Epidemiology pf Proliferative Diabetic Retinopathy RONALD KLEIN, MD, MPH BARBARA E.K. KLEIN, MD, MPH SCOT E. MOSS, MA

OBJECTIVE — This review examines recent epidemiological data about the prevalence and incidence of and risk factors for proliferative diabetic retinopathy. In addition, the relation of proliferative retinopathy to other systemic complications associated with diabetes is reviewed. RESEARCH DESIGN AND METHODS— The data come mostly from the baseline and 4-yr follow-up examinations of a large population-based study, the WESDR, which involved 996 younger-onset insulin-dependent people whose diabetes was diagnosed at erc

sured by direct ophthalmoscopy) in black Jamaicans with NIDDM compared with whites with NIDDM in a clinical series study. Too few of the participants had proliferative retinopathy to permit comparisons between the races.

10

RETINOPATHY PREVALENCE 4-YR INCIDENCE

43(0) 43(0)

86 (3.5) 83 (8.4)

Confined to 129 women who were 80 yr of age (Table 2).

Duration of diabetes Proliferative retinopathy is strongly related to the duration of diabetes (Fig. 1). In the WESDR, proliferative retinopathy was not found in any younger-onset participant with 14.2%) with those in the lowest (0.3

NM

NOT OBESE OBESE*

34 17

9 Ot

* Obese defined as BMI >27.8 kg/m2 for men and >27.3 kg/m2 for women. tPrevalence is 0.5%.

were taking insulin and had detectable C-peptide. In older-onset individuals who did not take insulin, after controlling for factors associated with proliferative diabetic retinopathy (GHb, blood pressure, and duration of diabetes) and factors associated with plasma C-peptide, plasma C-peptide was not associated with the frequency of diabetic retinopathy. This finding suggests that the level of glycemia and not the level of endogenous C-peptide is more important in determining the presence of retinopathy in individuals with NIDDM. One study has suggested exogenous insulin as a possible cause of retinopathy in obese NIDDM patients (67). No association was found between the amount or type of exogenous insulin used and the severity of diabetic retinopathy in the WESDR older-onset group that took insulin and had C-peptide levels >0.3 nM (66). These data, although

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cross-sectional, suggest that exogenous insulin itself is not causally related to diabetic retinopathy in diabetic people with normal C-peptide.

Blood pressure Studies of the relationship of high blood pressure to the development of proliferative retinopathy have not produced uniform findings (7,20,46,68-80). In the WESDR, at baseline, higher blood pressure was strongly associated with the prevalence of proliferative retinopathy in people with diabetes (7,8). Baseline systolic and diastolic blood pressures were significantly associated with an increasing 4-yr incidence of proliferative retinopathy in the younger-onset group only (Table 6) (80). However, the relationship between blood pressure and incidence of proliferative retinopathy disappeared after controlling for GHb and the level of retinopathy at the time of the baseline examination. No relationship was found in either older-onset group (Table 6). Other studies have suggested that uncontrolled blood pressure in people with a history of hypertension may be an important risk factor for the development of proliferative retinopathy in people with NIDDM (46,75). After controlling for use of antihypertensive medications and GHb level, no relationship was found between blood pressure level and the incidence of proliferative retinopathy in the WESDR older-onset groups (80). One possible reason for failure to find a relationship between blood pressure and the development of proliferative retinopathy may be selective mortality: those individuals with higher blood pressure who developed proliferative retinopathy may have died before their reexamination (81). Another possible reason—in the WESDR—could be misclassification: if blood pressure measured at the baseline examination was not a good surrogate for usual daytime ambulatory blood pressure. Alternatively, high blood pressure may not be related to the development of proliferative retinop-

athy in older-onset individuals. Regardless of whether blood pressure causes the progression of diabetic retinopathy, hypertension control is important in people with diabetes. Elevated blood pressure has been shown to be a significant cause of cardiovascular disease (82,83) and stroke (84,85) and may accelerate renal disease in diabetic patients (86,87).

Cigarette smoking Although data from a few studies suggest a positive relationship between cigarette smoking and diabetic retinopathy (88,89), most epidemiological studies have failed to confirm this relationship (19,74,90-94). In the WESDR, cigarette smoking was not related to prevalence or incidence of proliferative retinopathy (Table 7) (93.94). In the WESDR, after controlling for other risk factors, younger-onset people who smoked were 2.4 times and older-onset people were 1.6 times as likely to die than those who did not smoke (81). As with high blood pressure, diabetic people should be encouraged to refrain from smoking, as it is an important risk factor for cardiovascular disease, respiratory disease, and cancer (95,96).

Alcohol To date, few studies have addressed the relationship of alcohol to the development of proliferative retinopathy (97, 98). Data from one study suggested that increased alcohol consumption elevated the risk for developing proliferative retinopathy (97), whereas data from another study suggested it might have a beneficial effect (98). At the WESDR follow-up examination in 1984-1986, a negative relationship was found between alcohol consumption and the presence of proliferative retinopathy in the younger-onset group. This finding may have resulted if diabetic persons who developed proliferative retinopathy reduced their alcohol consumption or stopped drinking entirely after they developed the complication. No relationship was found in the

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Table 6—Four-year incidence of proliferative retinopathy by quartile of systolic and diastolic blood pressure for younger- and older-onset groups with no or nonproliferative retinopathy at baseline in the WESDR (1980-1982) DEVELOPED N AT

PROLIFERATIVE

RELATIVE

RISK

RETINOPATHY ( % )

