Cognitive Efficacy of Pharmacologic Treatments in Multiple Sclerosis: A Systematic Review

Abstract

Introduction: Cognitive impairment is prevalent and debilitating among persons with multiple sclerosis (MS). While many pharmacologic treatments have shown good efficacy in reducing clinical relapses, brain lesions, and improving certain physical symptoms, their efficacy for improving cognitive function is not well understood.

Objectives: The current systematic review aimed to evaluate the efficacy of pharmacologic treatments for improving cognitive function among persons with MS.

Methods: A literature search was conducted through the PubMed and PsycINFO databases. Two independent reviewers assessed each paper, and a third reviewer weighed in if the two reviewers could not reach a consensus. Classification of evidence was determined using the 2017 American Academy of Neurology (AAN) criteria for therapeutic trials. Standardized effect sizes (Cohen's d) were calculated to compare across studies.

Results: Eighty-seven journal articles published between 1990 and January 2020 were included in the current review. Overall, there is insufficient evidence to support the use of pharmacologic treatments to improve cognitive function in persons with MS. There were many contradictory findings observed in this review, which may be due to possible unidentified moderating treatment response variables and/or lack of standardization in assessment procedures. There was also an overreliance on statistical significance (most papers did not provide sizes of treatment effects), which may not be clinically meaningful.

Conclusions: Higher-quality randomized controlled trials are needed to establish the cognitive efficacy of pharmacologic treatments for MS-related cognitive dysfunction, with cognition as the primary endpoint. Researchers are urged to use standardized criteria (such as the AAN criteria) to guide their research designs. Clinicians should consider effect sizes of studies before deciding whether to prescribe certain medications to ameliorate cognitive symptoms.

Fig. 1

Study selection process

Fig. 2

Number of positive studies, stratified by A study type and B AAN class of evidence. The proportion of positive studies increased as the quality of evidence decreased. AAN American Academy of Neurology

Fig. 3

Summary of studies based on A study type and B AAN class of evidence. For disease-modifying therapies, the number of studies increased as the quality of evidence decreased. For symptomatic therapies, the majority of studies were randomized controlled trials, and AAN classification levels were evenly distributed. AAN American Academy of Neurology

Fig. 4

Proportion of cognition-focused studies, stratified by medication and study type. For disease-modifying therapies, more than half of the studies did not specify cognition as the primary endpoint. For symptomatic therapies, most studies examined cognition as the primary endpoint and these studies tended to be higher in quality compared with other medication types

Fig. 5

Summary of effect sizes in RCTs based on medication type. Effect sizes are expressed as Cohen’s d. Weighted effect size = ratio of positive measures to total measures × effect size. Only positive RCTs are included (n = 20). Additionally, there were three positive RCTs with insufficient data to calculate Cohen’s d, and 18 negative RCTs. On average, effect sizes for disease-modifying therapies were negligible, and effect sizes for symptomatic therapies were in the medium range. RCTs randomized controlled trials