Screening for diabetic retinopathy.

REVIEWS

Screening for Diabetic Retinopathy Daniel E. Singer, MD; David M. Nathan, MD; Howard A. Fogel, MD; and Andrew P. Schachat, MD

• Purpose: To determine the appropriate patients, methods, and timing for screening for diabetic retinopathy. • Data Sources: Relevant articles were identified through prominent review articles, the authors' files, recommendations from experts, and a MEDLINE search (1986 to the present); additional references were selected from the bibliographies of identified articles. • Study Selection: Selection of articles on the natural history of retinopathy was limited to large clinical series and formal epidemiologic studies of defined populations. Selection of articles on the therapeutic effect of photocoagulation and of glycemic control was limited to randomized trials. Sources bearing on the accuracy of screening modalities were necessarily more varied. • Data Extraction: For important variables, individual estimates from multiple studies are presented rather than a single meta-analytic summary estimate. • Results: Screening for retinopathy is justifiable if early detection leads to less vision loss at an acceptable cost. The evidence shows that 1) laser therapy reduces the rate of vision loss by 50% among patients with proliferative retinopathy and macular edema, conditions that are often asymptomatic; 2) duration of diabetes is the main risk factor for retinopathy; and 3) standard ophthalmoscopic examination has only moderate sensitivity (about 80% in research settings) and specificity (> 90% for proliferative retinopathy but lower for macular edema), making seven-field stereophotography a more accurate method. Estimates of cost effectiveness indicate that screening for retinopathy not only saves years of vision but may be cost saving from a societal perspective. • Conclusions: Screening for retinopathy in patients with diabetes, and subsequent photocoagulation therapy for those who have high risk macular edema or proliferative retinopathy, is clearly beneficial. [Note that sections in this review are numbered so that they can be identified with cross-references as supporting evidence in the article, "Screening Guidelines for Diabetic Retinopathy," published in the Clinical Guideline section of this issue; see pages 683-685.— The Editors]

1.1 D i a b e t i c retinopathy is a highly specific vascular complication of chronic diabetes mellitus. Indeed, the current glycemic thresholds for defining diabetes were selected on the basis of their relation to the risk for retinopathy (1). By 20 years after the onset of diabetes, nearly all insulin-dependent (type I) patients and more than 60% of non-insulin-dependent (type II) patients have some degree of retinopathy (2, 3). More than four fifths of the cases of blindness among type I patients and one third of the cases among type II patients are due to diabetic retinopathy (4). Diabetic retinopathy is estimated to be the most frequent cause of cases of new blindness among American adults 20 to 74 years of age (5). 1.2 The objective of our review is to determine the appropriate target population, methods, and timing for screening for diabetic retinopathy. To arrive at a supportable screening strategy, we review the natural history of diabetic retinopathy, identify risk factors for its development, review intervention studies that have defined the eye lesions that respond to laser therapy, and evaluate available screening modalities. Finally, we compare the resulting screening strategies with guidelines proposed by professional organizations. Many of the most important articles have been published in the ophthalmology literature. A supplementary goal of this review is to increase internists' awareness of these remarkable studies. Methods 2.1 Relevant journal articles were identified through prominent review articles, the authors' files, recommendations made by experts from the American Academy of Ophthalmology, and a MEDLINE search (1986 to the present); other articles were found by reviewing the bibliographies of articles identified during the initial search. Selection of articles on the natural history of retinopathy was limited to large clinical series and formal epidemiologic studies of defined populations. Selection of articles on the therapeutic effect of photocoagulation and of glycemic control was limited to randomized trials. Sources bearing on the accuracy of screening modalities were necessarily more varied. The analysis was driven by the theory of screening for asymptomatic disease (see reference 6). For estimates of important variables, values from the preeminent studies or ranges of values from multiple studies are presented, rather than a single meta-analytic summary estimate. The Natural History of Diabetic Retinopathy General Description

Annals of Internal Medicine. 1992;116:660-671. From Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and Johns Hopkins University and Hospital, Baltimore, Maryland. For current author addresses, see end of text. 660

3.1 Diabetic retinopathy is characterized by abnormal retinal vascular permeability, microaneurysm formation, capillary and arteriolar closure, neovascularization and associated hemorrhage, scarring, and tractional retinal distortion and detachment. Although the mechanisms underlying diabetic retinopathy are unclear, its clinical progression is well known (7). The earliest phase, back-

© 1992 American College of Physicians

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ground diabetic retinopathy, is characterized by capillary leakage with capillary microaneurysm formation, dot and blot intraretinal hemorrhages, and lipid exudates. Depending on the extent and location of capillary leakage, macular edema may develop. The next phase of the disease, preproliferative diabetic retinopathy, is characterized by capillary and arteriolar closure. Cotton-wool spots are a hallmark, representing infarctions of the retinal nerve fiber layer. Associated morphologic abnormalities include venous beading and irregular, segmental dilation of retinal capillaries ("intraretinal microvascular abnormalities"). Proliferative diabetic retinopathy is characterized by the growth of new blood vessels from the optic nerve head ("neovascularization of the disk") or from retinal blood vessels elsewhere ("neovascularization elsewhere"). The new blood vessels proliferate on the posterior surface of the vitreous face. As the vitreous contracts or otherwise changes, the new vessels may tear and bleed, producing vision loss through vitreous hemorrhage. Extensive fibrous tissue may accompany the abnormal new vessels. This retinal fibrovascular proliferation may contract, producing retinal distortion and detachment. Quantitating the Risk for Retinopathy 3.2 Studies of the natural history of diabetic retinopathy fall into three general categories: 1) observational follow-up studies of patients attending diabetes clinics (8); 2) epidemiological^ planned observational follow-up studies of geographically (9) or ethnically defined (10) cohorts of diabetic persons; and 3) observations from the control arm of randomized, controlled trials of therapy for retinopathy (11, 12). The first type of study often has the advantages of a very long follow-up period and a large number of patients followed from the time of first diagnosis of diabetes. However, these clinic-based studies are often retrospective, resulting in less uniform data collection, particularly regarding the frequency and quality of retinal examinations. Studies of geographically defined cohorts have the strengths of uniform, high-quality data collection and clear generalizability. Some of these studies have had a relatively short follow-up period (years rather than decades) and have not included many newly diagnosed diabetics. Studies of specific ethnic groups may be very informative, but findings may not apply to the general population. Data from randomized trials are often of high quality. However, these randomized trials have focused primarily on patients with more advanced retinopathy. Overall, these various studies provide a rich and generally consistent description of the progression of diabetic retinopathy. 3.3 Some features of the natural history of diabetic retinopathy vary according to the sensitivity of the diagnostic techniques. We draw heavily on the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) (9), a study in which fundus stereophotographs were taken and read by trained research personnel. Other studies we cite used less sensitive techniques. 3.4 The Diabetic Retinopathy Study (DRS) and the Early Treatment Diabetic Retinopathy Study (ETDRS) (11, 12) have identified the points in the natural history

