Research Design and Methods
The subjects and study design have previously been described in detail[30] and are summarized here. From September 2006 to May 2009, patients who had type 1 (13 of 81) or type 2 (68 of 81) diabetes and were between the ages of 18 and 75 years were consecutively recruited from the screening program for diabetic retinopathy at the Department of Ophthalmology, Karlstad, County Council of Värmland. This program uses fundus photography to grade vascular lesions and is open to all individuals with diabetes who are older than 10 years of age. Type 1 diabetes was defined as having a diagnosis of diabetes at age <30 years and receiving insulin treatment within 1 year of diagnosis. One randomly selected eye per subject was examined and included in the study. Patients were not included if they had previously received laser treatment or any other local treatment for diabetic retinopathy, were in need of such treatment, or had other conditions that were likely to affect the visual field. Intraocular pressure measurements ranging between 11 and 22 mmHg and normal optic discs on baseline photographs ruled out the presence of undiagnosed glaucoma. To be included, patients had to be able to perform reliable visual fields defined as ≤15% false-positive responses. The study was approved by the regional ethical review board of Lund University, Sweden, and all patients gave written informed consent.
Patients were scheduled for follow-up visits every 6 months for the first 3 years and thereafter annually until 5 years from baseline. All visits included an examination of visual acuity, SAP, fundus photography, and measurement of HbA1c and blood pressure.
Visual acuity was tested using Early Treatment of Diabetic Retinopathy Study (ETDRS) charts[31] and was expressed as the number of correctly read letters. Visual acuity was measured after refraction with manual adjustment of autorefractor (KR-8100P; Topcon, Tokyo, Japan) values in sphere and cylinder to 0.25-diopter accuracy. We considered a difference of five or more letters as a change in visual acuity based on our earlier results of measurements of short-term variation in visual acuity in diabetic patients.[32]
Visual fields were tested using a Humphrey Field Analyzer 750 (Carl Zeiss Meditec, Inc., Dublin, CA) with the SITA Standard 24-2 program, including 54 test point locations within the central 24° visual field. Normal limits are based on a multicenter collection of perimetric data from 330 healthy subjects between 19 and 84 years of age.[33] Before the initial visit during the study period, all subjects performed one visual field test to avoid perimetric learning effects during follow-up. The perimetric interpretation tool "single field analysis" provides probability maps that flag test locations with sensitivities that are significantly depressed compared with age-corrected normal values[34] (Fig. 1). The global perimetric index mean deviation (MD) describes the global status of the visual field; a value of 0 dB corresponds to a normal field, and approximately –30 dB corresponds to a blind field.
Figure 1.
Visual fields from baseline to 60 months of follow-up demonstrate significantly improved and deteriorated test points (top) in a 59-year-old subject with type 2 diabetes and mild retinopathy (i.e., microaneurysms only). The fundus photographs were taken at baseline (left) and at the last follow-up visit (right). The single field analysis revealed no meaningful deviation from normal age-corrected threshold values (middle), whereas visual field deterioration was apparent in the change maps (top). Visual acuity was >6/6 throughout the entire study period.
Longitudinal visual field change was assessed by comparing each follow-up field with the baseline field representing an average of the two tests performed at the first two visits during the study period. Differences in age-corrected threshold values were calculated for each test point, except for the two located in the blind spot area, and thereafter were compared with the limits for significant improvement and deterioration that we had previously defined for diabetic subjects.[18] This change analysis was developed in analogy with the glaucoma change probability maps used to assess glaucomatous progression.[35] Test locations with significant change (deterioration or improvement) at the P < 0.05 level (Fig. 1) were counted. As in our previous study,[30] fields with five or more significantly improved or deteriorated test locations were considered as showing a possible change from baseline, and repeated improvement or deterioration at five or more test locations in two or more consecutive field tests was regarded as indicating likely change. The risk for having at least five test points falsely flagged as deteriorated or improved at the P < 0.05 level is about 10% in a single test, and by requiring at least the same number in the consecutive test, the risk for false change diminishes considerably to 1%, assuming the tests are independent.
To confirm the results obtained by our method, we applied the established pointwise linear regression analysis[36,37] but used age-corrected threshold values over time to detect significant changes in visual fields. Eyes were considered deteriorated if five or more test points showed significantly negative regression slopes at the P < 0.05 level.
Stereo fundus photography of seven 35° fields was performed using a TRC 50IX retinal camera (Topcon) and Fujichrome Sensia 100 slide film (Fujifilm, Tokyo, Japan). The degree of retinopathy was graded according to the ETDRS final severity scale.[38] The grader (E.A.) was masked to patient characteristics, visit number, and outcome of the functional tests. Progression or regression of retinopathy was defined as a two-step change according to the ETDRS final severity scale.
HbA1c was analyzed by high-performance liquid chromatography initially using a Variant II Hemoglobin A1c Program (Bio-Rad, Hercules, CA) and from 2 February 2011 using a TOSOH G8 analyzer (Medinor, Tokyo, Japan): normal ranges are 27–42 and 31–46 mmol/mol (4.6–6.0% and 5.0–6.3% according to the National Glycohemoglobin Standardization Program) for individuals aged <50 and ≥50 years, respectively. Blood pressure was expressed as the mean of two measurements performed using an aneroid sphygmomanometer with the patient sitting.
Statistics
Depending on the type of data to be analyzed, parametric (paired t test) or nonparametric (McNemar, Wilcoxon sign rank, and Mann-Whitney) tests were used to compare changes in patient characteristics and perimetric MD values between baseline and the last follow-up visit. We also used κ statistics to analyze agreement between the two methods applied to assess changes in visual fields.
Diabetes. 2014;63(9):3104-3111. © 2014 American Diabetes Association, Inc.
