcomes were central retinal thickness (CRT) and best-corrected visual acuity (BCVA) at Day 29.

RESULTS: No significant decrease from baseline in CRT was observed overall; however, an exploratory analysis showed improvement in CRT (mean decrease of 89 μm) in patients with the CFH TT genotype who received 5 mg/mL TID (p=0.01, n=5). Mean increases in BCVA were observed in the 5 mg/mL TID overall (4.32 letters (p=0.002, n=26)) and in those that with CFH Y402H TT (6.96 letters (p=0.02, n=5)) and CT (4.09 letters (p=0.05, n=9)) genotypes. No safety signals that precluded continued investigation were detected.

CONCLUSIONS: 5 mg/mL pazopanib eye drops resulted in mean improvement in BCVA at Day 29 and improvements in vision. However, improvement in macular oedema for age-related macular degeneration was found only in the subset of subjects with the CFH Y402H TT genotype, warranting further investigation.

PMID:24227801 | DOI:10.1136/bjophthalmol-2013-303117

Ophthalmology. 2014 Feb;121(2):535-44. doi: 10.1016/j.ophtha.2013.10.027. Epub 2013 Nov 8.

ABSTRACT

OBJECTIVE: To determine whether home monitoring with the ForeseeHome device (Notal Vision Ltd, Tel Aviv, Israel), using macular visual field testing with hyperacuity techniques and telemonitoring, results in earlier detection of age-related macular degeneration-associated choroidal neovascularization (CNV), reflected in better visual acuity, when compared with standard care. The main predictor of treatment outcome from anti-vascular endothelial growth factor (VEGF) agents is the visual acuity at the time of CNV treatment.

DESIGN: Unmasked, controlled, randomized clinical trial.

PARTICIPANTS: One thousand nine hundred and seventy participants 53 to 90 years of age at high risk of CNV developing were screened. Of these, 1520 participants with a mean age of 72.5 years were enrolled in the Home Monitoring of the Eye study at 44 Age-Related Eye Disease Study 2 clinical centers.

INTERVENTIONS: In the standard care and device arms arm, investigator-specific instructions were provided for self-monitoring vision at home followed by report of new symptoms to the clinic. In the device arm, the device was provided with recommendations for daily testing. The device monitoring center received test results and reported changes to the clinical centers, which contacted participants for examination.

MAIN OUTCOME MEASURES: The main outcome measure was the difference in best-corrected visual acuity scores between baseline and detection of CNV. The event was determined by investigators based on clinical examination, color fundus photography, fluorescein angiography, and optical coherence tomography findings. Masked graders at a central reading center evaluated the images using standardized protocols.

RESULTS: Seven hundred sixty-three participants were randomized to device monitoring and 757 participants were randomized to standard care and were followed up for a mean of 1.4 years between July 2010 and April 2013. At the prespecified interim analysis, 82 participants progressed to CNV, 51 in the device arm and 31 in the standard care arm. The primary analysis achieved statistical significance, with the participants in the device arm demonstrating a smaller decline in visual acuity with fewer letters lost from baseline to CNV detection (median, -4 letters; interquartile range [IQR], -11.0 to -1.0 letters) compared with standard care (median, -9 letters; IQR, -14.0 to -4.0 letters; P = 0.021), resulting in better visual acuity at CNV detection in the device arm. The Data and Safety Monitoring Committee recommended early study termination for efficacy.

CONCLUSIONS: Persons at high risk for CNV developing benefit from the home monitoring strategy for earlier detection of CNV development, which increases the likelihood of better visual acuity results after intravitreal anti-VEGF therapy.

PMID:24211172 | PMC:PMC3918479 | DOI:10.1016/j.ophtha.2013.10.027

Ophthalmology. 2013 Dec;120(12):2666-2671. doi: 10.1016/j.ophtha.2013.07.047. Epub 2013 Oct 24.

ABSTRACT

OBJECTIVE: To develop a parameter that can assess the relative rate of progression of geographic atrophy (GA) based on the hypothesis that noncircular configuration of the atrophic lesion may be a risk factor for enlargement.

DESIGN: Cohort study.

PARTICIPANTS: Digitized color photographs of 593 eyes with GA from the Age-Related Eye Disease Study (AREDS).

METHODS: A novel parameter called the "Geographic Atrophy Circularity Index" (GACI) was developed on the basis of area and perimeter measurements to categorize the irregularity of the shape of GA. The GACI ranges from 0.0 to 1.0 and is categorized into 3 groups: 0.25 (very irregular), 0.25 to <0.75 (partly irregular), and ≥ 0.75 (circular).

MAIN OUTCOME MEASURES: Growth rate of GA.

RESULTS: The mean growth rate in the 3 categories was 0.40 (± 0.18), 0.36 (± 0.30), and 0.21 (± 0.22) mm/year, respectively (P < 0.001). By adjusting for known confounders, baseline area, duration of GA, and configuration, GACI categories were significantly associated with increased growth rate of GA (P < 0.001).

CONCLUSIONS: The GACI was associated with the progression rate of GA and may be a useful measure for clinical trial eligibility. The association also suggests that enlargement of GA may be related to the extent of the junctional zone of damaged retinal pigment epithelium, which increases with noncircularity for a given GA area.

PMID:24206616 | DOI:10.1016/j.ophtha.2013.07.047

Retina. 2014 Mar;34(3):568-75. doi: 10.1097/IAE.0b013e3182a487be.

ABSTRACT

PURPOSE: To determine the prevalence of retinal vascular abnormalities (RVA) in neovascular age-related macular degeneration (AMD).

