Michael D. Knudtson

The Wisconsin Epidemiologic Study of Diabetic Retinopathy XXII. The Twenty-Five-Year Progression of Retinopathy in Persons with Type 1 Diabetes

OBJECTIVE To examine the 25-year cumulative progression and regression of diabetic retinopathy (DR) and its relation to various risk factors. DESIGN Population-based study. PARTICIPANTS A total of 955 insulin-taking persons living in an 11-county area in southern Wisconsin with type 1 diabetes diagnosed before age 30 years who participated in a baseline examination (1980-1982) and at least 1 of 4 follow-up (4-, 10-, 14-, and 25-year) examinations or died before the first follow-up examination (n = 64). METHODS Stereoscopic color fundus photographs were graded using the modified Airlie House classification and the Early Treatment Diabetic Retinopathy Study retinopathy severity scheme. MAIN OUTCOME MEASURES Progression and regression of DR status. RESULTS The 25-year cumulative rate of progression of DR was 83%, progression to proliferative DR (PDR) was 42%, and improvement of DR was 18%. Progression of DR was more likely with less severe DR, male sex, higher glycosylated hemoglobin, an increase in glycosylated hemoglobin level, and an increase in diastolic blood pressure level from the baseline to the 4-year follow-up. Increased risk of incidence of PDR was associated with higher glycosylated hemoglobin, higher systolic blood pressure, proteinuria greater body mass index at baseline, and an increase in the glycosylated hemoglobin between the baseline and 4-year follow-up examinations. Lower glycosylated hemoglobin and male sex, as well as decreases in glycosylated hemoglobin and diastolic blood pressure during the first 4 years of follow-up, were associated with improvement in DR. Persons diagnosed most recently with a similar duration of diabetes had a lower prevalence of PDR independently of glycosylated hemoglobin level, blood pressure level, and presence of proteinuria. CONCLUSIONS These data show relatively high 25-year cumulative rates of progression of DR and incidence of PDR. The lower risk of prevalent PDR in more recently diagnosed persons possibly reflects improvement in care over the period of the study.

The Wisconsin Epidemiologic Study of Diabetic Retinopathy XXIII. The Twenty-Five-Year Incidence of Macular Edema in Persons with Type 1 Diabetes

OBJECTIVE To examine the 25-year cumulative incidence of macular edema (ME) and its relation to various risk factors. DESIGN Population-based study. PARTICIPANTS A total of 955 insulin-taking persons living in an 11-county area in southern Wisconsin with type 1 diabetes diagnosed before age 30 years who participated in baseline examinations (1980-1982) and at least 1 of 4 follow-up (4-, 10-, 14-, and 25-year) examinations (n=891) or died before the first follow-up examination (n=64). METHODS Stereoscopic color fundus photographs were graded using the modified Airlie House classification and the Early Treatment Diabetic Retinopathy Study retinopathy severity scheme. Competing risk of death was included in statistical models. MAIN OUTCOME MEASURES Incidence of ME and clinically significant ME (CSME). RESULTS The 25-year cumulative incidence was 29% for ME and 17% for CSME. Annualized incidences of ME were 2.3%, 2.1%, 2.3%, and 0.9% in the first, second, third, and fourth follow-up periods of the study, respectively. In univariate analyses, the incidence of ME was associated with male sex, more severe diabetic retinopathy, higher glycosylated hemoglobin, proteinuria, higher systolic and diastolic blood pressure, and more pack-years of smoking. Multivariate analyses showed that the incidence of ME was related to higher baseline glycosylated hemoglobin (hazard ratio [HR] per 1% 1.17; 95% confidence interval [CI], 1.10-1.25; P<0.001) and higher systolic blood pressure (HR per 10 mmHg 1.15; 95% CI, 1.04-1.26; P=0.004) and marginally to proteinuria (HR 1.43; 95% CI, 0.99-2.08; P=0.06). CONCLUSIONS These data show that relatively high 25-year cumulative rates of incidence of ME were related to glycemia and blood pressure. The lower risk of incident ME in the last period of the study may reflect recent improvement in care.

Refractive errors, intraocular pressure, and glaucoma in a white population.

