Optic Disc Cupping: Prevalence Findings from the WESDR

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Investigative Ophthalmology & Visual Science, Vol., o. 2, February 1989 Copyright Association for Research in Vision and Ophthalmology Optic Disc Cupping: Prevalence Findings from the WER Barbara E.

1 Investigative Ophthalmology & Visual Science, Vol., o. 2, February 1989 Copyright Association for Research in Vision and Ophthalmology Optic Disc Cupping: Prevalence Findings from the WER Barbara E. K. Klein, Scot E. Moss, Yvonne L. Mogli, Ronald Klein, Carol Hoyer, and Judyth Johnson Increased cupping of the optic disc is considered to be an indication of pressure-related damage of the optic nerve. This paper explores the relationship of intraocular pressure and cupping in persons with diabetes mellitus, a group of people whose optic nerves may be more susceptible to the effects of intraocular pressure. Stereoscopic fundus photographs of the seven standard fields were obtained in all persons participating in the Wisconsin Epidemiologic Study of Diabetic Retinopathy at the time of the initial prevalence survey. Measurements of disc and cup diameters in the vertical and horizontal meridia were made by two trained graders. Cup-to-disc ratios were computed for both diameters of each eye and the mean of the two gradings was used. A history of glaucoma was significantly associated with larger cup-to-disc ratios at the prevalence examination. Cup-to-disc ratios were not larger in those with high IOP, nor in those who had panretinal photocoagulation. Invest Ophthalmol Vis Sci :4-9,1989 Ocular hypertension and glaucoma have been reported to occur more commonly in persons with diabetes. 1 ' 4 In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WER), intraocular pressure (IOP) greater than 21 mm Hg occurred in 5.8% of "younger onset" persons whose age was less than years and in.1% of those who were years of age or older. In the "older onset" group, 8.1% of those -64 years of age and 8.9% of those 65 years of age or older had IOP greater than 21 mm Hg. In the younger onset group, the duration of diabetes was positively associated with intraocular pressure. 5 Armaly reported that eyes that developed visual field defects characteristic of glaucoma during the Collaborative Study had larger optic cups and higher mean IOP* than eyes remaining free of such defects. 6 If relatively greater optic disc cupping is, in part, a function of increased IOP, it is reasonable to hypothesize that an association of cupping and intraocular pressure may occur over a broad range of pressure. If the optic nerves of people with diabetes are more susceptible to pressure-related cupping because of circulatory or other disturbances and if they have, on the average, higher intraocular pres- From the Department of Ophthalmology, University of Wisconsin Medical School, Madison, Wisconsin. Supported by ational Institutes of Health Grants EY-0540 (BEK.K.) and EY-08 (RK). Submitted for publication: May 16, 1988; accepted September 15, Reprint requests: B. E. K. Klein, MD, MPH, Department of Ophthalmology, University of Wisconsin, 600 Highland Avenue, Madison, WI 592. sures these two may increase the risk of pathologic changes in disc. We sought to describe the distribution of cup-to-disc ratios and evaluate factors which may be related to cupping in people with diabetes. Population Materials and Methods The population has been described in detail in previous reports. " 9 Briefly, a sample of 2990 persons was selected for the baseline examination. This sample was composed of two groups. The first group consisted of all patients diagnosed as having diabetes before years of age who took insulin (1210 patients); this group will be referred to as "younger onset." The second group consisted of a probability sample of the 541 patients who were diagnosed as having diabetes at years of age or older and who had their diagnosis confirmed by a casual or a postprandial serum glucose level of at least 200 mg/dl, or a fasting serum glucose level of at least 140 mg/dl on at least two occasions (180 patients); this group will be referred to as "older onset." Of the 2990 eligible patients, 266 (9.1%) participated in the baseline examination from Reasons for nonparticipation and comparisons between participants and nonparticipants in WER have been presented elsewhere. 89 Informed consent was obtained from each participating subject. In the older onset group some people were using insulin at the time of the subsequent examination, others not. In analyses to follow, the data are given 4

