Non‐invasive visual evoked potentials to assess optic nerve involvement in the dark agouti rat model of experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein

Abstract

Experimental autoimmune encephalomyelitis (EAE) is the primary disease model of multiple sclerosis (MS), one of the most diffused neurological diseases characterized by fatigue, muscle weakness, vision loss, anxiety and depression. EAE can be induced through injection of myelin peptides to susceptible mouse or rat strains. In particular, EAE elicited by the autoimmune reaction against myelin oligodendrocyte glycoprotein (MOG) presents the common features of human MS: inflammation, demyelination and axonal loss. Optic neuritis affects visual pathways in both MS and in several EAE models. Neurophysiological evaluation through visual evoked potential (VEP) recording is useful to check visual pathway dysfunctions and to test the efficacy of innovative treatments against optic neuritis. For this purpose, we investigate the extent of VEP abnormalities in the dark agouti (DA) rat immunized with MOG, which develops a relapsing-remitting disease course. Together with the detection of motor signs, we acquired VEPs during both early and late stages of EAE, taking advantage of a non-invasive recording procedure that allows long follow-up studies. The validation of VEP outcomes was determined by comparison with ON histopathology, aimed at revealing inflammation, demyelination and nerve fiber loss. Our results indicate that the first VEP latency delay in MOG-EAE DA rats appeared before motor deficits and were mainly related to an inflammatory state. Subsequent VEP delays, detected during relapsing EAE phases, were associated with a combination of inflammation, demyelination and axonal loss. Moreover, DA rats with atypical EAE clinical course tested at extremely late time points, manifested abnormal VEPs although motor signs were mild. Overall, our data demonstrated that non-invasive VEPs are a powerful tool to detect visual involvement at different stages of EAE, prompting their validation as biomarkers to test novel treatments against MS optic neuritis.Castoldi et al VEPs in preclinical models of multiple sclerosis Brain Pathology 30 (2020) 137-150

Non-invasive visual evoked potentials under sevoflurane versus ketamine-xylazine in rats

“…Accordingly, VEPs under ketamine-xylazine displayed a significantly higher SNR. As already reported in previous studies ( Santangelo et al., 2018 ; Castoldi et al., 2020 ), N1 was the only VEP component always clearly detectable under sevoflurane, while P1 and P2 were less recognisable, even if still present. On the other side, with ketamine-xylazine it was possible to easily identify the peaks of all main VEP components.…”

“…Human subjects can undergo VEP recording in awake state ( Holder et al., 2010 ), whereas small animals, such as rodents, generally need anaesthesia to better control stimuli presentation, avoid movements and minimize external noise sources. Different types of anaesthetics or sedatives have been used to perform VEPs in animals, such as halothane ( Imas et al., 2004 ), sevoflurane ( Castoldi et al., 2020 ), isoflurane ( Aggarwal et al., 2019 ), urethane ( Porciatti et al., 1999 ), ketamine-xylazine ( Roth et al., 2018 ; Land et al., 2019 ), pentobarbital ( Maertz et al., 2006 ), fentanyl ( Kuroda et al., 2009 ), detomidine ( Ström and Ekesten, 2016 ), chloral hydrate ( Siegel et al., 1993 ), and morphine ( Kuroda et al., 2009 ). The focus of this work is the examination of VEP property changes depending on two types of anaesthesia.…”

Progressive hemifacial atrophy with characteristic ocular manifestations in a Chinese patient with aCRB1mutation

“…The abnormal pupillary light reflex suggested that the patient exhibited optic nerve abnormalities; these were investigated by electroretinography and VEP assessment. Delayed VEP latency was found in the affected eye; this was suggestive of demyelination in the visual pathway, 6 , 7 and confirmed that the affected eye exhibited optic nerve abnormalities (Table 1). The patient confirmed that these ocular findings and the abovementioned bone and skin findings were not present in other members of his family.…”

Functional evolution of visual involvement in experimental autoimmune encephalomyelitis

“…To investigate demyelination, axonal loss and microglia/macrophage cells, the optic nerve sections were stained with Luxol Fast Blue (LFB), SMI 312 and Iba 1, respectively. Demyelination and axonal loss were quantified as a percentage of damaged area on the whole optic nerve section, as previously reported, 26 using the following formula: demyelination area ðorÞ axonal loss area total optic nerve section area  100…”