Macular Degeneration: Ferris FL

Ferris FL. · No affiliation provided · N Engl J Med. · Pubmed #15625339 No free full text.

This publication has no abstract.

Ferris FL, Davis MD. · No affiliation provided · Arch Ophthalmol. · Pubmed #10326969 No free full text.

This publication has no abstract.

Wilkinson CP, Ferris FL, Klein RE, Lee PP, Agardh CD, Davis M, Dills D, Kampik A, Pararajasegaram R, Verdaguer JT, Anonymous00271. · Greater Baltimore Medical Center, Baltimore, Maryland, USA. · Ophthalmology. · Pubmed #13129861 No free full text.

Abstract: PURPOSE: To develop consensus regarding clinical disease severity classification systems for diabetic retinopathy and diabetic macular edema that can be used around the world, and to improve communication and coordination of care among physicians who care for patients with diabetes. DESIGN: Report regarding the development of clinical diabetic retinopathy disease severity scales. PARTICIPANTS: A group of 31 individuals from 16 countries, representing comprehensive ophthalmology, retina subspecialties, endocrinology, and epidemiology. METHODS: An initial clinical classification system, based on the Early Treatment Diabetic Retinopathy Study and the Wisconsin Epidemiologic Study of Diabetic Retinopathy publications, was circulated to the group in advance of a workshop. Each member reviewed this using e-mail, and a modified Delphi system was used to stratify responses. At a later workshop, separate systems for diabetic retinopathy and macular edema were developed. These were then reevaluated by group members, and the modified Delphi system was again used to measure degrees of agreement. MAIN OUTCOME MEASURES: Consensus regarding specific classification systems was achieved. RESULTS: A five-stage disease severity classification for diabetic retinopathy includes three stages of low risk, a fourth stage of severe nonproliferative retinopathy, and a fifth stage of proliferative retinopathy. Diabetic macular edema is classified as apparently present or apparently absent. If training and equipment allow the screener to make a valid decision, macular edema is further categorized as a function of its distance from the central macula. CONCLUSIONS: There seems to be a genuine need for consistent international clinical classification systems for diabetic retinopathy and diabetic macular edema that are supported with solid evidence. The proposed clinical classification systems provide a means of appropriately categorizing diabetic retinopathy and macular edema. It is hoped that these systems will be valuable in improving both screening of individuals with diabetes and communication and discussion among individuals caring for these patients.

McBee WL, Lindblad AS, Ferris FL. · The EMMES Corporation, Rockville, Maryland 20850, USA. · Curr Opin Ophthalmol. · Pubmed #12777936 No free full text.

Abstract: Oxidative damage to the retina has been proposed as a risk factor for age-related macular degeneration (AMD). Dietary or supplemental antioxidants may play a protective role. The Age-Related Eye Disease Study (AREDS), a randomized, multicenter, placebo-controlled clinical trial designed to test the effect of pharmacologic doses of antioxidants and zinc on the incidence and progression of AMD, reported a beneficial effect of high-dose supplements, taken for approximately 6 years, in delaying the progression of intermediate AMD to advanced AMD. AREDS and subsequent research on dietary intake or supplement use have not indicated a protective role of antioxidant or zinc intake or supplement use in the incidence or prevalence of early AMD. Numbers of cases were insufficient to investigate effects on late AMD. Persons with intermediate AMD and without contraindications should consider using antioxidant and zinc supplements. There is no evidence to date that earlier use conveys benefit.

Ferris FL. · Division of Epidemiology and Clinical Research, National Eye Institute, Bethesda, MD, USA. · Surv Ophthalmol. · Pubmed #12507624 No free full text.

This publication has no abstract.

SanGiovanni JP, Chew EY, Agrón E, Clemons TE, Ferris FL, Gensler G, Lindblad AS, Milton RC, Seddon JM, Klein R, Sperduto RD, Anonymous00450. · National Eye Institute, Bethesda, Maryland, USA. · Arch Ophthalmol. · Pubmed #18779490 No free full text.

Abstract: OBJECTIVE: To examine the association of dietary omega-3 long-chain polyunsaturated fatty acid and fish intake with incident neovascular age-related macular degeneration (AMD) and central geographic atrophy (CGA). METHODS: Multicenter clinic-based prospective cohort study from a clinical trial including Age-Related Eye Disease Study (AREDS) participants with bilateral drusen at enrollment. Main outcome measures were incident neovascular AMD and CGA, ascertained from annual stereoscopic color fundus photographs (median follow-up, 6.3 years). We estimated nutrient and food intake from a validated food frequency questionnaire (FFQ) at baseline, with intake of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), combined EPA and DHA, and fish as primary exposures. RESULTS: After controlling for known covariates, we observed a reduced likelihood of progression from bilateral drusen to CGA among people who reported the highest levels of EPA (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.23-0.87) and EPA+DHA (OR, 0.45; 95% CI, 0.23-0.90) consumption. Levels of DHA were associated with CGA in age-, sex-, and calorie-adjusted models (OR, 0.51; 95% CI, 0.26-1.00); however, this statistical relationship did not persist in multivariable models. CONCLUSIONS: Dietary lipid intake is a modifiable factor that may influence the likelihood of developing sight-threatening forms of AMD. Our findings suggest that dietary omega-3 long-chain polyunsaturated fatty acid intake is associated with a decreased risk of progression from bilateral drusen to CGA.