2 o. 2 OPTIC DISC CUPPIG I DIABETES / Klein er ol 5 Table 1. Differences in cup-to-disc ratios between left and right eyes Difference in horizontal ratios between left and right eyes < to to to+0.2 P* Difference in vertical ratios between left and right eyes < to to to+0.2 P * Paired t-test. no insulin insulin Younger onset two graders. Measurements were made of disc diame- ters (vertical and horizontal) and of cup diameters (vertical and horizontal). When the two graders had significant disagreement about a measurement, the eye was returned to the graders for regrading. In right eyes, for vertical and horizontal cup diameters, this occurred in 1.% (15/2295) and 9.2% (208/2268) of cases, respectively; for vertical and horizontal disc diameters this occurred in 1.0% (2/2295) and 1.2% (28/2268) of cases, respectively. When discrepancies remained after the regrading, these differences were adjudicated by a more senior grader who was one of the developers of the grading scheme (YLM). This occurred in 4.0% and.0% of vertical and horizontal cup diameters, and in 0.6% and 0.6% of vertical and horizontal disc diameters, respectively. Final diameter values were taken to be the adjudicated value, when present, or the mean of the two graders' measurements. Cup-to-disc ratios were com- for three groups, younger onset, older onset insulin users, and older onset nonusers of insulin. Procedures The baseline ( ) examinations were performed in a mobile examination van in or near the city where the participants resided. Pertinent parts of the ocular and physical examinations included: measuring the blood pressure, 10 intraocular pressure (IOP), 5 and best-corrected visual acuity (using the Early Treatment Diabetic Retinopathy Study [ETDRS] protocol)"; performing a slit-lamp examination for chamber depth and the presence of iris neovascularization; dilating the pupils; taking stereoscopic color fundus photographs of seven standard fields of each eye; and determining glycosylated hemoglobin levels from a fingerprick capillary blood sample using a resin microcolumn technique. 12 A structured interview was conducted. Participants were asked if they were ever told by a physician that they had glaucoma. A history of usage of glaucoma medications was obtained. If there was any question concerning the accuracy of reported medication or diagnosis, this usage was verified by contacting the participant's physician. Cup and Disc Diameter Measurements Stereoscopic photographs of the optic discs were graded according to a standard protocol using a plastic measuring template of circles of known diameters. Details of the grading scheme have been published elsewhere. 1 Each eye was graded independently by Table 2. Differences in cup-to-disc ratios between horizontal and vertical diameters Difference in horizontal and vertical ratios Right eye < to to to+0.2.p value* Left eye < to to to+0.2 P value* Older onset. no insulin < < insulin < Paired t-test based on actual differences in C/D ratios. Younger onset < < Table. Pearson correlation coefficients between eyes and diameters no insulin, right eye, left eye, left eye insulin, right eye, left eye, left eye Younger onset, right eye, left eye, left eye, right eye , right eye , left eye

3 6 IVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIECE / February 1989 Vol. ^10 A ', VERTICAL HORIZOTAL C/D RATIO C/D RATIO C/D RATIO Fig. 1. Frequency distributions of vertical and horizontal cup/ disc ratios in older onset persons not taking insulin (A), older onset persons taking insulin (B), and younger onset persons (C). puted for both horizontal and vertical diameters for each eye. Severity of Diabetic Retinopathy To determine retinopathy status, all fundus photographs were graded using a modification of the Airlie House Classification scheme that specified nine levels of retinopathy. 15 Briefly, level 1 represents no retinopathy; levels 1.5 to 5 represent microaneurysms and various other nonproliferative abnormalities of increasing severity; level 6 represents either fibrous proliferans only or early proliferative changes; level represents proliferative retinopathy with Diabetic Retinopathy Study High Risk Characteristics (DRS- HRC) for severe visual loss, 15 and level 8 represents the most severe retinopathy such that the eyes were ungradable because of vitreous hemorrhage or other complications of diabetic retinopathy. After examining all of the photographic fields, the presence or absence and the distribution of photocoagulation scars was determined for each eye. The type of photocoagulation treatment was judged by distribution and appearance of the scars and was classified into one of the following groups: (1) focal, if the scars were localized to Field 2 (macular area); and (2) panretinal scatter, if scars were found outside the temporal venous arcades. In eyes that could not be graded, previous photocoagulation treatment was determined from past history as recorded and documented in clinic records. Reasons for missing photos included refusal of the participant to be photographed and media opacities, including cataract, vitreous hemorrhage or other diabetic retinopathy that obscured adequate visualization of the disc. Definitions Current age was defined as the age at the time of the baseline examination in Age at diagnosis of diabetes was denned as the age at the time the diagnosis was first recorded by a physician on the patient's chart or on a hospital record. The duration of diabetes was that time period between the age at diagnosis and the age at the time of the baseline examination. Data Handling and Analysis Wisconsin Storage and Retrieval, an informationprocessing software system, was used for processing all subject files. 16 Statistical Analysis System was used for calculating the student t-test, analysis of variance, and multiple linear regression. 1 Results Of the 2990 participants at the baseline examination, disc photos of 2110 right eyes and 2049 left eyes were gradable for at least one meridian. Cup-to-disc ratios in two eyes of participants tended to be similar. Differences of 0.2 or more in both horizontal and vertical dimensions were infrequent (Table 1). In only the older onset persons taking insulin was the right cup-to-disc ratio likely to be larger than the left and this tendency just reached conventional levels of significance. ratios

