Clinical Neurophysiology 125 (2014) 872–873
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Editorial
Fasciculations, axonal hyperecitability, and motoneuronal death in amyotrophic lateral sclerosis See Article, pages 1059–1064
Wide-spread fasciculations are prominent clinical features in patients with amyotrophic lateral sclerosis (ALS), suggesting abnormally increased excitability of motor axons. Over the past 15 years, our understanding of the pathogenesis for fasciculations has been significantly expanded. Excitability studies have shown increased persistent sodium conductances and reduced axonal potassium conductances in ALS patients that may contribute to the axonal hyperexcitability, and thereby generation of fasciculations (Kanai et al., 2006). A recent immunohistochemical study has shown markedly reduced potassium channel expression in motor nerves of ALS patients (Shibuya et al., 2011). In ALS, fasciculations frequently arise from the motor nerve terminals (de Carvalho and Swash, 2013), and this suggests such altered ion channel function and hyperexcitability predominantly occur in distal motor axons. Separately, the diagnostic value of fasciculation potentials has recently been emphasized by proposal of the Awaji ALS criteria published in this journal, in which fasciculation potentials are regarded to be equivalent to denervation potentials such as fibrillation potentials and positive sharp waves (de Carvalho et al., 2008). Strictly this is not correct because fasciculation potentials are spontaneous ectopic firing of motor axons, different from fibrillation potentials and positive sharp waves, arising from denervated muscle fibers. However, practically it is acceptable because fasciculation would precede motor axonal/neuronal death, and therefore fasciculating motor axons would die soon, resulting in denervation. Furthermore, the continuous abnormal firing of axons leads to increased metabolic demand in the cell body (spinal motor neurons), and could enhance motor neuronal death. The features of fasciculation potentials observed in ALS patients are complexity and instability. Complex fasciculation potentials are defined as ones with polyphasia (5 or more phases), increased duration, and increased amplitude (de Carvalho et al., 2008). The complexity presumably results from collateral axonal sprouting associated with reinnervation of denervated muscle fibers. The complexity of fasciculation potentials may be associated with disease progression in ALS. If that is the case, the presence and extent of complex fasciculation potentials potentially reflect the speed of progression of ALS pathology. Additionally the frequency and number of fasciculations tend to decrease as ALS becomes more advanced, even though they become more complex with disease progression. In the current issue of Clinical Neurophysiology, a paper by Shimizu and colleagues nicely demonstrated that wider distribu-
tion of complex fasciculation potentials correlates with shorter survival in ALS patients (Shimizu et al., 2014). They prospectively performed EMG examinations in 85 consecutive patients with sporadic ALS. Complex and simple fasciculation potentials were respectively defined as potentials with >4 and 4 or less phases according to the Awaji criteria. Of the 85 patients, 55.3% had complex fasciculation potentials in at least one muscle. Kaplan–Myer curves showed significantly shorter survival in patients with complex fasciculations than in patients without them (p = 0.0017). The exact median survival time was not described in the manuscript, but from Fig. 2A it was approximately 2.5 years for patients with complex fasciculation potentials and 4.5 years for patients without them. Multivariate analyses showed that the presence of complex fasciculation potentials, as well as older onset age, was associated with shorter survival, indicating that it is an independent prognostic factor determining survival time. It is intuitively reasonable that detection of complex fasciculation potentials is a useful predictor of prognosis. Unfortunately the present study did not investigate morphology and instability of voluntary motor unit potentials, but complexity of fasciculation potentials is expected to reflect neurogenic motor unit potentials. An enlarged motor unit potential is not necessarily a sign of pathology of that motor unit. The enlargement indicates that the surviving motor unit is capable of reinnervating muscle fibers previously innervated by degenerated motor units, and could be viewed as a sign of health not disease. The greater instability then usually means that the reinnervation is recent, not that the reinnervating motor unit is necessarily diseased. This may apply to the fasciculation motor unit, although an alternative explanation is that the instability could be because an increasingly sicker motor unit is unable to maintain the enlarged population of muscle fibers. At least, fasciculation axons are surviving at the time of examination, and prominently had collateral sprouting. Axonal hyperexcitability and resulting ectopic firing of motor axons (fasciculations) could be an early event in ALS. A recent report has shown that increased nodal persistent sodium conductances estimated by strength-duration time constant and latent addition are also strong predictors for shorter survival in sporadic ALS patients (Kanai et al., 2012). Also transcranial magnetic stimulation with threshold tracking has revealed hyperexcitability of cortical circuitry (Vucic et al., 2013). Whereas nerve excitability testing and transcranial magnetic stimulation studies evaluate excitability of peripheral motor axons and cortical motor neurons respectively, it is possible that both neuronal and axonal
1388-2457/$36.00 Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2013.11.014
Editorial / Clinical Neurophysiology 125 (2014) 872–873
excitability increase in both upper and lower motor neurons. Modulation of the hyperexcitability of the motor pathway could be a useful neuro-protective strategy and therapeutic option for ALS. Clinical trials with mexiletine hydrochloride, a sodium channel blocker, for ALS are ongoing in Japan and the United States, and we hope positive results.
