A new role for evoked potentials in MS? Repurposing evoked potentials as biomarkers for clinical trials in MS

Hardmeier, Martin; Leocani, Letizia; Fuhr, Peter

doi:10.1177/1352458517707265

Cited by 73 publications

(69 citation statements)

References 65 publications

(103 reference statements)

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“…Implementation of neurophysiological examinations in clinical practice, with the aim of monitoring disease activity, may be useful. Several parameters have shown the ability to detect changes correlated to clinical and subclinical symptoms in PwMS, as most clinical symptoms of MS are related to alteration in impulse conduction in the CNS 81‐83 . Furthermore, some parameters have proven useful in discriminating between PwMS and HC, but also between MS subtypes.…”

Section: Discussionmentioning

confidence: 99%

Neurophysiological impairments in multiple sclerosis—Central and peripheral motor pathways

et al. 2020

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A systematic review of the literature was conducted comparing neurophysiological outcomes in persons with multiple sclerosis (PwMS) to healthy controls (HC), in studies of the central nervous system (CNS) function comprising motor evoked potentials (MEP) elicited by transcranial magnetic stimulation (TMS) and in studies of the peripheral nervous system (PNS) function comprising electroneuronography (ENG) outcomes elicited by peripheral nerve stimulation. Studies comparing neuromuscular function, assessed during maximal voluntary contraction (MVC) of muscle, were included if they reported muscle strength along with muscle activation by use of electromyography (EMG) and/or interpolated twitch technique (ITT). Studies investigating CNS function showed prolonged central motor conduction times, asymmetry of nerve conduction motor pathways, and prolonged latencies in PwMS when compared to HC. Resting motor threshold, amplitude, and cortical silent periods showed conflicting results. CNS findings generally correlated with disabilities. Studies of PNS function showed near significant prolongation in motor latency of the median nerve, reduced nerve conduction velocities in the tibial and peroneal nerves, and decreased compound muscle action potential amplitudes of the tibial nerve in PwMS. ENG findings did not correlate with clinical severity of disabilities. Studies of neuromuscular function showed lower voluntary muscle activation and increased central fatigue in PwMS, whereas EMG showed divergent muscle activation (ie, EMG amplitude) during MVC. When comparing the existing literature on neurophysiological motor examinations in PwMS and HC, consistent and substantial impairments of CNS function were seen in PwMS, whereas impairments of the PNS were less pronounced and inconsistent. In addition, impairments in muscle activation were observed in PwMS.

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Section: Discussionmentioning

confidence: 99%

Neurophysiological impairments in multiple sclerosis—Central and peripheral motor pathways

et al. 2020

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“…Beside methodological differences, discrepancies in the results of these two studies nicely illustrate the second aforementioned problem. Different studies used different numbers and different combinations of EP modalities, and although the severity of each EP score significantly correlated with the corresponding functional system score of the EDSS, this was not the case with AEPs, which have shown the weakest association to future disability and have a low overall frequency of abnormal conduction in MS . The brainstem is an incredibly complex structure with a very large number of neural pathways crossing it, and MS lesions can often be only a few millimetres large .…”

Section: Discussionmentioning

confidence: 99%

Evoked potentials can predict future disability in people with clinically isolated syndrome

