Abstract
Optic neuritis is a frequent first symptom of multiple sclerosis (MS) for which corticosteroids are a widely employed treatment option. The Optic Neuritis Treatment Trial (ONTT) reported that corticosteroid treatment does not improve long-term visual acuity, although the evolution of underlying pathologies is unclear. In this study, we employed non-invasive diffusion basis spectrum imaging (DBSI)-derived fiber volume to quantify 11% axonal loss 2 months after corticosteroid treatment (vs. baseline) in experimental autoimmune encephalomyelitis mouse optic nerves affected by optic neuritis. Longitudinal DBSI was performed at baseline (before immunization), after a 2-week corticosteroid treatment period, and 1 and 2 months after treatment, followed by histological validation of neuropathology. Pathological metrics employed to assess the optic nerve revealed axonal protection and anti-inflammatory effects of dexamethasone treatment that were transient. Two months after treatment, axonal injury and loss were indistinguishable between PBS- and dexamethasone-treated optic nerves, similar to results of the human ONTT. Our findings in mice further support that corticosteroid treatment alone is not sufficient to prevent eventual axonal loss in ON, and strongly support the potential of DBSI as an in vivo imaging outcome measure to assess optic nerve pathology.
Highlights
Multiple sclerosis (MS) is an inflammatory demyelinating disease affecting the central nervous system (CNS), including brain, optic nerves, and spinal cord
Two PBS-treated EAE mice died before the Magnetic resonance imaging (MRI) scan at 1 month after treatment
We used diffusion basis spectrum imaging (DBSI) to assess the effects of 2-week Dex treatment on optic nerve integrity in murine Optic neuritis (ON) serially over the subsequent 2 months, with immunohistochemistry at the conclusion of study time course to assess optic nerve neuropathology
Summary
Multiple sclerosis (MS) is an inflammatory demyelinating disease affecting the central nervous system (CNS), including brain, optic nerves, and spinal cord. Corticosteroids are thought to shorten duration of MS relapses but not to alter the long-term outcome. The seminal Optic Neuritis Treatment Trial (ONTT) reported no long-term functional benefits from either intravenous or oral corticosteroid treatment of acute ON, but did find expedited recovery of visual function (Valberg et al, 1981; Gal et al, 2015). Known adverse effects of corticosteroids in humans are many, including reduced glucose metabolism, cataract formation, joint injury and loss of bone density. We have taken a longitudinal and non-invasive imaging assessment of the evolution of optic nerve pathology in murine ON, culminating in histological assessment, to improve the understanding of the impact of corticosteroid treatment
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