RISK

95% Cl

200 216 100

5.0 11.1 10.9 18.0

1.0 2.2 2.2 3.6

1.1-4.5 1.1-4.5 1.7-7.5

207 189 170 140

2.9 11.6 10.0 20.0

1.0 4.0 3.4 6.9

1.7-9.7 1.4-8.6 2.9-16.2

109 114 114 80

5.5 3.5 9.6 11.2

1.0 0.6 1.7 2.0

0.2-2.2 0.7-4.6 0.8-5.5

88 111 112 106

4.5 7.2 8.0 8.5

1.0 1.6 1.8 1.9

0.5-5.2 0.6-5.6 0.6-6.0

132 137 105

1.5 3.6 0.9 2.9

1.0 2.4 0.6 1.9

0.5-12.3 0.1-6.6 0.3-11.4

116 124 119 123

2.6 0.8 2.5 3.3

1.0 0.3 1.0 1.3

0.0-2.9 0.2-4.7 0.3-5.5

YOUNGER-ONSET GROUP SYSTOLIC BLOOD PRESSURE (MMHG) QUARTILE

1ST (78-110) 2ND (111-120) 3RD (121-134) 4TH (135-221)

192

—

DIASTOLIC BLOOD PRESSURE (MMHG) QUARTILE

1ST (42-71) 2ND (72-78) 3RD (79-85) 4TH (86-117)

—

OLDER-ONSET GROUP TAKING INSULIN SYSTOLIC BLOOD PRESSURE (MMHG) QUARTILE

1ST (80-128) 2ND (129-144) 3RD (145-160) 4TH (161-263)

—

high school and college and history of laser treatment or blindness in people with 1DDM (99). In the WESDR, no relationship was found between physical activity or energy expenditure and the prevalence of proliferative retinopathy (100). However, it is difficult to examine this relationship in cross-sectional data, because the physical activity may decrease after proliferative retinopathy appears. Few data are available on the risk of vitreous hemorrhage caused by physical activity in people with proliferative retinopathy (101). Anderson (101) failed to find a relationship between specific physical activities and subsequent hemorrhage in patients with proliferative disease. He reported on 72 consecutive patients presenting with 95 episodes of vitreous hemorrhage; only 5 episodes were related by history to strenuous physical activity or to a Valsalva maneuver. Most of the vitreous hemorrhages occurred at rest or were noted on awakening.

DIASTOLIC BLOOD PRESSURE (MMHG) QUARTILE

1ST (45-69) 2ND (70-77) 3RD (78-86) 4TH (87-129)

—

OLDER-ONSET GROUP NOT TAKING 1NSUUN SYSTOLIC BLOOD PRESSURE (MMHG) QUARTILE

1ST (94-132) 2ND (133-145) 3RD (146-161) 4TH (162-236)

111

—

DIASTOLIC BLOOD PRESSURE (MMHG) QUARTILE

1ST (47-72) 2ND (73-79) 3RD (80-87) 4TH (88-121)

older-onset group, suggesting that alcohol consumption does not increase the risk of proliferative retinopathy (S.E.M., R.K., B.E.K.K., unpublished observations). Incidence data are needed to further evaluate this relationship.

—

Physical activity Few data are available that deal with the relationship between leisure time physical activity and proliferative retinopathy. One study suggested no relationship between participating in team sports in

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Proteinuria Diabetic nephropathy is strongly associated with the presence of proliferative retinopathy (102,103). People with microalbuminuria or macroalbuminuria have increased prevalences of proliferative retinopathy (Table 8) (103,104). In the WESDR, the presence of gross proteinuria (defined as >0.30 g/L) at baseline was related to an increased risk for development of proliferative retinopathy in the two insulin-taking diabetic groups 4 yr later (Fig. 2). However, this relationship was not significant after controlling for other risk factors. Oral contraceptives In the WESDR, the use of oral contraceptives by women with IDDM was not associated with the presence of proliferative retinopathy (105). Use of birth control pills was not related to increased GHb or blood pressure. These data suggest that with regard to retinopathy, oral contraceptives, if not otherwise contrain-

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Proliferative diabetic retinopathy

Table 7—Four-year incidence of proliferative retinopathy by smoking status and by pack-yr smoked while having diabetes in the WESDR DEVELOPED PROLIFERATIVE

RELATIVE

SIGNIFICANCE

N AT RISK

RETINOPATHY (%)

RISK

(P VALUE)*

298 79 153

12.4 12.7 13.1

1.0 1.0 1.1

0.84

312 94 124

12.2 10.6 15.3

1.0 0.9 1.3

0.31

219 134 65

6.4 9.0 7.7

1.0 1.4 1.2

0.54

287 49 82

5.2 8.2 14.6

1.0 1.6 2.8

0.03 g/L. tGross proteinuria defined as ^0.3 g/L

retinopathy had 20/40 or worse visual acuity, and 34% had 20/200 or worse acuity. The loss of vision was attributable in part to the direct effects of proliferative retinopathy (vitreous hemorrhage or tractional detachment of the macula). In addition, a high proportion of eyes with proliferative retinopathy have macular edema—47, 65, and 30%, respectively, in the younger-onset, older-onset group taking insulin, and older-onset group not taking insulin (117). The presence of proliferative diabetic retinopathy at baseline in the WESDR was associated with a significant 4-yr incidence of vision loss (Fig. 3) (2). Despite the availability of panretinal photocoagulation, the younger-onset participants with proliferative retinopathy with DRS-HRC for severe vision loss

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were 40 times as likely (23.8 vs. 0.6%) to become blind over the 4-yr period, compared with participants whose eyes had retinal microaneurysms only.

