Reprint of “EEG: Characteristics of drug-induced seizures in rats, dogs and non-human primates”

Simon Authier, Joseph Arezzo, Mylène Pouliot, Michael V. Accardi, Emmanuel Boulay, Eric Troncy, Michelle Dubuc Mageau, Wendy Tan, Audrey Sanfacon, Stephanie Mignault Goulet, Dominique Paquette

Research output: Contribution to journalArticle

Abstract

Seizures are amongst the most frequent neurological issues encountered in pre-clinical safety testing. The objective was to characterize EEG morphologies and premonitory signs in drug-induced seizures in preclinical species. A comparative (inter-species) retrospective analysis for drug-induced seizures recorded by video-telemetry was conducted in rats (n = 53), dogs (n = 195), and non-human primates (n = 234). The most frequent premonitory signs were, in rats, myoclonus (100%), tremors (93%), salivation (75%), partial ptosis (58%) and chewing/bruxism (58%); in dogs, tremors (77%), ataxia/uncoordination (60%), myoclonus (45%), salivation (43%), excessive licking (38%), high vocalization (38%) and decreased activity (34%); in non-human primates, tremors (79%), decreased activity (70%), myoclonus (57%), retching/emesis (37%), hunched posture (30%) and ataxia/uncoordination (27%). Seizure duration ranged from 3 s to 14 min with an average of 46 ± 21 s, comparable across species. At seizure onset, spike frequency averaged 9.4 Hz for the three species compared to 4.3 Hz at seizure end. Peak average amplitudes were attained at mid-seizure and amplitudes at seizure end decreased from peak but remained higher than onset amplitudes. Spike duration was inversely correlated with frequency and presented a crescendo pattern. Morphological characteristics can serve to refine automated EEG analysis. From a regulatory perspective, the most common paradigm is to use the most sensitive species in seizure liability studies but translational potential and clinical relevance may be under represented in the decision making process in some cases. EEG morphologies during drug-induced seizures presented remarkable similarities between species and tremors were identified as a predominant premonitory clinical sign in all species.

Original languageEnglish (US)
Article number106611
JournalJournal of Pharmacological and Toxicological Methods
Volume99
DOIs
StatePublished - 2019

Keywords

  • Convulsion
  • Electroencephalography
  • Safety pharmacology
  • Seizure
  • Sharp waves
  • Spikes
  • Toxicology

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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    Authier, S., Arezzo, J., Pouliot, M., Accardi, M. V., Boulay, E., Troncy, E., Dubuc Mageau, M., Tan, W., Sanfacon, A., Mignault Goulet, S., & Paquette, D. (2019). Reprint of “EEG: Characteristics of drug-induced seizures in rats, dogs and non-human primates”. Journal of Pharmacological and Toxicological Methods, 99, [106611]. https://doi.org/10.1016/j.vascn.2019.106611