Clemons TE, Milton RC, Klein R, Seddon JM, Ferris FL, Anonymous00135. · The EMMES Corporation, Rockville, Maryland 20850-1707, USA. · Ophthalmology. · Pubmed #15808240 links to  free full text

Abstract: PURPOSE: To describe the association of demographic, behavioral, medical, and nonretinal ocular factors with the incidence of neovascular age-related macular degeneration (AMD) and central geographic atrophy (CGA) in the Age-Related Eye Disease Study (AREDS), a randomized trial of antioxidants and zinc supplementation prophylaxis for development of advanced AMD. DESIGN: Clinic-based prospective cohort study. PARTICIPANTS: Of individuals with early or intermediate AMD at baseline with a median follow-up of 6.3 years, 788 were at risk of developing advanced AMD in one eye (the fellow eye had advanced AMD), and 2506 were at risk in both eyes. METHODS: The incidence of neovascular AMD and CGA was assessed from stereoscopic color fundus photographs taken at baseline and at annual visits beginning at year 2. MAIN OUTCOME MEASURES: Neovascular AMD was defined as photocoagulation for choroidal neovascularization, or photographic documentation at the reading center of any of the following: nondrusenoid retinal pigment epithelial detachment, serous or hemorrhagic retinal detachment, hemorrhage under the retina or the retinal pigment epithelium, and subretinal fibrosis. Central geographic atrophy was defined as geographic atrophy involving the center of the macula. RESULTS: In multivariable models, in persons at risk of advanced AMD in both eyes, while controlling for age, gender, and AREDS treatment group, the following variables were statistically significantly associated with the incidence of neovascular AMD: race (odds ratio [OR], white vs. black, 6.77; 95% confidence interval [CI], 1.24-36.9) and larger amount smoked (OR, >10 vs. < or =10 pack-years [a pack-year is an average of 1 pack of cigarette smoked per day for a year], 1.55; 95% CI, 1.15-2.09). The following were statistically significantly associated with the incidence of CGA: less education (OR, high school graduate or less vs. college graduate, 1.75; 95% CI, 1.10-2.78), greater body mass index (BMI) (OR, obese vs. nonobese, 1.93; 95% CI, 1.25-2.65), larger amount smoked (OR, >10 pack-years vs. < or =10 pack-years, 1.82; 95% CI, 1.25-2.65), and antacid use (OR, 0.29; 95% CI, 0.09-0.91). In persons at risk of developing advanced AMD in one eye, the incidence of neovascular AMD was associated with diabetes (OR, 1.88; 95% CI, 1.07-3.31), and the incidence of CGA was associated with use of antiinflammatory medications (OR, 0.22; 95% CI, 0.08-0.59). CONCLUSIONS: Results suggest that, among persons with early or intermediate AMD, smoking and BMI are modifiable factors associated with progression to advanced AMD, and suggest other associations (e.g., use of antacids and antiinflammatory medications) that warrant further study. This article contains additional online-only material available at http://www.ophsource.org/periodicals/ophtha. .

Chew EY, Ferris FL, Csaky KG, Murphy RP, Agrón E, Thompson DJ, Reed GF, Schachat AP. · National Eye Institute/National Institutes of Health, Division of Epidemiology and Clinical Research, Bethesda, Maryland 20892-2510, USA. · Ophthalmology. · Pubmed #13129862 No free full text.

Abstract: OBJECTIVES: To evaluate the long-term natural history and effects of laser photocoagulation treatment in patients with diabetic retinopathy. DESIGN: Follow-up study of the 214 surviving patients enrolled originally at the Johns Hopkins Clinical Center for the Early Treatment Diabetic Retinopathy Study (ETDRS), which was a clinical trial designed to evaluate the role of laser photocoagulation and aspirin treatment in patients with diabetic retinopathy. METHODS: Early Treatment Diabetic Retinopathy Study patients enrolled in the Johns Hopkins Clinical Center had complete eye examinations, including best-corrected visual acuity measurements, fundus photographs, and medical questionnaires throughout the 7-year study. They had the same examinations at the final long-term follow-up visit at the National Eye Institute, National Institutes of Health, 13 to 19.5 years after the initial laser photocoagulation (median, 16.7 years). MAIN OUTCOME MEASURES: The major outcomes were mortality and the rates of moderate and severe vision loss. The secondary outcomes were progression of diabetic retinopathy and need for other eye surgery. RESULTS: Of the 214 patients who were alive at the end of the original ETDRS in 1989, 130 (61%) were deceased at the time of the re-examination. Of the 84 who were alive, 71 (85%) were examined at their long-term follow-up visit at the National Institutes of Health. At the long-term follow-up examination, 42% had visual acuity of 20/20 or better, and 84% had visual acuity of 20/40 or better in the better eye. Compared with baseline, 20% of patients had moderate vision loss (loss of 3 lines or more vision) in the better eye at follow-up. Only one patient had visual acuity of 20/200 bilaterally. He had visual acuity loss secondary to age-related macular degeneration. No patient had severe vision loss (worse than 5/200). All the initially untreated eyes of patients who had severe nonproliferative diabetic retinopathy or worse by the time of the ETDRS closeout visit of the original study received scatter photocoagulation treatment. Focal photocoagulation was performed in 43% bilaterally and 22% unilaterally. Cataract surgery was performed in 31% of the patients, vitrectomy in 17%, and glaucoma surgery in one patient. CONCLUSIONS: As previously reported, the mortality rate of patients with diabetic retinopathy is much higher than that of the general population. For those who survived, aggressive follow-up, with treatment when indicated, seems to be associated with maintenance of good long-term visual acuity for most patients. The need for laser scatter photocoagulation with long-term follow-up seems to be high.