of diabetic retinopathy at which laser therapy is beneficial. In particular, these studies have shown that laser photocoagulation can retard the rate of visual loss once proliferative retinopathy with "high-risk characteristics" or "clinically significant" macular edema have appeared. To plan a sensible screening program, we need to know when, in the course of diabetes, these stages of retinopathy occur. Data from the WESDR directly bear on this question. 3.5 The WESDR (9) attempted to identify all diabetic patients treated by physicians in an 11-county area in southern Wisconsin during the period from July 1979 through June 1980. Diabetic patients were divided into those with "younger onset" diabetes (< 30 years of age at diagnosis who were taking insulin) and those with "older onset" diabetes (> 30 years of age at diagnosis who were or were not receiving insulin). Such a categorization operationally defines type I and type II patients, respectively. The investigators identified 1210 eligible younger-onset patients, 996 of whom (82%) participated in the study. A total of 5431 eligible olderonset patients were identified. A duration-stratified sample of 1780 patients with older-onset diabetes was selected, and three quarters of these patients participated in the study. Participants had various clinical assessments at entry, including ophthalmoscopic examination, seven-field color fundus photography, and determination of glycosylated hemoglobin levels. Retinal status was defined by careful grading of the fundus photographs. These baseline examinations provided the initial prevalence data. 3.6 Of the patients with younger-onset diabetes whose duration of disease was less than 5 years, none had proliferative retinopathy. The prevalence of proliferative retinopathy was 4% among those who had had diabetes for 10 years, rising to approximately 50% for those who had had diabetes for 20 years or more (2) (Figure 1, top). In very few cases did retinopathy occur before puberty. 3.7 Among older-onset patients, particularly among those taking insulin, duration of diabetes was again the major determinant of retinopathy (Figure 1, middle). These patients had a lower prevalence of proliferative retinopathy than younger-onset patients at any given duration of diabetes except for the first years after diagnosis, where the prevalence was 3% to 4% (3). This early appearance of proliferative retinopathy among type II patients may reflect biased underestimation of the duration of milder type II disease. Prevalence of proliferative retinopathy increased little with duration of diabetes among patients not taking insulin. For olderonset patients taking insulin, the prevalence increased to approximately 10% among those with a 10-year duration of diabetes and to 20% among those with a duration of diabetes of 15 or more years. 3.8 The prevalence of clinically significant macular edema was higher among older-onset than younger-onset patients, for those with a recent diagnosis of diabetes (Figure 1, bottom) (13). In all groups, the prevalence of macular edema rose with increased duration of diabetes. 3.9 Four-year follow-up examinations provided the W / F ^ n i ? i n r ' i H f n r ' f Hata

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progression. For example, younger-onset patients with soft exudates (retinal infarctions) and intraretinal microvascular abnormalities had a 4-year rate of progression to proliferative retinopathy of more than 40%. Fouryear progression also depended on the duration of diabetes. 3.10 In the older-onset group, progression to proliferative retinopathy again was primarily a function of the severity of retinopathy at first examination (15). Only 2 of 474 patients (0.4%) with no retinopathy at baseline developed proliferative retinopathy by the time of the 4-year follow-up examination. In patients with soft exudates and intraretinal microvascular abnormalities at baseline, this rate increased toward 20% and was higher in those with even more severe retinopathy at baseline. 3.11 Over 4 years, 8.2% of younger-onset patients and 5.2% of older-onset patients developed macular edema (16). Of great importance for screening, the incidence of macular edema strongly depended on the level of retinopathy at baseline. In particular, the 4-year rate of macular edema among patients with no retinopathy at first examination was 1.0% for younger-onset patients and 1.1% for older-onset patients. In approximately 50% of cases, macular edema was considered clinically significant. 3.12 Findings from several other large studies generally support those of the WESDR (8, 17-19); specifically, these studies indicate that severe retinopathy is uncommon in the first 5 years after the diagnosis of diabetes and that the risk for severe retinopathy rises substantially with increased duration of diabetes. Other Possible Risk Factors for Retinopathy

Figure 1. Findings from the Wisconsin Epidemiologic Study of Diabetic Retinopathy: the prevalence of various categories of diabetic retinopathy plotted as a function of the duration of diabetes. Top. Prevalence of any retinopathy and of proliferative retinopathy in patients with younger-onset diabetes (< 30 years-of age at diagnosis and taking insulin). Reprinted with the permission of Archives of Ophthalmology (1984;102:520-6). Middle. Prevalence of any retinopathy and of proliferative retinopathy in patients with older-onset diabetes (> 30 years of age at diagnosis who were taking or not taking insulin). Reprinted with permission of Archives of Ophthalmology (1984; 102:527-32). Bottom. Prevalence of clinically significant macular edema (CSME) in three groups of diabetic patients—those with older-onset disease who were taking insulin, those with older-onset disease who were not taking insulin, and those with younger-onset disease. Reprinted with permission of International Ophthalmology Clinics (27;230-8, 1987). progression to proliferative retinopathy was largely determined by the baseline status of the eye (14). Only 1 of 271 patients with no retinopathy at baseline developed proliferative diabetic retinopathy by the time of the 4-year follow-up examination. Patients with more advanced retinopathy at baseline had greater rates of 662

3.13 Hyperglycemia is the chemical hallmark of diabetes. The current glycemic thresholds for the diagnosis of diabetes were selected because they conferred a risk for developing retinopathy (1). High-quality studies have established a positive association between glycemia and both the risk for and progression of diabetic retinopathy (20-23). The most convincing studies have used accurate assays of chronic glucose control (in particular, assessments of glycated hemoglobin) and sophisticated statistical approaches to control confounding (most importantly, controlling for the effect of duration of diabetes). 3.14 In the WESDR, when patients in the highest quartile of glycosylated hemoglobin were compared with those in the lowest quartile, the risk ratio for developing new retinopathy was 1.9 among type I patients, 1.9 among type II patients taking insulin, and 4.0 among type II patients not taking insulin. Similarly constructed risk ratios for progression of retinopathy for these three groups were 4.0, 2.1, and 6.2, respectively. The effects persisted in logistic regression models that included terms for diabetes duration, age, sex, and severity of baseline retinopathy (in the regression model of retinopathy progression). 3.15 Hypertension has periodically been identified as a risk factor for diabetic retinopathy. Hypertension can produce retinal changes that partially overlap with diabetic retinopathy. A frequently cited study of diabetic Pima Indians (24) and a study from the Joslin Clinic (22)



both noted an association between retinopathy and hypertension. In the former study, hypertension was significantly associated with the occurrence of exudates but not with hemorrhages, the more specific marker of diabetic retinopathy. In the latter study, a step increase in risk occurred with diastolic blood pressure above 70 mm Hg, but no relation was found between risk and systolic blood pressure. 3.16 The recent analysis from the WESDR (25) found that blood pressure had a small association with retinopathy in younger-onset patients, but no relation was found in older-onset patients. 3.17 Other studies have assessed the effect of blood pressure on retinopathy (19, 26-29). Several large, welldesigned studies (19, 28, 29) have found no effect. Consequently, the etiologic role of hypertension in the development of diabetic retinopathy is in question. Hypertension may be a weak marker of retinopathy because of its relation to diabetic nephropathy (30). 3.18 Severe retinopathy and diabetic renal disease often occur together (8, 9, 31). Among younger onset patients in the WESDR (9), those with proteinuria (total protein level > 30 mg/dL by dipstick) had a threefold higher prevalence of macular edema and of proliferative retinopathy compared with those without proteinuria. Among older-onset patients, these prevalences were increased about twofold. 3.19 Other putative risk factors for retinopathy include ethnic group, smoking, and histocompatibility type. The San Antonio Heart Study has provided evidence that Mexican Americans who are diabetic face an increased risk for severe retinopathy (19), but a recent study of diabetic Hispanics in Colorado found no such increased risk (32). Otherwise, the data on the development of retinopathy in ethnic or racial groups are scant. Research implicating cigarette smoking or histocompatibility type is currently inconclusive (24, 33-35). 3.20 There is concern that pregnancy in patients with type I diabetes leads to acute worsening of retinopathy. Official guidelines counsel especially close monitoring in such patients (36, 37). One prospective, controlled study demonstrated a 2.3-fold increase in progression of retinopathy among pregnant women with type I diabetes compared with nonpregnant women with type I diabetes (38). However, women with gestational diabetes (that is, those whose diabetes first develops with pregnancy and usually remits after delivery) are not considered to be at risk for retinopathy.

