Stereoscopic Color Fundus Photographs Research Articles

Proliferative diabetic retinopathy is associated with microalbuminuria in patients with type 2 diabetes

Diabetic retinopathy is one of the leading causes of blindness in working-age individuals. Diabetic patients with proteinuria or those on dialysis usually present severe forms of diabetic retinopathy, but the association of diabetic retinopathy with early stages of diabetic nephropathy has not been entirely established. A cross-sectional study was conducted on 1214 type 2 diabetic patients to determine whether microalbuminuria is associated with proliferative diabetic retinopathy in these patients. Patients were evaluated by direct and indirect ophthalmoscopy and grouped according to the presence or absence of proliferative diabetic retinopathy. The agreement of diabetic retinopathy classification performed by ophthalmoscopy and by stereoscopic color fundus photographs was 95.1% (kappa = 0.735; P < 0.001). Demographic information, smoking history, anthropometric and blood pressure measurements, glycemic and lipid profile, and urinary albumin were evaluated. On multiple regression analysis, diabetic nephropathy (OR = 5.18, 95% CI = 2.91-9.22, P < 0.001), insulin use (OR = 2.52, 95% CI = 1.47-4.31, P = 0.001) and diabetes duration (OR = 1.04, 95% CI = 1.01-1.07, P = 0.011) were positively associated with proliferative diabetic retinopathy, and body mass index (OR = 0.90, 95% CI = 0.86-0.96, P < 0.001) was negatively associated with it. When patients with macroalbuminuria and on dialysis were excluded, microalbuminuria (OR = 3.3, 95% CI = 1.56-6.98, P = 0.002) remained associated with proliferative diabetic retinopathy. Therefore, type 2 diabetic patients with proliferative diabetic retinopathy more often presented renal involvement, including urinary albumin excretion within the microalbuminuria range. Therefore, all patients with proliferative diabetic retinopathy should undergo an evaluation of renal function including urinary albumin measurements.

Characteristics of progression of early Age-related macular degeneration: the Cardiovascular Health and Age-related maculopathy Study

To determine the risk of age-related macular degeneration (AMD) progression posed by the presence of each early AMD characteristic. A prospective cohort study of 254 participants aged 50 years and older, all with early AMD features at their baseline visit followed for an average of 7 years. Stereoscopic colour fundus photographs were graded for early AMD features using the International Classification System. AMD status was stratified into six exclusive levels along a continuum of disease severity according to drusen type, pigmentary abnormalities, or late AMD. Progression was assessed according to three definitions: a change between or within a severity level, or by side by side grading. The progression rate of early AMD ranged between 3.4 and 4.67% per annum depending upon the definition used. In total, 15 (6%) cases progressed from early AMD to the late complication of AMD. After controlling for age and smoking, cases with soft indistinct drusen at baseline were at a greater risk of progressing from early to late AMD than were cases without this characteristic (OR=3.72, 95%CI 1.20-11.54; P=0.02). Our proposed definitions of AMD progression give rates that are consistent with current knowledge of progression and its determinants. Each early AMD characteristic conveys its own risk of progression to an eye, with soft indistinct drusen carrying the greater risk. An international consensus on what defines AMD progression would greatly help the research community when trying to assess the importance of new risk factors and the effectiveness of novel interventions.

An Extension of the Early Treatment Diabetic Retinopathy Study (ETDRS) System for Grading of Diabetic Macular Edema in the Astemizole Retinopathy Trial