Chew EY, Benson WE, Remaley NA, Lindley AA, Burton TC, Csaky K, Williams GA, Ferris FL. · Division of Biometry and Epidemiology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892-2510, USA. · Arch Ophthalmol. · Pubmed #10604663 No free full text.

Abstract: OBJECTIVE: To assess the visual results after surgical lens removal in patients with diabetic retinopathy. DESIGN: A multicenter randomized clinical trial designed to assess the effect of photocoagulation and aspirin in patients with mild to severe nonproliferative or early proliferative diabetic retinopathy and/or macular edema. PARTICIPANTS: Of the 3711 patients enrolled in the Early Treatment Diabetic Retinopathy Study, lens surgery was performed on 205 patients (270 eyes) during follow-up that ranged from 4 to 9 years. OUTCOME MEASUREMENTS: Visual acuity, macular edema status, and degree of diabetic retinopathy. In addition, risk factors associated with lens extraction and with poor postoperative visual acuity (worse than 20/100) were assessed. RESULTS: The risk of lens extraction increased with increasing age, female sex, and baseline proteinuria. Ocular variables associated with increased risk of lens surgery included poor baseline visual acuity and vitrectomy performed during the course of the study. At 1 year after lens surgery, visual acuity improvement of 2 or more lines from preoperative levels occurred in 64.3% of the operated-on eyes assigned to early photocoagulation and 59.3% of eyes assigned to deferral of photocoagulation. In eyes assigned to early photocoagulation, 46% of eyes achieved visual acuity better than 20/40; 73%, better than 20/100; and 8%, 5/200 or worse at 1 year after surgery. Visual acuity results for eyes assigned to deferral of laser photocoagulation at 1 year were not as favorable; 36% achieved visual acuity better than 20/40; 55%, better than 20/100; and 17%, 5/200 or worse at 1 year after surgery. Evaluation of 1-year postoperative visual acuities for all eyes with mild to moderate nonproliferative diabetic retinopathy at the annual visit before lens surgery showed that 53% were better than 20/40; 90%, better than 20/100; and 1%, 5/200 or worse. However, for eyes with severe nonproliferative or worse retinopathy at the annual visit before lens surgery, only 25% were better than 20/40; 42%, better than 20/100; and 22%, 5/200 or worse at 1 year after lens surgery. There was little change in visual acuity between 1 and 2 years postoperatively. Increased severity of retinopathy and poor visual acuity before surgery were associated with visual acuity of worse than 20/100 at 1 year after surgery. Lens surgery was associated with a borderline statistically significant increased risk of progression of diabetic retinopathy in the adjusted analyses (P = .03). No statistically significant long-term increased risk of macular edema was documented after lens surgery. CONCLUSIONS: Visual acuity results after lens surgery in patients in the Early Treatment Diabetic Retinopathy Study were better than published results for similar patients. This may be because of more intensive photocoagulation for lesions of diabetic retinopathy in the Early Treatment Diabetic Retinopathy Study than in previously reported studies. Although patients with severe nonproliferative retinopathy or worse before lens surgery had poorer visual results, visual improvement was seen in 55% of these patients at 1-year follow-up. The main causes of poor visual results in eyes after lens surgery were complications of proliferative retinopathy and/or macular edema.

Chew EY, Sperduto RD, Milton RC, Clemons TE, Gensler GR, Bressler SB, Klein R, Klein BE, Ferris FL. · National Eye Institute, Bethesda, Maryland, USA. · Ophthalmology. · Pubmed #19091420 No free full text.

Abstract: PURPOSE: To assess the risk of advanced age-related macular degeneration (AMD) developing after cataract surgery. DESIGN: Cohort study. PARTICIPANTS: Four thousand five hundred seventy-seven participants (8050 eyes) from a multicenter, controlled, randomized clinical trial, the Age-Related Eye Disease Study (AREDS). METHODS: Development of advanced AMD, either neovascular (NV) AMD or geographic atrophy (GA), was evaluated with annual fundus photographs, and history of cataract surgery was assessed every 6 months. Cox proportional hazard models with time-dependent covariates were conducted for NV AMD and GA separately. MAIN OUTCOME MEASURES: Neovascular AMD, GA, and central GA (CGA; involving the center of the macula). RESULTS: The Cox proportional hazards model of right eyes showed nonsignificant hazard ratios of 1.20 (95% confidence interval [CI], 0.82-1.75) for NV AMD, 0.80 (95% CI, 0.61-1.06) for GA, and 0.87 (95% CI, 0.64-1.18) for CGA. Similar results were obtained for left eyes: 1.07 (95% CI, 0.72-1.58) for NV AMD, 0.94 (95% CI, 0.71-1.25) for GA, and 0.86 (95% CI, 0.63-1.19) for CGA. For participants with advanced AMD in 1 eye (AREDS category 4), the hazard ratios for fellow eyes were 1.08 (95% CI, 0.65-1.72) for NV AMD and 0.98 (95% CI, 0.64-1.49) for CGA. CONCLUSIONS: The AREDS results showed no clear effect of cataract surgery on the risk of progression to advanced AMD. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Coleman HR, Chan CC, Ferris FL, Chew EY. · Division of Epidemiology and Clinical Research, National Eye Institute, National Institutes of Health, Bethesda, MD, USA. · Lancet. · Pubmed #19027484 links to  free full text

