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Early polytherapy for benzodiazepine-refractory status epilepticus
Jerome Niquet1, Lucille Lumley2, Roger Baldwin3
1Department 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.
Epilepsy & Behavior : E&B
|October 23, 2019
Summary
Targeting receptor changes in status epilepticus (SE) with combined GABAAR modulators and NMDAR antagonists effectively treated drug-refractory SE (RSE). This approach reduced seizures, neuronal injury, and long-term epileptogenesis, offering a promising strategy beyond current therapies.
Area of Science:
- Neuroscience
- Pharmacology
- Epileptology
Background:
- Status epilepticus (SE) involves maladaptive trafficking of synaptic GABAA and glutamate receptors.
- This receptor trafficking is hypothesized to drive pharmacoresistance to antiepileptic drugs (AEDs) during SE.
- Drug-refractory SE (RSE) presents a significant clinical challenge, often unresponsive to standard treatments.
Purpose of the Study:
- To test the receptor trafficking hypothesis in models of RSE.
- To evaluate combination therapies targeting both GABAA receptor loss and glutamate receptor gain.
- To compare novel combination therapies with standard clinical approaches.
Main Methods:
- Utilized lithium-pilocarpine and soman-induced SE models in rodents, both refractory to benzodiazepines.
- Administered combinations of GABAAR modulators (midazolam, diazepam) and NMDAR antagonists (dizocilpine, ketamine).
- Assessed seizure termination, neuronal injury, cognitive deficits, and spontaneous recurrent seizures (SRS) post-SE.
- Analyzed drug interactions using 3D isobolograms and compared sequential vs. simultaneous drug administration.
Main Results:
- Combination therapy with GABAAR modulators and NMDAR antagonists terminated RSE unresponsive to monotherapy.
- This treatment reduced SE-associated neuronal injury, spatial memory deficits, and subsequent SRS.
- Positive cooperativity and increased therapeutic index were observed with midazolam-ketamine-valproate combination.
- Simultaneous administration was significantly more effective than sequential treatment.
Conclusions:
- Treatment strategies for RSE should address the underlying pathophysiology of receptor trafficking.
- Combined therapy targeting both GABAA receptor loss and glutamate receptor gain is crucial for overcoming pharmacoresistance.
- Future clinical trials should consider early polytherapy based on these principles.
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