Purpose: To compare the effects of astemizole, an antihistamine, versus placebo on the 1-year course of diabetic macular edema (DME) and to illustrate use of a modified ETDRS system for grading areas of retinal thickening and hard exudates that may be useful in clinical trials of treatments for this disorder. Methods: Between June 1994 and September 1997, at 2 clinics, 63 patients who had, in at least one eye (the study eye), DME that had not previously been treated with macular photocoagulation, and for which photocoagulation was not currently recommended by the investigator, were enrolled and randomly assigned to astemizole or placebo. Fifty-four of the 63 patients (86%, 26 in Clinic 1 and 28 in Clinic 2) completed 1 year of followup and had adequate 7-field stereoscopic film-based color fundus photographs of the study eye at the baseline and 1-year visits. DME was > 0.33 disc diameters (DD) from the center of the macula in 48% of study eyes and involved the center in 13%. Photographs were graded using the ETDRS protocol modified to allow estimates of areas of retinal thickening (RT) and hard exudate (HE) to be made on continuous scales in disc area (DA) units. Principal outcome measures were mean change in the square root of RT area (the average diameter of the area in DD), mean change in area of HE, and change in the degree to which RT involved or threatened the center of the macula. Results: At baseline, RT area in the 54 study eyes ranged from 0.09 to 4.0 DA (median 1.1). At the 1-year visit the square root of RT area (RTdd) had decreased by ≥ 0.3 DD in 10 eyes, increased by ≥ 0.3 DD in 19 and was about the same in 25. Mean change at 1 year was +0.09 DD (SD 0.57) for astemizole versus +0.19 DD (SD 0.48) for placebo, for a difference of −0.10 DD (95% CI −0.38, +0.19; p = 0.51). Adjustments for baseline and time-dependent risk factors did not change this result appreciably, although there was a trend towards a difference in favor of astemizole in the subgroup of patients with more severe retinopathy. Other morphologic outcomes paralleled change in RTdd. Change in RTdd did vary by clinic: −0.03 DD in Clinic 2, versus + 0.32 DD in Clinic 1, for a difference of −0.35 DD (95% CI −0.62, −0.07; p = 0.014). Clinic 1 is a tertiary retinal referral center in Pennsylvania and Clinic 2 a retinal clinic closely affiliated with a large diabetes clinic in Copenhagen. The unexpected clinic difference in outcome provided an opportunity for further analyses using the modified ETDRS system. In comparison to Clinic 1, Clinic 2 patients were more often male, were younger at diagnosis of diabetes, and had less severe retinopathy and better visual acuity, but these differences did not appear to explain the trend for lesser increase in RTdd. Conclusion: No effect of astemizole was found, but the confidence interval for the principal outcome, mean change in RTdd, included both a modest beneficial effect and a small harmful effect. This outcome measure did demonstrate a small difference in outcome by clinic, which could not be explained by baseline characteristics but may reflect differences in access to and/or continuity of care or other unmeasured differences associated with different referral patterns. Although optical coherence tomography may supplant photography as a measure of central RT, photographic assessments of change in RT and HE areas analyzed with the methods described herein may be useful outcomes in trials assessing treatment of early stages of DME. Application of these methods to other data sets is needed to confirm this conclusion.

The Age-Related Eye Disease Study Severity Scale for Age-Related Macular Degeneration

To develop a fundus photographic severity scale for age-related macular degeneration (AMD). 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. 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. 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.

Preferential Hyperacuity Perimeter (PreView PHP) for Detecting Choroidal Neovascularization Study

To assess the ability of the Preferential Hyperacuity Perimeter (PreView PHP; Carl Zeiss Meditec, Dublin, CA) to detect recent-onset choroidal neovascularization (CNV) resulting from age-related macular degeneration (AMD) and to differentiate it from an intermediate stage of AMD. Prospective, comparative, concurrent, nonrandomized, multicenter study. Eligible participants' study eyes had a corrected visual acuity of 20/160 or better and either untreated CNV from AMD diagnosed within the last 60 days or an intermediate stage of AMD. After obtaining consent, visual acuity with habitual correction, masked PHP testing, stereoscopic color fundus photography, and fluorescein angiography were performed. Photographs and angiograms were evaluated by graders masked to diagnosis and PHP results. The reading center's diagnosis determined if the patient was categorized as having intermediate AMD or neovascular AMD. A successful study outcome was defined a priori as a sensitivity of at least 80% and a specificity of at least 80%. Of 185 patients who gave consent to be enrolled, 11 (6%) had PHP results judged to be unreliable. An additional 52 were not included because they did not meet all eligibility criteria. Of the remaining 122 patients, 57 had an intermediate stage of AMD and 65 had neovascular AMD. The sensitivity to detect newly diagnosed CNV using PHP testing was 82% (95% confidence interval [CI], 70%-90%). The specificity to differentiate newly diagnosed CNV from the intermediate stage of AMD using PHP testing was 88% (95% CI, 76%-95%). Preferential Hyperacuity Perimeter testing can detect recent-onset CNV resulting from AMD and can differentiate it from an intermediate stage of AMD with high sensitivity and specificity. These data suggest that monitoring with PHP should detect most cases of CNV of recent onset with few false-positive results at a stage when treatment usually would be beneficial. Thus, this monitoring should be considered in the management of the intermediate stage of AMD.

Systemic Markers of Inflammation, Endothelial Dysfunction, and Age-Related Maculopathy

To examine the association of systemic markers of inflammatory disease and endothelial dysfunction with age-related maculopathy (ARM). (1) Nested case-control analysis of prevalent ARM and (2) prospective analyses of incident ARM in a random sample of a population-based cohort. Standardized protocols for blood collection, measurement of markers, administration of a questionnaire, and gradings of stereoscopic color fundus photography to determine ARM were used. Standard univariate and multivariate analyses were performed. participants: Included in the nested case-control study were 188 cases with moderate to advanced ARM and 195 controls matched for age, gender, and current smoking status at a baseline examination from 1988 to 1990, and living in Beaver Dam, Wisconsin. Included in the prospective analyses as a random sample of 321 persons were those who participated in a 5-year and/or 10-year follow-up. main outcome measures: Prevalent and incident ARM. Serum C-reactive protein, amyloid A, interleukin-6, tumor necrosis factor-alpha, intracellular adhesion molecule, E-selectin, folate, and Chlamydia pneumoniae IgG antibody were not associated with either prevalent or incident ARM. Contrary to other reports, we cannot confirm a strong or consistent relationship of markers of inflammation and endothelial dysfunction with ARM.

