Background: Cognitive dysfunction is very common in multiple sclerosis (MS) and it severely impairs patients' quality of life. Thus, we explored whether memantine might improve cognitive performance in patients with MS.

Methods: We conducted a pilot trial with memantine (30 mg/day) in patients with MS with cognitive impairment. The trial was designed as a 1-year, randomized, double-blind, crossover study comparing memantine against a placebo in 60 patients with MS and cognitive impairment. Cognitive impairment was defined as the performance 1.5 standard deviations below the normative data in at least two tests of two cognitive domains in the Brief Repeatable Battery–Neuropsychology. The primary endpoint was improvement of verbal memory and the secondary endpoints were safety and improvements in the other cognitive domains, disability and quality of life. The trial was registered at www.clinicaltrials.org: NCT00638833.

Results: Although 19 patients had been included, the trial was halted after nine patients reported a worsening of their neurologic symptoms that deteriorated their quality of life. Seven of the nine patients in the memantine arm had blurred vision, fatigue, severe headache, increased muscle weakness, walking difficulties, or unstable gait. Only two patients in the placebo group reported neurologic symptoms and in both cases they were related with changes in their disease-modifying therapy. The adverse events only occurred on reaching the maximum dose (30 mg/day). After stopping medication, the patients reverted to their baseline disability within a few days.

Conclusions: Memantine at a dose of 30 mg/day may induce transient worsening of neurologic symptoms of multiple sclerosis.