In the few studies that have reported on diabetic neuropathy and retinopathy, most have demonstrated an association of peripheral or autonomic neuropathy with retinopathy in people with diabetes (119-122). Preliminary results from the 10-yr follow-up examination of diabetic patients in the WESDR suggest that patients with proliferative diabetic retinopathy have a significantly higher fre-

25-

NCIDENCE (%)

20-

Diabetic nephropathy Proliferative disease is strongly associated with the presence of diabetic nephropathy. In the WESDR, youngeronset people with IDDM for > 10 yr and proliferative retinopathy were 3.5 times more likely to have diabetic nephropathy (102). These findings have important implications for managing patients with diabetes. It suggests that once proliferative retinopathy is present, a careful evaluation for the presence of diabetic nephropathy is indicated. Once end-stage renal disease develops—which requires dialysis or trans-

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161050-

YO

ii

I.I

OO-I

PROTEINURIA [ _ ) ABSENT

K l PRESENT

Figure 2—The 4-yr incidence of proliferative retinopathy by absence and presence of gross proteinuria at baseline examination in the younger-onset group (YO), the older-onset group that takes insulin (OO-l), and the older-onset group that does not take insulin (OO-N1) in the WESDR.

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Proliferative diabetic retinopaihy

quency of impotency (31%) compared with those without proliferative retinopathy (10%) (R.K, B.E.KK, S.E.M., unpublished observations).

601

40"

Macrovascular disease After controlling for age, proliferative retinopathy was associated with the presence and incidence of amputation, myocardial infarction, or stroke in the younger-onset group in the WESDR (Table 9). These relationships are not surprising in view of the association of proliferative retinopathy with high blood pressure and diabetic nephropathy (7,8). The relationship between proliferative retinopathy and cardiovascular disease may be attributable to abnormalities in the lipid profiles in diabetic patients (123-128). In one study, Kostraba et al. (125) found a significant association between serum HDL-cholesterol, fibrinogen, and triglyceride levels with proliferative retinopathy in people with IDDM who were >30 yr of age. The relationship of these cardiovascular disease risk factors to proliferative retinopathy was explained in part by the presence of diabetic nephropathy. The presence of proliferative retinopathy should alert the physician to the need for assessment and possible treatment of risk factors to prevent the development or progression of cardiovascular disease.

20"

1.5-2

3

4-5

6

7

RETINOPATHY, OD 601

40"

20"

1.5-2

3

4-5

6

7

RETINOPATHY, OD

601

40"

20"

Recent results from the ETDRS suggest that when aspirin has been indiRETINOPATHY, OD cated for prevention of stroke or myoFigure 3—The 4-yr rate of doubling of the visual cardial infarction, it does not increase the angle (for example, going from a visual acuity of risk of vitreous hemorrhage or vision loss 20/20 to 20/40 or from 20/30 to 20/60) by retinop- in people with proliferative retinopathy athy severity level at baseline in three groups: A, (129). However, aspirin was not found younger-onset; B, older-onset taking insulin; C, oldto prevent the progression to proliferaer-onset not taking insulin) who participated in the WESDR. I, none; 1.5-2, retinalmicroanewysms or tive retinopathy. blot hemorrhages only; 3, retinal microanewysms with hard exudates and/or small blot hemorrhages; MORTALITY— In the WESDR, the 4-5, retinal microanewysms with intraretinal mi- presence of proliferative retinopathy was crovascular abnormalities and/or cotton wool spots associated with decreased survival over a and/or venous beading and/or large blot hemor- 6-yr period in both younger- and olderrhages; 6, proliferative retinopathy without DR5onset groups (Figs. 4 and 5) (81). This HRCfor severe vision loss; 7, proliferative retinopalso has been reported by other researchathy with DRS-HRC for severe vision loss; 8, ers (130). However, after controlling for proliferative retinopathy that has caused severe viage and sex, younger-onset participants sion loss. From Klein and Moss (159). © Wiley. 1.5-2

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3

4-5

6-8

1

2

3

4

5

6

7

YEARS FROM EXAMINATION

Figure 4—Age- and sex-adjusted survival curves by diabetic retinopathy status at baseline examination in younger-onset participants in the WESDR (1980-1987). From Klein et al. (81). © Arch Intern Med.

with proliferative retinopathy at the baseline examination had a 6-yr survival rate of 66.2% compared with 95.9% in those with no retinopathy; for olderonset participants, the rates were 31.8 and 61.3%, respectively. However, after controlling for other factors associated with decreased survival, such as age at examination, sex, presence of proteinuria, smoking history, and GHb, the relationship between the presence of proliferative retinopathy and decreased survival was significant in the olderonset group, but not the younger-onset group. These data suggest that diabetic patients with proliferative retinopathy should be examined frequently by their primary care physicians to detect early renal disease, elevated blood pressure, or

1

2

3

4

5

6

7

YEARS FROM EXAMINATION

Figure 5—Age- and sex-adjusted survival curves by diabetic retinopathy status at baseline examination in older-onset individuals in the WESDR (1980-1987). From Klein et al. (81). © Arch Intern Med.

