Cognitive dysfunction is a well-recognized feature of multiple sclerosis (MS) that can be detected even in benign and pediatric cases. No evidence-based recommendations are available for the treatment of MS-related cognitive problems. Acetylcholinesterase inhibitors are used off-label in MS, on the basis of positive findings from several small-scale clinical trials reported primarily in abstract form. In the largest published trial (69 patients with MS), donepezil improved verbal learning and memory (J Neurol Sci 2006; 245:127). Intuitively, studying other medications approved for dementia, such as the N-methyl-D-aspartic acid (NMDA) receptor inhibitor memantine, might make sense. Moreover, memantine was proposed as a potential therapy for MS-related oligodendrocyte injury based on experimental data (Trends Pharmacol Sci 2007; 28:561) and was reported effective in MS-related pendular nystagmus (J Neurol1997; 244:9).

Now, researchers have conducted a randomized, double-masked, placebo-controlled, manufacturer-supported study of memantine in patients with MS and cognitive impairment. Doses were titrated up by 10 mg weekly, from 10 mg daily to 30 mg daily. The trial was terminated early, at 9 months, because 9 of 19 patients treated with memantine reported worsening of preexisting neurological symptoms, consistent with pseudoexacerbations. The authors conclude that studying NMDA-receptor inhibitors may help us understand the basic pathophysiology of MS-related pseudoattacks.

Comment: Because the authors do not report outcomes in patients who tolerated memantine, whether the medication improves cognitive outcomes remains unclear. The dose titration was relatively rapid in this study, which may have contributed to the adverse outcomes. As the authors note, a previous study of memantine doses up to 60 mg, with a slower titration schedule, to treat MS-related nystagmus did not demonstrate this problem.

More data are needed on NMDA-receptor inhibitors in MS before we can conclude that this class of medication definitely triggers pseudoattacks in MS. Nonetheless, the current data strongly suggest a true cause-effect relationship when the medication is used with a relatively rapid titration schedule. Therefore, memantine should not be used, or should be used with extreme caution, in patients with MS.