Ning Cheung

Natural history of central retinal vein occlusion: an evidence-based systematic review.

OBJECTIVE To describe the natural history of central retinal vein occlusion (CRVO) based on the best available evidence from the literature. CLINICAL RELEVANCE Central retinal vein occlusion is a common sight-threatening retinal vascular disease. Despite the introduction of new interventions, the natural history of CRVO is unclear. METHODS Systemic review of all English language articles retrieved using a keyword search of MEDLINE, EMBASE, Current Contents, and the Cochrane Library to November 13, 2008. This was supplemented by hand-searching references of review articles published within the last 5 years. Two investigators independently identified all relevant observational studies evaluating the natural history of RVO and all clinical trials evaluating interventions for CRVO; an untreated control arm was included. RESULTS Of 5966 citations retrieved, 53 studies were reviewed, providing 3271 eyes with CRVO for analysis of its natural history. Visual acuity (VA) was generally poor at baseline (<20/40) and decreased further over time. Although 6 studies reported an improvement in VA, none of these improvements resulted in VA better than 20/40. Up to 34% of eyes with nonischemic CRVO converted to ischemic CRVO over a 3-year period. In ischemic CRVO cases, neovascular glaucoma developed in at least 23% of eyes within 15 months. In nonischemic CRVO cases, macular edema resolved in approximately 30% of eyes over time, and subsequent neovascular glaucoma was rare. CONCLUSIONS Untreated eyes with CRVO generally had poor VA, which declined further over time. One quarter of eyes with nonischemic CRVO converted to ischemic CRVO.

Prevalence and Risk Factors for Diabetic Retinopathy : The Singapore Malay Eye Study

PURPOSE To describe the prevalence and risk factors of diabetic retinopathy in Asian Malays. DESIGN Population-based cross-sectional study. PARTICIPANTS Persons with diabetes of Malay ethnicity aged 40 to 80 years in Singapore. METHODS Diabetes mellitus was defined as random glucose of 11.1 mmol/l or more, use of diabetic medication, or a physician diagnosis of diabetes. Retinal photographs taken from both eyes were graded for diabetic retinopathy using the modified Airlie House classification system. MAIN OUTCOME MEASURES Any diabetic retinopathy, retinopathy grades, macular edema, or vision-threatening retinopathy. RESULTS Of the 3261 persons who participated in this study, 757 (23.1%) had diabetes and gradable retinal photographs. In persons with diabetes, the overall prevalence of any retinopathy was 35.0% (95% confidence interval [CI], 28.2-43.4), the overall prevalence of macular edema was 5.7% (95% CI, 3.2-9.9), and the overall prevalence of vision-threatening retinopathy was 9.0% (95% CI, 5.8-13.8). Compared with men, women had significantly higher proportions with more severe diabetic retinopathy, moderate (12% vs. 4%) and severe (3% vs. 0.2%) nonproliferative retinopathy, proliferative retinopathy (7% vs. 2%), and vision-threatening retinopathy (13% vs. 3%). In multiple logistic regression, independent risk factors for any retinopathy were longer diabetes duration (odds ratio [OR], 1.07; 95% CI, 1.04-1.09, per year increase), higher hemoglobin A1(c) (OR, 1.21; 95% CI, 1.10-1.33, per % increase), hypertension (OR, 1.85; 95% CI, 1.04-3.30), and higher pulse pressure (OR, 1.34, 95% CI, 1.19-1.51, per 10-mmHg increase); older age (OR, 0.73; 95% CI, 0.57-0.93, per decade increase) and higher total cholesterol levels (OR, 0.75; 95% CI, 0.63-0.89, per 1-mmol/l increase) were protective of any retinopathy. Vision-threatening retinopathy additionally was associated with previous stroke (OR, 3.74; 95% CI, 1.24-11.26), cardiovascular disease (OR, 2.23; 95% CI, 1.08-4.62), and chronic kidney disease (OR, 4.45; 95% CI, 2.18-9.07). Female gender was not an independent risk factor for diabetic retinopathy after adjusting for metabolic and socioeconomic risk factors. CONCLUSIONS One in 10 Malay adults with diabetes in Singapore has vision-threatening diabetic retinopathy. Risk factors for retinopathy in this population are largely similar to white populations elsewhere, suggesting that control of these risk factors may reduce both the prevalence and impact of retinopathy.

