Evoked potentials as a biomarker of remyelination

Abstract

Multiple sclerosis (MS) is a common cause of neurologic disease in young adults that is primarily treated with disease-modifying therapies which target the immune and inflammatory responses. Promotion of remyelination has opened a new therapeutic avenue, but how best to determine efficacy of remyelinating drugs remains unresolved. Although prolongation and then shortening of visual evoked potential (VEP) latencies in optic neuritis in MS may identify demyelination and remyelination, this has not been directly confirmed. We recorded VEPs in a model in which there is complete demyelination of the optic nerve, with subsequent remyelination. We examined the optic nerves microscopically during active disease and recovery, and quantitated both demyelination and remyelination along the length of the nerves. Latencies of the main positive component of the control VEP demonstrated around 2-fold prolongation during active disease. VEP waveforms were nonrecordable in a few subjects or exhibited a broadened profile which precluded peak identification. As animals recovered neurologically, the VEP latencies decreased in association with complete remyelination of the optic nerve but remained prolonged relative to controls. Thus, it has been directly confirmed that VEP latencies reflect the myelin status of the optic nerve and will provide a surrogate marker in future remyelination clinical trials.

Validation of Quantitative Scores Derived From Motor Evoked Potentials in the Assessment of Primary Progressive Multiple Sclerosis: A Longitudinal Study

“…Moreover, compensatory mechanisms may allow patients still to function, although marked damage has already occurred ( 29 ). In contrast, EPs are closely linked to the pathophysiology of disturbed signal conduction ( 7 , 8 , 14 ), regardless of whether delayed responses are clinically symptomatic or remain subclinical. The transformation of such subclinical pathology into clinical disability is the most likely explanation for the prognostic power of multimodal EP assessment [review in ( 9 )].…”

“…Evoked potentials yield complementary information to clinical assessment as they are closely related to demyelination and measure subclinical changes, which may transform only later into clinical disability. Animal models have not only shown close correlations between demyelination and latency delay ( 6 ), but also between the recovery of delayed latencies with remyelination, bidirectionally paralleled by clinical function ( 7 , 8 ). Several clinical studies have reported that scores from multimodal EP are predictive of disease course in relapsing and progressive multiple sclerosis (MS) [review in ( 9 )], and short-term test–retest variability is reasonably low for quantitative EP scores (qEPS) ( 10 ).…”

Dynamics of Central Remyelination and Treatment Evolution in a Model of Multiple Sclerosis with Optic Coherence Tomography

“…Six-week-old female C57/BL6 mice, bred at the CIB Margarita Salas-CSIC, were induced for EAE as has been done by our research group for a decade [ 68 , 69 , 70 , 71 ]. Mice were divided into three experimental groups as follows: EAE-VP3.15 (compound-treated EAE animals; n = 10), EAE-Vehicle (non-treated EAE animals; abbreviated as EAE-Veh; n = 7) and SHAM (same procedure as EAE animals except the MOG injection; n = 13).…”

Treatment Optimization in Multiple Sclerosis: Canadian MS Working Group Recommendations

“…Other paraclinical testing may include OCBs in CSF; examination of the visual system (e.g., evoked potentials, OCT) will help to characterize demyelination and may be useful in diagnosis and prognosis. [62][63][64] These measures may help to identify patients at higher risk of early worsening who may be candidates for a more aggressive treatment planeither initiation with a higher-efficacy agent, or closer monitoring and earlier planned escalation. A patient's risk status may become more apparent in the first few years after diagnosis so vigilance is needed to identify ongoing disease activity that may necessitate a prompt change to a more effective agent.…”