GUIDELINES FOR INTERPRETING RETINAL PHOTOGRAPHS AND CODING FINDINGS IN THE SUBMACULAR SURGERY TRIALS (SST)

To describe the guidelines followed by the Submacular Surgery Trials (SST) Research Group in the interpretation of color fundus photographs and fluorescein angiograms of subfoveal choroidal neovascular lesions evaluated in the SST and to assist ophthalmologists in applying the results of the SST. Stereoscopic color fundus photographs and fluorescein angiograms of the study eye and nonstudy eye of 1,015 patients with subfoveal choroidal neovascular lesions secondary to age-related macular degeneration, ocular histoplasmosis syndrome, or idiopathic choroidal neovascularization (CNV) were obtained and graded by certified SST fundus photograph readers at the baseline examination in three randomized clinical trials comparing surgery with observation. Adherence to the inclusion and exclusion criteria and ocular features that might affect visual outcome were documented. Stereoscopic color fundus photography and fluorescein angiography were repeated 1 month after randomization for patients assigned to surgery to provide documentation that surgery was performed and to assess compliance with the surgery protocol. Photographs and fluorescein angiograms of both the study eye and the fellow eye in all patients then were obtained 3 months, 6 months, and 12 months after randomization and then annually up to 48 months. The kappa statistic was used to evaluate interobserver reliability of photograph gradings. Lesion components at baseline included classic CNV, occult CNV, and features contiguous to CNV, including blood, fibrous tissue, hypofluorescence not corresponding to blood, serous detachment of the retinal pigment epithelium, and prior areas of laser photocoagulation. At follow-up, fluorescein leakage from CNV was assessed peripheral to or within the area of the retinal pigment epithelium abnormality after surgery. The lesion at follow-up could include any of the features identified at baseline as well as retinal pigment epithelium abnormalities, such as mottling of the retinal pigment epithelium with a subtle transition to normal retinal pigment epithelium or a very sharply demarcated, markedly hypopigmented area that was easily distinguished from the surrounding retinal pigment epithelium. kappa statistics for interobserver reliability ranged from good (0.47) to excellent (1.00) for features graded at baseline and follow-up. Although some of the definitions essential to the interpretation of the SST are similar to those used in the Macular Photocoagulation Study and randomized clinical trials of photodynamic therapy with verteporfin, this guideline provides new information regarding lesion components at baseline as well as standardized descriptions of lesions after submacular surgery. These descriptions from the SST assist in understanding what lesions were studied, when additional treatment was considered after surgery, and how anatomical results should be interpreted.

Risk Factors for the Incidence of Advanced Age-Related Macular Degeneration in the Age-Related Eye Disease Study (AREDS): AREDS report no. 19

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. Clinic-based prospective cohort study. 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. 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. 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. 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). 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. .

The Relationship of Diabetic Retinopathy to Preclinical Diabetic Glomerulopathy Lesions in Type 1 Diabetic Patients

Few epidemiological data exist regarding the correlation of anatomic measures of diabetic retinopathy and nephropathy, especially early in the disease processes. The aim of this study was to examine the association of severity of diabetic retinopathy with histological measures of diabetic nephropathy in normoalbuminuric patients with type 1 diabetes. The study included participants (n = 285) in the Renin-Angiotensin System Study (RASS; a multicenter diabetic nephropathy primary prevention trial) who were aged >/=16 years and had 2-20 years of type 1 diabetes with normal baseline renal function measures. Albumin excretion rate (AER), blood pressure, serum creatinine, and glomerular filtration rate (GFR) were measured using standardized protocols. Diabetic retinopathy was determined by masked grading of 30 degrees color stereoscopic fundus photographs of seven standard fields using the Early Treatment Diabetic Retinopathy Study (ETDRS) severity scale. Baseline renal structural parameters, e.g., fraction of the glomerulus occupied by the mesangium or mesangial fractional volume [Vv(Mes/glom)] and glomerular basement membrane width, were assessed by masked electron microscopic morphometric analyses of research percutaneous renal biopsies. No retinopathy was present in 36%, mild nonproliferative diabetic retinopathy in 53%, moderate to severe nonproliferative diabetic retinopathy in 9%, and proliferative diabetic retinopathy in 2% of the cohort. Retinopathy was not related to AER, blood pressure, serum creatinine, or GFR. All renal anatomical end points were associated with increasing severity of diabetic retinopathy, while controlling for other risk factors. These data demonstrate a significant association between diabetic retinopathy and preclinical morphologic changes of diabetic nephropathy in type 1 diabetic patients.