Summary 3.21 Type of diabetes, disease duration, and severity of baseline retinopathy are the prime determinants of both the onset and progression of diabetic retinopathy. In addition, we are on firm ground in asserting that poor glucose control is associated with retinopathy. Proteinuria also seems to be a marker of risk for retinopathy. Pregnancy appears to pose an additional risk. It is doubtful that any other suspected markers of the risk for retinopathy would be useful in modifying a screening strategy for most Americans.

Therapeutic Interventions for Diabetic Retinopathy 4.1 A critical prerequisite for rational screening programs is an effective preventive therapy. We review the clinical trials that have established the efficacy of retinal photocoagulation in reducing the risk for visual loss in patients with macular edema and proliferative retinopathy. We then outline current knowledge on the effect of near-normal glucose levels on diabetic retinopathy. We also briefly discuss studies of platelet-modifying agents. Retinal Photocoagulation 4.2 The beneficial effect of photocoagulation of the retina on proliferative retinopathy and macular edema was established by randomized clinical trials, most importantly the DRS (11) and the ETDRS (12), which included patients with both type I and type II diabetes. The essential findings of the DRS and the ETDRS are that photocoagulation therapy reduces the rate of developing visual loss in patients with proliferative retinopathy and macular edema by about 50%, that this effect is long-lasting, and that the effect is particularly impressive in certain high-risk groups. The effect of photocoagulation is primarily preventive. It generally does not reverse visual loss. 4.3 The DRS tested whether panretinal photocoagulation could improve the prognosis of patients with proliferative retinopathy. To be eligible, diabetic patients (either type I or II) had to have proliferative changes in at least one eye or severe nonproliferative retinopathy in both eyes. Retinal status was determined by stereophotography of the retina. Visual acuity had to be 20/ 100 or better in each eye. In each of the 1758 patients, one eye was randomly assigned to receive photocoagulation and the other eye to serve as a control. Panretinal photocoagulation was administered by either xenon arc or argon laser, as directed by protocol. The study's end point was severe visual loss, defined as acuity worse than 5/200 on two consecutive 4-month follow-up visits. 4.4 The results were dramatic (Figure 2) (39). By 2 years, severe visual loss had occurred in 15.9% of untreated eyes but in only 6.4% of treated eyes. Xenon arc seemed the slightly more effective modality, but because of the greater visual damage done by xenon arc, argon laser became the preferred treatment modality. The DRS identified a subgroup of patients who had the greatest likelihood for severe visual loss and who benefited the most from therapy (40). These patients had the following "high-risk characteristics": 1) newvessel proliferation within one disk diameter of the optic disk and exceeding 1/4 the disk area in size; 2) any proliferation within one disk diameter of the optic disk and associated with vitreous or pre-retinal hemorrhage; or 3) proliferation elsewhere at least 1/2 the disk area in size and associated with hemorrhage. Untreated eyes with these high-risk characteristics had a 2-year risk for severe visual loss of 26% compared with 11% in eyes receiving photocoagulation. The 2-year risk for severe visual loss in eyes not having high-risk characteristics was 7% in the control group compared with 3% in the treatment group, a clinically less important difference, given that argon laser photocoagulation produced small



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degrees of visual loss and a small reduction in visual field in about 10% of treated eyes. The 2-year analysis prompted a change in DRS protocol to allow treatment for all eyes with high-risk characteristics. Many eyes originally assigned to serve as a control were subsequently treated. As a result, the substantial longer-term benefit of treatment (see Figure 2) is almost certainly understated. The summary recommendations of the DRS Research Group were that eyes with high-risk characteristics should be treated promptly. For eyes with less severe proliferative retinopathy or severe nonproliferative retinopathy, the DRS did not provide a choice between prompt photocoagulation and close follow-up for the appearance of high-risk characteristics. 4.5 The recently completed ETDRS assessed argon laser photocoagulation therapy in patients with early proliferative retinopathy, mild to severe nonproliferative retinopathy, and diabetic macular edema. Patients were also randomly assigned to receive aspirin, 650 mg/d. Macular edema was defined by retinal characteristics seen on stereoscopic photographs. The most important results bearing on screening were found among patients with macular edema and mild to moderate retinopathy. This comparison was based on 1490 eyes randomly assigned to deferral of photocoagulation (until high-risk proliferative retinopathy developed) and 754 eyes randomly assigned to immediate focal photocoagulation. At 2 years, 16% of eyes in the deferred-therapy group had lost visual acuity compared with 7% in the immediatetreatment group (12). The benefit of photocoagulation was clearest among patients with clinically significant macular edema, which was defined by the following retinal features: 1) thickening of the retina within 500 microns of the center of the macula; 2) hard exudates within 500 microns of the center of the macula, occurring in association with thickening of the adjacent retina; or 3) zones of retinal thickening at least one disk diameter in size, any part of which is within one disk diameter of the center of the macula. At 2 years, among 664

patients with clinically significant macular edema, 20% of the untreated group had a doubling of the visual angle compared with 8% of the treated group (Figure 3). Several smaller trials have also demonstrated the benefit of photocoagulation therapy in patients with macular edema (41, 42). 4.6 The ETDRS recently provided the remainder of their findings (43-45): 1) Scatter laser photocoagulation for mild to moderate nonproliferative retinopathy (as opposed to focal treatment of macular edema) was of little net benefit; and 2) aspirin therapy did not alter the rates of moderate or severe visual loss, nor did it increase the risk for vitreous hemorrhage. 4.7 The findings of the ETDRS imply that patients with clinically significant macular edema should receive photocoagulation therapy and that patients with less severe macular edema should be followed for deterioration. The findings of the ETDRS may be somewhat less relevant to screening than those of the DRS because many patients with macular edema experience significant loss of acuity and might seek ophthalmologic evaluation on their own. Glycemic Control 4.8 There is now a fairly substantial and largely consistent set of observational studies demonstrating a strong association of retinopathy with glycemia. In addition, studies in diabetic animals have shown that normalization of blood glucose levels early in the course of diabetes can reduce retinopathy (46). However, clinical studies have thus far failed to demonstrate that improved glycemic control alters the progression of retinopathy. 4.9 Several small and relatively brief trials in patients with type I diabetes have assessed the benefit of nearnormal blood glucose levels achieved by multiple daily insulin injections or by continuous subcutaneous insulin infusion (47-49). Despite improved glucose control,



there has been no clear evidence for a beneficial effect on retinopathy. The Diabetes Control and Complications Trial, currently under way, was designed to be a more definitive test of the effect of intensive regimens in patients with type I diabetes (50). The only controlled clinical trial to examine the effects of improved glucose control in patients with type II diabetes was the University Group Diabetes Program (UGDP) trial, which demonstrated no differences in the occurrence of retinopathy among treatment groups (51). Platelet-modifying Agents 4.10 Interest in the use of platelet-modifying agents in patients with diabetic microvascular disease has been substantial, and some data suggest a benefit (52). However, the ETDRS investigators found no benefit of aspirin when they compared 1856 patients receiving 650 mg of aspirin per day and 1855 receiving placebo (44). 4.11 The nature of beneficial therapeutic interventions for the asymptomatic patient drives screening for diabetic retinopathy. Currently, photocoagulation therapy for severe macular edema or proliferative retinopathy is the established intervention for preventing vision loss. As a result, the goal of screening is to identify eyes with macular edema, pre-proliferative retinopathy, or proliferative retinopathy. Techniques for Screening for Diabetic Retinopathy 5.1 Various techniques can be used to detect and characterize diabetic retinopathy (Table 1). These include direct ophthalmoscopy through nondilated or dilated pupils, indirect ophthalmoscopy, fluorescein angiography, stereoscopic fundus photography (through

