Matthew D. Davis

The Wisconsin Epidemiologic Study of Diabetic Retinopathy: VI. Retinal Photocoagulation

The prevalence of focal and panretinal photocoagulation and its relationship to demographic and other characteristics were examined in a population-based study in southern Wisconsin. For participants whose age at diagnosis was less than 30 years and who were taking insulin (996 persons) the prevalence rate of panretinal photocoagulation (13.9%) was higher than that of focal photocoagulation (3.6%). For those whose age at diagnosis was 30 years or older (1370 persons), the prevalence rate for panretinal photocoagulation (3.6%) was slightly higher than that of focal photocoagulation (3.0%). Seventy-two percent of eyes of younger onset and 45% of eyes of older onset persons that had received panretinal photocoagulation treatment were found to have incomplete regression of retinal new vessels, and in approximately half of these eyes severe proliferative retinopathy (Diabetic Retinopathy Study High Risk Characteristics [DRS-HRC]) was present. Among eyes with DRS-HRC, 55% were found to be untreated.

Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales

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.

Retinopathy and nephropathy in patients with type I diabetes four years after a trial of intensive therapy

BACKGROUND Among patients with type 1 diabetes mellitus, intensive therapy (with the aim of achieving near-normal blood glucose and glycosylated hemoglobin concentrations [hemoglobin A1c]) markedly reduces the risk of microvascular complications as compared with conventional therapy. To assess whether these benefits persist, we compared the effects of former and intensive conventional therapy on the recurrence and severity of retinopathy and nephropathy for four years after the end of the Diabetes Control and Complications Trial (DCCT). METHODS At the end of the DCCT, the patients in the conventional-therapy group were offered intensive therapy, and the care of all patients was transferred to their own physicians. Retinopathy was evaluated on the basis of centrally graded fundus photographs in 1208 patients during the fourth year after the DCCT ended, and nephropathy was evaluated on the basis of urine specimens obtained from 1302 patients during the third or fourth year, approximately half of whom were from each treatment group. RESULTS The difference in the median glycosylated hemoglobin values between the conventional-therapy and intensive-therapy groups during the 6.5 years of the DCCT (average, 9.1 percent and 7.2 percent, respectively) narrowed during follow-up (median during 4 years, 8.2 percent and 7.9 percent, respectively, P<0.001). Nevertheless, the proportion of patients who had worsening retinopathy, including proliferative retinopathy, macular edema, and the need for laser therapy, was lower in the intensive-therapy group than in the conventional-therapy group (odds reduction, 72 percent to 87 percent, P<0.001). The proportion of patients with an increase in urinary albumin excretion was significantly lower in the intensive-therapy group. CONCLUSIONS The reduction in the risk of progressive retinopathy and nephropathy resulting from intensive therapy in patients with type 1 diabetes persists for at least four years, despite increasing hyperglycemia.

The Wisconsin Age-related Maculopathy Grading System

A new system for grading age-related maculopathy is described and measures of reliability are reported. A number of characteristics of age-related maculopathy are graded in a semiquantitative fashion from stereoscopic 30 degrees color fundus photographs, using a grid to define subfields, standard circles printed on plastic to assess size and area, and a specially designed lightbox to allow better discrimination of subtle drusen. The degree of exact agreement achieved between two trained graders across a variety of lesions ranged from 67.1% for drusen size to 99.6% for geographic atrophy. Kappa scores ranged from 0.55 (for drusen confluence) to 0.95 for geographic atrophy. This system will be useful in epidemiologic studies and clinical trials.

Methods for evaluation of retinal microvascular abnormalities associated with hypertension/sclerosis in the Atherosclerosis Risk in Communities Study