4 o. 2 OPTIC DISC CUPPIG I DIABETES / Klein er ol Table 4. cup-to-disc ratios by glaucoma history, right eye no insulin insulin Younger onset A* o glaucoma Table 5. intraocular pressure by glaucoma history, right eye no insulin insulin Younger onset SB o glaucoma tended to be larger than horizontal ratios in both eyes for all groups (Table 2). In order to assess similarities of ratios within and between eyes, Pearson correlation coefficients were computed (Table ). Correlations between diameters in the same eye were uniformly high, ranging from Between eyes, like meridia were more highly correlated than were those between measures of unlike meridia. Overall, correlations in the older onset people who took insulin were the lowest; for all but one correlation, the coefficients in the younger onset group were the highest. In all cases, coefficients were highly statistically significant. Because ratios for right and left eyes of a participant were not systematically different, and were highly correlated, we present further results for the right eye only. Figures 1A, B, and C describe the frequency distributions of the vertical and horizontal ratios for the three groups of study participants. Ratios of are the most common in all groups. More than 80% of values were between 0. and 0.59 for horizontal and vertical diameters for each group of people. Ratios of 0. or more are often regarded as suspicious for glaucoma. Values this extreme occurred infrequently; only in older onset persons who did not use insulin did these values exceed 1% of the respective totals. : Older onset persons with glaucoma, whether taking insulin or not, were more likely to have larger cup-to-disc ratios (vertical and horizontal) than people without glaucoma. (Table 4) There were too few eyes that had rubeosis and gradeable photographs to evaluate an effect on cupping. IOP: Although mean IOPs were uniformly higher in those with glaucoma (Table 5) there was no consistent relationship between IOP and cup-to-disc ratios within any group for either diameter; Figure 2 illustrates the relationships for vertical diameters. There were no significant differences in mean cupto-disc ratios in either the vertical or horizontal di- lo.4- i 0.4- OLDER. O-ISUU OLDER. O-ISUU OLDER. ISULI OLDER. ISULI VOU0ER TOUGER IOP (mmhg) Fig. 2. cup/disc ratios by intraocular pressure in three groups of diabetic persons AGE (yr) Fig.. cup/disc ratios by age in three groups of diabetic persons.

8 IVESTIGATIVE OPHTHALMOLOGY 6 VISUAL SCIECE / February 1989 Vol. 0.5i S0.4-0.-I OLDER. O-ISUU - OLDER, ISUU YOUGER 20 DURATIO (yr) Fig. 4.

