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Studies conducted by <jats:italic>Epilepsia<\/jats:italic>. 2005;46:142 demonstrated that the initiation and maintenance of cholinergic\u2010induced RSE are associated with trafficking and inactivation of gamma\u2010aminobutyric acid A receptors (GABA<jats:sub>A<\/jats:sub>R) thought to contribute to the development of benzodiazepine pharmacoresistance. In addition, Dr. Wasterlain's laboratory reported that increased N\u2010methyl\u2010<jats:sc>d<\/jats:sc>\u2010aspartate receptors (NMDAR) and alpha\u2010amino\u20103\u2010hydroxy\u20105\u2010methyl\u20104\u2010isoxazolepropionic acid receptors (AMPAR) contribute to enhanced glutamatergic excitation (<jats:italic>Neurobiol Dis<\/jats:italic>. 2013;54:225; <jats:italic>Epilepsia<\/jats:italic>. 2013;54:78). Thus, Dr. Wasterlain postulated that targeting both maladaptive responses of reduced inhibition and increased excitation that is associated with cholinergic\u2010induced RSE should improve therapeutic outcome. We currently review studies in several animal models of cholinergic\u2010induced RSE that demonstrate that benzodiazepine monotherapy has reduced efficacy when treatment is delayed and that polytherapy with drugs that include a benzodiazepine (eg midazolam and diazepam) to counter loss of inhibition, concurrent with an NMDA antagonist (eg ketamine) to reduce excitation provide improved efficacy. Improved efficacy with polytherapy against cholinergic\u2010induced seizure is demonstrated by reduction in (1) seizure severity, (2) epileptogenesis, and (3) neurodegeneration compared with monotherapy. Animal models reviewed include pilocarpine\u2010induced seizure in rats, organophosphorus nerve agent (OPNA)\u2010induced seizure in rats, and OPNA\u2010induced seizure in two mouse models: (1) carboxylesterase knockout (Es1<jats:sup>\u2212\/\u2212<\/jats:sup>) mice which, similarly to humans, lack plasma carboxylesterase and (2) human acetylcholinesterase knock\u2010in carboxylesterase knockout (KIKO) mice. We also review studies showing that supplementing midazolam and ketamine with a third antiseizure medication (valproate or phenobarbital) that targets a nonbenzodiazepine site rapidly terminates RSE and provides further protection against cholinergic\u2010induced SE. Finally, we review studies on the benefits of simultaneous compared with sequential drug treatments and the clinical implications that lead us to predict improved efficacy of early combination drug therapies. The data generated from seminal rodent studies of efficacious treatment of cholinergic\u2010induced RSE conducted under Dr. Wasterlain's guidance suggest that future clinical trials should treat the inadequate inhibition and temper the excess excitation that characterize RSE and that early combination therapies may provide improved outcome over benzodiazepine monotherapy.<\/jats:p>","DOI":"10.1002\/epi4.12713","type":"journal-article","created":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T05:53:14Z","timestamp":1676958794000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Treatment of cholinergic\u2010induced status epilepticus with polytherapy targeting <scp>GABA<\/scp> and glutamate receptors"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1005-0517","authenticated-orcid":false,"given":"Jerome","family":"Niquet","sequence":"first","affiliation":[{"name":"Department of 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