Risk of stroke under disease modifying therapies for multiple sclerosis: a systematic review

Abstract

Background: Epidemiological research indicates a heightened incidence of cerebrovascular disorders among patients with multiple sclerosis (MS).

Objectives: The aim of the present systematic review was to investigate the potential association between disease modifying therapies (DMTs) and the risk of stroke in MS patient populations.

Data sources and methods: A systematic literature search was performed in MEDLINE and SCOPUS databases up to April 6, 2024, to identify randomized-controlled clinical trials (RCT), registry-based and cohort-studies, case-series, and case-reports reporting on acute ischemic stroke (AIS) or intracerebral hemorrhage (ICH) in MS patients under different DMTs.

Results: Twenty-one studies were included: 1 RCT, 6 registry-based or cohort studies, 2 case-series and 11 case-reports. Overall, DMTs appear to reduce the risk of stroke in MS patients, with DMT exposure linked to a 50% reduction of the risk of stroke compared to no DMT exposure. Although glatiramer acetate and dimethyl fumarate appear to lower the risk of stroke, concerns about fingolimod exists due to an observed elevated risk for ischemic heart disease and hypertension. Despite the absence of detected safety concerns with alemtuzumab at the MS population level, alemtuzumab-related complications, although rare, signal the need for heightened clinical vigilance. Similarly, β-interferons have been linked to life-threatening adverse events, comprising thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS). No associations between the risk of stroke and other DMTs, comprising natalizumab and teriflunomide, were detected; yet, newly approved DMTs were underrepresented.

Conclusion: These findings highlight the importance of personalizing DMT selection and monitoring cardiovascular risk factors to reduce stroke risk in patients with MS.

Trial registration: PROSPERO CRD42024534470.

Keywords: cardiovascular risk factors; cerebrovascular disease; disease modifying therapies; intracerebral hemorrhage; multiple sclerosis; stroke.

Figure 1.

Flow chart presenting the selection of eligible studies.

Figure 2.

Traffic light plot presenting the quality assessment of the single included RCT using the RoB 2 tool. RCT, randomized-controlled clinical trials; RoB 2, risk of bias in randomized trials.

Figure 3.

Traffic light plot (a) and bar chart (b) presenting the quality assessment of included observational studies using the ROBINS-I tool. ROBINS-I, Risk of Bias in Non-randomized Studies of Interventions.