Methodology of the Singapore Indian Chinese Cohort (SICC) eye study: Quantifying ethnic variations in the epidemiology of eye diseases in Asians

Purpose: Current knowledge of ethnic variability in the epidemiology of major eye diseases in Asia is limited. This report summarizes the rationale and study design of the Singapore Indian Chinese Cohort (SICC) Eye Study, a population-based study of ethnic South Asian (Indians) and East Asian (Chinese) older adults in Singapore. Methods: The SICC examined a population-based cross-sectional sample of 3,300 ethnic Indians and 3,300 ethnic Chinese aged 40–80+ years residing in the South-Western part of Singapore. Results: From two lists of 12,000 names of each ethnic group provided by the Ministry of Home Affairs, age-stratified random sampling was used to select 6,350 names in each group, with a target sample size of 3,300. Invitations were sent to attend a central clinic using letters, telephone calls and home visits. Examination procedures included interviews, measurement of blood pressure, anthropometry, presenting and best-corrected visual acuity, subjective refraction, ocular biometry, Goldmann applanation tonometry, slit-lamp biomicroscopy, optic disc imaging and digital photography of the lens and retina, using a standardized protocol. Selected participants underwent gonioscopic examination, visual field testing, and anterior and posterior segment optical coherence tomography. Blood, tear, and urine samples were collected for biochemical analyses, and stored for genetic and proteomic studies. Conclusions: In conjunction with the Singapore Malay Eye Study, the SICC study will permit an in-depth evaluation of the prevalence, risk factors, and impact of major eye diseases in Chinese, Indians and Malays, three distinct Asian ethnic groups, whose combined numbers represent half the world’s population.

Diabetic Retinopathy and the Risk of Coronary Heart Disease: The Atherosclerosis Risk in Communities Study

OBJECTIVE— We sought to examine the relation of diabetic retinopathy to incident coronary heart disease (CHD). RESEARCH DESIGN AND METHODS— A population-based, prospective cohort study consisting of 1,524 middle-aged individuals with type 2 diabetes without prevalent CHD and stroke at baseline was conducted. Diabetic retinopathy signs were graded from retinal photographs according to the Early Treatment for Diabetic Retinopathy Study severity scale. Incident CHD events (myocardial infarction, fatal CHD, or coronary revascularization) were identified and validated following standardized protocols. RESULTS— In our study, 214 (14.7%) participants had diabetic retinopathy. Over an average follow-up of 7.8 years, there were 209 (13.7%) incident CHD events. After controlling for age, sex, race, study center, fasting glucose, A1C, duration of diabetes, blood pressure, antihypertensive treatment, cigarette smoking, BMI, and lipid profile, the presence of diabetic retinopathy was associated with a twofold higher risk of incident CHD events (hazard rate ratio [HR] 2.07 [95% CI 1.38–3.11]) and a threefold higher risk of fatal CHD (3.35 [1.40–8.01]). Further adjustments for inflammatory markers, carotid artery intima-media thickness, or nephropathy had minimal impact on the association. The increased risk of CHD was significant in both men (1.89 [1.08–3.31]) and women (2.16 [1.16–4.02]) with diabetic retinopathy. CONCLUSIONS— In individuals with type 2 diabetes, the presence of retinopathy signifies an increased CHD risk, independent of known risk factors. Our data support the role of microvascular disease in the pathogenesis of CHD in diabetes.

