title: Benzodiazepine-refractory status epilepticus: pathophysiology and principles of treatment.
abstract: Cholinergic status epilepticus (CSE) quickly becomes self-sustaining, independent of its initial trigger, and resistant to benzodiazepines and other antiepileptic drugs. We review a few of the many physiological changes associated with CSE, with an emphasis on receptor trafficking. Time-dependent internalization of synaptic γ-aminobutyric acid (GABA)Areceptors explains, in part, the loss of inhibition and the loss of response to benzodiazepines in the early stages of CSE. The increase in N-methyl-d-aspartate receptors may contribute to the runaway excitation and excitotoxicity of CSE. These changes have therapeutic implications. The time-dependent increase in maladaptive changes points to the importance of early treatment. The involvement of both inhibitory and excitatory systems challenges current therapeutic guidelines, which recommend treating only one system, and questions the rationale for monotherapy. It suggests that polytherapy may be needed, especially when treatment is delayed, so that drugs can only reach a much reduced number of GABAAreceptors. Finally, it raises the possibility that the current practice of waiting for one treatment to fail before starting the next drug may need to be reevaluated.
authors.affiliation: Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California. jniquet@ucla.edu.|Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, West Los Angeles, California. jniquet@ucla.edu.
authors.forename: Jerome
authors.initials: J
authors.lastname: Niquet
authors.affiliation: Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, West Los Angeles, California.
authors.forename: Roger
authors.initials: R
authors.lastname: Baldwin
authors.affiliation: Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, West Los Angeles, California.
authors.forename: Lucie
authors.initials: L
authors.lastname: Suchomelova
authors.affiliation: U.S. Army Medical Research Institute of Chemical Defense (USAMRICD), Aberdeen Proving Ground, Aberdeen, Maryland.
authors.forename: Lucille
authors.initials: L
authors.lastname: Lumley
authors.affiliation: Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California.
authors.forename: David
authors.initials: D
authors.lastname: Naylor
authors.affiliation: Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, West Los Angeles, California.
authors.forename: Roland
authors.initials: R
authors.lastname: Eavey
authors.affiliation: Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California.|Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, West Los Angeles, California.|Brain Research Institute, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California.
authors.forename: Claude G
authors.initials: CG
authors.lastname: Wasterlain
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000627:therapeutic use*; D058787:GABA-A Receptor Antagonists / Q000627:therapeutic use*; D006801:Humans; D011963:Receptors, GABA-A / Q000378:metabolism; D013226:Status Epilepticus / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D001569:Benzodiazepines
keywords: cholinergic seizures; nerve agent; pharmacoresistance; polytherapy; refractory status epilepticus