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.