873
Shibuya K, Misawa S, Arai K, Nakata M, Kanai K, Yoshiyama Y, et al. Markedly reduced axonal potassium channel expression in human sporadic amyotrophic lateral sclerosis: an immunohistochemical study. Exp. Neurol. 2011;232: 149–53. Vucic S, Ziemann U, Eisen A, Hallett M, Kiernan MC. Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights. J. Neurol. Neurosurg. Psychiatry 2013;84:1161–70.
⇑
References de Carvalho, M., Swash, M., 2013. Origin of Fasciculations in Amyotrophic Lateral Sclerosis and Benign Fasciculation Syndrome. JAMA Neurol. (in press) doi:10.1001/jamaneurol.2013.4437. de Carvalho M, Dengler R, Eisen A, England JD, Kaji R, Kimura J, et al. Electrodiagnostic criteria for diagnosis of ALS. Clin. Neurophysiol. 2008;119: 497–503. Kanai K, Kuwabara S, Misawa S, Tamura N, Ogawara K, Nakata M, et al. Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage. Brain 2006;129:953–62. Kanai K, Shibuya K, Sato Y, Misawa S, Nasu S, Sekiguchi Y, et al. Motor axonal excitability properties are strong predictors for survival in amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry 2012;83:734–8. Shimizu, T., Fujimaki, Y., Nakatani-Enomoto, S., Matsubara, S., Watabe, K., Rossini, P.M., et al. Complex fasciculation potentials and survival in amyotrophic lateral sclerosis. Clin. Neurophysiol 2014;125:1059–1064.
Satoshi Kuwabara Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 206-8670, Japan ⇑ Tel.: +81 43 222 7171x5414; fax: +81 43 226 2160. E-mail address: [email protected] Kazumoto Shibuya Sonoko Misawa Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, Japan Available online 28 November 2013
Contents lists available at ScienceDirect
Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph
Editorial
Fasciculations, axonal hyperecitability, and motoneuronal death in amyotrophic lateral sclerosis See Article, pages 1059–1064
Wide-spread fasciculations are prominent clinical features in patients with amyotrophic lateral sclerosis (ALS), suggesting abnormally increased excitability of motor axons. Over the past 15 years, our understanding of the pathogenesis for fasciculations has been significantly expanded. Excitability studies have shown increased persistent sodium conductances and reduced axonal potassium conductances in ALS patients that may contribute to the axonal hyperexcitability, and thereby generation of fasciculations (Kanai et al., 2006). A recent immunohistochemical study has shown markedly reduced potassium channel expression in motor nerves of ALS patients (Shibuya et al., 2011). In ALS, fasciculations frequently arise from the motor nerve terminals (de Carvalho and Swash, 2013), and this suggests such altered ion channel function and hyperexcitability predominantly occur in distal motor axons. Separately, the diagnostic value of fasciculation potentials has recently been emphasized by proposal of the Awaji ALS criteria published in this journal, in which fasciculation potentials are regarded to be equivalent to denervation potentials such as fibrillation potentials and positive sharp waves (de Carvalho et al., 2008). Strictly this is not correct because fasciculation potentials are spontaneous ectopic firing of motor axons, different from fibrillation potentials and positive sharp waves, arising from denervated muscle fibers. However, practically it is acceptable because fasciculation would precede motor axonal/neuronal death, and therefore fasciculating motor axons would die soon, resulting in denervation. Furthermore, the continuous abnormal firing of axons leads to increased metabolic demand in the cell body (spinal motor neurons), and could enhance motor neuronal death. The features of fasciculation potentials observed in ALS patients are complexity and instability. Complex fasciculation potentials are defined as ones with polyphasia (5 or more phases), increased duration, and increased amplitude (de Carvalho et al., 2008). The complexity presumably results from collateral axonal sprouting associated with reinnervation of denervated muscle fibers. The complexity of fasciculation potentials may be associated with disease progression in ALS. If that is the case, the presence and extent of complex fasciculation potentials potentially reflect the speed of progression of ALS pathology. Additionally the frequency and number of fasciculations tend to decrease as ALS becomes more advanced, even though they become more complex with disease progression. In the current issue of Clinical Neurophysiology, a paper by Shimizu and colleagues nicely demonstrated that wider distribu-