OBJECTIVE To examine the relation of refractive errors to glaucoma and intraocular pressure (IOP) in a defined white population. DESIGN Population-based cross-sectional and follow-up study. PARTICIPANTS Persons aged 43 to 86 years living in Beaver Dam, Wisconsin (n = 4926). METHODS All participants received a standardized assessment of refraction, IOP, and glaucoma at baseline (1988-1990), with IOP remeasured 5 years later (1993-1995). Refraction was defined at baseline as follows: myopia as spherical equivalent of -1.00 diopters (D) or less, emmetropia as -0.75 to +0.75 D, and hyperopia as +1.00 D or more. MAIN OUTCOME MEASURES Relation of baseline refraction to prevalent glaucoma (defined from IOP, optic disc, and visual field criteria) and incident ocular hypertension (defined as IOP more than 21 mmHg at the 5-year examination in eyes with IOP of 21 mmHg or less at baseline). RESULTS A myopic refraction was correlated with increasing IOP at baseline (P < 0.001). After controlling for age and gender, persons with myopia were 60% more likely to have prevalent glaucoma than those with emmetropia (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.1, 2.3). In contrast, controlling for age, gender, and baseline IOP, persons with hyperopia were 40% more likely to have incident ocular hypertension than those who were emmetropic at baseline (OR, 1.4; 95% CI, 1.0, 2.0). Myopia was not related to incident ocular hypertension. CONCLUSIONS In these population-based data, there was a cross-sectional association of myopia with higher IOP and prevalent glaucoma. Similar associations have been found in previous studies. Hyperopia may be associated with 5-year risk of ocular hypertension, a finding that needs further investigation.

Intraocular pressure and systemic blood pressure: longitudinal perspective: the Beaver Dam Eye Study

Aim: To investigate the relation between change in systemic blood pressures and change in intraocular pressure. Methods: This was a population based study of people 43–86 years old living in Beaver Dam, Wisconsin. Measurements at baseline (1988–90) and 5 year follow up of systemic blood pressures, intraocular pressures, and history of use of blood pressure medications. Results: Intraocular pressures were significantly correlated with systolic and diastolic blood pressures at both baseline and follow up. There were significant direct correlations between changes in systemic blood pressures and changes in intraocular pressure. There was a 0.21 (95% CI: 0.16 to 0.27) mm Hg increase in IOP for a 10 mm Hg increase in systolic and 0.43 (0.35 to 0.52) mm Hg increase in IOP for a 10 mm Hg increase in diastolic blood pressure. Further adjustment for diabetes and medication use did not alter these associations. Decreased systolic or diastolic blood pressures of more than 10 mm Hg over 5 years were significantly associated with decreased IOP. Conclusions: Reduced systemic blood pressure is associated with reduced intraocular pressure. This finding should be evaluated in other studies, especially with respect to the possibility of resultant decreased risk of open angle glaucoma.

Variation associated with measurement of retinal vessel diameters at different points in the pulse cycle

Background/aims: To assess the variability in retinal vessel measurements at different points in the pulse cycle. Methods: A healthy white male aged 19 years had 30 digitised images taken at three distinct points in the pulse cycle over a one hour period. A pulse synchronised ear clip trigger device was used to capture images at the desired point in the pulse cycle. Two trained graders measured the retinal vessel diameter of one large arteriole, one large venule, one small arteriole, and one small venule 10 times in each of these 30 images. Results: Within an image, variability was similar between graders, pulse point, and vessel type. Across images taken at the same point in the pulse period, the change from the minimum to maximum measurement was between 6% and 17% for arterioles and between 2% and 11% for venules. In addition, measurements of small vessels had greater changes than large vessels and no point in the pulse period was more variable than another. Ignoring pulse cycle increased variability across images in the large venule, but not in the other vessel types. Mixed effect models were fit for each of the vessel types to determine the greatest source of variability. Controlling for pulse point and grader, the largest source of variability for all four vessels measured was across images, accounting for more than 50% of the total variability. Conclusion: Measurements of large retinal venules is generally less variable than measurements of other retinal vessels. After controlling for pulse point and grader, the largest source of variation is across images. Understanding the components of variability in measuring retinal vessels is important as these techniques are applied in epidemiological studies.

Further observations on the association between smoking and the long-term incidence and progression of age-related macular degeneration: the Beaver Dam Eye Study.

