Abstract
Wide-spread fasciculations are a characteristic feature in amyotrophic lateral sclerosis (ALS), suggesting motor axonal hyperexcitability. Previous excitability studies have shown increased nodal persistent sodium conductances and decreased potassium currents in motor axons of ALS patients, both of the changes inducing hyperexcitability. Altered axonal excitability potentially contributes to motor neuron death in ALS, but the relationship of the extent of motor neuronal death and abnormal excitability has not been fully elucidated. We performed multiple nerve excitability measurements in the median nerve at the wrist of 140 ALS patients and analyzed the relationship of compound muscle action potential (CMAP) amplitude (index of motor neuronal loss) and excitability indices, such as strength-duration time constant, threshold electrotonus, recovery cycle and current-threshold relationships. Compared to age-matched normal controls (n = 44), ALS patients (n = 140) had longer strength-duration time constant (SDTC: a measure of nodal persistent sodium current; p < 0.05), greater threshold changes in depolarizing threshold electrotonus (p < 0.05) and depolarizing current threshold relationship (i.e. less accommodation; (p < 0.05), greater superexcitability (a measure of fast potassium current; p < 0.05) and reduced late subexcitability (a measure of slow potassium current; p < 0.05), suggesting increased persistent sodium currents and decreased potassium currents. The reduced potassium currents were found even in the patient subgroups with normal CMAP (> 5mV). Regression analyses showed that SDTC (R = -0.22) and depolarizing threshold electrotonus (R = -0.22) increased with CMAP decline. These findings suggest that motor nerve hyperexcitability occurs in the early stage of the disease, and precedes motor neuronal loss in ALS. Modulation of altered ion channel function could be a treatment option for ALS.
Highlights
From the date of Charcot, pathomechanisms of upper and lower motor neuron degeneration in amyotrophic lateral sclerosis (ALS) have not been fully elucidated [1]
ALS patients with over 5mV CMAP amplitude demonstrated similar findings, extents of these differences were less evident, and strength-duration time constant (SDTC) did not reach significant difference. These results suggest that decreased potassium currents are obvious even in patients with preserved CMAP amplitudes, and increased sodium and decreased potassium currents were more prominent in patients with severe axonal loss
SDTC (p = 0.01, R = -0.22) and threshold electrotonus (TEd) 90-100ms (p = 0.01, R = -0.22) were significantly related to CMAP amplitude and increased with CMAP decline. These findings suggest that increased persistent sodium and decreased slow potassium currents are significantly related to axonal loss and become prominent with axonal loss
Summary
From the date of Charcot, pathomechanisms of upper and lower motor neuron degeneration in amyotrophic lateral sclerosis (ALS) have not been fully elucidated [1]. Multiple pathomechanisms underlie the development of motor neuron death, with motor neuronal hyperexcitability potentially contributing to it [2]. Axonal Dysfunction Precedes Motor Neuronal Death in ALS axons, increased sodium and decreased potassium currents, both of these inducing hyperexcitability, have been reported [5,6,7,8]. Futhermore, ALS motor neuron has decreased capacity for Ca2+ influx [11]. Motor neuronal hyperexcitability appears to increase exposure to glutamate, Ca2+ influx and result in motor neuronal degeneration. Riluzole is known to lower the concentration of glutamate in the synaptic cleft and support this hypothesis [12]
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