Abstract: Age-related macular degeneration is the leading cause of blindness in elderly populations of European descent. The most consistent risk factors associated with this ocular condition are increasing age and cigarette smoking. Genetic investigations have shown that complement factor H, a regulator of the alternative complement pathway, and LOC387715/HtrA1 are the most consistent genetic risk factors for age-related macular degeneration. Although the pathogenesis of this disease is unknown, oxidative stress might have an important role. Treatment with antioxidant vitamins and zinc can reduce the risk of developing advanced age-related macular degeneration by about a quarter in those at least at moderate risk. Intravitreal injections of ranibizumab, a monoclonal antibody that inhibits all forms of vascular endothelial growth factor, have been shown to stabilise loss of vision and, in some cases, improve vision in individuals with neovascular age-related macular degeneration. These findings, combined with assessments of possible environmental and genetic interactions and new approaches to modulate inflammatory pathways, will hopefully further expand our ability to understand and treat age-related macular degeneration.

Tuo J, Ross RJ, Reed GF, Yan Q, Wang JJ, Bojanowski CM, Chew EY, Feng X, Olsen TW, Ferris FL, Mitchell P, Chan CC. · Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA. · Ophthalmology. · Pubmed #18718667 No free full text.

Abstract: OBJECTIVE: To assess the association and combined effect on the risk of age-related macular degeneration (AMD) by the HtrA1 and complement factor H (CFH) polymorphisms, smoking, and serum cholesterol. DESIGN: Clinic-based and population-based case control study. PARTICIPANTS: A total of 805 AMD cases and 921 controls from The Eye Clinic of National Eye Institute, Age-Related Eye Diseases Study, Blue Mountain Eye Study Cohort, and Minnesota Lions Eye Bank. METHODS: DNA samples were genotyped for polymorphisms of rs11200638 in HtrA1 promoter and rs380390 in CFH. HtrA1 protein in ocular tissue was measured. Interactions of the HtrA1 risk allele with the CFH risk variant, smoking status, and cholesterol were assessed. MAIN OUTCOME MEASURES: AMD was evaluated by retinal specialists, and AMD subtypes (geographic atrophy and neovascularization) were determined. RESULTS: Strong associations of the HtrA1 risk allele (A) with AMD were present in all sample sets. A similar magnitude of association was observed for central geographic atrophy and neovascular AMD. The combination of the HtrA1 and CFH risk alleles increased AMD susceptibility, as did the combination of the HtrA1 risk allele with smoking. No combined effect of HtrA1 risk allele and cholesterol level was found. Enhanced expression of HtrA1 protein was detected in retina with AMD. CONCLUSIONS: Findings from multiple samples support an AMD genetic variant harbored within HtrA1. The risk of advanced AMD increased when the presence of risk alleles from HtrA1 was combined with either CFH risk alleles or history of smoking.

Browning DJ, Glassman AR, Aiello LP, Bressler NM, Bressler SB, Danis RP, Davis MD, Ferris FL, Huang SS, Kaiser PK, Kollman C, Sadda S, Scott IU, Qin H, Anonymous00193. · Jaeb Center for Health Research, 15310 Amberly Drive, Suite 350, Tampa, FL 33647, USA. · Ophthalmology. · Pubmed #18675696 No free full text.

Abstract: OBJECTIVE: To evaluate optical coherence tomography (OCT) measurements and methods of analysis of OCT data in studies of diabetic macular edema (DME). DESIGN: Associations of pairs of OCT variables and results of 3 analysis methods using data from 2 studies of DME. PARTICIPANTS: Two hundred sixty-three subjects from a study of modified Early Treatment of Diabetic Retinopathy Study (mETDRS) versus modified macular grid (MMG) photocoagulation for DME and 96 subjects from a study of diurnal variation of DME. METHODS: Correlations were calculated for pairs of OCT variables at baseline and for changes in the variables over time. Distribution of OCT measurement changes, predictive factors for OCT measurement changes, and treatment group outcomes were compared when 3 measures of change in macular thickness were analyzed: absolute change in retinal thickness, relative change in retinal thickness, and relative change in retinal thickening. MAIN OUTCOME MEASURES: Concordance of results using different OCT variables and analysis methods. RESULTS: Center point thickness correlated highly with central subfield mean thickness (CSMT) at baseline (0.98-0.99). The distributions of changes in CSMT were approximately normally distributed for absolute change in retinal thickness and relative change in retinal thickness, but not for relative change in retinal thickening. Macular thinning in the mETDRS group was significantly greater than in the MMG group when absolute change in retinal thickness was used, but not when relative change in thickness and relative change in thickening were used. Relative change in macular thickening provides unstable data in eyes with mild degrees of baseline thickening, unlike the situation with absolute or relative change in retinal thickness. CONCLUSIONS: Central subfield mean thickness is the preferred OCT measurement for the central macula because of its higher reproducibility and correlation with other measurements of the central macula. Total macular volume may be preferred when the central macula is less important. Absolute change in retinal thickness is the preferred analysis method in studies involving eyes with mild macular thickening. Relative change in thickening may be preferable when retinal thickening is more severe.

