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Early polytherapy for benzodiazepine-refractory status epilepticus.
Epilepsy Behav 2019; 101(Pt B):106367EB

Abstract

The transition from single seizures to status epilepticus (SE) is associated with malaptive trafficking of synaptic gamma-aminobutyric acid (GABAA) and glutamate receptors. The receptor trafficking hypothesis proposes that these changes are key events in the development of pharmacoresistance to antiepileptic drugs (AEDs) during SE, and that blocking their expression will help control drug-refractory SE (RSE). We tested this hypothesis in a model of SE induced by very high-dose lithium and pilocarpine (RSE), and in a model of SE induced by sc soman. Both models are refractory to benzodiazepines when treated 40 min after seizure onset. Our treatments aimed to correct the loss of inhibition because of SE-associated internalization of synaptic GABAA receptors (GABAAR), using an allosteric GABAAR modulator, sometimes supplemented by an AED acting at a nonbenzodiazepine site. At the same time, we reduced excitation because of increased synaptic localization of NMDA and AMPA (?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate) receptors (NMDAR, AMPAR (?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, N-methyl-D-aspartate receptors)) with an NMDAR channel blocker, since AMPAR changes are NMDAR-dependent. Treatment of RSE with combinations of the GABAAR allosteric modulators midazolam or diazepam and the NMDAR antagonists dizocilpine or ketamine terminated RSE unresponsive to high-dose monotherapy. It also reduced RSE-associated neuronal injury, spatial memory deficits, and the occurrence of spontaneous recurrent seizures (SRS), tested several weeks after SE. Treatment of soman-induced SE also reduced seizures, behavioral deficits, and epileptogenesis. Addition of an AED further improved seizure outcome in both models. Three-dimensional isobolograms demonstrated positive cooperativity between midazolam, ketamine, and valproate, without any interaction between the toxicity of these drugs, so that the therapeutic index was increased by combination therapy. The midazolam-ketamine-valproate combination based on the receptor trafficking hypothesis was far more effective in stopping RSE than the midazolam-fosphenytoin-valproate combination inspired from clinical guidelines for the treatment of SE. Furthermore, sequential administration of midazolam, ketamine, and valproate was far less effective than simultaneous treatment with the same drugs at the same dose. These data suggest that treatment of RSE should be based at least in part on its pathophysiology. The search for a better treatment should focus on the cause of pharmacoresistance, which is loss of synaptic GABAAR and gain of synaptic glutamate receptors. Both need to be treated. Monotherapy addresses only half the problem. Improved pharmacokinetics will not help pharmacoresistance because of loss of receptors. Waiting for one drug to fail before giving the second drugs gives pharmacoresistance time to develop. Future clinical trials should consider treating both the failure of inhibition and the runaway excitation which characterize RSE, and should include an early polytherapy arm. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

Authors+Show Affiliations

Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.Neuroscience Department, US Army Medical Research Institute of Chemical Defense (USAMRICD), 8350 Ricketts Point Rd., Aberdeen Proving Ground, MD 21010, USA.Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.Military Psychiatry and Neuroscience Department, Walter Reed Army Institute of Research, Silver Spring, MD, USA.Neuroscience Department, US Army Medical Research Institute of Chemical Defense (USAMRICD), 8350 Ricketts Point Rd., Aberdeen Proving Ground, MD 21010, USA.Neuroscience Department, US Army Medical Research Institute of Chemical Defense (USAMRICD), 8350 Ricketts Point Rd., Aberdeen Proving Ground, MD 21010, USA; Military Psychiatry and Neuroscience Department, Walter Reed Army Institute of Research, Silver Spring, MD, USA.Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Epilepsy Research Laboratory (151), Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA; Brain Research Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Electronic address: wasterla@ucla.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31636007