Screening for diabetic retinopathy using a digital non‐mydriatic camera compared with standard 35‐mm stereo colour transparencies

To investigate the use of a digital non-mydriatic camera for determining the ETDRS clinical level of diabetic retinopathy, and to evaluate its use in a screening setting to appropriately determine the need for referral to an ophthalmologist (ETDRS level > or = 35). A total of 83 patients with diabetes were photographed with and without pharmacological pupil dilation at an ophthalmology department using a digital non-mydriatic camera, obtaining two sets of five non-stereoscopic, 45 degree field images of each eye. ETDRS seven standard field, 35-mm stereoscopic colour fundus photographs were also obtained. A subgroup of 59 patients was photographed at an optician's shop using the digital non-mydriatic camera without pupil dilation. There was substantial agreement between the clinical level of diabetic retinopathy assessed from the 35-mm photographs and the digital images: the ophthalmology department (kappa = 0.76) with pupil dilation and (kappa = 0.66) without pupil dilation, respectively, and at the optician's (kappa = 0.60 without pupil dilation). With respect to the need for referral to an ophthalmologist, there was almost perfect agreement in the ophthalmology department (kappa = 0.88) with pupil dilation and (kappa = 0.84) without pupil dilation, respectively, and those taken at the optician's (kappa = 0.87 without pupil dilation). A digital non-mydriatic camera may be used in a screening situation to appropriately determine the need for referral to an ophthalmologist (ETDRS level > or = 35).

Impact of aging and age-related maculopathy on activation of the a-wave of the rod-mediated electroretinogram.

To examine the impact of aging and age-related maculopathy (ARM) on the activation of phototransduction in rod photoreceptors by measuring the a-wave of the flash, full-field electroretinogram (ERG). Enrollees consisted of older adults (> or = 60 years of age) in normal retinal health (n = 41) and those with early (n = 39) or late ARM (n = 7), in whom disease presence and severity were defined based on grading of stereoscopic color fundus photographs according to the Wisconsin Age-Related Maculopathy grading system. Young adults (ages 16-30 years; n = 27) were enrolled for comparison purposes. Previously established procedures were used to estimate the ERG response to two families of flash intensities. By computer subtraction of responses, the isolated rod response was identified. Each participant's ensemble rod responses were fit with the following equation to describe the response (R) as function of flash intensity (I), and time (t): R(I,t) = [1 - exp[-I x S x (t - td)2]] x RmP3, where S is sensitivity, td is the delay before onset of the a-wave, and Rm(P3) is the maximum amplitude. In analyses of older adults, there was no impact of early ARM presence or severity on log S, Rm(P3), or td after adjustment for age and intraocular lens presence. Differences between young and old normal subjects in log S, RmP3, and td disappeared when analyses were limited to older adults with intraocular lenses. When the light absorption of the aged lens is taken into account and reliable definitions of normal retinal aging and ARM are used, the activation of the a-wave as measured by the rod-mediated full-field ERG is not affected by early ARM, nor is it impacted by normal retinal aging.

Risk factors for incident age-related macular degeneration: Pooled findings from 3 continents

Objective To examine risk factors for incident age-related macular degeneration (AMD) after combining data from 3 population-based cohort studies. Design Population-based cohort study. Population A population of 9523 adults (age range, 43–95 years at baseline) living in Australia, The Netherlands, and the United States who participated in a baseline examination and a follow-up examination on average 5 or 6 years later. Methods Similar procedures were used at all study sites. Examinations included a standardized questionnaire, pupillary dilation, and stereoscopic color fundus photography. Fundus photographs were graded for lesions associated with AMD using the Wisconsin and International Age-Related Maculopathy Grading Systems. Senior investigators from each site adjudicated all photos graded as late AMD. Main outcomes measure Incidence of late AMD. Results Among studies, distributions for most risk factors differed, and overall incidence rates were similar. In the Beaver Dam Eye Study, total serum cholesterol was inversely associated with incident neovascular AMD. In the Blue Mountains Eye Study, current smoking (defined as smoking at the time of the baseline examination) was associated with an increased risk of incident geographic atrophy and late AMD; increased total serum cholesterol, having diabetes, and older age at menopause were positively associated with incident geographic atrophy; and an increase in high-density lipoprotein serum cholesterol was inversely related to incident geographic atrophy. In the Rotterdam Study, current smoking was associated with an increased risk of incident geographic atrophy, neovascular AMD, and late AMD; past smoking was associated with an increased risk of incident neovascular AMD and late AMD; and an increased number of years between menarche and menopause was directly related to incident geographic atrophy. After pooling data, the only statistically significant relationships found were between smoking and total serum cholesterol and incident AMD. Current smoking was associated with an increased incidence of geographic atrophy and late AMD (odds ratios [ORs] relative to nonsmokers: 2.83 and 2.35, respectively; ORs relative to past smokers: 2.80 and 1.82, respectively), and total serum cholesterol was associated directly with incident geographic atrophy (OR: 1.08 per 10 mg/dl) and inversely with incident neovascular AMD (OR: 0.94 per 10 mg/dl). Conclusions Pooled data support a growing body of evidence indicating that smoking is related to an increased risk of incident AMD. Current smokers were at higher risk of incident AMD than both past smokers and those who never smoked. The relationships found in this study between total serum cholesterol and incident geographic atrophy and neovascular AMD are not readily explained.

