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Figure.
Predicted Values of Modified Fatigue Impact Scale (MFIS) Score vs Visit Months in Placebo and Riluzole Groups Using the Mixed-Effects Regression Model
Predicted Values of Modified Fatigue Impact Scale (MFIS) Score vs Visit Months in Placebo and Riluzole Groups Using the Mixed-Effects Regression Model
Table.  
Baseline Characteristics
Baseline Characteristics
1.
Kostic  M, Zivkovic  N, Stojanovic  I.  Multiple sclerosis and glutamate excitotoxicity. Rev Neurosci. 2013;24(1):71-88.PubMedArticle
2.
Dobryakova  E, Genova  HM, DeLuca  J, Wylie  GR.  The dopamine imbalance hypothesis of fatigue in multiple sclerosis and other neurological disorders. Front Neurol. 2015;6:52.PubMedArticle
3.
Waubant  E, Maghzi  A-H, Revirajan  N,  et al.  A randomized controlled phase II trial of riluzole in early multiple sclerosis. Ann Clin Transl Neurol. 2014;1(5):340-347.PubMedArticle
4.
Fisk  JD, Pontefract  A, Ritvo  PG, Archibald  CJ, Murray  TJ.  The impact of fatigue on patients with multiple sclerosis. Can J Neurol Sci. 1994;21(1):9-14.PubMed
5.
Lovera  JF, Frohman  E, Brown  TR,  et al.  Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-controlled trial. Mult Scler. 2010;16(6):715-723.PubMedArticle
6.
Villoslada  P, Arrondo  G, Sepulcre  J, Alegre  M, Artieda  J.  Memantine induces reversible neurologic impairment in patients with MS. Neurology. 2009;72(19):1630-1633.PubMedArticle
Research Letter
November 2015

Association Between Glutamate Blockade and Fatigue in Patients With Multiple Sclerosis

Author Affiliations
  • 1Department of Neurology, University of California–San Francisco
JAMA Neurol. 2015;72(11):1374-1375. doi:10.1001/jamaneurol.2015.2332

Excitotoxity, primarily mediated by excessive glutamate release, is one of the main proposed mechanisms for neurodegeneration in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis.1 However, a few clinical trials of medications with glutamate-blocking properties have not yet shown beneficial effects in patients with MS.

Fatigue is one of the most frequently reported MS symptoms and the underlying mechanisms of this potentially debilitating symptom are not well understood.2 Here, we report the effects of riluzole, a medication with glutamate-blocking properties, on fatigue in a randomized clinical trial in patients with early MS.

Methods

This is an analysis of a randomized, double-blind, placebo-controlled trial assessing the possible neuroprotective effects of riluzole in combination with intramuscular interferon β-1a that was conducted at 2 centers. The methods, including inclusion and exclusion criteria, the details of the randomization, and the results of primary and secondary outcomes of the study, are reported elsewhere.3 The institutional review boards at the University of California–San Francisco and Oregon Health and Science University approved this study; written informed consent was obtained from all participants.

In summary, 43 patients with clinically isolated syndrome or MS with symptom onset within the previous 12 months and with at least 2 silent T2 hyperintensities in the deep white matter on a clinical brain or cervical magnetic resonance imaging scan were invited to participate in the study. Patients were randomized to receive 50 mg of riluzole or placebo twice daily. After 3 months taking the study drug, patients also initiated weekly intramuscular interferon β-1a. Fatigue was evaluated by the Modified Fatigue Impact Scale (MFIS).4 The MFIS was administered at baseline; months 3, 6, 12, 18, and 24; and, in the first half of patients who completed the study, months 30 and 36.

To analyze the effect of riluzole on the MFIS score, a mixed-effects regression model was used with the treatment allocation (in an intent-to-treat analysis) as the predictor and the MFIS score as the outcome. The mixed model allowed patient-specific intercepts and slopes to accommodate the repeated-measures nature of the data and possible time trends during the course of the study. All analyses were conducted in Stata version 13.1 (StataCorp).

