Fasciculations and muscle cramp arise from motor neuronal/axonal hyperexcitability, and previous studies have indicated increased excitability in peripheral motor axons, as well as motor cortex, of amyotrophic lateral sclerosis (ALS) patients (Menon et al., 2015; Nihei et al., 1993; Kanai et al., 2003). In particular, threshold tracking studies indicate that persistent nodal sodium currents are higher in ALS patients than in normal controls (Kanai et al., 2006), and that the greater sodium currents are associated with shorter survival in ALS (Kanai et al., 2012). These findings suggest that axonal hyperexcitability not only causes fasciculations and muscle cramp, but also could contribute to motor neuronal death in ALS.
Mexiletine is a cardiac antiarrhythmic agent and a sodium channel blocker. Weiss and colleagues have performed a randomized trial of mexiletine in ALS and nicely revealed the agent significantly reduced the frequency and severity of muscle cramps. Sixty patients were randomized to placebo, mexiletine 300mg/day, or 900mg/day and were followed up for 12 weeks. The results are reasonable because mexiletine suppresses excessive axonal sodium currents, and thereby muscle cramp. However they found no effects on disease progression as assessed by functional and vital capacity testing. We also have just published results of a randomized clinical trial with mexiletine for ALS, using 300mg/day (n=30) or placebo (n=30). We monitored axonal sodium currents by excitability testing (strength-duration time constant measurements) for six months (Shibuya et al., 2015). While no effects of mexiletine on sodium currents or clinical progression were apparent, fasciculations decreased in the mexiletine group. In this regard, the two clinical trials showed similar results. In both trials, decline of clinical scores was similar in the mexiletine and placebo groups, but this might be due to the small sample size and short duration of the studies.
To detect the neuroprotective effects of mexiletine, we have to try larger doses for longer intervention periods. Furthermore, we may need to select an appropriate patient population with apparently increased axonal persistent sodium currents measured by strength-duration time constant. We are now planning such clinical trials with mexiletine or other sodium channel blockers.
References:
Menon P, Geevasinga N, Yiannikas C, Howells J, Kiernan MC, Vucic S.
Sensitivity and specificity of threshold tracking transcranial magnetic stimulation for diagnosis of amyotrophic lateral sclerosis: a prospective study.
Lancet Neurol. 2015 May;14(5):478-84. Epub 2015 Apr 3
PubMed.
Nihei K, McKee AC, Kowall NW.
Patterns of neuronal degeneration in the motor cortex of amyotrophic lateral sclerosis patients.
Acta Neuropathol. 1993;86(1):55-64.
PubMed.
Kanai K, Kuwabara S, Arai K, Sung JY, Ogawara K, Hattori T.
Muscle cramp in Machado-Joseph disease: altered motor axonal excitability properties and mexiletine treatment.
Brain. 2003 Apr;126(Pt 4):965-73.
PubMed.
Kanai K, Kuwabara S, Misawa S, Tamura N, Ogawara K, Nakata M, Sawai S, Hattori T, Bostock H.
Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage.
Brain. 2006 Apr;129(Pt 4):953-62. Epub 2006 Feb 8
PubMed.
Kanai K, Shibuya K, Sato Y, Misawa S, Nasu S, Sekiguchi Y, Mitsuma S, Isose S, Fujimaki Y, Ohmori S, Koga S, Kuwabara S.
Motor axonal excitability properties are strong predictors for survival in amyotrophic lateral sclerosis.
J Neurol Neurosurg Psychiatry. 2012 Jul;83(7):734-8. Epub 2012 May 7
PubMed.
Shibuya K, Misawa S, Kimura H, Noto Y, Sato Y, Sekiguchi Y, Iwai Y, Mitsuma S, Beppu M, Watanabe K, Fujimaki Y, Tsuji Y, Shimizu T, Mizuno T, Nakagawa M, Sawaguchi K, Hanaoka H, Kuwabara S.
A single blind randomized controlled clinical trial of mexiletine in amyotrophic lateral sclerosis: Efficacy and safety of sodium channel blocker phase II trial.
