Treating acute seizures with benzodiazepines: does seizure duration matter?

Abstract

Several clinical trials have shown improved seizure control and outcome by early initiation of treatment with benzodiazepines, before arrival in the emergency department and before intravenous access can be established. Here, evidence is provided and reviewed for rapid treatment of acute seizures in order to avoid the development of benzodiazepine pharmacoresistance and the emergence of self‐sustaining status epilepticus. Alterations in the physiology, pharmacology, and postsynaptic level of GABA‐A receptors can develop within minutes to an hour and hinder the ability of synaptic inhibition to stop seizures while also impairing the efficacy of GABAergic agents, such as benzodiazepines, to boost impaired inhibition. In addition, heightened excitatory transmission further exacerbates the inhibitory/excitatory balance and makes seizure control even more resistant to treatment. The acute increase in the surface expression of NMDA receptors during prolonged seizures also may cause excitotoxic injury, cell death, and other pathological expressions and re‐arrangements of receptor subunits that all contribute to long‐term sequelae such as cognitive impairment and chronic epilepsy. In conclusion, a short window of opportunity exists when seizures are maximally controlled by first‐line benzodiazepine treatment. After that, multiple pathological mechanisms quickly become engaged that make seizures increasingly more difficult to control with high risk for long‐term harm.

Excitatory GABAergic signalling is associated with acquired benzodiazepine resistance in status epilepticus

“…Secondly, the proportion of patients who responded patients who seize for longer prior to initial treatment were more likely to be resistant to benzodiazepine treatment. While previous studies and reviews have eluded to longer SE duration being associated with increased resistance to benzodiazepines (Deeb et al, 2012;Naylor, 2014;Fernández et al, 2015), our clinical data is the first to quantify this phenomenon. Notably, we show that the duration of SE can successfully be used as a binary classifier to detect benzodiazepine resistance in SE.…”

Benzodiazepine-refractory status epilepticus, neuroinflammation, and interneuron neurodegeneration after acute organophosphate intoxication

“…Benzodiazepines are safe treatment options for acute seizure and SE, which is a medical emergency associated with significant neurological morbidity and mortality [16, 50, 71–72]. Early treatment has significant protective action including better survival rate and faster SE termination.…”

“…However, a short window of opportunity exists when SE is effectively controlled by benzodiazepine therapy. After that, multiple pathological mechanisms quickly trigger to create benzodiazepine-refractory state that make seizures increasingly more difficult to control with high risk for long-term damage [71, 72]. Therefore, diazepam is less optimal for the treatment of nerve agent-induced seizures considering the therapeutic window of a delayed post-exposure scenario.…”

Cardiac-based vagus nerve stimulation reduced seizure duration in a patient with refractory epilepsy

“…In conclusion, our case provides evidence that additional VNSstimulation in response to seizure-related HR-increases is able to significantly reduce seizure duration. From a clinical point of view, a significant reduction of seizure duration may protect patients from the potential harm of prolonged seizures and maybe from evolution into generalised convulsive seizures [19]. Despite the limitations of our report, this promising result prompts larger studies to confirm the clinical benefit of this novel VNS-device.…”