Status epilepticus: Role for etiology in determining response to benzodiazepines. Issue 4 (10th April 2018)

• Record Type: Journal Article
• Authors: Joshi, Suchitra; Rajasekaran, Karthik; Hawk, Kyle M.; Chester, Stephen J.; Goodkin, Howard P.
• Is Part Of: Annals of neurology. Volume 83:Issue 4(2018)
• Page Start: 830
• Page End: 841
• Publication Date: 2018-04-10
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.25213
• Languages: English
• ISSNs: 0364-5134

Abstract

Abstract : Objective: Clinical factors contributing to benzodiazepine failure in treating status epilepticus (SE) include suboptimal dosing and seizure duration. As many benzodiazepine‐refractory episodes of SE arise from acute etiologies, we sought to determine whether etiology impacts SE treatment. Methods: The potency of diazepam to terminate SE induced by lithium‐pilocarpine (LiPilo‐SE) or kainic acid (KA‐SE) in 3‐week‐old rats was studied by video‐electroencephalography. Synaptic γ‐aminobutyric acid type A receptor (GABAR)‐mediated currents were recorded from dentate granule cells using voltage‐clamp electrophysiology. Surface expression of γ2 subunit–containing GABARs and Kv4.2 potassium channels in hippocampal slices was determined using a biotinylation assay. Expression of phosphorylated forms of β2/3 and γ2 subunits was determined using phosphospecific antibodies and Western blotting. Results: Diazepam failed to terminate late SE in LiPilo‐SE animals but was successful in terminating KA‐SE of 1‐ and 3‐hour duration. One hour after SE onset, GABAR‐mediated synaptic inhibition and γ2 subunit–containing GABAR surface expression were reduced in LiPilo‐SE animals. These were unchanged in KA‐SE animals at 1 and 3 hours. Phosphorylation of γ2 subunit residue S327 was unchanged in both models, although GABAR β3 subunit S408/409 residues were dephosphorylated in the LiPilo‐SE animals. Kv4.2 potassium channel surface expression was increased in LiPilo‐SE animals but reduced in KA‐SE animals. Interpretation: SE‐model–dependent differences support a novel hypothesis that the development of benzodiazepine pharmacoresistance may be etiologically predetermined. Further studies are required to investigate the mechanisms that underlie such etiological differences during SE and whether etiology‐dependent protocols for the treatment of SE need to be developed. Ann Neurol 2018;83:830–841