Crnošija

Gabelić

Barun

et al. 2019

Euro J of Neurology

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Background and purpose The aim was to evaluate whether the addition of evoked potentials (EPs) which evaluate brainstem function to the EP score improves its ability to predict disease progression in people with clinically isolated syndrome (pwCIS). Methods For 94 pwCIS, data on disease activity and progression after 2.9 (1.4–4.1) years of follow‐up were available. Baseline characteristics included magnetic resonance imaging (MRI) parameters, visual EPs, auditory EPs, somatosensory EPs of the median and tibial nerves, vestibular evoked myogenic potentials and tongue somatosensory EPs. Results A multivariable regression model including age, sex, total number of T2 lesions on baseline MRI and EP score >13 showed that the total number of T2 lesions on baseline MRI and EP score >13 increase the likelihood for sustained accumulation of disability (SAD). After controlling for age, sex and the total number of T2 lesions on baseline MRI, the hazard of SAD for participants with EP score >13 is 4.093 times that of participants with EP score ≤13. EP score >13 also increases the likelihood for progression measured with a composite measure of progression which uses the Expanded Disability Status Scale, the nine‐hole peg test and the timed 25‐ft walk (exp(B) = 5.577, 95% confidence interval 1.520–20.468, P = 0.01). Conclusion The addition of EPs that evaluate brainstem function to the EP score enables prediction of the progression of disability in pwCIS.

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“…107 The value of individual EP modalities as an outcome measure in phase 2 clinical trials in progressive MS depends on technical and methodological aspects and on the population under study. 109 It is generally accepted that brainstem auditory EPs (BAEPs) have the lowest sensitivity, 103,108 possibly due to the shortest pathway explored. Visual EPs (VEPs) are more sensitive than optical coherence tomography (OCT) in detecting involvement of the visual pathways in MS. 110 Although useful to quantify improvement after treatment in acute optic neuritis 111 and in chronic demyelination, [112][113][114] VEPs display poor cross-sectional and longitudinal correlation with EDSS, a lower rate of progression compared to lower limb motor EPs (MEPs), 109 and lower value in discriminating patients with active disease compared to OCT. 115 The recently developed technique of multifocal VEPs (mfVEPs) seems more sensitive to local optic nerve damage, 116,117 and more reproducible than standard, full-field VEPs.…”

Section: Electrophysiological Outcomesmentioning

confidence: 99%

Fluid biomarker and electrophysiological outcome measures for progressive MS trials

et al. 2017

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Progressive multiple sclerosis (MS) is characterized by insidious clinical worsening that is difficult to accurately quantify and predict. Biofluid markers and electrophysiological measures are potential candidate outcome measures in clinical trials, allowing the quantification of nervous damage occurring in the disease. Neurofilaments are highly specific neuronal proteins. They may have come closest to such applications by their higher concentrations repeatedly demonstrated in cerebrospinal fluid (CSF) in all stages of MS, during relapses, their responsiveness to disease-modifying treatments in relapsing and progressive MS and their associations with measures of inflammatory and degenerative magnetic resonance imaging (MRI) outcomes. Digital single-molecule array (Simoa) technology improves accuracy of bioassays in the quantification of neurofilament light chain (NfL) in serum and plasma. NfL seems to mark a common final path of neuroaxonal injury independent of specific causal pathways. CSF and blood levels of NfL are highly correlated across various diseases including MS, suggesting that blood measurements may be useful in assessing response to treatment and predicting future disease activity. Other biomarkers like matrix metalloproteinases, chemokines, or neurotrophic factors have not been studied to a similar extent. Such measures, especially in blood, need further validation to enter the trial arena or clinical practice. The broadening armamentarium of highly sensitive assay technologies in the future may shed even more light on patient heterogeneity and mechanisms leading to disability in MS. Evoked potentials (EPs) are used in clinical practice to measure central conduction of central sensorimotor pathways. They correlate with and predict the severity of clinical involvement of their corresponding function. Their validation for use in multicenter studies is still lacking, with the exception of visual EPs. If further validated, EPs and fluid biomarkers would represent useful outcome measures for clinical trials, being related to specific mechanisms of the ongoing pathologic changes.

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A new role for evoked potentials in MS? Repurposing evoked potentials as biomarkers for clinical trials in MS

Cited by 73 publications

References 65 publications

Neurophysiological impairments in multiple sclerosis—Central and peripheral motor pathways

Neurophysiological impairments in multiple sclerosis—Central and peripheral motor pathways

Evoked potentials can predict future disability in people with clinically isolated syndrome

Fluid biomarker and electrophysiological outcome measures for progressive MS trials

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