Central and Peripheral Nervous System changes as markers of disease progression in Multiple Sclerosis

Background: Multiple Sclerosis (MS) is an autoimmune and chronic neuroinflammatory demyelinating disorder of the central nervous system (CNS). Some studies have indicated that the peripheral nervous system (PNS) is also affected by MS. Nonetheless, the potential impact of MS on PNS is not fully understood. Demyelination leads to impaired neural conduction which contributes to neurodegeneration, neuro-axonal damage leading to neurological disabilities. These changes lead to neuromuscular impairments, such as reduced muscle strength, resulting in a reduced walking capacity, which is found in 75 % of persons with MS (PwMS).
Fampridine, which acts in both the CNS and PNS, inhibits potassium channels in demyelinated axons, preventing the efflux of potassium, which leads to improved nerve conduction and neurotransmitter release. It is the only pharmacological agent approved for the treatment of walking impairments in PwMS. However, only 35 – 43 % of PwMS are responders to treatment with Fampridine. Currently, there are no established predictors of Fampridine responsiveness in PwMS.

Purpose: The aims of this thesis are therefore (1) to identify neurophysiological impairments of motor pathways of the CNS and PNS in PwMS and healthy controls by doing a systematic review of the literature (Paper I), (2) to compare physical and cognitive performance, neurophysiological, and magnetic resonance imaging (MRI) outcomes of responders and non- responders to Fampridine treatment in PwMS (Paper IIa), (3) to compare performance, cognitive, neurophysiological and MRI outcomes of persons with relapsing-remitting (RRMS) and progressive MS (PMS), and examining associations between physical and cognitive performance, neurophysiological and MRI outcomes and the extended disability status scale (EDSS) and 12-item MS walking scale (MSWS-12) in the entire study population (Paper IIb), and (4) to compare longitudinal treatment responses to Fampridine treatment in responders and non-responders, on physical and cognitive performance, neurophysiological, and magnetic resonance imaging (MRI) outcomes (Paper III).

Methods: In Paper I, a systematic review of the literature was conducted of studies comparing neurophysiological outcomes in PwMS and healthy controls (HC). Reviewed studies compared the CNS function with transcranial magnetic stimulation (TMS) elicited motor evoked potentials (MEPs), PNS function comprised of electroneuronography (ENG), and neuromuscular function comprised of maximal voluntary contraction of muscle. In Paper IIa and IIb, 49 participants were included, of which, 41 were responders to Fampridine treatments and 8 were non-responders. The study population consisted of 27 PwMS with RRMS and 22 with PMS. Responsiveness to Fampridine treatment was established prior to inclusion. The participants underwent physical performance tests (Timed 25-Foot Walk Test (T25FW), Six Spot Step Test (SSST), Nine-Hole Peg Test (9-HPT), Five Times Sit-to-stand Test (5-STS)), cognitive performance test (Symbol Digit Modalities Test (SDMT)), TMS-elicited MEPs, and ENG examinations of the peroneal and tibial nerves. Brain MRI outcomes of brain volume, number- and volume T2-weighted lesions (lesion load), and lesion load normalized to brain volume were collected. In Paper III, 47 participants underwent a follow-up of physical and cognitive performance tests, neurophysiological examinations, and brain MRI.

Results: In the systematic review (Paper I), we identified prolonged central motor conduction times (CMCT), asymmetry of central motor conduction pathways, and prolonged motor evoked potential (MEP) latencies in PwMS, when compared to HC. Resting motor threshold, amplitude, and cortical silent periods in MEP showed conflicting results as did the ENG tests of the PNS. Furthermore, impairments in muscle activation were observed in PwMS. Paper IIa and IIb identified no cross-sectional differences between responders and non-responders to Fampridine treatment regarding physical performance, neurophysiology of the CNS and PNS, or MRI outcomes. Participants with RRMS performed better than PMS in walking (measured by the SSST), manual dexterity, and cognitive processing speed (measured by SDMT). In the entire study population, CMCT was associated with EDSS, MSWS-12, T25FW, and SSST. SDMT was associated with the number and volume of T2-weighted lesions, and lesion load normalized to brain volume. In Paper III longitudinal data demonstrated prolonged CMCT and PMCT in non-responders to Fampridine. MSWS-12 was associated with walking tests, unlike the EDSS. CMCT was associated with EDSS and MSWS-12, while the SDMT was associated with the number of T2-weighted lesions, lesion load, and lesion load normalized to brain volume.

Conclusions: The findings of the present thesis add to the understanding of underlying disease mechanisms in MS leading to different responsiveness to Fampridine treatment. PMCT may be a marker for Fampridine responsiveness. Furthermore, this present thesis may suggest that transcranial magnetic stimulation (TMS) elicited MEPs is a potential future marker of disability and walking impairment. SDMT can also be applied as a screening tool in PwMS as it is associated with white matter lesions visualized by MRI.