5 8 IVESTIGATIVE OPHTHALMOLOGY 6 VISUAL SCIECE / February 1989 Vol. 0.5i S I OLDER. O-ISUU - OLDER, ISUU YOUGER 20 DURATIO (yr) Fig. 4. cup/disc ratios by duration of diabetes in three groups of diabetic persons. mension across the range of intraocular pressure values for any of the three groups (smallest P = 0.05). Age: There was no significant tendency for increased ratios with increasing age for any group; Figure describes the data for vertical diameter. Duration of diabetes: The relationship of duration of diabetes and the vertical ratios is seen in Figure 4; there is no consistent effect within or between groups. Severity of diabetic retinopathy: There was no consistent effect of the severity of diabetic retinopathy nor of the presence of panretinal photocoagulation scars and cup-to-disc ratios (Table 6). To determine whether a combination of characteristics describe the cup-to-disc ratios better than single variables, multiple regression analyses were performed (Table ). The characteristics of interest were age, duration of diabetes, glycosylated hemoglobin, systolic blood pressure, diastolic blood pressure, use of antihypertensives or diuretics, intraocular pressure, history of glaucoma, severity of diabetic retinopathy, presence of panretinal photocoagulation, sex, and presence of proteinuria. In older onset persons who used insulin, increasing glycosylated hemoglobin was associated with increasing the vertical ratio. In younger onset persons, none of the characteristics, when examined together, was positively related to the ratios. Discussion In these data we found that mean vertical cup-todisc ratios tended to be greater than horizontal ratios. This finding is consistent with observations by Weisman et al' 8 who found differences between vertical and horizontal cups in people with and without glaucoma. Kirsch and Anderson 19 reported vertical elongation of the cup in glaucoma with a round contour more common in those free of disease. Thus, even though our technique of measurement differs from those used by previous investigators the anatomic findings are consistent; this despite the fact that our population is comprised entirely of persons with diabetes. To ascertain whether the presence and severity of diabetic retinopathy and its resultant destruction of retinal tissue was responsible for increased cupping that might obscure the effects of other variables, we included this in our multivariate analyses. This characteristic was not related to larger ratios. In order to assess whether including eyes with proliferative retinopathy, either on the disc where it might directly interfere with measuring, or elsewhere, where it might be responsible for vitreous hemorrhage that would obscure any view, we examined mean ratios by the severity of diabetic retinopathy. o particular pattern of cupping vis-a-vis retinopathy was apparent. People with a history of glaucoma had larger mean cup-to-disc ratios on the average than people without glaucoma but the distribution of ratios overlapped considerably. It may well be that there were people in the group with no history of glaucoma, who had undiagnosed disease. In fact, in younger onset persons 6.% of men, and 6.9% of women had intraocular pressures greater than 21 mm Hg; in older onset persons the corresponding rates were.6%, and 10.%, respectively. Some of these people and also those with Table 6. cup-to-disc ratios by the severity of diabetic retinopathy Level of severity of diabetic retinopathy &6O Laser* no insulin t * Panretinal photocoagulation; all but one person in this group had ev dence of proliferative retinopathy. insulin S Younger onset f Excludes one person with level 40 who had had panretinal photocoagulation.

o. 2 OPTIC DISC CUPPIG I DIABETES / Klein er ol 9 Table. Multiple linear regression of baseline characteristics and cup-to-disc ratios, right eye Cup-to-disc ratio no insulin r 2 = 0.% = 565 r 2 = 0.