dilated pupils), and nonmydriatic photographic techniques. 5.2 Studies comparing these techniques generally use seven-field fundus stereoscopic photography or fluorescein angiography, or both, as the "gold standard." The Diabetes Control and Complications Trial found excellent agreement between these two techniques (48). Fluorescein angiography would seem to have little role in screening because of the need for intravenous injection and the potential for hypersensitivity reactions. The importance of stereoscopic fundus photography was seen in the DRS and the ETDRS, where it defined the types of retinopathy that benefited from laser therapy (11, 12). 5.3 In the DRS, dilated ophthalmoscopy was compared with stereoscopic photography in the grading of retinopathy; correlation coefficients of 0.767 and 0.534 were obtained for the detection of neovascularization of the disk and detection of neovascularization elsewhere, respectively (53). Although calculated sensitivities and specificities were not provided, ophthalmoscopic examination appeared to be a mediocre substitute for photographic evaluation. 5.4 The ETDRS investigators compared clinical examination (including contact lens biomicroscopy and dilated ophthalmoscopy) by retinal specialists with photographic grading in the detection of macular edema. Kappa statistics ranged from 0.55 to 0.65, indicating fair agreement. When photographic grading was used as the standard, clinical examinations had a sensitivity of 0.82 and a specificity of 0.79 for detecting clinically significant macular edema (54). 5.5 The WESDR assessed ophthalmoscopy in a geographically based sample. Such a cohort is more comparable to a screened population. Patients were given a

Figure 3. The effect of focal photocoagulation in the Early Treatment Retinopathy Study. Patients were stratified by the presence or absence of clinically significant macular edema. Vision loss corresponded to at least a doubling of the visual angle. Reprinted with permission of Archives of Ophthalmology, (1985;103:1796-1806). 15 April 1992 • Annals of Internal Medicine • Volume 116 • Number 8


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Table 1. Operating Characteristics of Ophthalmoscopy for the Detection of Serious Retinopathy* Study (Reference)

Eyes, n

Methods

Assessment

1949 (170 with proliferative retinopathy) 1464 (44% with clinically significant macular edema) 99 (20 with proliferative retinopathy) 438 (6 with proliferative retinopathy)

Dilated direct and indirect ophthalmoscopy done by ophthalmologists and trained technicians Dilated direct and indirect ophthalmoscopy and contact lens biomicroscopy done by retinal specialists Undilated direct ophthalmoscopy done by experienced technicians

Sensitivity = 0.79 and specificity = 0.99 for proliferative retinopathy

Dilated direct ophthalmoscopy done by nurses and by diabetologist

Sussman et al. (56)

21 (7 with proliferative retinopathy)

Dilated direct and indirect ophthalmoscopy by internists and ophthalmologists with a wide range of experience

Velez et al. (60)

227 patients (12 with proliferative retinopathy)f 25 (1 with macular edema, 1 with preproliferative retinopathy, and 1 with proliferative retinopathy) 133 (25 with macular edema and 18 with proliferative retinopathy)

Dilated direct and indirect ophthalmoscopy by retinal specialists

Sensitivity = 0 and specificity = 1.0 for proliferative retinopathy when examinations were done by nurses; sensitivity = 0.17 and specificity = 0.99 for proliferative retinopathy when examinations were done by diabetologists Sensitivity = 0.49 and specificity = 0.84 for proliferative retinopathy when examinations were done by internists; sensitivity = 0.96 and specificity = 0.93 for proliferative retinopathy when examinations were done by ophthalmologists Sensitivity = 0.50 and specificity = 1.0 for proliferative retinopathy

WESDR (55) ETDRS (54)

Klein et al. (57) Forrest et al. (58)

Kleinstein et al. (63)

Nathan et al. (64)

Sensitivity = 0.82 and specificity = 0.79 for clinically significant macular edema Sensitivity = 0.50 and specificity = 0.90 for proliferative retinopathy

Dilated direct or indirect ophthalmoscopy, or both, done by optometrists

Sensitivity = 0.74 and specificity = 0.84 for any retinopathy

Nondilated direct ophthalmoscopy done by diabetologists; dilated indirect ophthalmoscopy done by ophthalmologists

Examination by diabetologist: Sensitivity = 0.38 and specificity = 0.97 for proliferative retinopathy; sensitivity = 0 and specificity = 1.0 for macular edema Examination by ophthalmologist: Sensitivity = 0.28 and specificity = 1 . 0 for proliferative retinopathy; sensitivity = 0.40 and specificity = 1.0 for macular edema

* Dilated retinal photography provides the diagnostic standard. ETDRS = Early Treatment Diabetic Retinopathy Study; WESDR = Wisconsin Epidemiologic Study of Diabetic Retinopathy. f Data were given for patients rather than eyes.

dilated examination by three principal examiners—an ophthalmologist, a specially trained optometrist, and an ophthalmic technician. The examiners could confer on cases, and indirect ophthalmoscopy could be used if needed. Seven-field fundus photography served as the standard. Analysis of 1949 right eyes revealed that for the detection of proliferative retinopathy, ophthalmoscopy had a sensitivity of 0.79 and a specificity of 0.99. Of the 35 eyes in which proliferative retinopathy was missed by ophthalmoscopy, 3 eyes were thought to have no retinopathy at all. In only one case of missed proliferative retinopathy did the eye have high-risk characteristics (55). 5.6 Several other studies have compared methods for detecting diabetic retinopathy, particularly lesions leading to treatment (56-64). Some of these studies used small samples of preselected patients who demonstrated specific eye lesions, whereas others were done in usual ophthalmologic or medical clinic settings. The results range widely. However, it seems clear that undilated 666

ophthalmoscopic examinations miss a large percentage of cases of proliferative retinopathy and macular edema. Dilated examinations by eye specialists are better but show only moderate sensitivity for important lesions (see Table 1). 5.7 There has been considerable interest in nonmydriatic fundus photography has arisen, with the expectation that it might provide a widely applicable technique for objectively recording retinal morphology. One 45-degree field photograph of the posterior pole of each eye is recorded without dilating the pupils. In a study of 99 persons in whom only one eye was assessed, all cases of proliferative retinopathy detected by stereoscopic photography were read as proliferative retinopathy or as severe nonproliferative retinopathy on the nonmydriatic photographs (57). In about 13% of nonmydriatic fundus photographs, quality was too poor for grading. However, nonmydriatic photography was substantially more accurate than an undilated examination done by a trained ophthalmoscopist. The weaknesses of



