Remyelination and neuroprotective effects of alemtuzumab therapy in patients with multiple sclerosis

Abstract

Multiple sclerosis (MS) is a demyelinating, inflammatory and potentially degenerative disorder of the central nervous system. Whereas, an initial event triggers immunemediated demyelination in MS, in the secondary progressive phase, axonal degeneration is thought to be due to impaired axoglial interaction, which leads to a gradual worsening of the disability. In the development of an efficient therapeutic strategy for MS, stimulating or enhancing remyelination is important because remyelination leads to improvement in impulse transmission and metabolic support to the underlying axon. Clemastine fumarate and opicinumab, which both target remyelination, have been reported to show reduced visual evoked potentials (VEP) latency in patients with MS and optic neuritis, respectively. Alemtuzumab, a humanised monoclonal antibody against the CD52 antigen, has been reported to be associated with disease stabilisation in patients with highly active relapsingremitting MS. Wang et al report the neuroprotective and remyelinating effects of alemtuzumab administered to patients with relapsing MS and healthy controls (HCs) over 24 months, by using multifocal VEP (mfVEP) and brain MRI. Thirty relapsing patients with MS and 20 HCs were enrolled. The primary endpoint was the change in mfVEP latency, and the secondary endpoints were the changes in low contrast visual acuity and optic radiation (OR) lesion diffusion metrics including axial diffusivity (AD) and fractional anisotropy (FA) over the 24 months. The most important finding of the study was that a mean shortening of mfVEP latency of 1.21 ms was observed in patients with MS treated with alemtuzumab. This finding was not altered after correction for age, gender, disease duration or change in OR T2 lesion volume. Shortening of mfVEP is attributed to the remyelination. Conversely, mean mfVEP was not significantly changed in HCs. For the secondary endpoints, chronic OR T2 lesions in patients with MS revealed an increased normalised FA and AD over the 24 months. Increases in FA and AD are associated with remyelination. These results indicate that alemtuzumab therapy facilitates remyelination in patients with MS. The novelty of the paper is that the study used mfVEP to assess remyelination. Traditionally, remyelination in patients with MS has been evaluated by VEP and brain MRI, including measurement of the magnetisation transfer ratio (MTR). Compared with VEP, mfVEP was reported to be superior in detecting amplitude and latency abnormalities when the affected area was located peripherally. mfVEP has previously been reported to show significant latency recovery in patients with optic neuritis, but this is the first report to use mfVEP for the remyelination assessment in patients with MS. mfVEP has some issues to be resolved, including the requirement for welltrained technicians and standardisation of the analysis of the results; however, it is a promising tool to assess remyelination in patients with MS. It would be desirable to focus on alemtuzumab effect on remyelination in future studies with larger numbers of patients with MS treated with alemtuzumab or placebo and by using MTR and mfVEP measurements.