Gangnon RE, Davis MD, Hubbard LD, Aiello LM, Chew EY, Ferris FL, Fisher MR, Anonymous00112. · Department of Population Health Sciences, University of Wisconsin, Madison, Wisconsin 53711-1068, USA. · Invest Ophthalmol Vis Sci. · Pubmed #18539929 No free full text.

Abstract: PURPOSE: To develop a severity scale for diabetic macular edema (DME) and to assess relationships between severity and duration of DME and visual acuity (VA). METHODS: From the Early Treatment Diabetic Retinopathy Study (ETDRS), mean baseline VA scores were tabulated for 7422 eyes cross-classified by (1) location of retinal thickening (RT) and its area within 1 disc diameter of the macular center, and (2) degree of RT at the center. Adjacent (row, column, and off-diagonal) cells with the greatest similarity in baseline VA (mean and SD) based on a Gaussian (normal) likelihood were merged. An initial eight-step scale was chosen using the Schwarz criterion (Bayesian information criterion; BIC) and was revised based on clinical judgment to nine steps. Relationships between baseline VA and other photographic and fluorescein angiographic characteristics were examined singly and in combination with the scale. RESULTS: Modeling baseline VA as a function of the nine-step scale yielded an R(2) of 38.0%, compared with 38.4% using the full cross-classification of these variables. Addition of each of the other baseline characteristics changed the adjusted R(2) for the combination very little. Between scale levels 1A and 5B mean (SD) VA decreased from 86.8 (5.8) letters to 59.8 (13.6) letters. In a model of change in VA as a function of time spent at each DME severity level, VA loss increased progressively from 1 letter per year at level 2 to 17 letters per year at level 5B. CONCLUSIONS: The scale facilitates documentation of the relationship of severity and duration of DME with VA.

Huang LL, Coleman HR, Kim J, de Monasterio F, Wong WT, Schleicher RL, Ferris FL, Chew EY. · Clinical Trials Branch, Division of Epidemiology and Clinical Research, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA. · Invest Ophthalmol Vis Sci. · Pubmed #18450596 No free full text.

Abstract: PURPOSE: Increased dietary intake of lutein/zeaxanthin and omega-long-chain polyunsaturated fatty acids (omega-3 LCPUFA) was found to be associated with reduced risk of advanced age-related macular degeneration (AMD). The purpose of the study was to examine the effect of oral supplementation of omega-3 LCPUFA on changes in serum levels of lutein/zeaxanthin during supplementation in persons 60 years of age and older, with or without AMD. METHODS: Forty participants with AMD of various degrees of severity received lutein (10 mg) and zeaxanthin (2 mg) daily and were equally randomized to receive omega-3 LCPUFA (350 mg docosahexaenoic acid [DHA] and 650 mg eicosapentaenoic acid [EPA]) or placebo for 6 months. Serum levels of lutein, zeaxanthin, and omega-3 LCPUFAs and macular pigment optical densities were measured at baseline, 1 week, and 1, 3, 6, and 9 months. RESULTS: By month 6, the median serum levels of lutein/zeaxanthin increased by two- to threefold compared with baseline. Increases in serum levels of lutein/zeaxanthin did not differ by omega-3 LCPUFA treatment (P > 0.5). After 1 month, in the omega-3 LCPUFA-treated group, the median levels of DHA and EPA increased and the placebo group had no changes. At month 6, participants with AMD had a lower increase in serum lutein concentration than did those without AMD (P < 0.05). CONCLUSIONS: The addition of omega-3 LCPUFA to oral supplementation of lutein/zeaxanthin did not change the serum levels of lutein and zeaxanthin. A long-term large clinical trial is necessary to investigate the benefits and adverse effects of these factors for the treatment of AMD.

Klein ML, Ferris FL, Armstrong J, Hwang TS, Chew EY, Bressler SB, Chandra SR, Anonymous00008. · Devers Eye Institute, Legacy Good Samaritan Hospital and Medical Center, Portland, Oregon, USA. · Ophthalmology. · Pubmed #17981333 No free full text.

Abstract: PURPOSE: To determine specific retinal precursor lesions and sequence of events preceding the onset of geographic atrophy (GA) in eyes with age-related macular degeneration (AMD). DESIGN: Retrospective review. PARTICIPANTS: All participants in the Age-Related Eye Disease Study (AREDS) at 2 clinical centers (Devers Eye Institute, Portland, Oregon, and University of Wisconsin, Madison, Wisconsin) in whom GA initially appeared in at least one eye a minimum of 4 years after the baseline study visit. METHODS: All stereoscopic fundus photographs taken before the appearance of GA in the involved (study) eye were reviewed. Fundus features at the site of future GA were graded and recorded. Three graders reviewed photographs, with independent grading and adjudication by mutual agreement. Features graded included drusen (classified by size and confluence), focal hyperpigmentation, hypopigmentation, and refractile deposits. The time between first appearance of these features and initial appearance of GA was recorded. MAIN OUTCOME MEASURE: Appearance of GA. RESULTS: Of all AREDS participants at the 2 sites, 95 eyes of 77 developed GA at least 4 years after entrance into the study. Average time from baseline to initial appearance of GA was 6.6 years (range, 4-11). Drusen were found in 100% of eyes at the site of later developing GA, drusen >125 mum in diameter in 96% of eyes, confluent drusen in 94%, hyperpigmentation in 96%, drusen > 250 mum in 83%, hypopigmentation in 82%, and refractile deposits in 23%. Time from lesion appearance to onset of GA varied by lesion type, ranging from 5.9 years for drusen confluence to 2.5 years for hypopigmentation or refractile deposits. Lesions generally followed a uniform sequence of appearance. CONCLUSIONS: By focusing on the location of initial GA appearance and then retrospectively analyzing prior photographs, we were able to identify specific precursor lesions and the most common sequence of events leading to GA formation in eyes with AMD. The progression was usually characterized by large drusen formation and development of hyperpigmentation, followed by regression of drusen, appearance of hypopigmentation, and ultimately development of GA, sometimes preceded by the appearance of refractile deposits.

