Progression of Early Retinal Dysfunction in Diabetes Over Time

Results of a Long-term Prospective Clinical Study

Karl-Johan Hellgren; Elisabet Agardh; Boel Bengtsson

Disclosures

Diabetes. 2014;63(9):3104-3111. 

In This Article

Discussion

To our knowledge, this is the first prospective longitudinal study to use SAP to evaluate diabetic subjects with no or mild/moderate diabetic retinopathy. This approach detected progression of early retinal dysfunction, even though the ETDRS final severity scale indicated stable retinopathy. Because visual field deterioration did not differ between subjects without and those with any signs of microvascular abnormalities and because the ETDRS level of retinopathy was stable over time, we propose that the neuronal dysfunction could represent an early feature of diabetic retinopathy due to primary neurodegeneration. A limitation of the study is that the number of subjects with progression of retinopathy during the 4 years of follow-up was insufficient to explore whether SAP is able to predict the development of microvascular impairment.

We used empirically derived limits for change based on test–retest variability previously measured in an independent sample of diabetic patients.[18] Knowledge of such variability, together with longitudinal comparisons within individuals, allows more sensitive monitoring of visual function than is provided by cross-sectional comparisons of individuals. Had the limits been too narrow, a substantial proportion of significantly changed—both deteriorated and improved—test points would have been found. Our analysis yielded a substantial number of test locations showing significant deterioration but very few locations exhibiting improvement. In 27 eyes (36%), at least five test points showed deterioration in the last test. Furthermore, deterioration of at least five test points was noted in 16 eyes (22%) in the two last tests, which indicated a likely change, and those 16 eyes also had decreased MD values. Agreement was good between our method and the pointwise linear regression technique, although the latter identified fewer eyes with deterioration, indicating that our method is more sensitive. Our approach has long been applied to assess the eyes of patients with glaucoma,[35] and in that disease has been reported to identify significant deterioration earlier than is possible with the regression method.[39][41] Therefore, as expected, in the current study we found the regression method revealed fewer deteriorated eyes than our method.

To evaluate sensitive methods for detecting change over time, it is necessary to use a longitudinal study design. However, such an approach always entails the risk of dropouts, which can weaken the interpretation of the results. Fortunately, the dropout rate in our study was low: more than 90% of the subjects completed the 3 years of follow-up.

Several cross-sectional investigations using various perimetric and electrophysiological methods have suggested slight dysfunction in eyes with no diabetic retinopathy,[12,13,16,20,21,23][26] but few longitudinal studies have considered this issue. One longitudinal investigation was conducted by Di Leo et al.[28] in 1994, who found that patients with type 1 diabetes, but without retinopathy, exhibited significant changes in ERG responses 3 years after baseline, and two studies demonstrated that slight depression of SAP[19] and delayed ERG response[29] predicted later onset of diabetic retinopathy. The strength of our study is that we performed a longitudinal collection of more functional data. By using SAP to test the visual field every 6 months for up to 3 years and thereafter annually, we were able to identify consistent deterioration in 22% of the eyes that were evaluated.

Factors other than diabetes-induced retinal dysfunction (e.g., cataract) can explain decreased perimetric sensitivity. Although cataract is known to increase with age,[42] we found no significant difference in age between patients with and those without a likely visual field change. Cataract typically leads to general depression of the visual field and might also have a more pronounced effect on paracentral than on peripheral test points,[43] but such a pattern was not discerned in our 16 subjects with likely deterioration. Although we did not specifically grade lens changes, that the functional changes detected by our method were caused by cataract is unlikely. Furthermore, we did not find any difference in change in perimetric foveal (central) threshold values between the 16 eyes with repeated deterioration and those without. The mean change in foveal threshold was −0.6 dB among the 16 eyes and −1.1 dB among the other 58 eyes. Thus, cataract development is unlikely to explain our finding of repeated deterioration in some eyes.

There was a poor correlation between likely visual field deterioration and visual acuity change, and most eyes with a likely visual field deterioration did not lose visual acuity. A limitation of the study is the lack of explanation for vision loss in a subset of subjects. The present five-letter cutoff for visual acuity change can be discussed, but test–retest variability is lower in eyes with good visual acuity, as was the case for the eyes in our study. Had the cutoff been set at nine letters, which has been reported as the overall coefficient of repeatability for diabetic subjects with various visual acuity,[44] six subjects would have had a worsening of visual acuity at follow-up, and merely one of those had a likely visual field deterioration.

We found no association between SAP deterioration and duration of diabetes or HbA1c levels in our cohort of diabetic subjects with stable metabolic control, which agrees with results obtained by Nitta et al..[45] Di Leo et al.[28] and Verrotti et al.[19] have also reported a lack of correlation between ERG and SAP, respectively, and metabolic control. We previously demonstrated that quite extensive intraindividual blood glucose fluctuations on a 1-month basis had no or little influence on SAP deterioration in a different cohort of diabetic subjects.[18] Whether fluctuating HbA1c levels on a long-term basis may affect visual function, including SAP, can only be speculated about.

This prospective longitudinal study is the first of its kind, and our results demonstrate that SAP with an analysis tailored for monitoring the eyes of patients with diabetes over time can reveal repeated deterioration of retinal neuronal function in this disease. We believe our method provides reliable assessments of visual function early in the course of diabetic retinopathy. Moreover, it can serve as an alternative end point for investigation of early visual disturbances, which can be useful when evaluating new treatment strategies for diabetic retinal disease, including neuroprotection.

processing....