nonmydriatic photography highlighted in this study were the limited retinal field covered by one 45-degree photograph, the decreased magnification produced by the nonmydriatic camera, and the poor ability to detect macular edema without stereoscopic imaging. Several British reports find nonmydriatic photography to be about as accurate as a dilated ophthalmoscopic examination (58, 61, 62). Summary 5.8 Stereoscopic fundus photographs, taken and read by trained personnel, are the gold standard for the detection and staging of diabetic retinopathy. Dilated ophthalmoscopic examination misses at least 20% of cases of advanced retinopathy. Nondilated ophthalmoscopic examinations miss even more cases, particularly when the examinations are done by general medical personnel. Nonmydriatic fundus photography, an evolving technique, is roughly as accurate as dilated ophthalmoscopic examination. Cost-Effectiveness Analyses of Screening for Diabetic Retinopathy 6.1 At least four cost-effectiveness analyses of screening for diabetic retinopathy have been done: These include two from the United Kingdom (65, 66) and two from the United States (67-69). The analyses from the two countries provide an interesting contrast in health care costs but reach qualitatively similar conclusions. 6.2 The analyses from the United States were methodologically more sophisticated. Javitt and colleagues (67, 68) analyzed the effect of current recommendations for diabetic retinopathy screening on a hypothetical cohort with type I diabetes. Incidence was estimated from WESDR data, the benefits from DRS and ETDRS data, and the costs from Medicare charges. The analysis used Monte Carlo simulation to model the progression of diabetic retinopathy, the development of visual loss, and survival for each member of the inception cohort of type I diabetics estimated to arise each year in the United States. Visual loss due to macular edema ("reading loss" or visual acuity of 20/80 or worse) and that due to proliferative retinopathy ("severe vision loss" or visual acuity of 5/200 or worse) were modeled concurrently. The model's 2-month cycles were repeated over the lifetime of each member of the cohort. The model was based on the assumption that macular edema and proliferative retinopathy would be treated in the year in which they were discovered. Five different screening strategies were compared in the model: 1) dilated ophthalmoscopic examination every 2 years; 2) dilated ophthalmoscopic examination every year; 3) dilated ophthalmoscopic examination every year plus additional 6-month examinations for those with any retinopathy; 4) dilated ophthalmoscopic examination plus fundus photography every year; and 5) dilated ophthalmoscopic examination plus fundus photography every year, with 6-month examinations for patients with retinopathy. All screening was assumed to begin 5 years after the onset of type I diabetes.

6.3 This model has the advantage of providing an explicit description of the time course of resource expenditures and the realization of benefits. For example, proliferative retinopathy does not lead to immediate severe vision loss in most patients but rather confers a 10% per year rate of visual loss; thus, the benefits of screening and photocoagulation therapy occur gradually over time, but much of the cost of screening is incurred immediately. The model incorporates the effect of increased mortality rates among patients with greater degrees of diabetic retinopathy and takes into account the partially independent progression of diabetic retinopathy in paired eyes. Medicare charges from 1986 provided the medical cost: $50 per screening ophthalmoscopic examination and $1950 for laser treatment to both eyes. Costs for Social Security benefits to the blind were also factored into the model. Costs were discounted, but gains in vision saved were not (68). The investigators calculated an average expected benefit of about 2.7 person-years of sight saved per person screened (a similar benefit was calculated for reading vision) over the lifetime of the cohort, at a net savings (to the government, which is assumed to bear all medical and Social Security costs) of about $3300 per person screened. All five strategies were cost-saving. Examinations every year were actually more cost-saving than examinations every other year. The addition of fundus photography was not very efficient. This finding does not address substitution of photography for ophthalmoscopy but only the effect of adding photography to ophthalmoscopy. Another assumption in the model was that most cases of advanced retinopathy missed on initial ophthalmoscopic examination would be detected on repeat examination. This assumption of independence of ophthalmoscopic error rates is questionable. 6.4 Dasbach and colleagues (69) constructed a Markov model of the natural history of diabetic retinopathy to assess the effect of six screening strategies. These strategies included examination every year or every other year by dilated ophthalmoscopy, by mydriatic fundus photography, or by nonmydriatic fundus photography. These strategies were implemented in three different populations of diabetic patients: type I patients with diabetes for 5 or more years, type II patients taking insulin, and type II patients not taking insulin (the categories used in the WESDR). The WESDR, DRS, and ETDRS data provided the basis for assumptions in this model as well. Only vision loss due to proliferative retinopathy was considered. Unlike that of Javitt and colleagues (67, 68), this model factored in imperfect compliance with prescribed screening and therapy and also discounted years of sight gained as well as dollar costs. Such discounting substantially reduced the estimate of (present value) years of sight gained by screening. Nonetheless, for patients with type I or type II diabetes who take insulin, nearly all screening strategies seem to be cost-saving. For patients with type II diabetes who do not take insulin, annual screening ophthalmoscopic examinations yielded additional years of sight at a cost of about $1500 per year of sight saved. Screening was much more efficient when applied to patients with type I diabetes because the incidence of advanced retinopathy is much higher and survival after



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screening much longer than in patients with type II diabetes. For patients with the highest risk (those with type I diabetes), annual screening was preferable. Screening by photography was slightly more effective than screening by ophthalmoscopy. Summary 6.5 Despite differences in modeling approaches and in assumptions, the various cost-effectiveness analyses indicate that widespread screening for diabetic retinopathy appears to be wise health policy. Certainly, among patients with type I diabetes, blindness can be prevented at a cost that is less than the disability payments that are averted. For patients with type II diabetes, screening is much less dramatically beneficial, but even in these patients, screening can be expected to efficiently provide additional years of sight. Screening for retinopathy among patients with type II diabetes might be made more efficient by targeting higher-risk groups. Official Recommendations for Screening for Diabetic Retinopathy 7.1 Guidelines for diabetic retinopathy screening have been developed by the American Diabetes Association (36), the Department of Health and Human Services National Diabetes Advisory Board (70), the American Optometric Association (71), and the American Academy of Ophthalmology (37, 72). The following guidelines were endorsed by the American Academy of Ophthalmology (37): "People between ages 10 and 30 years with a diagnosis of diabetes mellitus of five years' duration should have a baseline eye examination including. . .ophthalmoscopic examination through dilated pupils. . . .People older than the age of 30 years should have a baseline ophthalmic examination. . .at the time of diagnosis of diabetes. . . .After the initial eye examination, it is suggested that persons with diabetes mellitus receive the above ophthalmic examinations annually unless more frequent examinations are indicated by the presence of abnormalities." The guidelines further suggest that women with insulin-dependent diabetes receive ophthalmologic care for a year before a planned pregnancy; that a woman with preexisting diabetes receive an ophthalmologic examination in the first trimester of pregnancy; and that patients with advanced background diabetic retinopathy, macular edema, or proliferative diabetic retinopathy be referred for ophthalmologic management. 7.2 The American Diabetes Association guidelines (36) are similar, except to suggest that first eye examinations might start at 12 rather than at 10 years of age in those who have had diabetes for 5 years. These guidelines are somewhat vague about who should be doing the screening ophthalmoscopic examinations. For example, the American Diabetes Association indicates in its guidelines that the primary care physician should be referring patients to a skilled "eye doctor." In their published Preferred Practice Pattern, the American Academy of Ophthalmology recommends that these examinations be done by ophthalmologists (72). (Independent of screening for retinopathy, current Academy of 668

