title: Riluzole exerts transient modulating effects on cortical and axonal hyperexcitability in ALS.
abstract: Riluzole is an established therapy for amyotrophic lateral sclerosis (ALS), although its effects are modest, prolonging survival by three months on average. While the neuroprotective effects of riluzole appear to be mediated by inhibition of glutaminergic transmission and antagonization of Na+channel function, the duration of these effects remains to be elucidated. Consequently, the present study combined assessment of cortical and peripheral function to determine the longitudinal effects of riluzole in ALS patients. Assessment of cortical function by threshold tracking transcranial magnetic stimulation (TMS) combined with peripheral nerve function excitability studies were longitudinally undertaken on 19 sporadic ALS patients, with assessment occurring at baseline, four, eight, and 12 weeks post riluzole initiation. Baseline results were compared to 31 healthy controls. Results showed that, at baseline, cortical hyperexcitability was a feature of ALS as indicated by a marked reduction in averaged short interval intracortical inhibition [SICI] (3.6 ± 6.9%, p < 0.0001) and cortical silent period duration (p < 0.05) as well as an increase in motor evoked potential amplitude (p < 0.05). Riluzole therapy resulted in individual patient increase in SICI of 4.3% (p < 0.01) and 5.2% (p < 0.01) at four and eight weeks, respectively. At a peripheral level, riluzole therapy lead to a transient increase at four weeks in the relative refractory period (p < 0.05), superexcitability (p < 0.05) and late subexcitability (p < 0.05), all of which returned to baseline levels eight weeks after initiation of riluzole. In conclusion, the present study has established that riluzole exerts transient effects on cortical and axonal hyperexcitability, potentially accounting for the modest clinical effectiveness in ALS.
authors.affiliation: a Western Clinical School, University of Sydney , Sydney.
authors.forename: Nimeshan
authors.initials: N
authors.lastname: Geevasinga
authors.affiliation: a Western Clinical School, University of Sydney , Sydney.
authors.forename: Parvathi
authors.initials: P
authors.lastname: Menon
authors.affiliation: b Department of Neurology , Royal North Shore Hospital, St. Leonards, University of Sydney , Sydney.
authors.forename: Karl
authors.initials: K
authors.lastname: Ng
authors.affiliation: c Department of Neurology , Westmead Hospital , Sydney , Australia.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Van Den Bos
authors.affiliation: d Westmead Hospital, Research and Education Network, Sydney, Australia NHMRC Clinical Trials Centre , University of Sydney , Sydney , and.
authors.forename: Karen
authors.initials: K
authors.lastname: Byth
authors.affiliation: e Brain and Mind Center, University of Sydney , Sydney , Australia.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Kiernan
authors.affiliation: a Western Clinical School, University of Sydney , Sydney.
authors.forename: Steve
authors.initials: S
authors.lastname: Vucic
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000473:pathology*; D019054:Evoked Potentials, Motor / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009044:Motor Cortex / Q000503:physiopathology*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011446:Prospective Studies; D011930:Reaction Time / Q000187:drug effects; D019782:Riluzole / Q000627:therapeutic use*; D012720:Severity of Illness Index; D050781:Transcranial Magnetic Stimulation
chemical_list: D018696:Neuroprotective Agents; D019782:Riluzole
keywords: Riluzole; cortical hyperexcitability; short interval intracortical inhibition; treatment