Results

Baseline characteristics of patients who were recruited in the study are shown in the Table. Twenty-two patients were randomized to riluzole and 21 patients to placebo. The mean MFIS score in the riluzole and placebo groups were 24.1 and 33.2, respectively. Compared with the placebo group, the MFIS score worsened by 4.6 points per year in the riluzole group (95% CI, 1.1-8.1; P = .01) (Figure). Adjusting for baseline MFIS score or age (that was significantly different between the 2 groups at baseline) or T2-lesion volume and normalized gray matter volume (the primary study outcome was adjusted for these variables owing to baseline imbalance) did not change the results.

Discussion

Despite increasing evidence of involvement of glutamate excitotoxicity in the pathogenesis of neurodegeneration in MS, pharmacologic blockade of glutamate in human studies have not shown clinical benefits and may have detrimental effects on patients’ symptoms. A 16-week clinical trial examining the symptomatic effects of memantine, a noncompetitive antagonist of glutamate N-methyl-D-aspartate receptor, on cognitive function of patients with MS reported statistically important worsening of fatigue as measured by a fatigue severity scale in the memantine group.5 Another clinical trial to assess the effect of memantine on neuropsychological performance in MS was prematurely halted after 9 patients reported a worsening of neurological symptoms. Interestingly, 4 of 7 patients in the memantine group reported worsening fatigue.6

While our results including appropriate adjustments might be a false-positive finding related to multiple comparisons, they are in line with previous reports of worsening fatigue in patients with MS receiving a medication with antiglutamatergic properties. In our case, the trend over time of fatigue worsening during the 36-month trial questions the possibility of worsening of MS processes as opposed to just a negative symptomatic effect on fatigue.

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Article Information

Corresponding Author: Bardia Nourbakhsh, MD, Department of Neurology, University of California–San Francisco, 675 Nelson Rising Ln, PO Box 3206, Room 221F, San Francisco, CA 94158 (bardia.nourbakhsh@ucsf.edu).

Author Contributions: Dr Nourbakhsh had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Nourbakhsh, Waubant.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Nourbakhsh, Waubant.

Critical revision of the manuscript for important intellectual content: Revirajan, Waubant.

Statistical analysis: Nourbakhsh, Waubant.

Obtained funding: Waubant.

Administrative, technical, or material support: Revirajan, Waubant.

Study supervision: Waubant.

Conflict of Interest Disclosures: This research was conducted while Dr Nourbakhsh was a Biogen Idec postdoctoral fellow. No other disclosures were reported.

Funding/Support: This research was performed as a research grant funded by the National MS Society (principal investigator, Dr Waubant; RG3932-A-2). Dr Nourbakhsh is a grantee of the National MS Society.

Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Kostic  M, Zivkovic  N, Stojanovic  I.  Multiple sclerosis and glutamate excitotoxicity. Rev Neurosci. 2013;24(1):71-88.PubMedArticle
2.
Dobryakova  E, Genova  HM, DeLuca  J, Wylie  GR.  The dopamine imbalance hypothesis of fatigue in multiple sclerosis and other neurological disorders. Front Neurol. 2015;6:52.PubMedArticle
3.
Waubant  E, Maghzi  A-H, Revirajan  N,  et al.  A randomized controlled phase II trial of riluzole in early multiple sclerosis. Ann Clin Transl Neurol. 2014;1(5):340-347.PubMedArticle
4.
Fisk  JD, Pontefract  A, Ritvo  PG, Archibald  CJ, Murray  TJ.  The impact of fatigue on patients with multiple sclerosis. Can J Neurol Sci. 1994;21(1):9-14.PubMed
5.
Lovera  JF, Frohman  E, Brown  TR,  et al.  Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-controlled trial. Mult Scler. 2010;16(6):715-723.PubMedArticle
6.
Villoslada  P, Arrondo  G, Sepulcre  J, Alegre  M, Artieda  J.  Memantine induces reversible neurologic impairment in patients with MS. Neurology. 2009;72(19):1630-1633.PubMedArticle
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