Anonymous00220, SanGiovanni JP, Chew EY, Clemons TE, Ferris FL, Gensler G, Lindblad AS, Milton RC, Seddon JM, Sperduto RD. · The EMMES Corporation, 401 N Washington St, Ste 700, Rockville, MD 20850-1707, USA. · Arch Ophthalmol. · Pubmed #17846363 links to  free full text

Abstract: OBJECTIVE: To evaluate the relationship of dietary carotenoids, vitamin A, alpha-tocopherol, and vitamin C with prevalent age-related macular degeneration (AMD) in the Age-Related Eye Disease Study (AREDS). METHODS: Demographic, lifestyle, and medical characteristics were ascertained on 4519 AREDS participants aged 60 to 80 years at enrollment. Stereoscopic color fundus photographs were used to categorize participants into 4 AMD severity groups and a control group (participants with < 15 small drusen). Nutrient intake was estimated from a self-administered semiquantitative food frequency questionnaire at enrollment. Intake values were energy adjusted and classified by quintiles. The relationship between diet and AMD status was assessed using logistic regression analyses. RESULTS: Dietary lutein/zeaxanthin intake was inversely associated with neovascular AMD (odds ratio [OR], 0.65; 95% confidence interval [CI], 0.45-0.93), geographic atrophy (OR, 0.45; 95% CI, 0.24-0.86), and large or extensive intermediate drusen (OR, 0.73; 95% CI, 0.56-0.96), comparing the highest vs lowest quintiles of intake, after adjustment for total energy intake and nonnutrient-based covariates. Other nutrients were not independently related to AMD. CONCLUSION: Higher dietary intake of lutein/zeaxanthin was independently associated with decreased likelihood of having neovascular AMD, geographic atrophy, and large or extensive intermediate drusen.

SanGiovanni JP, Chew EY, Clemons TE, Davis MD, Ferris FL, Gensler GR, Kurinij N, Lindblad AS, Milton RC, Seddon JM, Sperduto RD, Anonymous00204. · AREDS Coordinating Center, The EMMES Corporation, 401 N. Washington Street, Rockville, MD 20850, USA. · Arch Ophthalmol. · Pubmed #17502507 links to  free full text

Abstract: OBJECTIVE: To evaluate the association of lipid intake with baseline severity of age-related macular degeneration (AMD) in the Age-Related Eye Disease Study (AREDS). METHODS: Age-Related Eye Disease Study participants aged 60 to 80 years at enrollment (N = 4519) provided estimates of habitual nutrient intake through a self-administered semiquantitative food frequency questionnaire. Stereoscopic color fundus photographs were used to categorize participants into 4 AMD severity groups and a control group (participants with <15 small drusen). RESULTS: Dietary total omega-3 long-chain polyunsaturated fatty acid (LCPUFA) intake was inversely associated with neovascular (NV) AMD (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.41-0.90), as was docosahexaenoic acid, a retinal omega-3 LCPUFA (OR, 0.54; 95% CI, 0.36-0.80), comparing highest vs lowest quintile of intake, after adjustment for total energy intake and covariates. Higher fish consumption, both total and broiled/baked, was also inversely associated with NV AMD (OR, 0.61; 95% CI, 0.37-1.00 and OR, 0.65; 95% CI, 0.45-0.93, respectively). Dietary arachidonic acid was directly associated with NV AMD prevalence (OR, 1.54; 95% CI, 1.04-2.29). No statistically significant relationships existed for the other lipids or AMD groups. CONCLUSION: Higher intake of omega-3 LCPUFAs and fish was associated with decreased likelihood of having NV AMD.

Ross RJ, Bojanowski CM, Wang JJ, Chew EY, Rochtchina E, Ferris FL, Mitchell P, Chan CC, Tuo J. · Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA. · Invest Ophthalmol Vis Sci. · Pubmed #17325155 links to  free full text