6 o. 2 OPTIC DISC CUPPIG I DIABETES / Klein er ol 9 Table. Multiple linear regression of baseline characteristics and cup-to-disc ratios, right eye Cup-to-disc ratio no insulin r 2 = 0.% = 565 r 2 = 0.9% = 561 insulin HbA i r 2 = 2.0% = 49 r 2 = 1.2% = 490 Younger onset 8O = 9 lower pressures who had glaucoma may be included in the upper end of the distribution of cup-to-disc ratios of persons classified as not having glaucoma. The biologic importance of glycosylated hemoglobin in describing vertical cup-to-disc ratios in older onset insulin users is not apparent. It may be that this indicates an effect of more severe diabetes, or of diabetes that is less well controlled. The influence of chance must be considered, especially as this was a unique finding among the several analyses. Panretinal photocoagulation is an ablative procedure which, by its nature, destroys retinal tissue decreasing the number of functioning nerve fibers leaving the eye. We did not find larger cups in persons who had this treatment. It may be that the number of people who had this procedure was too small to demonstrate an effect. Cup-to-disc ratios are anatomic characteristics. The shape and dimensions of the cup may be influenced by hereditary and environmental factors. In a recent study in adult monozygotic and dizygotic twins, there were greater similarities in ratios between monozygotic than dizygotic pairs. 20 This suggests that these ratios have significant genetic determinants. Thus, the importance of the influence of environmental factors may be limited. In none of the regressions in the study, including those for the left eyes, was the r-square greater than 2%, reflecting the relatively minor importance of the factors under study to determining the ratios. Key words: cup-disc ratio, diabetes, epidemiology, intraocular pressure Acknowledgments The authors wish to thank Judyth Johnson for grading optic discs, Stacy M. Meuer for photograph and data management, and Mae Wildt for manuscript preparation. References 1. Armstrong JR, Daily RK, and Dobson HL: The incidence of glaucoma in diabetes mellitus. Am J Ophthalmol 50:55, Christianson J: Intraocular pressure in diabetes mellitus. Acta Ophthalmologica 9:155, Safir A, Paulsen EP, Klayman J, and Gerstenfeld J: Ocular abnormalities in juvenile diabetics. Arch Ophthalmol 6:52, Jain IS and Luthra CL: Diabetic retinopathy: Its relationship with intraocular pressure. Arch Ophthalmol 8:198, Klein BEK, Klein R, and Moss SE: Intraocular pressure in diabetic persons. Ophthalmology 91:156, Armaly MF: Lessons to be learned from the Collaborative Study. Surv Ophthalmol 25:19, Klein R, Klein BEK, Syrjala SE, Davis MD, Meuer MM, and Magli Y: The Wisconsin Epidemiologic Study of Diabetic Retinopathy: 1. Relationship of diabetic retinopathy to management of diabetes: Preliminary report. In Diabetic Renal- Retinal Syndrome, Friedman EA and L'Esperance FA, editors. ew York, Grune and Stratton, 1982, pp Klein R, Klein BEK, Moss SE, Davis MD, and DeMets DL: The Wisconsin Epidemiologic Study of Diabetic Retinopathy: 11. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than years. Arch Ophthalmol 102:520, Klein R, Klein BEK, Moss SE, Davis MD, and DeMets DL: The Wisconsin Epidemiologic Study of Diabetic Retinopathy: III. Prevalence and risk of diabetic retinopathy when age at diagnosis is or more years. Arch Ophthalmol 102:52, Hypertension Detection and Follow-up Program Cooperative Group. The hypertension detection and follow-up program. Prev Med 5:20, Early Treatment Diabetic Retinopathy Study. Manual of Operations. Baltimore: Early Treatment Diabetic Retinopathy Study Coordinating Center, Department of Epidemiology and Preventive Medicine, University of Maryland, 1985; Chapter 12. U.S. Department of Commerce. ational Technical Information Service, 5285 Port Royal Road, Springfield, Virginia, 22161, Accession #PB852206/AS. 12. Isolab (Akron, OH) Quik-Step, Fast Hemoglobin Test System, 1-8, Klein BEK, Magli YL, Richie KA, Moss SE, Meuer SM, and Klein R: Quantitation of optic disc cupping. Ophthalmology 92:1654, Diabetic Retinopathy Study Research Group: Report : A modification of the Airlie House Classification of diabetic retinopathy. Invest Ophthalmol Vis Sci 21:210, Diabetic Retinopathy Study Research Group: Report #8: Photocoagulation treatment of proliferative diabetic retinopathy: Clinical application of Diabetic Retinopathy Study findings. Ophthalmology 88:58, Entine S, Holladay D, and Oschesky T: WISAR: Wisconsin Storage and Retrieval System. Madison, University of Wisconsin Clinical Cancer Center, SAS Institute, Inc. SAS User's Guide: Statistics, Version 5 edition. Cary, orth Carolina, SAS Institute, Inc., 1985, p Weisman RL, AssefTCF, Phelps CD, Podos SM, and Becker B: elongation of the optic cup. Trans Am Acad Ophthalmol :15, Kirsch RE and Anderson DR: Identification of the glaucomatous disc. Trans Am Acad Ophthalmol :14, Farber M, Klein BEK, and Klein R: Quantification of macular drusen, cup/disk ratios, and intraocular pressures in 6 pairs of monozygotic and 2 pairs of dizygotic twins. ARVO Abstracts. Invest Ophthalmol Vis Sci 29(Suppl):120, 1988.

Optic Disc Cupping: Four Year Follow-up from the WESDR

Investigative Ophthalmology & Visual Science, Vol. 30, o., February 989 Copyright Association for Research in Vision and Ophthalmology Optic Disc Cupping: Four Year Follow-up from the WER Barbara E. K.