The prevalence of diabetes has been accelerating at an alarming rate in the last decade; some describe it as an epidemic. Diabetic eye complications are the leading cause of blindness in adults aged 25-74 in the United States. Early diagnosis and development of effective preventatives and treatments of diabetic retinopathy are essential to save sight. We describe efforts to establish functional indicators of retinal health and predictors of diabetic retinopathy. These indicators and predictors will be needed as markers of the efficacy of new therapies. Clinical trials aimed at either prevention or early treatments will rely heavily on the discovery of sensitive methods to identify patients and retinal locations at risk, as well as to evaluate treatment effects.We report on recent success in revealing local functional changes of the retina with the multifocal electroretinogram (mfERG). This objective measure allows the simultaneous recording of responses from over 100 small retinal patches across the central 45 degree field. We describe the sensitivity of mfERG implicit time measurement for revealing functional alterations of the retina in diabetes, the local correspondence between functional (mfERG) and structural (vascular) abnormalities in eyes with early nonproliferative retinopathy, and longitudinal studies to formulate models to predict the retinal sites of future retinopathic signs. A multivariate model including mfERG implicit time delays and 'person' risk factors achieved 86% sensitivity and 84% specificity for prediction of new retinopathy development over one year at specific locations in eyes with some retinopathy at baseline. A preliminary test of the model yielded very positive results. This model appears to be the first to predict, quantitatively, the retinal locations of new nonproliferative diabetic retinopathy development over a one-year period. In a separate study, the predictive power of a model was assessed over oneand two-year follow-ups. This permitted successful prediction of new retinopathy development in eyes with and without retinopathy at baseline. Finally, we briefly describe our current research efforts to (a) locally predict future sight-threatening diabetic macular edema, (b) investigate local retinal function change in adolescent patients with diabetes, and (c) better understand the physiological bases of the mfERG delays.The ability to predict the retinal locations of future retinopathy based on mfERG implicit time provides clinicians a powerful tool to screen, follow up, and even consider early prophylactic treatment of the retinal tissue in diabetic patients. It also aids identification of 'at risk' populations for clinical trials of candidate therapies, which may greatly reduce their cost by decreasing the size of the needed sample and the duration of the trial.

It is often difficult to find consistent changes in the retinal microvasculature due to large intersubject variability. However, with a novel application of AOSLO imaging, it is possible to visualize parafoveal capillaries and identify AV channels noninvasively. AV channels are disrupted in type 2 diabetes, even before the onset of diabetic retinopathy.

Localized functional abnormalities of the retina reflected by mfERG delays often precede the onset of new structural signs of diabetic retinopathy. Those functional abnormalities predict the local sites of new retinopathy observed 1 year later.

mfERG IT is a good predictor of DR onset, 1 year later, in patients with diabetes without DR. It can be used to assess the risk for DR development in these patients and may be a valuable outcome measure in evaluation of novel prophylactic therapeutics directed at impeding DR.

The local responses of the multifocal ERG reveal continuous changes in the second order waveforms from the nasal to the temporal retina. Scrutiny of these changes suggests the presence of an additive component whose latency increases with the distance of the stimulus from the optic nerve head. This observation led to the hypothesis of a contributing source in the vicinity of the optic nerve head whose signal is delayed in proportion to the fiber length from the stimulated retinal patch to the nerve head. The hypothesis was tested with two independent methods. In Method 1, a set of different local response waveforms was approximated by two fixed components whose relative latency was allowed to vary and the fit of this two component model was evaluated. In Method 2, two signals were derived simultaneously using different placements for the reference electrode. The placements were selected to produce a different ratio of the signal contributions from the retina and the nerve head in the two recording channels. The signals were then combined at a ratio that canceled the retinal component. Method 1 yielded an excellent fit of the two component model. Waveforms and latencies of the hypothetical optic nerve head component derived from the two methods agree well with each other. The local latencies also agree with the propagation delays measured in the nerve fiber layer of the monkey retina. In combination, these findings provide strong evidence for a signal source near the optic nerve head.

The development of recurring retinopathy over a 3-year period can be well predicted by using a multivariate model based on mfERG implicit time. Multifocal ERG delays are promising candidate measures for trials of novel therapeutics directed at preventing or slowing the progression of NPDR.

Conventional electroretinographic techniques do not permit efficient mapping of retinal responsiveness for the detection of small dysfunctional areas. This study explores the application of a new technique that makes such mapping possible. It utilizes a multifocal electroretinogram technique based on binary m sequences that simultaneously tests a large number of small retinal areas by multiplexing their responses onto a single signal derived from the human cornea. The focal responses are subsequently extracted for the derivation of high-resolution maps that characterize retinal responsiveness. The required recording times are short enough to make such testing feasible in the clinic. In this study we demonstrate the high sensitivity of the technique by mapping a small area that has been partially bleached by a strobe flash in a normal retina and by mapping dysfunctional areas in three patients with different, well-documented retinal pathologies. The results suggest that the multifocal electroretinogram has the potential to become a valuable clinical tool.

Purpose This cross-sectional study examines the existence and frequency of functional and structural abnormalities in the adolescent type 1 diabetic retina. We also compare the results to those of adolescents with type 2 diabetes. Methods Thirty-two adolescents with type 1 diabetes (5.7 ± 3.6 yrs; mean duration ± SD), 15 with type 2 diabetes (2.1 ± 1.3 yrs) and 26 age-matched control subjects were examined. Multifocal electroretinogram (mfERG) responses from 103 retinal regions were recorded. Optical coherence tomography was used to measure retinal thickness. Vascular diameter around the optic nerve was also assessed. Results Nine of the 32 (28%) adolescents with type 1 diabetes and 6 of the 15 (40%) with type 2 diabetes had significant mfERG implicit time delays compared to 2 of the 26 controls (8%). Retinal thicknesses in both patient groups were significantly (p ≤ 0.01) thinner than controls. The type 2 group also showed significant (p ≤ 0.03) retinal venular dilation (235.8 ± 5.9μm) compared to controls (219.6 ± 4.0μm). Conclusions The present study illustrates that subtle but significant functional and structural changes occur very early in type 1 diabetes. Adolescents with type 2 diabetes appear to be more affected than those with type 1 diabetes. Further longitudinal examination of the etiology and progression of these abnormalities is warranted.