Ophthalmology recommendations emphasize the benefits of frequent examinations in detecting glaucoma, cataract, and other treatable diseases [73]). 7.3 The National Diabetes Advisory Board recommends that ophthalmologic consultation be arranged for all patients who have had type I diabetes for more than 5 years and for all patients with type II diabetes. Alternatively, practitioners experienced in the diagnosis of diabetic retinopathy could elect to do yearly dilated examinations (70). The American Optometric Association recommends yearly examinations, including dilated ophthalmoscopy, for all diabetic patients, closer follow-up for pregnant diabetic patients, and referral to a retinal specialist for patients with maculopathy or preproliferative or proliferative retinopathy (71). Summary Analysis 8.1 The clinical studies that bear on screening for diabetic retinopathy are of remarkably high quality. They have demonstrated that the incidence of diabetic retinopathy increases slowly with the duration of diabetes but that over decades most diabetic patients develop at least background retinopathy. After several years of background retinopathy, a minority of patients will develop vision-threatening proliferative retinopathy or macular edema. These conditions may not produce symptoms, but if left untreated, they can lead to irreversible vision loss. Photocoagulation therapy can reduce the risk for vision loss due to macular edema or proliferative retinopathy by approximately 50%. Dilated ophthalmoscopic examination by skilled examiners has a sensitivity for treatable lesions of probably less than 80%, with a much higher specificity. Undilated examinations, or examinations done by less trained ophthalmoscopists, have poorer operating characteristics. Skilled reading of seven-field stereoscopic photographs of the fundus serves as the diagnostic gold standard. 8.2 It seems clear that screening diabetic patients for macular edema and proliferative retinopathy will result in a substantial decrease in the incidence of vision loss. Further, the formal cost analyses indicate that the cost per year of vision saved through screening is relatively low and, for most patient subgroups, appears to be less than the yearly governmental costs of supporting blind persons. 8.3 The current recommendations for diabetic retinopathy screening are reasonable. However, changes in the recommended screening program might add efficiency and aggregate benefit: These changes are related and include: 1) reducing the frequency of screening in the initial years after the diagnosis of diabetes in selected patients with type 2 diabetes and 2) encouraging the wider use of stereoscopic fundus photography for screening. 8.4 Current recommendations for the frequency of ophthalmoscopic screening have the goal of missing no cases of treatable diabetic retinopathy. This goal is laudable but it adds substantial inefficiency by loading the screening process with many patients at very low risk. Indeed, screening is not recommended for patients with type I diabetes who have had diabetes for less than 5 years because the chance of finding proliferative ret-



Table 2. Findings of the \Yisconsin Epidemiologic Study of Diabetic Retirlopathy That Are Relevant to Screening Frequency Variable

Patients with diabetes Younger onset Older onset

Prevalence of Retinal Abnormalities in Patients Who Have Had Diabetes for Less than 5 Years Macular Proliferative Edema Retinopathy

4-Year Incidence of Retinal Abnormalities in Patients without Retinopal :hy at Baseline Proliferative Macular Retinopathy Edema*

%

n/n

0 -5

3/286 5/450

0 3.5

1/211 2/474

* Overall, approximately 50% ol: patients with macular e:dema had clinically significant macul ar edema.

inopathy is so small. Yearly screening of patients newly diagnosed with type II diabetes is recommended because rare cases of treatable diabetic retinopathy have occurred early in the course of type II diabetes. However, the incidence of diabetic retinopathy warranting treatment among patients with type II diabetes in the first 5 years after the diagnosis of diabetes is very low (Table 2). Moreover, this incidence rate is a function of baseline retinal morphology. In the WESDR, only 2 of 474 older-onset patients (regardless of duration of diabetes) with no retinopathy on first examination developed proliferative retinopathy by the time of the 4-year follow-up examination. Similarly, only 5 of 450 olderonset patients with no retinopathy on first examination developed macular edema by the time of the 4-year follow-up examination, and one can assume that only half of these had clinically significant macular edema. 8.5 These data suggest that patients with type II diabetes who do not have diabetic retinopathy on initial screening examination could safely wait 4 years for their next screening examination, with subsequent screening examinations occurring annually. This change from the current recommendations could result in a reduction in the number of screening examinations by approximately 18% among the more than 90% of diabetics who are type II. (Based on data from the WESDR, 43% of all older-onset patients are within 4 years of diagnosis, and about 70% have no retinopathy at the baseline examination.) 8.6 Although the screening strategy reflected in these calculations might be efficient, it cannot currently be implemented on a national scale. Safely lengthening the screening interval depends on the accurate classification of retinopathy status by high-quality stereoscopic fundus photographs. Facilities for doing stereoscopic photography may not be widely available, and the accuracy of this technique in actual practice is untested. Ophthalmoscopy alone is too insensitive to provide a safe basis for less frequent screening. In settings where high-quality fundus stereoscopic photography is unavailable, current recommendations for yearly screening are supportable, assuming that more frequent ophthalmoscopic examinations compensate for their reduced sensitivity. However, the data clearly show that more widespread use of stereoscopic photography could increase the accuracy of screening and allow more efficient strategies. Future research should test such systems for screening. 8.7 Considerations about the details of screening

strategy should not obscure the basic conclusions of the many studies of diabetic retinopathy. Screening and appropriate laser therapy can substantially decrease the incidence of vision loss from diabetic retinopathy. Yet, many patients with diabetes are not being screened (74). Creative approaches may be needed to reach a larger proportion of patients at risk. Recommendations 9.1 Patients with type I diabetes should be screened annually for diabetic retinopathy beginning 5 years after the onset of diabetes. In general, screening is not indicated before puberty. 9.2 Patients with type II diabetes should have an initial screening examination for diabetic retinopathy shortly after the diagnosis of diabetes is made. If dilated ophthalmoscopy is used, then examinations should be repeated yearly. If skilled reading of seven-field stereoscopic photographs is available and the photographs show no diabetic retinopathy at the initial screen, then the next screening examination for diabetic retinopathy does not need to be done for 4 years. Care should be taken that these patients are not lost to follow-up. After this 4-year examination, subsequent screening with stereoscopic photography or dilated ophthalmoscopy should be done annually. Patients with persistently elevated glucose levels (for example, mean plasma glucose level above 280 mg/dL) or proteinuria should have yearly examinations, regardless of screening technique. 9.3 Women with preexisting diabetes who become pregnant should have a comprehensive eye examination in the first trimester and close follow-up throughout pregnancy. This recommendation is not meant to apply to women who develop gestational diabetes. 9.4 Patients with macular edema, advanced nonproliferative retinopathy, or proliferative retinopathy require the prompt care of an ophthalmologist knowledgable and experienced in the management of diabetic retinopathy. Acknowledgments: This study was commissioned by the American College of Physicians. Grant Support: In part by a grant from the Agency for Health Care Policy and Research (1 ROl HS06665). Dr. Singer was supported, in part, by a Henry J. Kaiser Family Foundation Faculty Scholar Award in general internal medicine. Requests for Reprints: Daniel E. Singer, MD, General Internal Medi-

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cine Unit, Bulfinch 1, Massachusetts General Hospital, Boston, MA 02114. 24. Current Author Addresses: Dr. Singer: General Internal Medicine Unit, Bulfinch 1, Massachusetts General Hospital, Boston, MA 02114. Dr. Nathan: Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114. Dr. Fogel: Diabetes Center, New England Sinai Hospital, 150 York Street, Stoughton, MA 02072. Dr. Schachat: The Wilmer Ophthalmological Institute, The Johns Hopkins University and Hospital, Wilmer 200, 600 North Wolfe Street, Baltimore, MD 21205.