OBJECTIVE To examine the association between smoking and the 15-year cumulative incidence of age-related macular degeneration (AMD). METHODS Population-based longitudinal cohort study of people in Beaver Dam, Wisconsin, who were aged 43 to 84 years (N = 4926) in 1987-1988. Participants were examined in 1988-1990 and were reexamined at 5-year intervals during a 15-year period. Age-related macular degeneration status was determined by grading stereoscopic color fundus photographs. RESULTS Controlling for age, sex, and baseline AMD severity, people who were current smokers at baseline, compared with those who never smoked, were at increased risk of incident early AMD (odds ratio, 1.47; 95% confidence interval, 1.08-1.99; P = .01) and for progression of AMD (odds ratio, 1.43; 95% confidence interval, 1.05-1.94; P = .02) during a 15-year follow-up. There were few associations of specific characteristics of smoking (eg, intensity, pack-years smoked, duration, and age at initiation and quitting) with AMD outcomes. CONCLUSIONS Smoking appears to be related to the long-term incidence and progression of AMD. This has important health care implications because early AMD increases the risk of developing late AMD and smoking behavior is modifiable.

The epidemiology of progression of pure geographic atrophy: the Beaver Dam Eye Study.

PURPOSE To examine the change in size and location of pure geographic atrophy (GA). DESIGN Population-based cohort study. METHODS Ninety-five persons with GA either at baseline or at the one of the three five-year follow-up examinations, or both, were identified. Using computer-assisted software, the lesion area and greatest linear dimension (GLD) were calculated. Thirty-two persons (53 multiple eye-visit pairs) were seen at multiple visits five years apart with GA in the same eye to evaluate changes in total area and GLD. RESULTS At the first occasion when pure GA was identified (n = 95), 45% had a single GA lesion, 18% had multifocal GA lesions, and 37% had a merged GA lesion. Of 53 eyes with multiple visits, the overall increase in atrophy was 6.4 mm(2) over a five-year period. The atrophy progressed to involve the foveal center in 47% of 19 eyes, and there was a mean decrease of 17 letters read correctly. Eyes with multifocal GA were most likely to have the area of atrophy increase (mean, 12 mm(2)), to have atrophy progress to the foveal center (83%), and to have a decrease in vision (mean, 22 letters), whereas eyes with a single GA lesion were least likely to have the area of atrophy increase (mean, 2 mm(2)), to have the lesion progress to the foveal center (22%), and to have a decrease in vision (mean, 10 letters). CONCLUSIONS These are the first population-based data describing the five-year change in eyes with pure GA. Information on progression of GA will be useful for clinical trials of new interventions for GA.

The relation of markers of inflammation and endothelial dysfunction to the prevalence and progression of diabetic retinopathy: Wisconsin epidemiologic study of diabetic retinopathy.

OBJECTIVE To determine the relation of glycemia, blood pressure, and serum total cholesterol level as systemic markers of inflammation and endothelial dysfunction to the prevalence and incidence of diabetic retinal outcomes in persons with long-duration type 1 diabetes mellitus. METHODS Longitudinal population-based study of persons with type 1 diabetes mellitus who received care for their diabetes in south central Wisconsin from July 1, 1979, to June 30, 1980. Data for this investigation were obtained from the 1990-1992 through the 2005-2007 follow-up examinations. Main outcome measures included the severity of diabetic retinopathy (DR) and macular edema (ME). RESULTS In the 1990-1992 prevalence data, soluble vascular cell adhesion molecule, tumor necrosis factor, and homocysteine levels were associated with increased odds of more severe DR (odds ratios [highest vs lowest quartile], 3.95 [95% confidence interval, 1.66-9.39], 5.46 [2.38-12.52], and 7.46 [2.91-19.16], respectively) in those with kidney disease while controlling for relevant confounders. Similar odds were found for proliferative DR. Only total homocysteine level was associated with increased odds of ME (3.80 [95% confidence interval, 1.91-7.54]), irrespective of kidney disease. None of the markers were associated with incidence of proliferative DR, ME, or progression of DR 15 years later. CONCLUSIONS A limited number of markers are associated with increased odds of prevalent retinal outcomes in persons with type 1 diabetes mellitus and kidney disease. Only homocysteine level is associated with ME in those with and without kidney disease. In the absence of kidney disease, the markers do not add to the more conventional descriptors and predictors of DR in persons with type 1 diabetes mellitus. This may reflect the close association of DR and kidney disease in diabetic persons.

