title: Motor axonal excitability properties are strong predictors for survival in amyotrophic lateral sclerosis.
abstract: OBJECTIVE
  The aim of this study was to investigate whether axonal excitability indices are associated with survival in patients with amyotrophic lateral sclerosis (ALS). Previous nerve excitability studies suggested increased persistent sodium currents in motor axons of patients with ALS, which lead to axonal hyperexcitability and potentially enhance neuronal death.
  
  
  METHODS
  112 patients with sporadic ALS were followed up until endpoint (death or tracheostomy). Multivariate analyses were performed using the Cox proportional hazard model. Threshold tracking was used to measure multiple axonal excitability indices in median motor axons, such as strength-duration time constant (SDTC; a measure of nodal persistent sodium current). Latent addition was also used to estimate the magnitude of persistent sodium currents.
  
  
  RESULTS
  The overall median tracheostomy-free survival from onset was 37 months. Prolonged SDTC was strongly associated with shorter survival (adjusted HR 4.07; 95% CI 1.7 to 9.8; p=0.0018) compared with older onset age (>60 years; HR=1.80) and bulbar onset (HR=1.80). Estimated median survival was 34 months in the longer SDTC group and 51 months in the shorter SDTC group. This index was highly statistically significant even after multiple testing adjustments with age and site of onset (bulbar or limb). Latent addition study results were consistent with these findings.
  
  
  CONCLUSIONS
  Axonal persistent sodium currents, estimated by SDTC and latent addition, are strong and independent predictors for shorter survival in patients with ALS. Membrane hyperexcitability is possibly associated with motor neuronal death, and modulation of excessive sodium currents could be a novel therapeutic option for ALS.
authors.affiliation: Department of Neurology, Chiba University, Chuo-ku, Chiba, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Kanai
authors.forename: Kazumoto
authors.initials: K
authors.lastname: Shibuya
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Sato
authors.forename: Sonoko
authors.initials: S
authors.lastname: Misawa
authors.forename: Saiko
authors.initials: S
authors.lastname: Nasu
authors.forename: Yukari
authors.initials: Y
authors.lastname: Sekiguchi
authors.forename: Satsuki
authors.initials: S
authors.lastname: Mitsuma
authors.forename: Sagiri
authors.initials: S
authors.lastname: Isose
authors.forename: Yumi
authors.initials: Y
authors.lastname: Fujimaki
authors.forename: Shigeki
authors.initials: S
authors.lastname: Ohmori
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Koga
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kuwabara
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000401:mortality* / Q000503:physiopathology; D001369:Axons / Q000502:physiology*; D016022:Case-Control Studies; D018450:Disease Progression; D004594:Electrophysiology; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000502:physiology*; D015999:Multivariate Analysis; D009431:Neural Conduction / Q000502:physiology; D011379:Prognosis; D016016:Proportional Hazards Models; D015222:Sodium Channels / Q000502:physiology
chemical_list: D015222:Sodium Channels