Location of lesions associated with age-related maculopathy over a 10-year period: the Beaver Dam Eye Study.

To describe cumulative incidence and changes in retinal lesions associated with age-related maculopathy (ARM) by location over a 10-year period and to examine the relation of location of those lesions to progression of ARM. Persons ranging in age from 43 to 84 years and living in Beaver Dam, Wisconsin, at the time of a census (1987-1988) were examined two to three times over a 10-year period (n = 3684). Drusen area, size, and type; retinal pigment epithelium depigmentation; increased pigment; geographic atrophy; and neovascular macular degeneration were determined in each of nine macular subfields: central, inner and outer superior, inner and outer nasal, inner and outer inferior, and inner and outer temporal by grading of stereoscopic color fundus photographs. Late ARM was defined as presence of either geographic atrophy or neovascular ARM. Lesions were more likely to change or develop in specific locations. Drusen area increased most in the central circle. Compared with other quadrants, drusen greater than 125 micro m in diameter and soft indistinct or reticular drusen were most likely to develop in the superior or temporal quadrants, whereas pigmentary abnormalities were most likely to occur in the nasal or superior quadrants. In general, large drusen, soft indistinct drusen, and pigmentary abnormalities were more likely to develop in the inner circle versus the central and outer circles. The quadrant location of early ARM lesions in 72 persons in whom late ARM developed was generally similar to that in persons who did not have late ARM. However, persons who had geographic atrophy were more likely to have large drusen in the inner circle than in the outer circle, while those who did not have late ARM were more likely to have large drusen in the outer circle. Lesions associated with early ARM were more likely to develop in specific locations in the macular area, and persons with lesions closer to the fovea may be related to a higher risk of development of late ARM. The quadrant location of early ARM lesions does not appear to add additional information to the risk of development of late ARM.

Is medication use associated with the incidence of early age-related maculopathy?: Pooled findings from 3 continents

Objective To investigate whether there is an association between the use of medication and the incidence of early age-related maculopathy (ARM). Design Pooled data from 3 prospective, population-based cohort studies. Participants Subjects without early and late ARM at baseline who participated in the follow-up of the Beaver Dam Eye Study (n = 3012), the Rotterdam Study (n = 3434), and the Blue Mountains Eye Study (n = 2203). Methods Stereoscopic color fundus photographs of all participants were graded according to a standardized protocol. At baseline, current use of prescription and over-the-counter medication was assessed by interview, and the drug name was confirmed at the research centers. Procedures and definitions were similar at both baseline and follow-up across the 3 study sites. Main outcome measures Incidence of early ARM, defined as the presence at follow-up of either soft distinct drusen with pigmentary changes or soft indistinct or reticular drusen. Results In the pooled cohort, 53.3% of participants used at least one of the medications selected for this study. Within a mean period of 5.6 years, a total of 683 subjects developed early ARM. Users of antihypertensive medication in general, and β-blockers in particular, had a borderline statistically significant increased risk of early ARM (odds ratio [OR] for β-blockers, 1.3; 95% confidence interval [CI], 1.0–1.6) when adjusted for systolic (or diastolic) blood pressure and other confounders. A protective effect of borderline significance was found among women using hormone replacement therapy (OR, 0.6; 95% CI, 0.4–1.0) and in persons using tricyclic antidepressants (OR, 0.4; 95% CI, 0.2–1.0). In contrast with β-blockers, the direction and magnitude of the association with hormone replacement therapy and tricyclic antidepressants were inconsistent among the 3 study populations. Conclusions Pooled data from 3 population-based studies showed no strong associations between medication use and the incidence of early ARM. Of borderline significance were a slightly increased risk among users of β-blockers and a reduced risk among users of hormone replacement therapy and users of tricyclic antidepressants. Although β-blocker use could be a proxy for systemic hypertension, these findings warrant further investigations, preferably including information on the dosage and duration of drug exposure.

Sunlight and the 10-year incidence of age-related maculopathy: the Beaver Dam Eye Study.