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Table 9—Relative risk for the prevalence and 4-yr incidence of myocardial infarction, stroke, and amputation of lower extremities associated with the presence of proliferative retinopathy, corrected for age, in the WESDR

this may be the result of several physician and patient factors that have been summarized previously (Table 10) (4,5,134-142). MYOCARDIAL AMPUTATION OF Numerous guidelines for the deSTROKE LOWER EXTREMITY INFARCTION tection and management of eye disease have been developed and distributed RELATIVE RELATIVE RELATIVE (4,143). However, these guidelines may RISK RISK RISK 95% CI 95% CI 95% CI not be used for their intended purpose. YOUNGER-ONSET GROUP In 1984, the Michigan Department of PREVALENCE 0.7-9.7 7.1 3.5 1.5-7.9 2.6 2.6-19.7 Health developed and distributed diaINCIDENCE 1.3-15.4 0.4-5.7 6.0 4.5 2.1-16.9 1.6 betic retinopathy referral guidelines for OLDER-ONSET GROUP health-care providers in that state (144). TAKING INSULIN One year later, a survey found that many PREVALENCE 1.2 4.2 0.8 0.4-1.4 0.6-2.4 2.3-7.9 INCIDENCE 3.4 0.5-3.4 1.2-6.8 0.9-13.2 health care providers who received the 2.9 1.2 guidelines had not read them. Only 26% OLDER-ONSET GROUP NOT TAKING INSULIN of diabetic patients of the health care PREVALENCE 5.2 0-2.4 2.9 0.9-9.4 0.6-45.0 professionals surveyed reported that they 0.3 INCIDENCE 7.0 0.2-12.5 0.8-64.4 had been given the complete recommen6.0 1.5 1.1-32.6 dations for eye care outlined in the guidelines. One suggested intervention cardiovascular disease, because it may be vere proliferative retinopathy with panstrategy to reduce blindness is to screen possible to intervene and minimize their retinal photocoagulation (1). However, people with diabetes who are not cureffects. in the WESDR, we found that 37% of rently receiving eye care (4). Data from younger-onset individuals and 50% of SOCIOECONOMIC cost-effectiveness studies byjavitt et al. older-onset individuals with proliferative RELATIONSHIPS— Occupational retinopathy had not seen an ophthalmol- (145, 146) and Dasbach et al. (147) sugstatus has been reported to be related to ogist within 2 yr of the examination (3). gest that earlier detection of proliferative the severity of retinopathy in people with In addition, 51% of those whose eyes retinopathy by screening with various diabetes (77,131). Hanna et al. (77) re- had proliferative retinopathy with DRS- strategies is a cost-effective approach for ported a significant association between HRC had not been treated with panreti- people who require insulin. In the study proliferative retinopathy and occupa- nal photocoagulation (132). Little by Dasbach et al. (147), the cost of tional status (working class) in a study in change was noted when the cohort was screening programs for high-risk prolifCanada. reexamined 4 yr later (133). Similar find- erative retinopathy generally was not reAt the baseline WESDR examina- ings have been reported by others, and covered by avoiding costs of blindness in tion, the presence of proliferative retinopathy was significantly related to higher rates of earlier retirement because of disability in adult younger-onset per- Table 10—Physician and patient factors associated with not receiving ophthalmologic sons and in older-onset diabetic men. care Younger-onset men with proliferative PHYSICIAN FACTORS retinopathy who were holding a full-time LACK OF KNOWLEDGE ABOUT BENEFITS OF PHOTOCOAGULATION TREATMENT (134) job at the time of the baseline examinaPOOR OPHTHALMOSCOPY SKILLS (135) tion had a significantly lower rate of fullO P H T H A L M O S C O P Y THROUGH AN UND1LATED PUPIL ( 1 3 6 ) time employment and a higher rate of N O OR INADEQUATE REFERRAL TO OPHTHALMOLOGISTS ( 1 3 7 ) disability or unemployment at the 4-yr PATIENT FACTORS follow-up examination compared with VISION-THREATENING RETINOPATHY MAY BE ASYMPTOMATIC (138) LACK OF KNOWLEDGE ABOUT BENEFITS OF TIMELY DETECTION BY DILATED EYE EXAMINATION AND men without proliferative disease (28.8 TREATMENT WITH PHOTOCOAGULATION ( 1 3 9 ) vs. 8.8%). LACK OF MOTIVATION, OR DENIAL

Detection and management The DRS demonstrated the benefits of timely detection and treatment of se-

INABILITY TO AFFORD OPHTHALMOLOGICAL CARE (5,140) UNAVAILABLE OR INACCESSIBLE OPHTHALMOLOGICAL CARE (141,143) T O O BUSY TO GO FOR OPHTHALMOLOGICAL CARE ( 1 3 9 )

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Proliferatixe diabetic retinopathy

the older-onset population subgroup that did not take insulin (147). Recently, newer strategies, adapted in part from previously successful blood pressure and cancer education programs, have been developed by the National Eye Health Education Program under the auspices of the National Eye Institute (148). The primary aim of this program, which is largely directed at diabetic patients, is to educate people regarding the need for eye care. It is hoped that spreading information will lead to a change in behavior regarding the seeking of eye care and to an increase in the number of patients who, although at risk for vision loss, are treated in a timely fashion with photocoagulation. In addition, other public (e.g., the Centers for Disease Control) and professional organizations (e.g., the American Academy of Ophthalmology Diabetes 2000) also have developed programs designed to reduce blindness resulting from diabetic retinopathy (149,150). Although these programs offer great promise, new solutions will be needed to solve one most important reason that patients fail to seek care—the inability to pay for such care. In some studies, this has been found to be the most important reason for patients' not seeing an ophthalmologist (5,140). This is a complex social and political problem, as well as a medical one.

