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Background: Multiple sclerosis (MS), a disabling demyelinating disease of the central nervous system, is associated with cognitive impairment, spasticity, and fatigue. There are still no established guidelines on the management of MS-related sequela. Memantine has the potential to reduce glutamate toxicity, thereby reducing consequent cognitive impairment, spasticity, and fatigue.

Objectives: This study aims to determine the efficacy and safety of memantine in preventing cognitive impairment, reducing spasticity and fatigue, and controlling disability in MS patients through a review of relevant randomized trials.

Methods: MEDLINE, CENTRAL, Scopus, Embase, LILACS, ClinicalTrials.gov, and HERDIN were searched from inception to May 2020 for relevant trials.

Results: The search yielded 203 articles; four studies were included in the analysis. Pooled evidence shows that memantine compared with placebo does not significantly improve PASAT, ASS, MFIS, and EDSS scores of patients with MS. Memantine is associated with mild adverse drug events such as dizziness, fatigue, and anxiety.

Conclusion: There is not enough evidence to support the efficacy of memantine in preventing cognitive decline, controlling spasticity, reducing fatigue, and preventing disability. Future researches should consider the different MS subtypes, effect of co-administration of disease-modifying therapies, longer duration of administration, and more sensitive outcome measures to evaluate the potential benefit of memantine in MS.