To examine the association of sunlight exposure and indicators of sun sensitivity with the 10-year incidence of age-related maculopathy (ARM). Population-based cohort study. We included persons aged 43 to 86 years at the baseline examination from 1988 to 1990, living in Beaver Dam, Wis, of whom 3684 persons underwent 5-year follow-up and 2764 underwent 10-year follow-up. Data on sun exposure and indicators of sun sensitivity were obtained from a standardized questionnaire administered at baseline and/or follow-up. We determined ARM status by grading stereoscopic color fundus photographs using the Wisconsin Age-Related Maculopathy Grading System. Incidence and progression of ARM. While controlling for age and sex, we found that participants exposed to the summer sun for more than 5 hours a day during their teens, in their 30s, and at the baseline examination were at a higher risk of developing increased retinal pigment (risk ratio [RR], 2.99; 95% confidence interval [CI], 1.18-7.60; P =.02) and early ARM (RR, 2.20; 95% CI, 1.02-4.73; P =.04) [corrected] by 10 years than those exposed less than 2 hours per day during the same periods. In participants reporting the highest summer sun exposure levels in their teens and 30s, the use of hats and sunglasses at least half the time during the same periods was associated with a decreased risk of developing soft indistinct drusen (RR, 0.55; 95% CI, 0.33-0.90; P =.02) and retinal pigment epithelial depigmentation (RR, 0.51; 95% CI, 0.29-0.91; P =.02). Participants who experienced more than 10 severe sunburns during their youth were more likely than those who experienced 1 or no burn to develop drusen with a 250-microm diameter or larger (RR, 2.52; 95% CI, 1.29-4.94 [corrected] P =.01) by the 10-year examination. No relationships were found between UV-B exposure, winter leisure time spent outdoors, skin sun sensitivity, or number of bad sunburns experienced by the time of the baseline examination and the 10-year incidence and progression of ARM or its associated lesions. Few significant relationships between environmental exposure to light and the 10-year incidence and progression of ARM were found in the Beaver Dam Eye Study. Consistent with results from the baseline and 5-year follow-up examinations, significant associations were found between extended exposure to the summer sun and the 10-year incidence of early ARM and increased retinal pigment. A protective effect of hat and sunglasses use by participants while in their teens and 30s against the 10-year incidence of soft indistinct drusen and retinal pigment epithelial depigmentation was also found, but only in those who reported the highest amount of sun exposure during the same periods.

Effects of aldose reductase inhibitors and galactose withdrawal on fluorescein angiographic lesions in galactose-fed dogs.

To assess the effect of aldose reductase inhibitor (ARI) M79175 (2-methyl-6-fluoro-spiro-chroman-4-5'-imidazolidine-2',4'-dione) administration and galactose withdrawal on the progression of retinal changes using fluorescein angiography in galactose-fed dogs. Thirty male beagles were randomized into 4 groups. Three dogs were fed a normal control diet containing 30% nonnutritive fiber for 74 months (control group), 11 dogs a 30% galactose diet for 74 months (continuous galactose group), 8 dogs a 30% galactose diet for 36 months followed by replacement with a normal diet for 36 months (galactose withdrawal group), and 8 dogs a 30% galactose diet supplemented with M79175 for 34 months followed by replacement with a normal diet and removal of M79175 treatment for 38 months (ARI-treated galactose withdrawal group). Stereoscopic color fundus photography and fluorescein angiography, performed at baseline and follow-up, were assessed for the clinical development of retinopathy, including the first appearance of hyperfluorescence, varying severity of retinal nonperfusion, and retinal neovascularization. Histopathologic features were examined in selected dogs. All dogs in the 3 groups fed the 30% galactose diet developed areas of hyperfluorescence and nonperfusion. Of these dogs, only those supplemented with the ARI did not develop areas of nonperfusion greater than or equal to half the field and retinal neovascularization. Parametric survival analysis showed significant differences (galactose withdrawal group vs ARI-treated galactose withdrawal group) in the median times to the development of nonperfusion greater than or equal to half the field (P =.003) and retinal neovascularization (P =.03). Normalization of glycemic control with galactose withdrawal and ARI treatment may delay the onset and progression of retinal lesions in galactose-fed dogs. Clinical Relevance Perfect glycemic control after a period of poor control does not completely prevent the progression of retinal lesions. Therapy with ARIs may potentially be important in the prevention of retinal lesions associated with diabetic eye disease.