Amyotroph Lateral Scler Frontotemporal Degener. 2015;16(5-6):353-8. Epub 2015 May 11
PubMed.
This is a well-designed study that attacks a novel ALS mechanism, hyperexcitability. It shows that mexiletine is safe at these doses and that it appears very effective against cramps (a common symptom in patients with ALS, and one for which we have no other evidence-based treatment). I look forward to seeing a larger study that is powered to look for slowing of ALS progression.
I appreciate the comments from Drs. Bedlack and Kuwabara. I concur with Dr. Bedlack that only a bigger study with sufficient power will be able to determine if mexiletine can slow progression in addition to its effects on muscle cramps. Dr. Kuwabara may prove to be correct that future studies of mexiletine or other medications that block sodium channels are more likely to be successful by including only subjects with evidence for increased persistent sodium current and peripheral nerve hyperexcitability reflected by the strength-duration time constant. One question also is how well muscle cramp severity and frequency correlate with this measure. The new mexiletine study will hopefully answer this question.
Muscle cramps are a challenging problem in patients with ALS, and many of the currently available options for treatment are not effective or have unwanted side effects. There have been few randomized, placebo-controlled trials focused on ameliorating this symptom. This study was originally conceived not as a symptomatic treatment, but as a way to decrease hyperexcitability. Abnormal neuronal excitability has become increasingly recognized in multiple neurodegenerative syndromes, including ALS. Mexiletine may be a well-tolerated (at the lower dose tested) symptomatic therapeutic for cramps in ALS. A larger trial will be needed to confirm this finding.
In summary, mexiletine was overall safe in ALS patients, paving the way for a larger trial to test whether modulating hyperexcitability may be beneficial in ALS. The current trial was not powered to show a benefit on ALS disease progression. A major challenge for this and other excitability targeted therapeutics in ALS will be defining clinical read outs for the effect of the drug on modulating excitability.
Comments
Chiba University
Fasciculations and muscle cramp arise from motor neuronal/axonal hyperexcitability, and previous studies have indicated increased excitability in peripheral motor axons, as well as motor cortex, of amyotrophic lateral sclerosis (ALS) patients (Menon et al., 2015; Nihei et al., 1993; Kanai et al., 2003). In particular, threshold tracking studies indicate that persistent nodal sodium currents are higher in ALS patients than in normal controls (Kanai et al., 2006), and that the greater sodium currents are associated with shorter survival in ALS (Kanai et al., 2012). These findings suggest that axonal hyperexcitability not only causes fasciculations and muscle cramp, but also could contribute to motor neuronal death in ALS.
Mexiletine is a cardiac antiarrhythmic agent and a sodium channel blocker. Weiss and colleagues have performed a randomized trial of mexiletine in ALS and nicely revealed the agent significantly reduced the frequency and severity of muscle cramps. Sixty patients were randomized to placebo, mexiletine 300mg/day, or 900mg/day and were followed up for 12 weeks. The results are reasonable because mexiletine suppresses excessive axonal sodium currents, and thereby muscle cramp. However they found no effects on disease progression as assessed by functional and vital capacity testing. We also have just published results of a randomized clinical trial with mexiletine for ALS, using 300mg/day (n=30) or placebo (n=30). We monitored axonal sodium currents by excitability testing (strength-duration time constant measurements) for six months (Shibuya et al., 2015). While no effects of mexiletine on sodium currents or clinical progression were apparent, fasciculations decreased in the mexiletine group. In this regard, the two clinical trials showed similar results. In both trials, decline of clinical scores was similar in the mexiletine and placebo groups, but this might be due to the small sample size and short duration of the studies.
To detect the neuroprotective effects of mexiletine, we have to try larger doses for longer intervention periods. Furthermore, we may need to select an appropriate patient population with apparently increased axonal persistent sodium currents measured by strength-duration time constant. We are now planning such clinical trials with mexiletine or other sodium channel blockers.
