Natalizumab Demonstrates Significant Impacts on Motor Fatigue in Relapsing MS

Two weeks after natalizumab infusion, patients demonstrated significantly less central fatigue, with a trend for a reduction in supraspinal fatigue, among other notable findings.

By modulating cortical network dynamics, preliminary findings from a study of patients with multiple sclerosis (MS) demonstrated that treatment with natalizumab (Tysabri; Biogen), an FDA-approved recombinant humanized antibody, improved motor function in weeks following infusion.1

In a cohort of 24 patients with relapsing-remitting MS, treatment with natalizumab resulted in significantly lower Fatigue Symptoms and Impacts Questionnaire score (P = .003) significantly higher motor endurance index (P = .049), significantly less central fatigue (P = .034) and a trend for a reduction in supraspinal fatigue (P = 0.05) in the 14 days after infusion. These findings were presented by senior author Anna Conte, MD, associate professor, Sapienza University of Rome, at the 38th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), October 26-28, in Amsterdam, Netherlands.

Natalizumab, an approved therapeutic for relapsing MS since 2004, has been previously shown to reduce inflammation, lending to the hypothesis that the agent could have an impact on fatigue symptoms. To test this hypothesis, 24 participants were assessed on clinical scales 7 (±2) days before (T0) and 14 (±2) days after (T1) natalizumab infusion. They were first asked to perform repeated blocks of first dorsal interosseous muscle (FDA) maximal voluntary contraction (MVC) until exhaustion. The motor endurance index was measured as the number of completed blocks and force exerted, normalized across participants.

Peripheral, central, and supraspinal motor fatigue were assessed by twitch interpolation methods using peripheral nerve stimulation and transcranial magnetic stimulation (TMS) over the primary motor cortex. Additionally, using a means of source reconstructed TMS-evoked potential (TEP), investigators assessed sensorimotor network activation. Fatigue-related changes in brain networks resting connectivity was analyzed by means of resting-state EEG-based small world index (SWI).

Findings from the study showed that fatigue was associated with opposite effects on SWI in theta frequency band (P = .02) and on TEPs (FDR corrected permutation-based analysis P <.05) at pre-infusion compared with T1. Theta SWI and TEPs were increased post-fatigue at T0, whereas both were decreased post-fatigue at T1 as previously observed in healthy controls.

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Natalizumab was previously assessed in the TYNERGY study (NCT00884481), which included a real-world cohort of 195 patients with MS. Published in 2013, the Fatigue Scale for Motor and Cognitive functions (FSMC) was used both before and after 12 moths of treatment to evaluate a possible change in fatigue experienced by patients. All told, at the conclusion of the study, all measure variables, including fatigue score, quality of life, sleepiness, depression, cognition, and disability progression were improved from baseline (all P <.0001). Furthermore, walking speed, assessed by the 6-minute walk test, was also increased at month 12 (P = .0016).2

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REFERENCES
1. Mancuso M, Leodori G, Maccarrone D, et al. Natalizumab improves motor fatigue by restoring abnormal brain networks connectivity and sensorimotor network activation in people with multiple sclerosis. Presented at: 2022 ECTRIMS Congress; October 26-28; Amsterdam, Netherlands. Abstract O090
2. Svenningsson A, Falk E, Celius EG, et a. Natalizumab treatment reduces fatigue in multiple sclerosis: results from the TYNERGY trial: a study in the real life setting. PLoS One. 2013;8(3):e58643. doi:10.1371/journal.prone.0058643.
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