OBJECTIVE To develop protocols to photograph and evaluate retinal vascular abnormalities in the Atherosclerosis Risk in Communities (ARIC) Study; to test reproducibility of the grading system; and to explore the relationship of these microvascular changes with blood pressure. DESIGN Population-based, cross-sectional study. PARTICIPANTS Among 4 examination centers, 11,114 participants (48-73 years of age) at their third triennial examination, after excluding persons with diabetes from this analysis. METHODS One eye of each participant was photographed by technicians with nonmydriatic fundus cameras. Reading center graders evaluated focal arteriolar narrowing, arteriovenous (AV) nicking, and retinopathy by examining slides on a light box and measured diameters of all vessels in a zone surrounding the optic disc on enhanced digitized images. To gauge generalized narrowing, vessel diameters were combined into central arteriolar and venular equivalents with formulas adjusting for branching, and the ratio of equivalents (A/V ratio) was calculated. MAIN OUTCOME MEASURES Retinal vascular abnormalities, mean arteriolar blood pressure (MABP). RESULTS Among 11,114 participants, photographs were obtained of 99%, with quality sufficient to perform retinal evaluations in 81%. In the 9040 subjects with usable photographs, A/V ratio (lower values indicate generalized arteriolar narrowing) ranged from 0.57 to 1.22 (median = 0.84, interquartile range = 0.10), focal arteriolar narrowing was found in 7%, AV nicking in 6%, and retinopathy in 4%. Because of attrition of subjects and limitation of methods, prevalence of abnormality was likely underestimated. Controlling for gender, race, age, and smoking status, these retinal changes were associated with higher blood pressure. For every 10-mmHg increase in MABP, A/V ratio decreased by 0.02 unit (P < 0.0001), focal arteriolar narrowing had an odds ratio (OR) of 2.00 (95% confidence interval [CI] = 1.87-2.14), AV nicking had an OR of 1.25 (95% CI = 1.16-1.34), and retinopathy had an OR of 1.25 (95% CI = 1.15-1.37). For any degree of generalized narrowing, individuals with focal narrowing had MABP approximately 8 mmHg higher than those without (P < 0.0001). Masked replicate assessment of a sample found the following reproducibility: for A/V ratio, correlation coefficient = 0.79 and median absolute difference = 0.03; for focal arteriolar narrowing, kappa = 0.45; for AV nicking, kappa = 0.61; and for retinopathy, kappa = 0.89. CONCLUSION Protocols have been developed for nonmydriatic fundus photography and for evaluation of retinal vascular abnormalities. Several microvascular changes were significantly associated with higher blood pressure; follow-up will show whether these are predictive of later cerebrovascular or cardiovascular disease independently of other known risk factors.

Effects of medical therapies on retinopathy progression in type 2 diabetes.

BACKGROUND We investigated whether intensive glycemic control, combination therapy for dyslipidemia, and intensive blood-pressure control would limit the progression of diabetic retinopathy in persons with type 2 diabetes. Previous data suggest that these systemic factors may be important in the development and progression of diabetic retinopathy. METHODS In a randomized trial, we enrolled 10,251 participants with type 2 diabetes who were at high risk for cardiovascular disease to receive either intensive or standard treatment for glycemia (target glycated hemoglobin level, <6.0% or 7.0 to 7.9%, respectively) and also for dyslipidemia (160 mg daily of fenofibrate plus simvastatin or placebo plus simvastatin) or for systolic blood-pressure control (target, <120 or <140 mm Hg). A subgroup of 2856 participants was evaluated for the effects of these interventions at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale (as assessed from seven-field stereoscopic fundus photographs, with 17 possible steps and a higher number of steps indicating greater severity) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy. RESULTS At 4 years, the rates of progression of diabetic retinopathy were 7.3% with intensive glycemia treatment, versus 10.4% with standard therapy (adjusted odds ratio, 0.67; 95% confidence interval [CI], 0.51 to 0.87; P=0.003); 6.5% with fenofibrate for intensive dyslipidemia therapy, versus 10.2% with placebo (adjusted odds ratio, 0.60; 95% CI, 0.42 to 0.87; P=0.006); and 10.4% with intensive blood-pressure therapy, versus 8.8% with standard therapy (adjusted odds ratio, 1.23; 95% CI, 0.84 to 1.79; P=0.29). CONCLUSIONS Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control, reduced the rate of progression of diabetic retinopathy. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov numbers, NCT00000620 for the ACCORD study and NCT00542178 for the ACCORD Eye study.)

The Wisconsin Epidemiologic Study of Diabetic Retinopathy: IV. Diabetic Macular Edema

The prevalence of macular edema and its relationship to a number of risk factors were examined in a population-based study in southern Wisconsin. Macular edema was determined from its presence on stereoscopic fundus photographs or from past history as recorded and documented in clinic records and photographs. For participants whose age at diagnosis of diabetes was less than 30 years and who were taking insulin (n = 919), prevalence rates of macular edema varied from 0% in those who had diabetes less than 5 years to 29% in those whose duration of diabetes was 20 or more years. In these persons, macular edema was associated with longer duration of diabetes, presence of proteinuria, diuretic use, male gender and higher glycosylated hemoglobin. For those whose age at diagnosis was 30 years or older (n = 1121), prevalence rates of macular edema varied from 3% in those who had diabetes less than 5 years to 28% in those whose duration of diabetes was 20 or more years. In these persons, presence of macular edema was associated with longer duration of diabetes, higher systolic blood pressure, insulin use, higher glycosylated hemoglobin, and presence of proteinuria.

