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      Peripapillary Retinal Nerve Fiber Layer Swelling Predicts Peripapillary Atrophy in a Primate Model of Nonarteritic Anterior Ischemic Optic Neuropathy

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          Abstract

          Purpose

          To determine the relationship between peripapillary retinal nerve fiber layer (PRNFL) swelling and eventual PRNFL atrophy, and between PRNFL swelling/atrophy and neural function, in a nonhuman primate model of nonarteritic anterior ischemic optic neuropathy (pNAION).

          Methods

          pNAION was induced in five normal, adult male rhesus monkeys by laser activation of intravenously injected rose bengal at the optic nerve head. Spectral-domain optical coherence tomography measurements of the PRNFL were performed at baseline; 1 day; 1, 2, and 4 weeks; and several later times over a period of an additional 2 to 3 months. Simultaneous pattern-reversal electroretinograms (PERGs) and visual evoked potentials (VEPs) were recorded and color fundus photographs taken at the same time points.

          Results

          In all cases, initial PRNFL swelling was associated with atrophy, and the greater the initial swelling, the greater the degree of eventual atrophy ( r = 0.65, P = 0.0002). The change in PRNFL thickness closely correlated with VEP amplitude loss ( r = 0.90), although this relationship was only a strong trend ( P = 0.083). Furthermore, VEP amplitude loss closely correlated with PERG N95 amplitude loss ( r = 0.80, P = 0.00002)

          Conclusions

          In our model of human NAION, the degree of initial PRNFL swelling correlated with the severity of atrophy. Areas that did not swell developed little to no atrophy. The amount of PRNFL loss was reflected in VEP and PERG N95 amplitude reductions.

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          Most cited references8

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          ISCEV standard for clinical visual evoked potentials (2009 update).

          Visual evoked potentials (VEPs) can provide important diagnostic information regarding the functional integrity of the visual system. This document updates the ISCEV standard for clinical VEP testing and supersedes the 2004 standard. The major change in this revision is that test parameters have been made more precise to achieve better consistency of results within and between test centers. The ISCEV standard VEP protocols are defined for a single recording channel with a midline occipital active electrode. These protocols are intended for assessment of prechiasmal function; additional electrode sites are recommended for evaluation of chiasmal and postchiasmal function. ISCEV has selected a subset of stimulus and recording conditions that provide core clinical information and can be performed by most clinical electrophysiology laboratories throughout the world. These are: 1. Pattern-reversal VEPs elicited by checkerboard stimuli with large 1 degrees (i.e., 60 min of arc; min) and small 0.25 degrees (15 min) checks. 2. Pattern onset/offset VEPs elicited by checkerboard stimuli with large 1 degrees (60 min) and small 0.25 degrees (15 min) checks. 3. Flash VEP elicited by a brief luminance increment, a flash, which subtends a visual field of at least 20 degrees.
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            Functional and cellular responses in a novel rodent model of anterior ischemic optic neuropathy.

            Anterior ischemic optic neuropathy (AION) is caused by sudden loss of vascular supply to retinal ganglion cell (RGC) axons in the anterior portion of the optic nerve and is a major cause of optic nerve dysfunction. There has been no easily obtainable animal model of this disorder. The current study was conducted to design a novel model of rodent AION (rAION), to enable more detailed study of this disease. A novel rodent photoembolic stroke model was developed that is directly analogous to human AION. Using histologic, electrophysiological, molecular- and cell biological methods, the early changes associated with isolated RGC axonal ischemia were characterized. Functional (electrophysiological) changes occurred in RGCs within 1 day after rAION, with a loss of visual evoked potential (VEP) amplitude that persisted in the long term. The retinal gene expression pattern rapidly changed after rAION induction, with an early (<1 day) initial induction of c-Fos mRNA, and loss of RGC-specific gene expression. RGC-specific protein expression declined 2 days after detectable mRNA level changes, and immunostaining suggested that multiple retinal layers react to isolated RGC axonal ischemia. rAION rapidly results in electrophysiological and histologic changes similar to clinical AION, with reactive responses in primary and supporting neuronal cell layers. The rAION model can enable a detailed analysis of the individual retinal and optic nerve changes that occur after optic nerve stroke, which may be useful in determining possible therapeutic interventions for this disorder.
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              A primate model of nonarteritic anterior ischemic optic neuropathy.

              Nonarteritic anterior ischemic optic neuropathy (NAION) is an optic nerve (ON) stroke and a leading cause of sudden ON-related vision loss. A primate (p)NAION model is crucial to further understanding of the clinical disorder and can provide information regarding the pathophysiology of other central nervous system (CNS) ischemic axonopathies. In the current study, a primate model of NAION was developed, and short-and long-term responses to this condition were characterized. pNAION was induced with a novel photoembolic mechanism. Short-and long-term responses were evaluated by minimally invasive testing (electrophysiology, fundus photography, indocyanine green and fluorescein angiography, and magnetic resonance imaging) and compared with histologic and immunohistochemical findings. Optic disc edema, similar to that observed in cases of human NAION was seen 1 day after induction, with subsequent resolution associated with the development of optic disc pallor. Magnetic resonance imaging (MRI) performed 3 months after induction revealed changes consistent with ON atrophy. Electrophysiological studies and vascular imaging suggest an ON-limited infarct with subsequent axonal degeneration and selective neuronal loss similar to that seen in human NAION. ON inflammation was evident 2 months after induction at the site of the lesion and at distant sites, suggesting that inflammation-associated axonal remodeling continues for an extended period after ON infarct. pNAION resembles human NAION in many respects, with optic disc edema followed by loss of cells in the retinal ganglion cell (RGC) layer and ON remodeling. This model should be useful for evaluating neuroprotective and other treatment strategies for human NAION as well as for other ischemic processes that primarily affect CNS white-matter tracts.
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                Author and article information

                Journal
                Invest Ophthalmol Vis Sci
                Invest. Ophthalmol. Vis. Sci
                iovs
                iovs
                iovs
                Investigative Ophthalmology & Visual Science
                The Association for Research in Vision and Ophthalmology
                0146-0404
                1552-5783
                11 February 2016
                February 2016
                : 57
                : 2
                : 527-532
                Affiliations
                [1 ]Department of Ophthalmology and Visual Sciences, University of Maryland School of Medicine, Baltimore, Maryland, United States
                [2 ]The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
                [3 ]Department of Veterinary Resources, University of Maryland School of Medicine, Baltimore, Maryland, United States
                [4 ]Department of Anatomy & Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland, United States
                Author notes
                Correspondence: Mary A. Johnson, Department of Ophthalmology and Visual Sciences, University of Maryland, Baltimore, 10 S. Pine Street, Suite 5-00A MSTF, Baltimore, MD 21201, USA; maryjohnson@ 123456som.umaryland.edu .
                Article
                iovs-57-01-65 IOVS-15-17880
                10.1167/iovs.15-17880
                4758301
                26868755
                e98e3d9e-8184-4b14-93c3-d3478f35ec58

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

                History
                : 4 August 2015
                : 12 January 2016
                Categories
                Eye Movements, Strabismus, Amblyopia and Neuro-Ophthalmology

                anterior ischemic optic neuropathy,optical coherence tomography,nerve fiber layer thickening,animal model,visual evoked potential

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