Abstract: PURPOSE: Age-related macular degeneration (AMD) is a multifactorial blinding disease in the elderly. LOC387715 harbors a single-nucleotide polymorphism that has an association with AMD. This study was conducted to confirm the association between LOC387715 and AMD and to refine estimates of the impact of this gene variation in using samples from three studies: an Australian population-based study and two U.S. clinic-based case-control studies. METHODS: Cases and controls were collected from a National Eye Institute (NEI) clinical protocol (n = 240), the Age-Related Eye Disease Study (AREDS; n = 488), and the Blue Mountains Eye Study (BMES; n = 851). After DNA extraction, subjects were genotyped for the LOC387715 Ala69Ser polymorphism (rs10490924). RESULTS: The combined NEI and AREDS samples yielded odds ratios (ORs) of 2.61 (95% CI 1.89-3.61, P = 1.42 x 10(-9)) and 8.59 (95% CI 4.49-16.5, P = 3.56 x 10(-13)) for the heterozygous and homozygous risk alleles, respectively. The corresponding odds ratios in the BMES sample were 1.69 (95% CI: 1.25-2.28, P = 0.0007) and 2.20 (95% CI: 1.05-4.62, P = 0.038) for the heterozygous and homozygous groups. Neither set of samples showed statistically significant interaction with smoking, although there appeared to be a trend of interaction between smoking and LOC387715 for risk of advanced AMD. CONCLUSIONS: Although these data from three case-control samples support an AMD genetic risk marker harbored within LOC387715, the nested case-control data from the population-based BMES samples showed lower estimates than from the clinic-based samples. This may be because the BMES samples consisted of largely early AMD cases while the clinic-based AMD samples consisted exclusively of advanced cases.

Khachik F, de Moura FF, Chew EY, Douglass LW, Ferris FL, Kim J, Thompson DJ. · Department of Chemistry and Biochemistry, Joint Institute for Food Safety and Applied Nutrition (JIFSAN), University of Maryland, College Park, MD 20742-2021, USA. · Invest Ophthalmol Vis Sci. · Pubmed #17122108 links to  free full text

Abstract: PURPOSE: To investigate the effect of lutein supplementation at doses of 2.5, 5.0, and 10 mg/d for 6 months on distribution of these carotenoids and their metabolites in the serum of elderly human subjects, with and without age-related macular degeneration. To determine whether supplementation with lutein can interact with the serum levels of other dietary carotenoids, retinol, and alpha-tocopherol. METHODS: Forty-five subjects received daily supplements of lutein (containing 5% zeaxanthin) for 6 months and were followed up for another 6 months after supplementation. Blood was collected at various intervals and lutein, zeaxanthin, and their metabolites in the sera were quantified by normal-phase high-performance liquid chromatography (HPLC)-UV/visible detection. Other dietary carotenoids, retinol, and alpha-tocopherol were identified and quantified on a C18 reversed phase HPLC column. RESULTS: After 6 months of supplementation with 10 mg of lutein, the increases in the mean serum levels from baseline were: 210 to 1000 nM/L (P < 0.0001) for lutein and 56 to 95 nM/L (P < 0.0001) for zeaxanthin. Similarly, the mean concentrations (nM/L) of carotenoid metabolites increased from 49 to 98 (P < 0.0001) for 3-hydroxy-beta,epsilon-caroten-3'-one (3'-oxolutein); 31 to 80 (P < 0.0001) for 3'-hydroxy-epsilon,epsilon-caroten-3-one; and 19 to 25 (P < 0.0001) for epsilon,epsilon-carotene-3,3'-dione. The serum levels of these carotenoids gradually decline within 6 months after supplementation. CONCLUSIONS: The increase in the serum levels of lutein/zeaxanthin correlates with increases in the serum levels of their metabolites that have previously been identified in the ocular tissues. Elderly human subjects with and without AMD can safely take supplements of lutein up to 10 mg/d for 6 months with no apparent toxicity or side effects.

Rosenthal JM, Kim J, de Monasterio F, de Monastario F, Thompson DJ, Bone RA, Landrum JT, de Moura FF, Khachik F, Chen H, Schleicher RL, Ferris FL, Chew EY. · Clinical Trials Branch, Division of Epidemiology and Clinical Research, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA. · Invest Ophthalmol Vis Sci. · Pubmed #17122107 links to  free full text

Abstract: PURPOSE: To examine the dose-response relationship between oral lutein supplementation and serum lutein concentrations in persons aged 60 years and older, with or without age-related macular degeneration (AMD). METHODS: Forty-five participants with no AMD, large drusen, or advanced AMD, were randomized to receive one of three doses (2.5, 5, or 10 mg) of lutein for 6 months and to be observed for 6 additional months after the cessation of lutein supplementation. RESULTS: The mean age of the participants (33 women) was 71 years (range: 60-91). The serum lutein concentrations of each dose group were similar before supplementation, increased at 1 month, and peaked by 3 months. Median serum concentrations of the 2.5-, 5-, and 10-mg groups from baseline to month 6 increased from 18.7 to 35.1 microg/dL (2-fold increase), from 17.8 to 59.2 microg/dL (2.9-fold increase), and from 15.1 to 66.8 microg/dL (4-fold increase), respectively (all P < 0.001). The increases in lutein serum concentrations did not vary with AMD disease severity (P = 0.98). No toxicity was observed with any dose of lutein. No significant changes were detected in visual acuity or visual field tests. CONCLUSIONS: Increasing doses of lutein supplements significantly increased the serum levels of lutein and zeaxanthin, and doses up to 10 mg were safely administered. A long-term large clinical trial is necessary to investigate the safety and efficacy of lutein in reducing the risk of the development of advanced AMD.

Nussenblatt RB, Kim J, Thompson DJ, Davis MD, Chew E, Ferris FL, Buggage R. · Laboratory of Immunology, National Eye Institute, National Institutes of Health, Building 10, Rm. 10S219, 10 Center Drive, Bethesda, MD 20892, USA. · Am J Ophthalmol. · Pubmed #16386999 No free full text.

