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Vascular Changes and Neurodegeneration in the Early Stages of Diabetic Retinopathy: Which Comes First?

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      Introduction: Neurodegeneration is an early component of diabetic retinopathy (DR). It is unclear whether neurodegeneration is an independent factor or a consequence of damaged retinal vasculature. The aims of this study were to review the literature concerning neurodegeneration in diabetic patients without or with early DR, and to examine whether neurodegeneration precedes visible vasculopathy in the pathogenesis of DR. Methods: A systematic literature search was performed to identify studies which used optical coherence tomography (OCT) or multifocal electroretinography (mfERG) to detect neurodegeneration in patients with no or mild DR as compared to healthy controls. Outcome measures were mean retinal thickness (RT), mean retinal nerve fiber layer (RNFL) thickness and ganglion cell layer (GCL) thickness. Also, mfERG amplitude and implicit time were analyzed. Results: Eleven studies which used mfERG and/or OCT to detect neurodegeneration were included. Two OCT studies found significant thinning of RT, 2 found thinning of RNFL, whereas 1 found thickening of RT, RNFL and GCL in patients without DR. Two mfERG studies found a significant delay of implicit time in the same patient group. Retinal thinning and delay of implicit time were also detected in patients with mild DR. Conclusion: Retinal neurodegeneration is an early component of DR, which can precede visible vasculopathy.

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      Most cited references 26

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      Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales.

      To develop consensus regarding clinical disease severity classification systems for diabetic retinopathy and diabetic macular edema that can be used around the world, and to improve communication and coordination of care among physicians who care for patients with diabetes. Report regarding the development of clinical diabetic retinopathy disease severity scales. A group of 31 individuals from 16 countries, representing comprehensive ophthalmology, retina subspecialties, endocrinology, and epidemiology. An initial clinical classification system, based on the Early Treatment Diabetic Retinopathy Study and the Wisconsin Epidemiologic Study of Diabetic Retinopathy publications, was circulated to the group in advance of a workshop. Each member reviewed this using e-mail, and a modified Delphi system was used to stratify responses. At a later workshop, separate systems for diabetic retinopathy and macular edema were developed. These were then reevaluated by group members, and the modified Delphi system was again used to measure degrees of agreement. Consensus regarding specific classification systems was achieved. A five-stage disease severity classification for diabetic retinopathy includes three stages of low risk, a fourth stage of severe nonproliferative retinopathy, and a fifth stage of proliferative retinopathy. Diabetic macular edema is classified as apparently present or apparently absent. If training and equipment allow the screener to make a valid decision, macular edema is further categorized as a function of its distance from the central macula. There seems to be a genuine need for consistent international clinical classification systems for diabetic retinopathy and diabetic macular edema that are supported with solid evidence. The proposed clinical classification systems provide a means of appropriately categorizing diabetic retinopathy and macular edema. It is hoped that these systems will be valuable in improving both screening of individuals with diabetes and communication and discussion among individuals caring for these patients.
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        A new view of diabetic retinopathy: a neurodegenerative disease of the eye.

         Cheryl Barber (2003)
        Diabetic retinopathy (DR) is a common complication of diabetes and a leading cause of legal blindness in working-age adults. The clinical hallmarks of DR include increased vascular permeability, leading to edema, and endothelial cell proliferation. Much of the research effort has been focused on vascular changes, but it is becoming apparent that other degenerative changes occur beyond the vascular cells of the retina. These include increased apoptosis, glial cell reactivity, microglial activation, and altered glutamate metabolism. When occurring together, these changes may be considered as neurodegenerative and could explain some of the functional deficits in vision that begin soon after the onset of diabetes. This review will present the current evidence that neurodegeneration of the retina is a critical component of DR. There are two basic hypotheses that account for loss of cells in the neural retina. First, the loss of blood-retinal barrier integrity, which initially manifests as an increase in vascular permeability, causes a failure to control the composition of the extracellular fluid in the retina, which in turn leads to edema and neuronal cell loss. Alternatively, diabetes has a direct effect on metabolism within the neural retina, leading to an increase in apoptosis, which in turn causes breakdown of the blood-retinal barrier. It is not clear which hypothesis will be found to be correct, and, in fact, it is likely that vascular permeability and neuronal apoptosis are closely linked components of DR. However, the gradual loss of neurons suggests that progress of the disease is ultimately irreversible, since these cells cannot usually be replaced. In light of this possibility, new treatments for DR should be preventive in nature, being implemented before overt clinical symptoms develop. While vascular permeability is the target that is primarily considered for new treatments of DR, evidence presented here suggests that apoptosis of neurons is also an essential target for pharmacological studies. The vision of people with diabetes will be protected only when we have discovered a means to prevent the gradual but constant loss of neurons within the inner retina.
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          Grading Diabetic Retinopathy from Stereoscopic Color Fundus Photographs—An Extension of the Modified Airlie House Classification


            Author and article information

            aResearch Unit of Ophthalmology, Institute of Clinical Research, University of Southern Denmark, and bDepartment of Ophthalmology, Odense University Hospital, Odense, Denmark
            Ophthalmic Res
            Ophthalmic Research
            Ophthalmic Res
            S. Karger AG (Basel, Switzerland karger@ )
            May 2016
            02 April 2016
            : 56
            : 1
            : 1-9
            Ophthalmic Res 2016;56:1-9
            © 2016 S. Karger AG, Basel

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            Figures: 1, Tables: 7, References: 30, Pages: 9
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