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A trial of memantine for MS patients with cognitive problems was halted after they experienced worsening symptoms. Independent commentators said they suspect the effect was related to the dosing in the trial.

A clinical trial of the Alzheimer disease drug, memantine, on MS patients with cognitive decline was halted last March after nine patients experienced a worsening of the neurological symptoms, according to a study to be published May 12 in Neurology

The patients had blurred vision, fatigue, severe headache, increased limb weakness, and unstable gait. The family of one study participant reported that the patient showed signs of cognitive deterioration, including disorientation and decreased initiative.

The problems surfaced after patients reached the full dose of memantine being tested — 30 mg daily. “After stopping medication, the patients reverted to their baseline disability within a few days,” the researchers said.

“Our study indicates that intermediate to high doses of memantine might induce reversible neurological impairment in patients with MS suffering from moderate to severe physical disability,” reported a team led by Pablo Villoslada, MD, director of the Neuroimmunology Group at the Institute for Biomedical Research August Pi Sunyer, Hospital Clinic of Barcelona, Spain. The research was done when he was at the University of Navarra in Pamplona. “The impairment involves the functional systems frequently affected in MS patients, including the visual, motor, or cerebellar pathways.”


DR. PABLO VILLOSLADA: “In addition to the clinical implications, we found that our findings provide interesting insights about how MS damages the brain and how the brain works in the presence of brain damage.”

Dr. Villoslada told Neurology Today that the study results were important for neurologists because cognitive-enhancing drugs are already being prescribed off label for MS. “In addition to the clinical implications, we found that our findings provide interesting insights about how MS damages the brain and how the brain works in the presence of brain damage,” he said. He said the findings might also enhance the understanding of “pseudoexacerbations in MS, a common and very inconvenient phenomena.”

Dr. Villoslada's team did not rule out memantine. They said the fact that the drug induced transient neurological symptoms does not mean “it might not also improve cognition in MS or exert neuroprotective effects that might be beneficial against neurodegeneration in MS. Further studies are warranted to address this question.”


Lauren Krupp told Neurology Today she found the study results disappointing. But she said it was reasonable to think that memantine might be helpful because the drug's mechanism overlaps with that of donepezil, and early studies involving other drugs, including L-amphetamine sulfate, suggest it is possible to improve cognitive function of MS patients. Memantine, a noncompetitive NMDA receptor antagonist, is approved at a dose of 20 mg a day for the treatment of moderate to severe Alzheimer disease.

“This study may provide an opportunity to learn if we can get at and understand what caused the worsening of disease,” she said. “Some good might come of this.”


DIAGRAM OF HUMAN BRAIN pathways supporting declarative verbal memory in MS. Temporo-thalamo-frontal pathways support both memory storage and retrieval (mauve). In addition, memory retrieval is also supported by temporo-parietofrontal paramedian bundles, mainly including the cingulum and the fronto-occipital fasciculus (red). The right uncinate fasciculus, involved in storage, is represented in blue. Courtesy: Pablo Villoslada


Cognitive dysfunction is found in about 65 percent of MS patients, according to background information included in the study, which has already been posted online by Neurology. “Because the symptoms of MS first appear in young adults with significant family and work commitments, cognitive impairment might have an important effect on their quality of life. However, there is no therapy to treat such cognitive symptoms,” the researchers wrote.

The MS study was set up as a randomized, double-blind, placebo-controlled trial. The study's primary goal was to assess whether memantine improved verbal memory. The study was to include 60 patients at ages 18 to 65 with any MS subtype, but they could not have had a relapse in the previous month. Participants had to have moderate cognitive impairment, which was defined as performing 1.5 standard deviations below the normative data in at least two neuropsychological subtests of the Brief Repeatable Battery-Neuropsychology (BRB-N).


COGNITIVE DECLINE IN MS: Axial and 3D projections show white matter clusters correlated with verbal declarative memory storage. Four white matter lesion clusters correlated with the score of verbal memory storage, three in the left hemisphere — (La) white matter in the temporal lobe, lateral to the hippocampus and amygdala and extending to the anterior temporal stem; (Lb) perithalamic and thalamic white matter; (Lc) the anterior limb of the internal capsule — and one (R) in the anterior temporal region of the right hemisphere. Courtesy: Pablo Villoslada


Recruitment began in October 2007 and patients in the drug arm of the trial were started on 10 mg of memantine a day, which was then increased by 10 mg each week until the full dose of 30 mg was reached. By the time 19 patients had been enrolled, seven of nine patients taking memantine and two of 10 placebo patients were reporting new or worsening neurological symptoms, including blurred vision, increased limb weakness, and unstable gait. For the patient whose family reported worsening cognitive impairment, follow-up testing using the BRB-N revealed moderate impairment compared to baseline.

Because all of the patients in the trial had moderate to severe disability to begin with (as measured by the Expanded Disability Status Scale), researchers suspected the neurological symptoms were due to “pseudoexacerbations.” After possible explanations such as urinary tract infection, fever, or changes in MS drug therapy were ruled out, medication was reduced by 10 mg a day or stopped for one week.

“All patients reported remission of symptoms to baseline disability within 24 to 48 hours of the reduction or suppression of the medication,” according to the report, and examination confirmed the return to baseline. “However, the patient with increased cognitive impairment did not return to baseline performance, suggesting that she might have suffered progression of her disease.”


DR. LAUREN KRUPP: “This study may provide an opportunity to learn if we can get at and understand what caused the worsening of disease. Some good might come of this.”


The researchers noted that because the patients in the study were moderately to severely disabled both cognitively and physically, they were a “subtype of patients with severe widespread brain damage who might be more susceptible to the side effects of memantine.”

“The biological bases of such symptoms are unknown,” they said, but offered some possible explanations.

“We hypothesize that the partial inhibition of overactive glutamatergic pathways by memantine coupled with the presence of demyelinated axons may contribute to produce transient axonal blockage. Memantine is a non-competitive inhibitor of NMDA receptors, implying that the blocking effect is enhanced when glutamatergic pathways are more strongly activated, as associated with brain plasticity. The block of conduction in demyelinated axons seems to be secondary to the energy failure associated with ion channel and mitochondrial dysfunction.”

“Other explanations might include direct synaptic blockage produced by Memantine, its effects on serotoninergic, dopaminergic, and cholinergic pathways, or a direct effect of Memantine on immune mediators, although there are no biological data to support these hypotheses.”

Stuart Lipton, MD, PhD, who holds patents for memantine use in neurodegenerative diseases and serves as scientific director at the Burnham Institute for Medical Research in La Jolla, CA, said the trial involving MS patients may have turned problematic because the dosing was increased too quickly. In the case of Alzheimer disease, he said, “the FDA-approved dosing schedule calls for a slower ramp-up in the dose, starting at 5 mg per day during the first week, because it is better tolerated clinically.”

Dr. Krupp agreed the dosing in the MS may have been too fast, but even so, she said she doubted researchers would be eager to further test memantine for MS. But Dr. Villoslada said he thought more research was warranted, with “the caution of dose escalation and maximal dosage of 20 mg/day and advising on the possibility of pseudoexacerbations.”


• Villoslada P, Arrondo G, Arieda J, et al. Memantine induces reversible neurological impairment in patients with MS. Neurology 2009; E-pub 2008 Dec. 17.