Functional/Neural Mapping Discoveries in the Diabetic Retina: Advancing Clinical Care with the Multifocal ERG

systemic factors that are known to be associated with type 2 diabetes before and after the appearance of NPDR and using other known risk factors to further increase an already excellent predictive model, are the next logical research steps. Both offer promise of improved patient care and more personal patient management options.

DIABETES AND AN UNRESOLVED DIABETIC

EYE MANAGEMENT PROBLEM

The Diabetes Epidemic

In the United States, 17.9 million people, 5.9% of the population, have diabetes [1]. There are also an estimated 5.7 million who have undiagnosed diabetes and 57 million who are prediabetic [1]. Diabetic retinopathy, the vascular eye complication, is the leading cause of blindness in the US among adults aged 20–74 years [1].

Current Treatment Focus

Treatments of the potentially devastating retinal complications are currently aimed at slowing the progression of vision loss after vascular-related structural damage within the retina which is funduscopically obvious. Laser photocoagulation, an invasive treatment that destroys retinal tissue, is used in cases of clinically significant macular edema (CSME). In cases of advanced retinopathy, panretinal laser treatment is applied to as many as thousands, or more, of retinal locations to destroy tissue and consequently reduce the retina’s demand for oxygen, thereby slowing progression of neovascularization. Although these gold-standard treatments significantly reduce the loss of visual acuity, they have side effects, including loss of paracentral vision (important for reading and other tasks) and peripheral and night vision, and they are also associated with many adverse events [2]. Furthermore, despite these treatments, vision loss still continues at a disturbing rate [3–5]. Additional treatments are emerging, including intraocular and retrobulbar injection of steroids, anti-VEGF agents, PKC inhibitors, PEDF (pigment endothelium-derived factor) inducers, and several indirect growth factor modulators. These therapies are targeted at reducing macular edema, treating advanced disease, or reducing the risks of neovascularization. These important treatment improvements remain focused on the relatively advanced stages of vision loss produced by diabetes complications.

Vasculopathy and Neuropathy of the Retina

Increasing attention is being paid to the fact that there are both neural and vascular components involved in very early stages of diabetic retinopathy. The concept that diabetes directly affects the neurosensory retina, independent of clinically observed vascular changes, has been proposed for decades [6]. Bresnick proposed, almost 25 years ago, to redefine diabetic retinopathy as a neurosensory disorder resulting from both metabolic and systemic insults to the retina, in addition to the clinically apparent vascular changes [7]. Many sensitive human electrophysiological measurements of retinal neural function and psychophysical measurements of visual function now indicate that there are early abnormalities that appear before the clinical signs of diabetic retinopathy (vasculopathy) [8–10]. Consistent with this, results obtained in animal models of diabetes show that

there are increased inflammatory factors, structural changes of the glia, and ganglion cell apoptosis in the retina before there are overt vascular changes associated with clinical retinopathy [11].

THE NEED TO GO BEYOND VISUAL ACUITY

AND BEYOND FOVEAL FUNCTION

The Early Efforts

For almost three decades, research in our laboratory has involved the pursuit of retinal function and vision markers early in, or preceding, the diabetes complications of the retina. Quite clearly, visual acuity and visual fields are poor candidates, being quite late consequences of retinal vascular complications. Indeed, visual acuity is reduced only with edema in the foveal area of the macula, or as a result of fairly obstructive retinal/ vitreous hemorrhages. For more than a century, there had been clinical reports of blue– yellow color vision changes in diabetes, even with foveal testing with fairly traditional clinical tests. Based on this, we began our first studies trying to isolate the vision function underlying specific cone photoreceptor types using a suprathreshold variation of the “two-color threshold” technique known to allow individual populations of cone receptor activity to be manifest in vision measures. In the early 1980s, we found quite dramatic reductions in the blue cone (S cone) sensitivity when deep violet patches of light were detected only by S cones against a bright yellow background [12, 13]. These losses of blue cone system sensitivity were even present prior to the clinically observable onset of the vascular retinopathy of diabetes. Later, we developed a method to make these same measurements across the retina and found losses in localized areas across the central 50° of the retina [14, 15]. [Parenthetically, our work on this followed on with Chris Johnson, then at UC Davis and led to the development of “blue-cone” (S cone) automated perimetry [16], which later was referred to as SWAP perimetry [17] with many applications in glaucoma patient management.]

In patients with diabetes, we much later reported that blue-cone perimetry revealed about 40% of central visual field zones as abnormal in the patients who had mild to moderate retinopathy and even 20% abnormal in the retinas of those with diabetes and no retinopathy [18]. However, disappointingly, we found little correlation of these field abnormalities with the locations of visible retinopathy.

Some Breakthroughs

By marked contrast, our first efforts with measuring local neural function across the retina with a newly emerging tool, the multifocal electroretinogram (mfERG), provided clear association of abnormal neural function (observed as delays in the local mfERG responses) with visible retinopathy [19]. This encouraged us to pursue the measures further with both cross-sectional and longitudinal studies. With evidence of association of neural dysfunction and visible retinopathy, the correlation between abnormality and retinopathy severity and the observation that many patches of retina without retinopathy had abnormal mfERG responses [19], we enrolled patients without retinopathy and with minimal retinopathy. Our goal was to see if the abnormal mfERG delays were present in