Psychosocial factors and rehabilitation Rehabilitation of patients with severe visual impairment caused by proliferative diabetic retinopathy is an important area of care that often is neglected. The visually impaired insulin-taking diabetic person is confronted with difficulties in determining of the amount of insulin in the vial, measuring the dose, identifying the type of insulin, and locating the injection sites (151). In addition, these patients are responsible for monitoring glucose levels with blood-test strips. Besides vision loss, as discussed above, these patients often are extremely ill with neuropathy,

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amputations, and cardiovascular and renal disease. Often they are without adequate financial support. Loss of jobs, the inability to control their lives, and concern about being burdensome to others can lead to guilt, anger, anxiety, loss of self-esteem, and difficulties in social adjustment (152-157). Unfortunately, such patients do not always have access to support systems. In one study, only 51.2% of diabetic people interviewed (none of whom were as yet legally blind) were found to have an adequate support system (153). It is for these reasons that successful rehabilitation must involve a team approach, consisting of psychologists, orientation and mobility instructors, social workers, and rehabilitation teachers, who are aware of the numerous, but specific, problems faced by people with diabetes who are visually impaired. Helping the diabetic patient accept vision loss is probably the most important step in planning living arrangements and in developing coping strategies (155,157).

Acknowledgments—This work was supported by National Eye Institute Grant EY03083 (R.K.). We are grateful to Drs. Karen J. Cruickshanks, Matthew D. Davis, David L. DeMets, and Polly Newcomb for collaboration, consultation, and criticism. We thank Colleen Comeau and Luann Dohm for providing secretarial assistance.

References 1. Diabetic Retinopathy Study Group: Photocoagulation treatment of proliferative diabetic retinopathy: clinical application of Diabetic Retinopathy Study (DRS) findings. DRS Report No. 8. Ophthalmology 88:583-600, 1981 2. Moss SE, Klein R, Klein BEK The incidence of vision loss in a diabetic population. Ophthalmology 95:1340-48, 1988 3. Witkin SR, Klein R: Ophthalmologic care for persons with diabetes. JAMA 251:2534-37, 1984

4. Klein R, Moss SE, Klein BEK: New management concepts for timely diagnosis of diabetic retinopathy treatable by photocoagulation. Diabetes Care 10: 633-38, 1987 5. SprafkaJM, Fritsche TL, Baker R, Kurth D, Wipple D: Prevalence of undiagnosed eye disease in high risk diabetic individuals. Arch Intern Med 150:85761, 1990 6. Klein R, Klein BEK, Moss SE, DeMets DL, Kaufman I, Voss PS: Prevalence of diabetes mellitus in southern Wisconsin. Am J Epidemiol 119:54-61, 1984 7. Klein R, Klein BEK, 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 102:520-26, 1984 8. Klein R, Klein BEK, 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 102:52732, 1984 9. Klein R, Klein BEK, Moss SE, Davis MD, DeMets DL: The Wisconsin Epidemiologic Study of Diabetic Retinopathy. DC Four-year incidence and progression of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol 107:237-43, 1989 10. Klein R, Klein BEK, 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 107:244-49, 1989 11. Early Treatment Diabetic Retinopathy Study (ETDRS). Manual of Operations. Baltimore: ETDRS Coordinating Center, Department of Epidemiology and Preventive Medicine, University of Maryland, 1985; Chapter 12. Department of Commerce: Accession #PB85223006/AS. Springfield, VA, National Technical Information Service 12. Klein BEK, Davis MD, Segal P, LongJA, Harris A, Haug GA, Magli YL, Syrjala S: Diabetic retinopathy: assessment of se-

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verity and progression. Ophthalmology 91:10-17, 1984 13. Klein R, Klein BEK, Magli YL, Brothers RJ, Meuer SM, Moss SE, Davis MD: An alternative method of grading diabetic retinopathy. Ophthalmology 93:118387, 1986^ 14. Early Treatment Diabetic Retinopathy Study Research Group: Grading diabetic retinopathy from stereoscopic color fundus photographs: an extension of the modified Airlie House Classification. ETDRS Report No. 10. Ophthalmology 98:786-806, 1991 15. Haffher SM, Fong D, Stern MP, Pugh JA, Hazuda HP, Patterson JK, van Heuven WAJ, Klein R: Diabetic retinopathy in Mexican Americans and non-Hispanic whites. Diabetes 37:878-84, 1988 16. Hafiher SM, Mitchell BD, Moss SE, Stem MP, Hazuda HP, Patterson J, van Heuven WAJ, Klein R: Is there an ethnic difference in the effects of risk factors for diabetic retinopathy? Ann Epidemiol. In press 17. Hamman RF, Franklin GA, Mayer EJ, Marshall SM, Marshall JA, Baxter J, Kahn LB: Microvascular complications of NIDDM in Hispanics and nonHispanic whites. San Luis Valley Diabetes Study. Diabetes Care 14 (Suppl. 3): 655-64, 1991 18. Nelson RG, Wolder JA, Horton MB, Pettitt DJ, Bennett PH, Knowler WC: Proliferative retinopathy in NIDDM: incidence and risk factors in Pima Indians. Diabetes 38:435-40, 1989 19. Rabb MF, Gagliano DA, Sweeny NE: Diabetic retinopathy in blacks. Diabetes Care 13:1202-206, 1990 20. Cruickshank JK, Alleyne SA: Black West Indian and matched white diabetics in Britain compared with diabetics in Jamaica: body mass, blood pressure, and vascular disease. Diabetes Care 10: 170-79, 1987 21. Barbosa J, Ramsay RC, Knobloch WH, Cantrill HL, Noreen H, King R, Yunis E: Histocompatibility antigen frequencies in diabetic retinopathy. Am J Ophthalmol 90:148-53, 1980 22. Dornan TL, Ting A, McPherson CK, Peckar CO, Mann JI, Turner RC, Morris

