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Neuronal or axonal ion channel function can be impaired or altered in a number of disorders, such as acquired (autoantibody-mediated, toxic, and metabolic) and genetic channelopathies, and even neurodegenerative (motor neuron disease) or inflammatory diseases (multiple sclerosis, immune-mediated neuropathies). When specific channels are affected, axonal/neuronal excitability primarily alters according to original function of the corresponding channels. Separately, in the 1990s, axonal excitability testing was developed to assess ion channel function, membrane potential, and passive membrane properties non-invasively in human subjects. Using this technique, numerous papers on altered axonal excitability in a variety of disorders have been published since 2000. In a recent issue of Experimental Neurology, Park et al. demonstrated changes in peripheral axonal excitability in limbic encephalitis and acquired neuromyotonia with anti-voltage gated potassium channel antibodies. Unexpectedly, the results were not consistent with those caused by simple potassium channel blockade, suggesting that multiple other factors contribute to altered axonal excitability. In contrast it was reported that patients with episodic ataxia type 1 (genetic channelopathy with mutation of Kv1.1 channel gene) show prominent excitability changes exactly compatible with fast potassium channel blockade. This commentary aims to highlight findings of this study in a broader context, and provides possible explanations for the discrepancy of patterns of axonal excitability changes in acquired and genetic potassium channelopathies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Although autoantibodies targeted against voltage-gated potassium channel (VGKC)-associated proteins have been identified in limbic encephalitis (LE) and acquired neuromyotonia (aNMT), the role of these antibodies in disease pathophysiology has not been elucidated. The present study investigated axonal function across the spectrum of VGKC-complex antibody associated disorders., Methods: Peripheral axonal excitability studies were undertaken in a cohort of patients with LE (N=6) and aNMT (N=11), compared to healthy controls (HC; N=20)., Results: Patients with LE demonstrated prominent abnormalities in peripheral axonal excitability during the acute phase, with reduced threshold change in threshold electrotonus (depolarizing 10-20 LE: 58.5±3.1%; HC: 67.4±0.9%; P<.005; S2 accommodation LE: 17.2±1.4%; HC: 22.2±0.6%; P≤.005) and in recovery cycle parameters (superexcitability LE: -16.0±0.9%; HC: -23.4±1.1%; P<.01; subexcitability LE: 8.5±1.2%; HC: 13.8±0.7%; P≤.005). The pattern of change in LE patients was dissimilar to the effects of antiepileptic medications, suggesting that these factors did not underlie excitability changes in LE. Normalization of excitability parameters was associated with recovery (TEd peak correlation coefficient=.868; P=.002), suggesting that peripheral excitability studies may provide a marker associated with clinical improvement. In contrast, patients with aNMT demonstrated no significant changes at the site of stimulation., Conclusions: The lack of prominent excitability abnormalities in patients with aNMT likely reflects a distal origin of hyperexcitability, expected to be at the motor nerve terminal, while the prominent changes observed in patients with LE likely represent a complex disturbance at the level of the axonal membrane, combined with electrolyte imbalance and adaptive change., (Copyright © 2014 Elsevier Inc. All rights reserved.)