METHODS: A post hoc subanalysis of images acquired during a Phase III randomized controlled trial was undertaken, selecting images from participants with untreated, neovascular AMD in at least one eye. Protocol mandated fundus photographs and fluorescein angiograms were acquired at baseline and Year 2, from 107 sham-treated study eyes with neovascular AMD and 107 untreated fellow eyes. Images were reanalyzed by an independent reading center for the presence of RVA, defined as at least one of the following: microaneurysms, vessel staining or leakage, dilated or tortuous vessels, intraretinal hemorrhage, vessel sheathing or narrowing, capillary nonperfusion, or capillary infarcts.

RESULTS: The baseline prevalence of RVA in the sham-treated study eyes was 14.4% (15 of 104 gradable images) versus 8.3% (5 of 60) in the fellow eyes with dry AMD. The baseline prevalence of individual RVAs in study eyes was: microaneurysms (6.7%), vessel staining or leakage (6.7%), dilated or tortuous vessels (4.8%), intraretinal hemorrhage (4.8%), vessel sheathing or narrowing (2.9%), capillary nonperfusion (0%), and capillary infarcts (0%). Results were similar at 24 months.

CONCLUSION: Compared with several studies that relied solely on fundus photographs, this study included fluorescein angiography and found a higher prevalence of RVAs occurring in eyes with neovascular AMD.

PMID:24045343 | DOI:10.1097/IAE.0b013e3182a487be

Ophthalmology. 2013 Dec;120(12):2580-2586. doi: 10.1016/j.ophtha.2013.06.002. Epub 2013 Jul 24.

ABSTRACT

PURPOSE: This study sought to determine the validity of self-report of prior panretinal photocoagulation (PRP) and focal photocoagulation (FP) compared with fundus photography.

DESIGN: Prospective cohort study.

PARTICIPANTS: One thousand three hundred sixty-three type 1 diabetic subjects from the Epidemiology of Diabetes Interventions and Complications (EDIC) study, a subset of the 1441 subjects originally enrolled in the multicenter Diabetes Control and Complications Trial.

METHODS: At each annual visit, subjects were asked by EDIC staff whether they had undergone PRP, FP, or both since the last completed annual clinic visit. Fundus photographs were collected from one quarter of the cohort each year and from the entire cohort at EDIC years 4 and 10. Photographs were graded for the presence and extent of PRP and FP. Seventeen years of subject reporting and photograph grading of PRP and FP were compared in EDIC subjects.

MAIN OUTCOME MEASURES: The κ, sensitivity, specificity, and positive and negative predictive values were calculated for subject-reported PRP and FP. Factors influencing subject misreporting were investigated.

RESULTS: For subject reporting, 1244 (96%) of 1296 subjects with gradable photographs accurately reported whether they had a history of PRP in one or both eyes, and 1259 (97.5%) of 1291 with valid photographs correctly reported their history of FP. For PRP and FP, sensitivities were 90.4% and 74.0%, respectively; specificities were 96.0% and 98.8%, respectively; positive predictive values were 75.9% and 80.3%, respectively; negative predictive values were 98.9% and 98.4%, respectively; and κ values were 0.80 and 0.76, respectively. Risk factors associated with misreporting included prior laser for diabetic retinopathy and prior ocular surgery (each P<0.04).

CONCLUSIONS: For subjects with type 1 diabetes, in the absence of a clinical examination or fundus photographs, subject self-report could be a reliable tool in a well-monitored study for assessing laser treatment type in diabetic retinopathy.

PMID:23890420 | PMC:PMC3818390 | DOI:10.1016/j.ophtha.2013.06.002

Invest Ophthalmol Vis Sci. 2013 Sep 5;54(9):5989-94. doi: 10.1167/iovs.13-12301.

ABSTRACT

PURPOSE: We described the system for grading lens opacities using stereoscopic digital fundus reflex photographs in the Age-Related Eye Disease Study 2 (AREDS2) and compared reproducibility with the AREDS lens grading system, which used retroillumination film images.

METHODS: Stereoscopic fundus reflex photographs were acquired in a standardized fashion at baseline and annually. Images were enhanced and evaluated in the red channel at a central reading center. Percentage involvement of cortical and posterior subcapsular (PSC) lens opacities within the central 5 mm diameter zone of a modified AREDS lens grid was estimated. Reproducibility was assessed for contemporaneous variability (ongoing, monthly regrade on 5% of submissions, n = 777 eyes) and temporal drift (regrading a subset of baseline photographs annually, n = 88).

RESULTS: In the contemporaneous exercise, the agreement for presence of cortical opacities was 93% (κ = 0.86) and for PSC opacities it was 97% (κ = 0.83). Intraclass correlation (ICC) for area of central zone involvement was 0.95 for cortical and 0.99 for PSC opacities. Historic data for contemporaneous regrading of film-based images in AREDS showed an ICC of 0.94 for cortical and 0.82 for PSC. The final annual temporal drift exercise had a reproducibility of 95% for cortical and PSC opacities.

CONCLUSIONS: Digital grading using fundus reflex images with image enhancing tools has reproducibility comparable to film-based retroillumination images, and may be useful for centralized objective lens opacity assessment in clinical trials using widely available fundus cameras. Red reflex images limit evaluation to cortical and PSC opacities, and do not permit assessment of nuclear opacities. (ClinicalTrials.gov number, NCT00345176.).

PMID:23887802 | PMC:PMC3771555 | DOI:10.1167/iovs.13-12301