Inflammation, Complement Factor H, and Age-Related Macular Degeneration: The Multi-Ethnic Study of Atherosclerosis

OBJECTIVE To describe the relationship of systemic inflammatory disease, complement factor H (CFH) Y402H (1277T-->C) genotype status and age-related macular degeneration (AMD) prevalence in a multiethnic population of whites, blacks, Hispanics, and Chinese. DESIGN Population-based, cross-sectional study. PARTICIPANTS We included 5887 persons aged 45 to 84 years with gradable AMD. METHODS Digital fundus photographs were used to measure AMD. Two years earlier, biomarkers of inflammation were measured and history of inflammatory disease and use of antiinflammatory agents obtained. MAIN OUTCOME MEASURE Prevalence of AMD. RESULTS While controlling for age, gender, race/ethnicity, and study site, there were no associations between systemic inflammatory factors and AMD severity. Higher levels of high-sensitivity C-reactive protein (odds ratio [OR] per standard deviation [SD] increase in natural log [ln] units, 2.34; 95% confidence interval [CI], 1.33-4.13) and interleukin-6 (OR per SD in ln, 2.06; 95% CI, 1.21-3.49) were associated with geographic atrophy but not other AMD end points. History of periodontal disease (OR, 1.68; 95% CI, 1.14-2.47) was related to increased retinal pigment. A history of arthritis was associated with soft distinct drusen (OR, 1.24; 95% CI, 1.06-1.46). A history of oral steroid use was related to large drusen (OR, 2.13; 95% CI, 1.14-3.97) and soft distinct drusen (OR, 1.76; 95% CI, 1.00-3.10) and history of cyclooxygenase 2 inhibitor use were associated with large drusen (OR, 1.50; 95% CI, 1.10-2.04), soft indistinct drusen (OR, 1.84; 95% CI, 1.09-3.10), and large drusen area (OR, 1.66; 95% CI, 1.02-2.71). Whites, blacks, and Hispanics with CFH Y402H CC variant genotype had the highest frequency of early AMD compared with those with wild TT genotype. The frequency of CFH did explain some of the difference in AMD prevalence between Chinese and Hispanics compared with whites, but did not explain the difference in prevalence between whites and blacks. CONCLUSIONS This study confirmed associations of the Y402H CFH gene variant with AMD in nonwhite populations, but neither explained the lack of association between inflammatory factors and AMD in the cohort nor the basis for the observed differences in AMD prevalence across ethnic groups.

Physical activity and the 15‐year cumulative incidence of age‐related macular degeneration: the Beaver Dam Eye Study

Background: Cardiovascular disease and age-related macular degeneration (AMD) may share common risk factors. Physical activity improves the cardiovascular risk profile; however, there have been few studies investigating a relationship between physical activity and the long-term incidence of AMD. Methods: The 15-year cumulative incidence of AMD was determined through four examination phases at 5-year intervals of a population-based study conducted in Beaver Dam, Wisconsin, USA, initiated in 1988–90 (n = 3874 men and women between ages 43 and 86 years). Early AMD (pigment abnormalities or soft indistinct drusen), exudative AMD and geographic atrophy were determined by grading stereoscopic colour fundus photographs. Measures of physical activity were obtained through a questionnaire administered at the baseline examination. Results: After controlling for age, sex, history of arthritis, systolic blood pressure, body mass index, smoking and education, people with an active lifestyle (defined as regular activity ⩾3 times/week) at baseline were less likely to develop exudative AMD (odds ratio (OR) 0.3, 95% confidence interval (CI) 0.1 to 0.7) compared with people without an active lifestyle. After multivariate adjustment, increased categories of number of blocks walked per day decreased the risk of exudative AMD (OR 0.7, 95% CI 0.6 to 0.97). Physical activity was not related to the incidence of early AMD or pure geographic atrophy. Conclusions: These data show a protective effect of physical activity for incident exudative AMD, independent of body mass index and other confounders. They also suggest a possible modifiable behaviour that might be protective against developing AMD.