Blood Pressure and Retinal Arteriolar Narrowing in Children

Retinal arteriolar narrowing is a known response of hypertension and independently predicts cardiovascular mortality in adults. Whether elevated blood pressure leads to retinal arteriolar narrowing in young children is unknown. We examined the relationship of retinal vascular caliber and blood pressure levels in 2 population-based cohorts among children aged 6 to 8 years in Sydney, Australia (1572 children) and Singapore (380 children). Participants had digital retinal photographs and measurement of retinal arteriolar (or small artery) and venular (or small vein) caliber. Children with higher quartiles of blood pressure had significantly narrower retinal arterioles than those with lower blood pressure (retinal arteriolar caliber 162.8, 161.0, 157.8, and 157.1 &mgr;m (P for trend<0.001), comparing increasing quartiles of systolic blood pressure in Sydney, and 164.9.5, 164.0, 159.1, and 159.4 &mgr;m (P for trend=0.0024 in Singapore). After controlling for age, sex, race, body mass index, refraction, and birth parameters, each 10-mm Hg increase in systolic blood pressure was associated with narrowing of the retinal arterioles by 2.08 &mgr;m (95% confidence interval: 1.38 to 2.79; P<0.0001) in Sydney children and 1.43 &mgr;m (95% confidence interval: 0.27 to 2.59; P=0.016) in Singapore children. These associations were consistent across age, sex, body mass index, and birth parameters. Retinal venules were not affected by blood pressure. We conclude that higher childhood blood pressure is associated with retinal arteriolar narrowing. Our data provide evidence that the effects of elevated blood pressure may manifest early in life.

Genome-Wide Association Study of Retinopathy in Individuals without Diabetes

Background Mild retinopathy (microaneurysms or dot-blot hemorrhages) is observed in persons without diabetes or hypertension and may reflect microvascular disease in other organs. We conducted a genome-wide association study (GWAS) of mild retinopathy in persons without diabetes. Methods A working group agreed on phenotype harmonization, covariate selection and analytic plans for within-cohort GWAS. An inverse-variance weighted fixed effects meta-analysis was performed with GWAS results from six cohorts of 19,411 Caucasians. The primary analysis included individuals without diabetes and secondary analyses were stratified by hypertension status. We also singled out the results from single nucleotide polymorphisms (SNPs) previously shown to be associated with diabetes and hypertension, the two most common causes of retinopathy. Results No SNPs reached genome-wide significance in the primary analysis or the secondary analysis of participants with hypertension. SNP, rs12155400, in the histone deacetylase 9 gene (HDAC9) on chromosome 7, was associated with retinopathy in analysis of participants without hypertension, −1.3±0.23 (beta ± standard error), p = 6.6×10−9. Evidence suggests this was a false positive finding. The minor allele frequency was low (∼2%), the quality of the imputation was moderate (r2 ∼0.7), and no other common variants in the HDAC9 gene were associated with the outcome. SNPs found to be associated with diabetes and hypertension in other GWAS were not associated with retinopathy in persons without diabetes or in subgroups with or without hypertension. Conclusions This GWAS of retinopathy in individuals without diabetes showed little evidence of genetic associations. Further studies are needed to identify genes associated with these signs in order to help unravel novel pathways and determinants of microvascular diseases.

Diabetic retinopathy and systemic vascular complications

Retinopathy is the most common complication of diabetes. The assessment of retinopathy signs presents clinicians a unique opportunity to directly visualize and assess the actual morphology of diabetic microvascular damage. Extensive studies have now shown that people with diabetic retinopathy have excess risks of systemic vascular complications, including subclinical and clinical stroke, coronary heart disease, heart failure, and nephropathy. There is also emerging evidence to suggest that diabetic retinopathy may share common genetic linkages with systemic vascular complications. The extant literature, therefore, supports the theory that diabetic retinopathy reflects widespread microcirculatory disease not only in the eye but also vital organs elsewhere in the body. Being a uniquely specific and non-invasively assessable measure of diabetic microvascular damage, retinopathy may also be envisioned as a novel biomarker of vascular disease risk in asymptomatic patients with diabetes. This review summarizes recent studies on the systemic associations of diabetic retinopathy, and discusses their pathophysiological significance and clinical implications.