Abstract: PURPOSE: To investigate whether high-dose alpha-tocopherol (vitamin E) could reduce vision loss and retinal thickening associated with uveitis-associated cystoid macular edema. DESIGN: A double-masked, randomized study. METHODS: Uveitis patients with macular edema seen at the NIH were randomized and received either 1600 IU/day of vitamin E or placebo for 4 months. Visual acuity and retinal thickening were collected for the efficacy and the safety of the high dose of vitamin E. RESULTS: Changes in visual acuity and retinal thickening. CONCLUSIONS: Four-month oral supplementation with 1600 IU/d of vitamin E had no apparent effect on uveitis-associated macular edema or visual acuity in this small study.

Ferris FL, Davis MD, Clemons TE, Lee LY, Chew EY, Lindblad AS, Milton RC, Bressler SB, Klein R, Anonymous00307. · AREDS Coordinating Center, The EMMES Corporation, Rockville, MD 20850-1707, USA. · Arch Ophthalmol. · Pubmed #16286620 links to  free full text

Abstract: OBJECTIVE: To develop a simplified clinical scale defining risk categories for development of advanced age-related macular degeneration (AMD). METHODS: Following development of a detailed scale for individual eyes based on gradings of fundus photographs in the Age-Related Eye Disease Study, rates of progression to advanced AMD were assessed in cross-tabulations of presence or absence in each eye of 2 easily identified retinal abnormalities, drusen and pigment abnormalities. Large drusen and any pigment changes were particularly predictive of developing advanced AMD. RESULTS: The scoring system developed for patients assigns to each eye 1 risk factor for the presence of 1 or more large (> or = 125 microm, width of a large vein at disc margin) drusen and 1 risk factor for the presence of any pigment abnormality. Risk factors are summed across both eyes, yielding a 5-step scale (0-4) on which the approximate 5-year risk of developing advanced AMD in at least one eye increases in this easily remembered sequence: 0 factors, 0.5%; 1 factor, 3%; 2 factors, 12%; 3 factors, 25%; and 4 factors, 50%. For persons with no large drusen, presence of intermediate drusen in both eyes is counted as 1 risk factor. CONCLUSION: This simplified scale provides convenient risk categories for development of advanced AMD that can be determined by clinical examination or by less demanding photographic procedures than used in the Age-Related Eye Disease Study.

Davis MD, Gangnon RE, Lee LY, Hubbard LD, Klein BE, Klein R, Ferris FL, Bressler SB, Milton RC, Anonymous00306. · AREDS Coordinating Center, EMMES Corp, Rockville, MD 20850-1707, USA. · Arch Ophthalmol. · Pubmed #16286610 links to  free full text

Abstract: OBJECTIVE: To develop a fundus photographic severity scale for age-related macular degeneration (AMD). METHODS: In the Age-Related Eye Disease Study, stereoscopic color fundus photographs were taken at baseline, at the 2-year follow-up visit, and annually thereafter. Photographs were graded for drusen characteristics (size, type, area), pigmentary abnormalities (increased pigment, depigmentation, geographic atrophy), and presence of abnormalities characteristic of neovascular AMD (retinal pigment epithelial detachment, serous or hemorrhagic sensory retinal detachment, subretinal or sub-retinal pigment epithelial hemorrhage, subretinal fibrous tissue). Advanced AMD was defined as presence of 1 or more neovascular AMD abnormalities, photocoagulation for AMD, or geographic atrophy involving the center of the macula. We explored associations among right eyes of 3212 participants between severity of drusen characteristics and pigmentary abnormalities at baseline and development of advanced AMD within 5 years of follow-up. RESULTS: A 9-step severity scale that combines a 6-step drusen area scale with a 5-step pigmentary abnormality scale was developed, on which the 5-year risk of advanced AMD increased progressively from less than 1% in step 1 to about 50% in step 9. Among the 334 eyes that had at least a 3-step progression on the scale between the baseline and 5-year visits, almost half showed stepwise progression through intervening severity levels at intervening visits. Replicate gradings showed agreement within 1 step on the scale in 87% of eyes. CONCLUSIONS: The scale provides convenient risk categories and has acceptable reproducibility. Progression along it may prove to be useful as a surrogate for progression to advanced AMD.

Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, Henning AK, SanGiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J. · Laboratory of Statistical Genetics, Rockefeller University, 1230 York Avenue, New York, NY 10021, USA. · Science. · Pubmed #15761122 links to  free full text

Abstract: Age-related macular degeneration (AMD) is a major cause of blindness in the elderly. We report a genome-wide screen of 96 cases and 50 controls for polymorphisms associated with AMD. Among 116,204 single-nucleotide polymorphisms genotyped, an intronic and common variant in the complement factor H gene (CFH) is strongly associated with AMD (nominal P value <10(-7)). In individuals homozygous for the risk allele, the likelihood of AMD is increased by a factor of 7.4 (95% confidence interval 2.9 to 19). Resequencing revealed a polymorphism in linkage disequilibrium with the risk allele representing a tyrosine-histidine change at amino acid 402. This polymorphism is in a region of CFH that binds heparin and C-reactive protein. The CFH gene is located on chromosome 1 in a region repeatedly linked to AMD in family-based studies.