References 1. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. National Diabetes Data Group. Diabetes. 1979;28:1039-57. 2. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy: II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol. 1984;102:520-6. 3. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy: III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol. 1984;102:527-32. 4. Klein R, Klein BE, Moss SE. Visual impairment in diabetes. Ophthalmology. 1984;91:1-9. 5. National Society to Prevent Blindness. Vision problems in the United States. New York: National Society to Prevent Blindness; 1980. 6. Singer DE, Samet JH, Coley CM, Nathan DM. Screening for diabetes mellitus. Ann Intern Med. 1988;109:639-49. 7. Frank RN. Etiologic mechanisms in diabetic retinopathy. In: Ryan SJ, ed. Retina, vol. II. St. Louis: CV. Mosby Company; 1989:30126. 8. Krolewski AS, Warram JH, Rand LI, Christlieb AR, Busick EJ, Kahn CR. Risk of proliferative diabetic retinopathy in juvenile-onset type I diabetes: a 40-yr follow-up study. Diabetes Care. 1986;9:44352. 9. Klein R. The epidemiology of diabetic retinopathy: findings from the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Int Ophthalmol Clin. 1987;27:230-8. 10. Pettitt DJ, Knowler WC, Lisse JR, Bennett PH. Development of retinopathy and proteinuria in relation to plasma-glucose concentrations in Pima Indians. Lancet. 1980;2:1050-3. 11. Photocoagulation treatment of proliferative diabetic retinopathy: the second report of diabetic retinopathy study findings. Ophthalmology. 1978;85:82-106. 12. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 1985; 103:1796-806. 13. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy: IV. Diabetic macular edema. Ophthalmology. 1984;91:1464-74. 14. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: IX. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol. 1989;107:237-43. 15. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: X. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is 30 years or more. Arch Ophthalmol. 1989;107:244-9. 16. Klein R, Moss SE, Klein BE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy: XI. The incidence of macular edema. Ophthalmology. 1989;96:1501-10. 17. Dwyer MS, Melton LJ 3d, Ballard DJ, Palumbo PJ, Trautmann JC, Chu CP. Incidence of diabetic retinopathy and blindness: a population-based study in Rochester, Minnesota. Diabetes Care. 1985;8: 316-22. 18. Nelson RG, Wolfe JA, Horton MB, Pettitt DJ, Bennett PH, Knowler WC. Proliferative retinopathy in NIDDM. Incidence and risk factors in Pima Indians. Diabetes. 1989;38:435-40. 19. Haffner SM, Fong D, Stern MP, Pugh J A, Hazuda HP, Patterson JK, et al. Diabetic retinopathy in Mexican Americans and non-Hispanic Whites. Diabetes. 1988;37:878-84. 20. Nathan DM, Singer DE, Godine JE, Harrington CH, Perlmuter LC. Retinopathy in older type II diabetics, association with glucose control. Diabetes. 1986;35:797-801. 21. Howard-Williams J, Hillson RM, Bron A, Awdry P, Mann JI, Hockaday TD. Retinopathy is associated with higher glycaemia in maturity-onset type diabetes. Diabetologia. 1984;27:198-202. 22. Janka HU, Warram JH, Rand LI, Krolewski AS. Risk factors for progression of background retinopathy in long-standing IDDM. Diabetes. 1989;38:460-4. 23. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. Glycosylated 670


of Internal

Medicine

25.

26. 27.

28.

29.

30.

31.

32.

33. 34.

35.

36. 37.

38. 39.

40.

41.

42.

43.

44.

45.

46. 47.

48.

49.

50.

hemoglobin predicts the incidence and progression of diabetic retinopathy. JAMA. 1988;260:2864-71. Knowler WC, Bennett PH, Bailintine EJ. Increased incidence of retinopathy in diabetics with elevated blood pressure. A six-year follow-up study in the Pima Indians. N Engl J Med. 1980;302:64550. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. Is blood pressure a predictor of the incidence or progression of diabetic retinopathy? Arch Intern Med. 1989;149:2427-32. Karma A, Gummerus S, Kujansuu E, Pitkajarvi T. Predicting diabetic retinopathy. Acta Ophthalmol Suppl (Copenh). 1987;182:136-9. Monson JP, Kios G, Toms GC, Kopelman PG, Boucher BJ, Evans SJ, et al. Relationship between retinopathy and glycaemic control in insulin-dependent and non-insulin-dependent diabetes. J Roy Soc Med. 1986;79:274-6. Ballard DJ, Melton LJ 3d, Dwyer MS, Trautmann JC, Chu CP, O'Fallon WM, et al. Risk factors for diabetic retinopathy: a population-based study in Rochester, Minnesota. Diabetes Care. 1986;9: 334-42. Rand LI, Prud'homme GJ, Ederer F, Canner PL. Factors influencing the development of visual loss in advanced diabetic retinopathy. Diabetic Retinopathy Study (DRS) Report No. 10. Invest Ophthalmol Vis Sci. 1985;26:983-91. Ishihara M, Yukimura Y, Aizawa T, Yamada T, Ohto K, Yoshizawa K. High blood pressure as risk factor in diabetic retinopathy development in NIDDM patients. Diabetes Care. 1987;10:20-5. West KM, Erdreich LJ, Stober JA. A detailed study of risk factors for retinopathy and nephropathy in diabetes. Diabetes. 1980;29: 501-8. Hamman RF, Mayer EJ, Moo-Young GA, Hildebrant W, Marshall JA, Baxter J. Prevalence and risk factors of diabetic retinopathy in non-Hispanic whites and Hispanics with NIDDM. San Luis Valley Diabetes Study. Diabetes. 1989;38:1231-7. Paetkau ME, Boyd TA, Winship B, Grace M. Cigarette smoking and diabetic retinopathy. Diabetes Care. 1977;26:46-9. Rand LI, Krolewski AS, Aiello LM, Warram JH, Baker RS, Maki T. Multiple factors in the prediction of risk of proliferative diabetic retinopathy. N Engl J Med. 1985;313:1433-8. Groop LC, Teir H, Koskimies S, Groop PH, Matikainen E, Verkkala E, et al. Risk factors and markers associated with proliferative retinopathy in patients with insulin-dependent diabetes. Diabetes. 1986;35:1397-403. Eye care guidelines for patients with diabetes mellitus. American Diabetes Association. Diabetes Care. 1988;11:745-6. Guidelines for eye care in patients with diabetes mellitus. Results of a symposium. The Kentucky Diabetic Retinopathy Group. Arch Intern Med. 1989;149:769-70. Klein BE, Moss SE, Klein R. Effect of pregnancy on progression of diabetic retinopathy. Diabetes Care. 1990;13:34-40. Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8. The Diabetic Retinopathy Study Research Group. Ophthalmology. 1981;88:583-600. Indications for photocoagulation treatment of diabetic retinopathy: Diabetic Retinopathy Study Report no. 14. The Diabetic Retinopathy Study Research Group. Int Ophthalmol Clin. 1987;27:239-53. Photocoagulation for diabetic maculopathy. A randomized controlled clinical trial using the xenon arc. British Multicentre Study Group. Diabetes. 1983;32:1010-6. Blankenship GW. Diabetic macular edema and argon laser photocoagulation: a prospective randomized study. Ophthalmology. 1979; 86:69-75. Early Treatment Diabetic Retinopathy Study design and baseline patient characteristics. ETDRS report number 7. Ophthalmology. 1991;98:741-56. Effects of aspirin treatment on diabetic retinopathy. ETDRS report number 8. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1991;98:757-65. Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1991;98:766-85. Engerman RL, Kern TS. Is diabetic retinopathy preventable? Int Ophthalmol Clin. 1987;27:225-9. Lauritzen T, Frost-Larsen K, Larsen HW, Deckert T. Effect of 1 year of near-normal blood glucose levels on retinopathy in insulindependent diabetics. Lancet. 1983;1:200-4. Blood glucose control and the evolution of diabetic retinopathy and albuminuria. A preliminary multicenter trial. The Kroc Collaborative Study Group. N Engl J Med. 1984;311:365-72. Brinchmann-Hansen O, Dahl-Jorgensen K, Hanssen KF, Sandvik L. The response of diabetic retinopathy to 41 months of multiple insulin injections, insulin pumps, and conventional insulin therapy. Arch Ophthalmol. 1988;106:1242-6. Color photography vs fluorescein angiography in the detection of diabetic retinopathy in the diabetes control and complications trial.