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PJ: Genetic susceptibility to the development of retinopathy in insulindependent diabetics. Diabetes 31:22631, 1982 23. 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 113:1433-38, 1985 24. Jervell J, Solheim B: HLA-antigens in long standing insulin dependent diabetics with terminal nephropathy and retinopathy with and without loss of vision. Diabetologia 17:391, 1979 25. Cruickshanks Kf, Vadheim CM, Moss SE, Roth MP, Riley WJ, Maclaren NK, Langfield D, Sparkes RS, Klein R, Rotter JI: Genetic marker associations with proliferative retinopathy in persons diagnosed with diabetes prior to 30 years of age. Diabetes 41:879-85, 1992 26. Knowles HC Jr, Guest GM, Lampe J, Kessler M, Skillman TG: The course of juvenile diabetes treated with unmeasured diet. Diabetes 14:239-73, 1965 27. Frank RN, Hoffman WH, Podgor MJ, Joondeph HC, Lewis RA, Margherio RR, Nachazel DPJr, Weiss H, Christophersen KW, Cronin MA: Retinopathy in juvenile-onset type I diabetes of short duration. Diabetes 31:874-82, 1982 28. Palmberg P, Smith M, Waltman S, Krupin T, Singer P, Burgess D, Wendtland T, Achtenberg J, Cryer P, Santiago J, White N, Kilo C, Daughaday W: The natural history of retinopathy in insulin-dependent juvenile-onset diabetes. Ophthalmology 88:613-18, 1981 29. Klein R, Klein BEK, Moss SE, Davis MD, DeMets DL: Retinopathy in youngonset diabetic patients. Diabetes Care 8:311-15, 1985 30. Klein BEK, Moss SE, Klein R: Is menarche associated with diabetic retinopathy? Diabetes Care 13:1034-38, 1990 31. Murphy RP, Nanda M, Plotnick L, Enger C, Vitale S, Patz A: The relationship of puberty to diabetic retinopathy. Arch Ophthalmol 108:215-18, 1990 32. Kostraba JN, Dorman JS, Orchard TJ, Becker DJ, Ohki Y, Ellis D, Doft BH, Lobes LA, LaPorte RE, Drash AL: Contribution of diabetes duration before

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puberty to development of microvascular complications in IDDM subjects. Diabetes Care 12:686-93, 1989 33. Peters GFFM, Smals AGH, Kloppenborg PWC: Defective suppression of growth hormone after glucose loading in adolescence. J Clin Endocrinol Metab

51:265-70, 1980 34. Dills DG, Moss SE, Klein R, Klein BEK, Davis M: Is insulinlike growth factor I associated with diabetic retinopathy? Diabetes 39:191-95, 1990 35. Blethen SL, Sargeant DT, Whitlow MG, Santiago JV: Effect of pubertal stage and recent blood glucose control on plasma somatomedin C in children with insulin-dependent diabetes mellitus. Diabetes 30:868-72, 1981 36. Klein R, Klein BEK, Moss SE, Shrago ES, Spennetta TL: Glycosylated hemoglobin in a population-based study of diabetes. Am] Epidemiol 126:415-28, 1987 37. Klein R, Klein BEK, Moss SE, DeMets DL: Blood pressure and hypertension in diabetes. Am J Epidemiol 122:75-89, 1985 38. Sizonenko P: Endocrinology in preadolescents and adolescents. I. Hormonal changes during normal puberty. Am J Dis Child 132:704-12, 1978 39. Haffner SM, Klein R, Dunn JF, Moss SE, Klein BEK: Increased testosterone in type I diabetic subjects with severe retinopathy. Ophthalmology 97:1270-74, 1990 40. Engerman RL, Bloodworth JMB, Nelson SL: Relationship of microvascular disease in diabetes to metabolic control. Diabetes 26:760-69, 1977 41. Engerman RL, Kern TS: Progression of incipient diabetic retinopathy during good glycemic control. Diabetes 36: 808-12,1987 42. Doft BH, Kingsley LA, Orchard TJ, Kuller L, Drash A, Becker D: The association between long-term diabetic control and early retinopathy. Ophthalmology 91:763-69, 1984 43. Howard-Williams J, Hillson RM, Bron A, Audry P, Mann JI, Hockaday TDR: Retinopathy is associated with higher glycemia in maturity-onset type diabetes. Diabetologia 27:198-202, 1984

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44. Nathan DM, Singer DE, Godine JE, Hodgson-Harrington C, Perlmutter C: Retinopathy in older-onset type II diabetics: association with glucose control. Diabetes 35:797-801, 1986 45. Krolewski AS, Warram JH, Rand LI, Christlieb AR, Busick EJ, Kahn CR: Risk of proliferative diabetic retinopathy in juvenile-onset type I diabetes: a 40year follow-up study. Diabetes Care 9:443-52, 1986 46. Teuscher A, Schnell H, Wilson PWF: Incidence of diabetic retinopathy and relationship to baseline plasma glucose and blood pressure. Diabetes Care 11: 246-51, 1988 47. Chase HP, Jackson WE, Hoops SL, Cockerham RS, Archer PG, O'Brien D: Glucose control and the renal and retinal complications of insulin-dependent diabetes. JAMA 261:1155-60, 1989 48. Klein R, Klein BEK, Moss SE, Davis MD, DeMets DL: Glycosylated hemoglobin predicts the incidence and progression of diabetic retinopathy. JAMA 260: 2864-71, 1988 49. University Group Diabetes Program: Effects of hypoglycemic agents on vascular complications in patients with adultonset diabetes. Diabetes 31 (Suppl. 5): 1-81, 1982 50. The Kroc Collaborative Study Group: Blood glucose control and the evolution of diabetic retinopathy and albuminuria: a preliminary multicenter trial. N EnglJ Med 311:365-72, 1984 51. The Kroc Collaborative Study Group: Diabetic retinopathy after two years of intensified insulin treatment: follow-up of The Kroc Collaborative Study. JAMA 260:37-41, 1988 52. Lauritzen T, Frost-Larsen K, Larsen HW, Deckert T: Effect of one year of near-normal blood glucose levels on retinopathy in insulin-dependent diabetics. Lancet 1:200-204, 1983 53. Lauritzen T, Frost-Larsen K, Larsen HW, Deckert T, Steno Study Group: Two-year experience with continuous subcutaneous insulin infusion in relation to retinopathy and neuropathy. Diabetes 34 (Suppl. 3):74-79, 1985 54. Dahl-Jorgensen K, Brinchmann-Hansen O, Hanssen KF, Sandvik L, Aagenaes O,