Central retinal artery occlusion.: Retinal survival time

Purpose. To investigate the retinal survival time following central retinal artery occlusion (CRAO). Methods. In 38 elderly, atherosclerotic and hypertensive rhesus monkeys, transient CRAO (varying from 97 to 240 min) was produced by temporarily clamping the CRA at its site of entry into the optic nerve. Stereoscopic color fundus photography, fluorescein fundus angiography, electroretinography (ERG), and visual evoked potential (VEP) recording were performed before and during CRA clamping, after unclamping, and serially thereafter. After unclamping of the CRA, the animals were followed for variable lengths of time (median duration 8·14 weeks). Finally, the eyes and optic nerves were examined histologically. The data on ERG changes were analyzed in the following four time frames: (1) baseline before CRA clamping, (2) during CRA clamping, (3) immediately after unclamping, and (4) at the end of follow-up. Duration of CRAO was divided into four groups: 97, 105–120, 150–165, and ≥180 min. Results. A ‘negative ERG’ appeared during CRA clamping. With removal of the CRA clamp, there was b-wave recovery, with differential rates of recovery of ERG-eyes with shorter CRAO recovered sooner than those with longer occlusion. On removal of clamp, recovery was seen in scotopic 24 dB b-wave, photopic 0 dB single flash b-wave and 30 Hz flicker, with the b/a ratio of the combined rod and cone response and selective rod response showing statistically significant differences amongst the shorter and longer periods of CRAO. A delayed normalization of the depressed b/a ratio immediately after CRA reperfusion may indicate high-grade ischemic damage. At the final follow-up test session, no clear-cut derangement of any ERG parameter was seen for any group, with subtotal b-wave amplitude recovery for all groups. Longer CRAO produced incomplete VEP recovery. On histology, in the macular retina, eyes with CRAO for 97 min showed practically no damage, but duration of CRAO was found to be significantly associated with the amount of damage in the ganglion cell layer ( p=0·009) and inner nuclear layer ( p=0·017). Outer nuclear and plexiform layers and photoreceptors showed no damage at all with CRAO. There was no significant association of the ERG measures and histologic changes with any of the residual retinal circulation variables. Conclusions. Our electrophysiologic, histopathologic and morphometric studies showed that the retina of old, atherosclerotic, hypertensive rhesus monkeys suffers no detectable damage with CRAO of 97 min but above that level, the longer the CRAO, the more extensive the irreversible damage. The study suggests that CRAO lasting for about 240 min results in massive irreversible retinal damage.

The association of cardiovascular disease with the long-term incidence of age-related maculopathy: The beaver dam eye study

Purpose To examine the association between cardiovascular disease and its risk factors and the 10-year incidence of age-related maculopathy. Design Population-based cohort study. Participants Persons 43 to 86 years of age at baseline examination from 1988 to 1990, living in Beaver Dam, Wisconsin, of whom 3684 persons participated in a 5-year follow-up examination and 2764 participated in a 10-year follow-up examination. Methods Standardized protocols for physical examination, blood collection, administration of a questionnaire, and stereoscopic color fundus photography to determine age-related maculopathy. The Kaplan–Meier (product–limit) survival approach and discrete linear logistic regression were used in the data analysis. Main outcome measures Incidence and progression of age-related maculopathy. Results When age, gender, and history of heavy drinking, smoking, and vitamin use were controlled for, higher systolic blood pressure at baseline was associated with the 10-year incidence of retinal pigment epithelial depigmentation (risk ratio [RR] per 10 mmHg systolic blood pressure, 1.10; 95% confidence interval [CI], 1.01–1.18; P = 0.02) and exudative macular degeneration (RR, 1.22; 95% CI, 1.06–1.41; P = 0.006). Higher pulse pressure at baseline was associated with the incidence of retinal pigment epithelial depigmentation (RR per 10 mmHg, 1.17; 95% CI, 1.07–1.28; P < 0.001), increased retinal pigment (RR, 1.10; 95% CI, 1.01–1.19; P = 0.03), exudative macular degeneration (RR, 1.34; 95% CI, 1.14–1.60; P < 0.001), and progression of age-related maculopathy (RR, 1.08; 95% CI, 1.01–1.17; P = 0.03). Higher serum high-density lipoprotein cholesterol at baseline was associated with pure geographic atrophy (RR per 10 mg/dl high-density lipoprotein cholesterol, 1.29; 95% CI, 1.05–1.58; P = 0.01). Physical activity at baseline was associated with the incidence of geographic atrophy (RR in those who worked up a sweat 5 times a week compared with those who did not, 0.12; 95% CI, 0.02–0.91; P = 0.04) exudative macular degeneration (RR, 0.27; 95% CI, 0.08−0.87; P = 0.05), and progression of age-related maculopathy (RR, 0.69; 95% CI, 0.47–1.00; P = 0.05). Neither a history of stroke nor heart attack was associated with the incidence or progression of age-related maculopathy. Conclusions These findings indicate relationships between higher pulse pressure (a presumed indicator of age-related elastin and collagen changes in Bruch’s membrane) and systolic blood pressure with an increased 10-year incidence of some lesions defining early age-related maculopathy and exudative macular degeneration.

