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Gregory Lihau Fu, Steven L Bernstein; Clinical and experimental evidence for post-stroke demyelination in nonarteritic anterior ischemic optic neuropathy (NAION). Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4868.
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© ARVO (1962-2015); The Authors (2016-present)
Many NAION patients experience a progressive decline in vision during the first three months post-infarct, but the mechanism for this decline is poorly understood. Using visual evoked potentials (VEPs), our lab recently determined that isolated optic nerves (ONs) from the rat NAION (rAION) model exhibit both reduced VEP amplitudes and slowing of conduction velocity. We wanted to test the hypothesis that post-infarct ON demyelination could be responsible for progressive post-infarct vision loss with preservation of axons using animal models and a human donor diagnosed with NAION.
We analyzed ON tissue sections from rAION models, primate NAION (pAION) models, and a human donor previously diagnosed with bilateral NAION. Controls included tissue from uninduced contralateral eyes, and tissue from human donors without history of eye disease. We evaluated demyelination using both ON ultrastructure analysis via transmission electron microscopy (TEM), and immunohistochemistry for axons (SMI312) and myelin basic protein (MBP). We evaluated myelin thicknesses, and demyelination ratios were measured from TEM images using measuring wheel and architectural scale (Scalex MapWheel at a scale of 1:1500).
TEM analysis and quantification revealed marked signs of axonal loss and demyelination post-stroke in both rAION and pAION models. At both 1650x and 6500x magnifications, there was noticeable myelin loss and unwinding in individual ON axons in the presence of normal and healthy axons. Demyelination ratios were significantly different (p<0.0001) between the pAION model and controls, regardless of axon size (n=42 per size): small, 72.8±4.0%; medium, 73.8 ±3.9%; large 78.7±3.8% . Immunohistochemistry analysis of pAION ON slices demonstrated discernible areas of both healthy myelinated axons and demyelinated functional axons.
NAION and its models induce post-infarct demyelination with regional axonal preservation seen in the NAION animal models. Our results are consistent with previously determined VEP results, suggesting that ON axonal demyelination likely contributes to visual loss. Useful future treatments for NAION may focus on preventing or reducing the demyelination component of ON damage, and provide an alternative novel treatment option for improving progressive vision loss in NAION patients after the initial ischemic event.
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