Photocoagulation Treatment of Proliferative Diabetic Retinopathy: The Second Report of Diabetic Retinopathy Study Findings

Data from the Diabetic Retinopathy Study (DRS) show that photocoagulad inhibited the progression of retinopathy. These beneficial effects were noted to some degree in all those stages of diabetic retinopathy which were included in the Study. Some deleterious effects of treatment were also found, including losses of visual acuity and constriction of peripheral visual field. The risk of these harmful effects was considered acceptable in eyes with retinopathy in the moderate or severe retinopathy in the moderate or severe proliferative stage when the risk of severe visual loss without treatment was great. In early proliferative or severe nonproliferative retinopathy, when the risk of severe visual loss without treatment was less, the risks of harmful treatment effects assumed greater importance. In these earlier stages, DRS findings have not led to a clear choice between prompt treatment and deferral of treatment unless and until progression to a more severe stage occurs.

A randomized, controlled trial of foscarnet in the treatment of cytomegalovirus retinitis in patients with AIDS

OBJECTIVE To evaluate foscarnet sodium in treating cytomegalovirus retinitis in patients with AIDS. PATIENTS Twenty-four previously untreated persons with AIDS and cytomegalovirus retinitis who were at low risk for loss of their visual acuity. INTERVENTION PATIENTS were randomly assigned to receive either no therapy (delayed treatment, control group) or immediate treatment with intravenous foscarnet at a dose of 60 mg/kg body weight three times a day for 3 weeks (induction regimen) followed by a maintenance regimen of 90 mg/kg once a day. MEASUREMENTS PATIENTS were examined weekly until they reached the primary clinical end point, defined as progression of their retinitis border by 750 microns or the development of a new retinal lesion due to cytomegalovirus. Progression was evaluated using retinal photographs by masked readers. Secondary evaluations included changes in visual acuity, cytomegalovirus shedding in the blood and urine, serum levels of human immunodeficiency virus type 1 (HIV-1) p24 antigen, and total CD4 T lymphocyte counts. RESULTS The mean time to progression of retinitis was 3.2 weeks in the control group (n = 11) compared with 13.3 weeks in the treatment group (n = 13) (P less than 0.001). Nine of 13 patients in the treatment group had positive blood cultures for cytomegalovirus at entry and all nine cleared their blood of cytomegalovirus by the end of the induction period (P = 0.004) compared with one of six patients in the control group. No reductions in p24 levels were seen in the control patients compared with a reduction of more than 50% in p24 levels for all four patients on treatment for whom follow-up levels were available. The main adverse effects of foscarnet treatment were seizures (2 of 13 patients), hypomagnesemia (9 of 13), hypocalcemia (11 of 13), and elevations in serum creatinine above 176.8 mumol/L (2.0 mg/dL) (3 of 13). The control patients received an average of 0.2 units of blood per week compared with an average of 0.6 units of blood per week for the patients on treatment. CONCLUSIONS The administration of foscarnet decreases the rate of progression of cytomegalovirus retinitis in persons with AIDS. Its judicious use is likely to prevent loss of vision in these patients. In this study, however, there was little change in visual acuity in patients in either the immediate or delayed treatment group because only patients with non-sight-threatening disease were selected.

An Alternative Method of Grading Diabetic Retinopathy

The purpose of this report is to present a system for grading the severity of diabetic retinopathy that is a rapid, relatively inexpensive, and standardized alternative to the more detailed Early Treatment Diabetic Retinopathy Study (ETDRS) system; present data on its reproducibility; and compare it to the detailed ETDRS grading system. The alternative system was used to grade fundus photographs obtained during a large prevalence study, the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR). The alternative method involved grading seven stereoscopic standard fields as a whole, and assigning a level of severity for the eye according to the greatest degree of retinopathy using a modified Airlie House Classification scheme. Using an eight-level classification system of increasing severity of retinopathy, there was 78.3% exact agreement between the alternative and ETDRS systems. A grader regraded all 503 disagreements, and was in exact agreement 49.3% of the time with the alternative system, 35.7% of the time with the detailed system, and 15.0% with neither the alternative or detailed systems. Interobserver agreement for the alternative system was 78.5%; intraobserver agreement over a 9 month to 1 year period was 90.0% for grader 1 and 84.0% for grader 2. The alternative system of grading, when used by experienced graders, is a reproducible method for objectively determining retinopathy status in epidemiologic studies.