• V o l u m e 116 • N u m b e r 8


51.

52.

53. 54.

55.

56. 57.

58.

59.

60.

61.

62.

63.

Arch Ophthalmol. The Diabetes Control and Complications Trial Research Group. 1987;105:1344-51. Knatterud GL, Klimt CR, Levin ME, Jacobson ME, Goldner MG. Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. VII. Mortality and selected nonfatal events with insulin treatment. JAMA. 1976;240:37-42. Effect of aspirin alone and aspirin plus dipyridamole in early diabetic retinopathy. A multicenter randomized controlled clinical trial. The DAMAD Study Group. Diabetes. 1989;38:491-8. Diabetic retinopathy study. Report Number 6. Design, methods, and baseline results. Invest Ophthalmol Vis Sci. 1981;21:149-209. Kinyoun J, Barton F, Fisher M, Hubbard L, Aiello L, Ferris F 3d. Detection of diabetic macular edema. Ophthalmoscopy versus photography—Early Treatment Diabetic Retinopathy Study Report Number 5. The ETDRS Study Group. Ophthalmology. 1989;96:74651. Moss SE, Klein R, Kessler SD, Richie KA. Comparison between ophthalmoscopy and fundus photography in determining severity of diabetic retinopathy. Ophthalmology. 1985;92:62-7. Sussman EJ, Tsiaris WG, Soper KA. Diagnosis of diabetic eye disease. JAMA. 1982;247:3231-4. Klein R, Klein BE, Neider MW, Hubbard LD, Meuer SM, Brothers RJ. Diabetic retinopathy as detected using ophthalmoscopy, a nonmydriatic camera and a standard fundus camera. Ophthalmology. 1985;92:485-91. Forrest RD, Jackson CA, Yudkin JS. Screening for diabetic retinopathy—comparison of a nurse and a doctor with retinal photography. Diabetes Res. 1987;5:39-42. Jones D, Dolben J, Owens DR, Vora J P , Young S, Creagh FM. Non-mydriatic Polaroid photography in screening for diabetic retinopathy: evaluation in a clinical setting. Br Med J (Clin Res Ed). 1988;296:1029-30. Velez R, Haffner S, Stern MP, Van Heuven WA. Ophthalmologist versus retinal photographs in screening for diabetic retinopathy [Abstract]. Clin Res. 1987;35:363A. Williams R, Nussey S, Humphry R, Thompson G. Assessment of non-mydriatic fundus photography in detection of diabetic retinopathy. Br Med J (Clin Res Ed). 1986;293:1140-2. Barrie T, MacCuish AC. Assessment of non-mydriatic fundus photography in detection of diabetic retinopathy [Letter]. Br Med J (Clin Res Ed). 1986;293:1304-5. Klenistein RN, Roseman JM, Herman WH, Holcombe J, Louv WC.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.


Detection of diabetic retinopathy by optometrists. J Am Optom Assoc. 1987;58:879-82. Nathan DM, Fogel HA, Godine JE, Lou PL, D'Amico DJ, Regan CD, et al. Role of diabetologist in evaluating diabetic retinopathy. Diabetes Care. 1991;14:26-33. Foulds WS, McCuish A, Barrie T, Green F, Scobie IN, Ghafour IM, et al. Diabetic retinopathy in the West of Scotland: its detection and prevalence, and the cost-effectiveness of a proposed screening. Health Bull (Edinb). 1983;41:318-26. Savolainen EA, Lee QP. Diabetic retinopathy—need and demand for photocoagulation and its cost-effectiveness: evaluation based on services in the United Kingdom. Diabetologia. 1982;23:138-40. Javitt JC, Canner JK, Sommer A. Cost effectiveness of current approaches to the control of retinopathy in type I diabetics. Ophthalmology. 1989;96:255-64. Javitt JC, Canner JK, Frank RG, Steinwachs DM, Sommer A. Detecting and treating retinopathy in patients with type I diabetes mellitus. A health policy model. Ophthalmology. 1990;97:483-95. Dasbach EJ, Fryback DG, Newcomb PA, Klein R, Klein BE. Costeffectiveness of strategies for detecting diabetic retinopathy. Med Care. 1991;29:20-39. National Diabetes Advisory Board. The prevention and treatment of five complications of diabetes: a guide for primary care practitioners. Atlanta, Georgia: Centers for Disease Control; 1983:3-8. Available from the Division of Diabetes Control, Center for Prevention Services, Centers for Disease Control, Atlanta, Georgia. Board of Trustees, American Optometric Association. Information on the care of diabetic patients: guidelines for the optometric care of diabetic patients in the Centers for Disease Control (CDC) Programs. St. Louis: American Optometric Association; 1987. Available from the American Optometric Association, 243 North Lindbergh Boulevard, St. Louis, MO 63141. American Academy of Ophthalmology. Quality of Care Committee. Retina Panel. Diabetic Retinopathy: Preferred Practice Pattern. San Francisco, California: American Academy of Ophthalmology; 1989. Available from the American Academy of Ophthalmology. American Academy of Ophthalmology. Quality of Care Committee. Comprehensive Adult Eye evaluation. San Francisco: American Academy of Ophthalmology; 1989. Available from the American Academy of Ophthalmology. Witkin SR, Klein R. Ophthalmologic care for persons with diabetes. JAMA. 1984;251:2534-7.

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Screening for diabetic retinopathy.

Diabetic retinopathy screening service.

Retinal Imaging Techniques for Diabetic Retinopathy Screening.

Screening for diabetic retinopathy by general practitioners.

Screening Intervals for Diabetic Retinopathy and Implications for Care.

The Scottish Diabetic Retinopathy Screening programme.

Nonmydriatic fundus photography in screening for treatable diabetic retinopathy.

Validation of Smartphone Based Retinal Photography for Diabetic Retinopathy Screening.

Current and Next Generation Portable Screening Devices for Diabetic Retinopathy.

Cost-effectiveness of alternative methods for diabetic retinopathy screening.

The Need for Diabetic Retinopathy Screening in Low-Resource Settings.

The Diabetic Retinopathy Screening Workflow: Potential for Smartphone Imaging.

Screening for diabetic retinopathy using non-mydriatic fundus photography.

Detection of Glaucoma and Its Association With Diabetic Retinopathy in a Diabetic Retinopathy Screening Program.

Photocoagulation for diabetic retinopathy.

Diabetic retinopathy screening and the use of telemedicine.

Factors determining uptake of diabetic retinopathy screening in Oxfordshire.

Cost-effectiveness of Different Diabetic Retinopathy Screening Modalities.

Telemedicine and Diabetic Retinopathy: Review of Published Screening Programs.

Diabetic Retinopathy Screening Using Telemedicine Tools: Pilot Study in Hungary.

Full-field ERG in diabetic retinopathy: a screening tool?

Fully automated diabetic retinopathy screening using morphological component analysis.

Cost of a community-based diabetic retinopathy screening program.

Improving patient compliance with diabetic retinopathy screening and treatment.