Citation

Niquet, Jerome, et al. "Early Polytherapy for Benzodiazepine-refractory Status Epilepticus." Epilepsy & Behavior : E&B, vol. 101, no. Pt B, 2019, p. 106367.
Niquet J, Lumley L, Baldwin R, et al. Early polytherapy for benzodiazepine-refractory status epilepticus. Epilepsy Behav. 2019;101(Pt B):106367.
Niquet, J., Lumley, L., Baldwin, R., Rossetti, F., Schultz, M., de Araujo Furtado, M., ... Wasterlain, C. G. (2019). Early polytherapy for benzodiazepine-refractory status epilepticus. Epilepsy & Behavior : E&B, 101(Pt B), p. 106367. doi:10.1016/j.yebeh.2019.06.011.
Niquet J, et al. Early Polytherapy for Benzodiazepine-refractory Status Epilepticus. Epilepsy Behav. 2019;101(Pt B):106367. PubMed PMID: 31636007.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Early polytherapy for benzodiazepine-refractory status epilepticus. AU - Niquet,Jerome, AU - Lumley,Lucille, AU - Baldwin,Roger, AU - Rossetti,Franco, AU - Schultz,Mark, AU - de Araujo Furtado,Marcio, AU - Suchomelova,Lucie, AU - Naylor,David, AU - Franco-Estrada,Ireri, AU - Wasterlain,Claude G, Y1 - 2019/10/18/ PY - 2019/05/04/received PY - 2019/06/08/accepted PY - 2019/10/23/pubmed PY - 2019/10/23/medline PY - 2019/10/23/entrez KW - Acute seizures KW - Epilepsy KW - Pharmacoresistance KW - Polytherapy KW - Status epilepticus SP - 106367 EP - 106367 JF - Epilepsy & behavior : E&B JO - Epilepsy Behav VL - 101 IS - Pt B N2 - The transition from single seizures to status epilepticus (SE) is associated with malaptive trafficking of synaptic gamma-aminobutyric acid (GABAA) and glutamate receptors. The receptor trafficking hypothesis proposes that these changes are key events in the development of pharmacoresistance to antiepileptic drugs (AEDs) during SE, and that blocking their expression will help control drug-refractory SE (RSE). We tested this hypothesis in a model of SE induced by very high-dose lithium and pilocarpine (RSE), and in a model of SE induced by sc soman. Both models are refractory to benzodiazepines when treated 40 min after seizure onset. Our treatments aimed to correct the loss of inhibition because of SE-associated internalization of synaptic GABAA receptors (GABAAR), using an allosteric GABAAR modulator, sometimes supplemented by an AED acting at a nonbenzodiazepine site. At the same time, we reduced excitation because of increased synaptic localization of NMDA and AMPA (?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate) receptors (NMDAR, AMPAR (?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, N-methyl-D-aspartate receptors)) with an NMDAR channel blocker, since AMPAR changes are NMDAR-dependent. Treatment of RSE with combinations of the GABAAR allosteric modulators midazolam or diazepam and the NMDAR antagonists dizocilpine or ketamine terminated RSE unresponsive to high-dose monotherapy. It also reduced RSE-associated neuronal injury, spatial memory deficits, and the occurrence of spontaneous recurrent seizures (SRS), tested several weeks after SE. Treatment of soman-induced SE also reduced seizures, behavioral deficits, and epileptogenesis. Addition of an AED further improved seizure outcome in both models. Three-dimensional isobolograms demonstrated positive cooperativity between midazolam, ketamine, and valproate, without any interaction between the toxicity of these drugs, so that the therapeutic index was increased by combination therapy. The midazolam-ketamine-valproate combination based on the receptor trafficking hypothesis was far more effective in stopping RSE than the midazolam-fosphenytoin-valproate combination inspired from clinical guidelines for the treatment of SE. Furthermore, sequential administration of midazolam, ketamine, and valproate was far less effective than simultaneous treatment with the same drugs at the same dose. These data suggest that treatment of RSE should be based at least in part on its pathophysiology. The search for a better treatment should focus on the cause of pharmacoresistance, which is loss of synaptic GABAAR and gain of synaptic glutamate receptors. Both need to be treated. Monotherapy addresses only half the problem. Improved pharmacokinetics will not help pharmacoresistance because of loss of receptors. Waiting for one drug to fail before giving the second drugs gives pharmacoresistance time to develop. Future clinical trials should consider treating both the failure of inhibition and the runaway excitation which characterize RSE, and should include an early polytherapy arm. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures". SN - 1525-5069 UR - https://www.unboundmedicine.com/medline/citation/31636007/Early_polytherapy_for_benzodiazepine-refractory_status_epilepticus L2 - https://linkinghub.elsevier.com/retrieve/pii/S1525-5050(19)30432-9 DB - PRIME DP - Unbound Medicine ER -