Early polytherapy for benzodiazepine-refractory status epilepticus

Abstract

The transition from single seizures to status epilepticus (SE) is associated with malaptive trafficking of synaptic gamma-aminobutyric acid (GABA A) 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 GABA A receptors (GABA A R), using an allosteric GABA A R 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 GABA A R allosteric modulators midazolam or diazepam and the NMDAR antagonists dizocilpine or ketamine terminated RSE unresponsive to high-dose monotherapy. It also reduced RSEassociated 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 GABA A R 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 ch...

Delayed Adjunctive Treatment of Organophosphate-Induced Status Epilepticus in Rats with Phenobarbital, Memantine, or Dexmedetomidine

“…Pre-treatment is unrealistic in our exposure scenario, and our data suggest that delayed treatment with the high dose of MEM would not be beneficial due to the increase in mortality, despite our finding that the surviving rats experienced less neuronal death. This increase in mortality combined with decreased neuronal death is similar to a recent report for the treatment of soman-induced SE (Jackson et al, 2019); however, it may not be a general feature of adjunctive NMDAreceptor antagonist therapies, given that MK-801 and ketamine have been reported to have beneficial effects in both OP and non-OP induced SE animal models (Borris et al, 2000;Niquet et al, 2019;Niquet et al, 2020). Furthermore, case studies support the potential use of ketamine in the treatment of refractory SE in both children and adults (Fang and Wang, 2015).…”

Delayed midazolam dose effects against soman in male and female plasma carboxylesterase knockout mice

“…[5][6][7][8] The delayed administration of MDZ or DZP to GD-or sarin-exposed rats does not prevent the development of spontaneous recurrent seizure (SRS), or the brain damage, neuroinflammatory responses, and behavioral deficits caused by CWNA-induced seizure. 3,4,[8][9][10][11][12][13][14][15] However, although delayed MDZ treatment fails to quickly terminate seizure and is not fully neuroprotective, it may reduce seizure severity in the first hour after treatment and dose-dependently reduce mortality compared with rats that were not given MDZ. 3,15,16 Although the rat and other rodent models of GD exposure have traditionally been used for the identification of novel therapies that counteract the aforementioned effects of CWNA-induced SE, the presence of plasma carboxylesterase activity in such animals may confound results.…”

“…3,4,[8][9][10][11][12][13][14][15] However, although delayed MDZ treatment fails to quickly terminate seizure and is not fully neuroprotective, it may reduce seizure severity in the first hour after treatment and dose-dependently reduce mortality compared with rats that were not given MDZ. 3,15,16 Although the rat and other rodent models of GD exposure have traditionally been used for the identification of novel therapies that counteract the aforementioned effects of CWNA-induced SE, the presence of plasma carboxylesterase activity in such animals may confound results. Because GD binds irreversibly to carboxylesterase, it reduces the systemic concentration of the organophosphorus agent that is freely available to inhibit AChE, 17 thereby providing some protection against lethal doses of certain organophosphorus compounds, including GD.…”

“…The internalization of synaptic γ‐aminobutyric acid (GABA) receptors is believed to underlie the time‐dependent reduction of the anticonvulsant potency of benzodiazepines (reviewed in Refs. 2–4 ). In line with the latter mechanism, in both rats and guinea pigs, the benzodiazepines MDZ and DZP are less effective in terminating GD‐ or sarin‐induced seizure when treatment is delayed to 30–60 min after seizure activity when compared with treatment 1–5 min after exposure; in addition, higher doses are needed to alleviate seizure activity 5–8 .…”

“…In line with the latter mechanism, in both rats and guinea pigs, the benzodiazepines MDZ and DZP are less effective in terminating GD‐ or sarin‐induced seizure when treatment is delayed to 30–60 min after seizure activity when compared with treatment 1–5 min after exposure; in addition, higher doses are needed to alleviate seizure activity 5–8 . The delayed administration of MDZ or DZP to GD‐ or sarin‐exposed rats does not prevent the development of spontaneous recurrent seizure (SRS), or the brain damage, neuroinflammatory responses, and behavioral deficits caused by CWNA‐induced seizure 3,4,8–15 . However, although delayed MDZ treatment fails to quickly terminate seizure and is not fully neuroprotective, it may reduce seizure severity in the first hour after treatment and dose‐dependently reduce mortality compared with rats that were not given MDZ 3,15,16 …”