tion of complex fasciculation potentials correlates with shorter survival in ALS patients (Shimizu et al., 2014). They prospectively performed EMG examinations in 85 consecutive patients with sporadic ALS. Complex and simple fasciculation potentials were respectively defined as potentials with >4 and 4 or less phases according to the Awaji criteria. Of the 85 patients, 55.3% had complex fasciculation potentials in at least one muscle. Kaplan–Myer curves showed significantly shorter survival in patients with complex fasciculations than in patients without them (p = 0.0017). The exact median survival time was not described in the manuscript, but from Fig. 2A it was approximately 2.5 years for patients with complex fasciculation potentials and 4.5 years for patients without them. Multivariate analyses showed that the presence of complex fasciculation potentials, as well as older onset age, was associated with shorter survival, indicating that it is an independent prognostic factor determining survival time. It is intuitively reasonable that detection of complex fasciculation potentials is a useful predictor of prognosis. Unfortunately the present study did not investigate morphology and instability of voluntary motor unit potentials, but complexity of fasciculation potentials is expected to reflect neurogenic motor unit potentials. An enlarged motor unit potential is not necessarily a sign of pathology of that motor unit. The enlargement indicates that the surviving motor unit is capable of reinnervating muscle fibers previously innervated by degenerated motor units, and could be viewed as a sign of health not disease. The greater instability then usually means that the reinnervation is recent, not that the reinnervating motor unit is necessarily diseased. This may apply to the fasciculation motor unit, although an alternative explanation is that the instability could be because an increasingly sicker motor unit is unable to maintain the enlarged population of muscle fibers. At least, fasciculation axons are surviving at the time of examination, and prominently had collateral sprouting. Axonal hyperexcitability and resulting ectopic firing of motor axons (fasciculations) could be an early event in ALS. A recent report has shown that increased nodal persistent sodium conductances estimated by strength-duration time constant and latent addition are also strong predictors for shorter survival in sporadic ALS patients (Kanai et al., 2012). Also transcranial magnetic stimulation with threshold tracking has revealed hyperexcitability of cortical circuitry (Vucic et al., 2013). Whereas nerve excitability testing and transcranial magnetic stimulation studies evaluate excitability of peripheral motor axons and cortical motor neurons respectively, it is possible that both neuronal and axonal
1388-2457/$36.00 Ó 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2013.11.014
Editorial / Clinical Neurophysiology 125 (2014) 872–873
excitability increase in both upper and lower motor neurons. Modulation of the hyperexcitability of the motor pathway could be a useful neuro-protective strategy and therapeutic option for ALS. Clinical trials with mexiletine hydrochloride, a sodium channel blocker, for ALS are ongoing in Japan and the United States, and we hope positive results.
873
Shibuya K, Misawa S, Arai K, Nakata M, Kanai K, Yoshiyama Y, et al. Markedly reduced axonal potassium channel expression in human sporadic amyotrophic lateral sclerosis: an immunohistochemical study. Exp. Neurol. 2011;232: 149–53. Vucic S, Ziemann U, Eisen A, Hallett M, Kiernan MC. Transcranial magnetic stimulation and amyotrophic lateral sclerosis: pathophysiological insights. J. Neurol. Neurosurg. Psychiatry 2013;84:1161–70.
⇑
References de Carvalho, M., Swash, M., 2013. Origin of Fasciculations in Amyotrophic Lateral Sclerosis and Benign Fasciculation Syndrome. JAMA Neurol. (in press) doi:10.1001/jamaneurol.2013.4437. de Carvalho M, Dengler R, Eisen A, England JD, Kaji R, Kimura J, et al. Electrodiagnostic criteria for diagnosis of ALS. Clin. Neurophysiol. 2008;119: 497–503. Kanai K, Kuwabara S, Misawa S, Tamura N, Ogawara K, Nakata M, et al. Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage. Brain 2006;129:953–62. Kanai K, Shibuya K, Sato Y, Misawa S, Nasu S, Sekiguchi Y, et al. Motor axonal excitability properties are strong predictors for survival in amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry 2012;83:734–8. Shimizu, T., Fujimaki, Y., Nakatani-Enomoto, S., Matsubara, S., Watabe, K., Rossini, P.M., et al. Complex fasciculation potentials and survival in amyotrophic lateral sclerosis. Clin. Neurophysiol 2014;125:1059–1064.
Satoshi Kuwabara Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba 206-8670, Japan ⇑ Tel.: +81 43 222 7171x5414; fax: +81 43 226 2160. E-mail address: [email protected] Kazumoto Shibuya Sonoko Misawa Department of Neurology, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, Japan Available online 28 November 2013