References:
Menon P, Geevasinga N, Yiannikas C, Howells J, Kiernan MC, Vucic S. Sensitivity and specificity of threshold tracking transcranial magnetic stimulation for diagnosis of amyotrophic lateral sclerosis: a prospective study. Lancet Neurol. 2015 May;14(5):478-84. Epub 2015 Apr 3 PubMed.
Nihei K, McKee AC, Kowall NW. Patterns of neuronal degeneration in the motor cortex of amyotrophic lateral sclerosis patients. Acta Neuropathol. 1993;86(1):55-64. PubMed.
Kanai K, Kuwabara S, Arai K, Sung JY, Ogawara K, Hattori T. Muscle cramp in Machado-Joseph disease: altered motor axonal excitability properties and mexiletine treatment. Brain. 2003 Apr;126(Pt 4):965-73. PubMed.
Kanai K, Kuwabara S, Misawa S, Tamura N, Ogawara K, Nakata M, Sawai S, Hattori T, Bostock H. Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage. Brain. 2006 Apr;129(Pt 4):953-62. Epub 2006 Feb 8 PubMed.
Kanai K, Shibuya K, Sato Y, Misawa S, Nasu S, Sekiguchi Y, Mitsuma S, Isose S, Fujimaki Y, Ohmori S, Koga S, Kuwabara S. Motor axonal excitability properties are strong predictors for survival in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2012 Jul;83(7):734-8. Epub 2012 May 7 PubMed.
Shibuya K, Misawa S, Kimura H, Noto Y, Sato Y, Sekiguchi Y, Iwai Y, Mitsuma S, Beppu M, Watanabe K, Fujimaki Y, Tsuji Y, Shimizu T, Mizuno T, Nakagawa M, Sawaguchi K, Hanaoka H, Kuwabara S. A single blind randomized controlled clinical trial of mexiletine in amyotrophic lateral sclerosis: Efficacy and safety of sodium channel blocker phase II trial. Amyotroph Lateral Scler Frontotemporal Degener. 2015;16(5-6):353-8. Epub 2015 May 11 PubMed.
View all comments by Satoshi KuwabaraDuke University
This is a well-designed study that attacks a novel ALS mechanism, hyperexcitability. It shows that mexiletine is safe at these doses and that it appears very effective against cramps (a common symptom in patients with ALS, and one for which we have no other evidence-based treatment). I look forward to seeing a larger study that is powered to look for slowing of ALS progression.
View all comments by Richard BedlackUniversity of Washington
I appreciate the comments from Drs. Bedlack and Kuwabara. I concur with Dr. Bedlack that only a bigger study with sufficient power will be able to determine if mexiletine can slow progression in addition to its effects on muscle cramps. Dr. Kuwabara may prove to be correct that future studies of mexiletine or other medications that block sodium channels are more likely to be successful by including only subjects with evidence for increased persistent sodium current and peripheral nerve hyperexcitability reflected by the strength-duration time constant. One question also is how well muscle cramp severity and frequency correlate with this measure. The new mexiletine study will hopefully answer this question.
View all comments by Michael WeissMuscle cramps are a challenging problem in patients with ALS, and many of the currently available options for treatment are not effective or have unwanted side effects. There have been few randomized, placebo-controlled trials focused on ameliorating this symptom. This study was originally conceived not as a symptomatic treatment, but as a way to decrease hyperexcitability. Abnormal neuronal excitability has become increasingly recognized in multiple neurodegenerative syndromes, including ALS. Mexiletine may be a well-tolerated (at the lower dose tested) symptomatic therapeutic for cramps in ALS. A larger trial will be needed to confirm this finding.
In summary, mexiletine was overall safe in ALS patients, paving the way for a larger trial to test whether modulating hyperexcitability may be beneficial in ALS. The current trial was not powered to show a benefit on ALS disease progression. A major challenge for this and other excitability targeted therapeutics in ALS will be defining clinical read outs for the effect of the drug on modulating excitability.
View all comments by Timothy MillerMake a Comment
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