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45, 1986 64. Snehalatha C, Mohan R, Mohan V, Ramachandran A, Viswanathan M: Pancreatic P-cell function in relation to diabetic retinopathy in Asian Indian NIDDM patients. Acta Diabetol hat 25: 95-100, 1988 65. Sbema P, Valentini U, Cimino A, Sabatti C, Rotondi A, Crisetig M, Spandrio S: Residual P-cell function in the insulin-dependent (type 1) diabetes with and without retinopathy. Acta Diabetol hat 23:339-44, 1986

56. Beck-Nielsen H, Rickelsen B, Mogensen CE, Olsen T, Ehlers N, Nielsen CB, Charles P: Effect of insulin pump treatment for one year on renal function and retinal morphology in patients with IDDM. Diabetes Care 8:585-89, 1985 57. The DCCT Research Group: The Diabetes Control and Complications Trial (DCCT): Design and methodologic considerations for the feasibility phase. Diabetes 35:530-45, 1986 58. Smith RBW, Pyke DA, Watkins PJ, Binder C, Faber OK: C-peptide response to glucagon in diabetics with and without complications. NZ Med J 89:304-306, 1979 59. Sjoberg S, Gunnarsson R, Gjotterberg M, Lefvert AK, Persson A, Ostman J: Residual insulin production, glycaemic control and prevalence of microvascular lesions and polyneuropathy in longterm type I (insulin dependent) diabetes mellitus. Diabetologia 30:208-13, 1987 60. Sjoberg S, Gjotterberg M, Lefvert AK, Gunnarsson R, Ostman J: Significance of residual insulin production in longterm type I diabetes mellitus. Transplant Proc 18:1498-99, 1986 61. Suzuki K, Watanabe K, Motegi T, Kajinuma H: High prevalence of proliferative retinopathy in diabetic patients with low pancreatic p-cell capacity. Diabetes Res Clin Pract 6:45-52, 1989 62. Mosier MA: Circulating C-peptide and diabetic retinopathy. Diabetes Res 1:151-54, 1984 63. Madsbad S, Lauritzen E, Faber OK, Binder C: The effect of residual betacell function on the development of diabetic retinopathy. Diabetic Med 3:42-

66. Klein R, Moss SE, Klein BEK, Davis MD, DeMets DL: Wisconsin Epidemiologic Study of Diabetic Retinopathy. XII. Relationship of C-peptide and diabetic retinopathy. Diabetes 39:1445-50, 1990 67. Serghieri G, Bartolomei G, Pettenello C, Mammini P, DeGiorgio LA: Raised retinopathy prevalence rate in insulintreated patients: a feature of obese type II diabetes. Transplant Proc 18:157677, 1986 68. Davis MD: Diabetic retinopathy, diabetic control and blood pressure. Transplant Proc 18:1565-68, 1986 69. Bamett AH, BrittonJR, Leatherdale BA: Study of possible risk factors for severe retinopathy in noninsulin dependent diabetes. BrMedJ 287:529, 1983 70. Ibsen KK, Rotner H, Hougaard P: Blood pressure in children with diabetes mellitus. Acta Paediatr Scand 72:191-96, 1983 71. Nilsson SE, Nilsson JE, Frostberg N, Emilsson T: The Kristianstad Survey II Studies in a representative adult diabetic population with special reference to comparison with an adequate control group. Acta Med Scand 469:1-42, 1967 72. Houston A: Retinopathy in the Poole area: an epidemiological inquiry. In Advances in Diabetes Epidemiology. Eschege

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84. Palumbo PJ, Elyeback LR, Whishnaut JP: Neurologic complications of diabetes mellitus: transient ischaemic attack, stroke, and peripheral neuropathy. Adv Neurol 19:593-601, 1978 85. Asplund K Hagg E, Helmers C, Lithner T, Strand T, Webster PO: The natural history of stroke in diabetic patients. Acta Med Scand 207:417-24, 1980 86. Mogensen CE: Long-term antihypertensive treatment inhibiting the progression of diabetic neuropathy. Acta Endocrinol 242 (Suppl.):31-32, 1981 87. Parving HH, Andersen AR, Hommel E, Smidt UM: Effects of long-term antihypertensive treatment on kidney function in diabetic nephropathy. Hypertension 35 (Suppl. 2):114-17, 1985 88. Paetkau ME, Boyd TAS, Winship B, Grace M: Cigarette smoking and diabetic retinopathy. Diabetes 26:46-49, 1977 89. Muhlhauser I, Sawicki P, Berger M: Cigarette-smoking as a risk factor for macroproteinuria and proliferative retinopathy in type 1 (insulin-dependent) diabetes. Diabetologia 29:500-502, 1986 90. Barnett AH, BrittonJR, Leatherdale BA: Study of possible risk factors for severe retinopathy in non-insulin dependent diabetes. BrMedJ 287:529, 1983 91. Yanko L, Goldbourt U, Michaelson IC, Shapiro A, Yaari S: Prevalence and 15year incidence of retinopathy and associated characteristics in middle-aged and elderly diabetic men. Br J Ophthalmol 67:759-65, 1983 92. Ballard DJ, Melton LJ 111, Dwyer MS, TrautmannJC, Chu C-P, O'Fallon WM, Palumbo PJ: Risk factors for diabetic retinopathy: a population-based study in Rochester, Minnesota. Diabetes Care 9:334-42, 1986 93. Klein R, Klein BEK Davis MD: Is cigarette smoking associated with diabetic retinopathy? Am] Epidemiol 118:22838, 1983 94. Moss SE, Klein R, Klein BEK: Association of cigarette smoking with diabetic retinopathy. Diabetes Care 14:119-26, 1991 95. Department of Health, Education, and Welfare: The Health Consequences of

