JOURNAL ARTICLE

How can a Na + channel inhibitor ameliorate seizures in Lennox-Gastaut syndrome?

Yun-Chu Lin, Yi-Chen Lai, Ping Chou, Shu-Wei Hsueh, Tien-Hung Lin, Chen-Syuan Huang, Ren-Wei Wang, Ya-Chin Yang, Chung-Chin Kuo
Annals of Neurology 2021 March 21
33745195

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy frequently associated with multiple types of seizures. The classical Na+ channel inhibitors are in general ineffective against the seizures in LGS. Rufinamide is a new Na+ channel inhibitor, but approved for the treatment of LGS. This is not consistent with a choice of antiseizure drugs (ASD) according to simplistic categorical grouping.

METHODS: The effect of rufinamide on the Na+ channel, cellular discharges, and seizure behaviors were quantitatively characterized in native neurons and mammalian models of epilepsy, and compared with the other Na+ channel inhibitors.

RESULTS: With a much faster binding rate to the inactivated Na+ channel than phenytoin, rufinamide is distinctively effective if the seizure discharges chiefly involve short bursts interspersed by hyperpolarized interburst intervals, exemplified by spike and wave discharges (SWD) in electroencephalograms. Consistently, rufinamide, but not phenytoin, suppresses SWD-associated seizures in pentylenetetrazole or AY-9944 models, which recapitulate the major electrophysiological and behavioral manifestations in typical and atypical absence seizures including LGS.

INTERPRETATION: Na+ channel inhibitors must have sufficiently fast binding to exert an action during the short bursts and then suppress SWD, in which cases rufinamide is superior. For the other epileptiform discharges where the interburst intervals are not so hyperpolarized, phenytoin could be better because of the higher affinity. Na+ channel inhibitors with different binding kinetics and affinity to the inactivated channels may have different antiseizure scope. A rational choice of ASD according to in-depth molecular pharmacology and the attributes of ictal discharges is advisable. This article is protected by copyright. All rights reserved.

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