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      Peripapillary Retinal Nerve Fiber Layer Changes in Preclinical Diabetic Retinopathy: A Meta-Analysis

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          Abstract

          Background

          Diabetic retinopathy is a microvascular neurodegenerative disorder in diabetic patients. Peripapillary retinal nerve fiber layer changes have been described in patients with preclinical diabetic retinopathy, but study results have been inconsistent.

          Objective

          To assess changes in peripapillary retinal nerve fiber layer thickness in diabetic patients with preclinical diabetic retinopathy.

          Methods

          A literature search was conducted through PubMed, EMBASE, Web of Science and Cochrane Library. Case-control studies on RNFL thickness in preclinical diabetic retinopathy patients and healthy controls were retrieved. A meta-analysis of weighted mean difference and a sensitivity analysis were performed using RevMan 5.2 software.

          Results

          Thirteen case-control studies containing 668 diabetic patients and 556 healthy controls were selected. Peripapillary RNFL thickness was significantly reduced in patients with preclinical diabetic retinopathy compared to healthy controls in studies applying Optical Coherence Tomography (-2.88μm, 95%CI: -4.44 to -1.32, P = 0.0003) and in studies applying Scanning Laser Polarimeter (-4.21μm, 95%CI: -6.45 to -1.97, P = 0.0002). Reduction of RNFL thickness was significant in the superior quadrant (-3.79μm, 95%CI: -7.08 to -0.50, P = 0.02), the inferior quadrant (-2.99μm, 95%CI: -5.44 to -0.54, P = 0.02) and the nasal quadrant (-2.88μm, 95%CI: -4.93 to -0.82, P = 0.006), but was not significant in the temporal quadrant (-1.22μm, 95%CI: -3.21 to 0.76, P = 0.23), in diabetic patients.

          Conclusion

          Peripapillary RNFL thickness was significantly decreased in preclinical diabetic retinopathy patients compared to healthy control. Neurodegenerative changes due to preclinical diabetic retinopathy need more attention.

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          Most cited references40

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          Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group.

          (1985)
          Data from the Early Treatment Diabetic Retinopathy Study (ETDRS) show that focal photocoagulation of "clinically significant" diabetic macular edema substantially reduces the risk of visual loss. Focal treatment also increases the chance of visual improvement, decreases the frequency of persistent macular edema, and causes only minor visual field losses. In this randomized clinical trial, which was supported by the National Eye Institute, 754 eyes that had macular edema and mild to moderate diabetic retinopathy were randomly assigned to focal argon laser photocoagulation, while 1,490 such eyes were randomly assigned to deferral of photocoagulation. The beneficial effects of treatment demonstrated in this trial suggest that all eyes with clinically significant diabetic macular edema should be considered for focal photocoagulation. Clinically significant macular edema is defined as retinal thickening that involves or threatens the center of the macula (even if visual acuity is not yet reduced) and is assessed by stereo contact lens biomicroscopy or stereo photography. Follow-up of all ETDRS patients continues without other modifications in the study protocol.
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            Death of retinal neurons in streptozotocin-induced diabetic mice.

            Neuronal cell death has been reported in retinas of humans with diabetic retinopathy and in diabetic rat models. Little is known about neuronal cell death in mouse models of diabetic retinopathy. This study was designed to determine whether neurons are lost in diabetic mouse retinas and whether the loss involves an apoptotic process. Three-week-old C57Bl/6 mice were made diabetic with streptozotocin. They were studied over the course of 14 weeks after onset of diabetes. Eyes were processed for morphometric analysis and detection of apoptotic cells by TUNEL analysis and activated caspase-3 and were subjected to electron microscopy. Morphometric analysis of retinal cross sections of mice that had been diabetic 14 weeks showed approximately 20% to 25% fewer cells in the ganglion cell layer compared with age-matched control mice. There was a modest, but significant, decrease in the thickness of the whole retina and the inner and outer nuclear layers in mice that had been diabetic for 10 weeks. TUNEL analysis and detection of active caspase-3 revealed that cells of the ganglion cell layer were dying by apoptosis. Electron microscopic analysis detected morphologic features characteristic of apoptosis, including margination of chromatin and crenated nuclei of cells in the ganglion cell layer. The data suggest that in diabetic mouse retinas, neurons in the ganglion cell layer die, and this death occurs through an apoptotic pathway. Diabetic mice may be appropriate and valuable models for studies of neuronal cell death in diabetes. Copyright Association for Research in Vision and Ophthalmology
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              Glial reactivity, an early feature of diabetic retinopathy.

              To characterize early structural gliotic reactions in retinal Müller cells, astrocytes, and microglia in experimentally induced diabetes. Rats were rendered diabetic by streptozotocin injection and killed after 2, 4, 12, or 20 weeks. Cell densities were determined in flatmounted retinas or transverse semithin sections. Expression of glial fibrillary acidic protein (GFAP) was localized on frozen sections or flatmounts by immunofluorescence and confocal microscopy, and GFAP content was evaluated by Western blot analysis. Microglial cells were visualized by binding of isolectin B4 or staining with antibodies to phosphotyrosine residues. The integrity of the blood-retinal barrier was assessed by intravenous injection of Evans blue. The density of Müller cells and microglia was significantly increased at 4 weeks of diabetes compared with nondiabetic controls. GFAP expression in Müller cells was not detected at 4 weeks but was prominent at 12 weeks. The number of astrocytes was significantly reduced at 4 weeks in the peripapillary and far peripheral retina. Shape changes of microglial cells indicated functional activation. Leakage of the blood-retinal barrier was observed at 2 weeks of hyperglycemia, the earliest time point investigated. The leakage of the blood-retinal barrier before glial reactivity suggests that glia are early targets of vascular hyperpermeability. The individual glial cell types react differentially to the diabetic state. Müller cells undergo hyperplasia preceding GFAP expression, and microglial cells are activated, whereas astrocytes regress. This glial behavior may contribute decisively to the onset and development of neuropathy in the diabetic retina.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                12 May 2015
                2015
                : 10
                : 5
                : e0125919
                Affiliations
                [001]Department of Ophthalmology, Chinese PLA General Hospital, Beijing, China
                Queen's University Belfast, UNITED KINGDOM
                Author notes

                Competing Interests: The authors have declared that no competing interest exist.

                Conceived and designed the experiments: MZ SW XC. Performed the experiments: XC CN YG MZ. Analyzed the data: YZ XJ. Wrote the paper: XC MZ.

                Article
                PONE-D-14-49708
                10.1371/journal.pone.0125919
                4429076
                25965421
                f544b845-9a32-47c2-b05c-f185401b3038
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 27 November 2014
                : 17 March 2015
                Page count
                Figures: 7, Tables: 2, Pages: 12
                Funding
                The authors have no support or funding to report.
                Categories
                Research Article
                Custom metadata
                All relevant data are within the paper and its supporting information files.

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