Association of emphysema, gout, and inflammatory markers with long-term incidence of age-related maculopathy.

To examine the relationship of 2 diseases associated with systemic inflammatory response, emphysema and gout, and selected markers of systemic inflammation with the 10-year incidence of age-related maculopathy. Population-based cohort study. We included persons aged 43 to 86 years at baseline examination from 1988 to 1990 living in Beaver Dam, Wis, of whom 3684 subjects participated in a 5-year follow-up examination and 2764 participated in a 10-year follow-up. Standardized protocols for physical examination, blood collection, administration of a questionnaire, and stereoscopic color fundus photography to determine the presence of age-related maculopathy. Standard univariate and multivariate analyses were performed. Incidence and progression of age-related maculopathy. While controlling for age, sex, and other factors (history of heavy drinking or smoking, systolic blood pressure, and vitamin use), a higher white blood cell count at baseline was associated with the 10-year incidence of drusen 125 microm or greater in diameter (risk ratio [RR] per 10(6)/ microL = 1.10; 95% confidence interval [CI], 1.03-1.17), retinal pigment epithelial depigmentation (RR = 2.08; 95% CI, 1.01-1.16), and progression of age-related maculopathy (RR = 1.09; 95% CI, 1.03-1.15). A lower serum albumin level was associated with the incidence of exudative macular degeneration (RR per grams per deciliter = 0.31; 95% CI, 0.13-0.76). A history of emphysema at baseline was associated with the incidence of retinal pigment epithelial depigmentation (RR = 2.84; 95% CI, 1.40-5.78), increased retinal pigment (RR = 2.20; 95% CI, 1.11-4.35), and exudative macular degeneration (RR = 5.12; 95% CI, 1.63-16.06); a history of gout was associated with the incidence of pure geographic atrophy (RR = 3.48; 95% CI, 1.27-9.53). These findings indicate modest relationships between both increased white blood cell count and emphysema and the increased 10-year incidence of lesions defining early and late age-related maculopathy. Further investigation of these relationships in other studies is needed.

The association of cardiovascular disease with the long-term incidence of age-related maculopathy: The Beaver Dam eye study

Purpose To examine the association between cardiovascular disease and its risk factors and the 10-year incidence of age-related maculopathy. Design Population-based cohort study. Participants Persons 43 to 86 years of age at baseline examination from 1988 to 1990, living in Beaver Dam, Wisconsin, of whom 3684 persons participated in a 5-year follow-up examination and 2764 participated in a 10-year follow-up examination. Methods Standardized protocols for physical examination, blood collection, administration of a questionnaire, and stereoscopic color fundus photography to determine age-related maculopathy. The Kaplan–Meier (product–limit) survival approach and discrete linear logistic regression were used in the data analysis. Main outcome measures Incidence and progression of age-related maculopathy. Results When age, gender, and history of heavy drinking, smoking, and vitamin use were controlled for, higher systolic blood pressure at baseline was associated with the 10-year incidence of retinal pigment epithelial depigmentation (risk ratio [RR] per 10 mmHg systolic blood pressure, 1.10; 95% confidence interval [CI], 1.01–1.18; P = 0.02) and exudative macular degeneration (RR, 1.22; 95% CI, 1.06–1.41; P = 0.006). Higher pulse pressure at baseline was associated with the incidence of retinal pigment epithelial depigmentation (RR per 10 mmHg, 1.17; 95% CI, 1.07–1.28; P < 0.001), increased retinal pigment (RR, 1.10; 95% CI, 1.01–1.19; P = 0.03), exudative macular degeneration (RR, 1.34; 95% CI, 1.14–1.60; P < 0.001), and progression of age-related maculopathy (RR, 1.08; 95% CI, 1.01–1.17; P = 0.03). Higher serum high-density lipoprotein cholesterol at baseline was associated with pure geographic atrophy (RR per 10 mg/dl high-density lipoprotein cholesterol, 1.29; 95% CI, 1.05–1.58; P = 0.01). Physical activity at baseline was associated with the incidence of geographic atrophy (RR in those who worked up a sweat 5 times a week compared with those who did not, 0.12; 95% CI, 0.02–0.91; P = 0.04) exudative macular degeneration (RR, 0.27; 95% CI, 0.08−0.87; P = 0.05), and progression of age-related maculopathy (RR, 0.69; 95% CI, 0.47–1.00; P = 0.05). Neither a history of stroke nor heart attack was associated with the incidence or progression of age-related maculopathy. Conclusions These findings indicate relationships between higher pulse pressure (a presumed indicator of age-related elastin and collagen changes in Bruch’s membrane) and systolic blood pressure with an increased 10-year incidence of some lesions defining early age-related maculopathy and exudative macular degeneration.