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perance FA, Eds. New York, Grune & Stratton, 1982, p. 427-35 Lorini R, Larizza D, Livieri C, Cammareri V, Zandrini C, Seven F: Relationship between nerve function, retinopathy, and duration of diabetes. EurJ Pediatr 145:580-81, 1986 Clark CV: Ocular autonomic nerve function in proliferative diabetic retinopathy. Eye 2:96-101, 1988 Karma A, Gummerus S, Kujansuu E, Pitkajarvi T: Predicting diabetic retinopathy. Acta Ophthalmol 65:136-39, 1987 Orchard TJ, Dorman JS, Maser RE, Becker DJ, Ellis D, LaPorte RE, Kuller LH, Wolfson SKJr, Drash AL: Factors associated with avoidance of severe complications after 25 Yr of 1DDM: Pittsburgh Epidemiology of Diabetes Complications Study 1. Diabetes Care 13:741-47, 1990 Borch-Johnsen K, Kreiner S: Proteinuria: value as predictor of cardiovascular mortality in insulin dependent diabetes mellitus. Br MedJ 294:1651-54, 1987 Winocour PH, Durrington PN, Ishola M, Anderson DC, Cohen H: Influence of proteinuria on vascular disease, blood pressure, and lipoproteins in insulin dependent diabetes mellitus. Br MedJ 294:1648-51, 1987 Kostraba JN, Klein R, Dorman JS, Becker DJ, Drash AL, Maser RE, Orchard TJ: The Epidemiology of Diabetes Complications Study. IV. Correlates of diabetic background and proliferative retinopathy. Am J Epidemiol 133:38191, 1991 Doman TL, Carter RD, Bron AJ, Turner RC, Mann JI: Low density lipoprotein cholesterol: an association with the severity of diabetic retinopathy. Diabetologia 22:167-70, 1982 Miccoli R, Odello G, Giampietro O, Marchetti P, Christofani R, Penno G, Meucci G, Navalesi R: Circulating lipid levels and severity of diabetic retinopathy in type I diabetes mellitus. Ophthalmic Res 19:52-56, 1987 Klein BEK, Moss SE, Klein R, Surawicz TS: The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XIII. Re-

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JavittJC, CannerJK, Frank RG, Steinwachs DM, Sommer A: Detecting and treating retinopathy in type I diabetics: 153. a health policy model. Ophthalmology 97:483-95, 1990 Dasbach E, Fryback D, Newcomb PA, Klein R, Klein BEK: Cost-effectiveness 154. of strategies for detecting diabetic retinopathy. Med Care 29:20-39, 1991 National Eye Institute National Eye 155. Health Education Program: From vision research to eye health education: planning the partnership. March 1990. Washing- 156. ton, DC, U.S. Govt. Printing Office, 1990 Smith RE, Patz A: Diabetes 2000- 157. closing the gap (Editorial). Ophthalmology 97:153-54, 1990 Herman WH, Teutsch SM, Sepe SJ, Sinnock P, Klein R: An approach to the prevention of blindness in diabetes. Di- 158. abetes Care 6:608-13, 1983 Klein R: Retinopathy and other ocular complications in diabetes. In Diabetes Mellitus, Management and Complications. Olefsky JM, Sherwin RS, Eds. New York, Churchhill Livingstone, 1985, p. 101-58 159. Stribe M, Haire-Joshu D, Yost J: Psychological adjustment in insulin-dependent diabetes mellitus: the relationship of coping style and diabetes

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knowledge (Abstract). Diabetes 37 (Suppl. l):20A, 1988 Sinzato R, Fukikno O, Tamai H, Isizu H, Nakagawa T, Ikemi Y: Coping behaviors of severe diabetes. Psychother Psychosom 43:219-26, 1985 Wulsin LR, Jacobson AM, Rand LI: Psychosocial correlates of mild visual loss. Psychol Med 53:109-17, 1991 Cleary ME, Fahy C: Lighting a lamp for persons who are visually challenged. Diab Educ 15:331-35, 1989 Wulsin LR, Jacobson AM, Rand LI: Psychosocial aspects of diabetic retinopathy. Diabetes Care 10:367-73, 1987 Bembaum M, Albert SG, Duckro PN: Psychosocial profiles in patients with visual impairment due to diabetic retinopathy. Diabetes Care 11:551-57, 1988 Klein R, Davis MD, Moss SE, Klein BEK, DeMets DL: A comparison of retinopathy in younger and older onset diabetic person. In Comparison of Type I and Type II Diabetes. Vranic M, Hollenberg CH, Steiner G, Eds. New York, Plenum, 1985, p. 321-35 Klein R, Moss SE: Visual impairment and diabetes. In International Textbook of Diabetes Mellitus. Alberti KGMM, DeFronzo RA, Keen H, Zimmet P, Eds. New York, Wiley, 1992, p. 1373-84

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