Quantitative Assessment of Early Diabetic Retinopathy Using Fractal Analysis

OBJECTIVE—Fractal analysis can quantify the geometric complexity of the retinal vascular branching pattern and may therefore offer a new method to quantify early diabetic microvascular damage. In this study, we examined the relationship between retinal fractal dimension and retinopathy in young individuals with type 1 diabetes. RESEARCH DESIGN AND METHODS—We conducted a cross-sectional study of 729 patients with type 1 diabetes (aged 12–20 years) who had seven-field stereoscopic retinal photographs taken of both eyes. From these photographs, retinopathy was graded according to the modified Airlie House classification, and fractal dimension was quantified using a computer-based program following a standardized protocol. RESULTS—In this study, 137 patients (18.8%) had diabetic retinopathy signs; of these, 105 had mild retinopathy. Median (interquartile range) retinal fractal dimension was 1.46214 (1.45023–1.47217). After adjustment for age, sex, diabetes duration, A1C, blood pressure, and total cholesterol, increasing retinal vascular fractal dimension was significantly associated with increasing odds of retinopathy (odds ratio 3.92 [95% CI 2.02–7.61] for fourth versus first quartile of fractal dimension). In multivariate analysis, each 0.01 increase in retinal vascular fractal dimension was associated with a nearly 40% increased odds of retinopathy (1.37 [1.21–1.56]). This association remained after additional adjustment for retinal vascular caliber. CONCLUSIONS—Greater retinal fractal dimension, representing increased geometric complexity of the retinal vasculature, is independently associated with early diabetic retinopathy signs in type 1 diabetes. Fractal analysis of fundus photographs may allow quantitative measurement of early diabetic microvascular damage.

The Retinal Vasculature as a Fractal: Methodology, Reliability, and Relationship to Blood Pressure

OBJECTIVE Fractals represent a type of derived geometric pattern that permits the characterization of the branching pattern of retinal vessels. We examined a new semiautomated method to measure retinal vessel fractals. DESIGN Methodology study. PARTICIPANTS Three hundred randomly selected participants from the population-based Blue Mountains Eye Study. METHODS We developed a semiautomated computer program to measure the fractal dimension (D(f)) of the retinal vessels from digitized images of disk-centered retinal photographs. Two trained graders masked to participant characteristics measured D(f) of right eye images of participants. Reliability was determined by repeat grading of the images from 60 participants, and association with systolic and diastolic blood pressure was examined in all 300 participants. MAIN OUTCOME MEASURE D(f) of the retinal vessels. RESULTS Mean D(f) was 1.437 with a standard deviation of 0.025. Intragrader and intergrader reliability estimates were high with intraclass correlation ranging from 0.93 to 0.95. D(f) was inversely correlated with age (r = -0.42, P = 0.001) and systolic blood pressure (r = -0.29, P<0.0001). After adjustment for age and sex, mean D(f) was significantly lower in participants with than without hypertension (D(f) difference 0.01, P = 0.02). CONCLUSIONS The D(f) of the retinal vessels can be reliably measured from photographs and shows a strong inverse correlation with blood pressure. These data suggest that the D(f) may be a measure of early microvascular alterations from elevated blood pressure. Further studies to examine the systemic and ocular correlates of the D(f) of the retinal vessels are needed.

Aortic Distensibility and Retinal Arteriolar Narrowing. The Multi-Ethnic Study of Atherosclerosis

Increased aortic stiffness and retinal arteriolar narrowing are subclinical vascular effects of chronic hypertension and predict future cardiovascular events. The relationship between these 2 vascular measures is uncertain and is examined in the Multi-Ethnic Study of Atherosclerosis. This cross-sectional analysis involves 3425 participants (aged 45 to 85 years) free of clinical cardiovascular disease. Retinal vascular caliber was quantified from digital retinal photographs using standardized protocols. Aortic distensibility was determined from chest MRI. After controlling for age, squared age, gender, race, study center, height, weight, heart rate, cigarette smoking, past and current systolic blood pressure, use of antihypertensive medications, diabetes, fasting glucose, lipid profile, and C-reactive protein, reduced aortic distensibility (first versus fourth distensibility quartile) was associated with increased odds of retinal arteriolar narrowing (odds ratio: 1.72; 95% CI: 1.15 to 2.58, comparing lowest to highest quartile of arteriolar caliber). Further adjustments for atherosclerotic measures (carotid intima-media thickness, coronary calcium score, and ankle brachial index) had minimal impact on this association (odds ratio: 1.70; 95% CI: 1.13 to 2.55). Reduced aortic distensibility was not associated with retinal venular caliber. We conclude that increased aortic stiffness is associated with retinal arteriolar narrowing, independent of measured blood pressure levels and vascular risk factors. These data suggest that changes in the microvasculature may play a role linking aortic stiffness with clinical cardiovascular events.