Mechanisms of drug resistance in status epilepticus.

Refractory status epilepticus (RSE) is a major medical emergency, defined as severe form of SE that does not respond to first (benzodiazepines) and second (phenytoin, phenobarbital) treatment efforts with antiepileptic drugs (AEDs). Understanding the mechanisms of RSE is important to prevent or reverse its development. Based on both clinical experience and data from rat models of SE, seizures that last more than 30 min become very hard to control by AEDs. Experimental studies have shown that the prolonged seizures of SE lead to progressive alterations of GABAA receptors, including reduced surface expression of these receptors by receptor trafficking, which would explain the loss of efficacy of benzodiazepines. In addition to AED target alterations, SE-induced overexpression of drug efflux transporters, such as P-glycoprotein (Pgp), in the brain may be involved in the resistance to AEDs (including phenytoin and phenobarbital) that are Pgp substrates. However, recent experiments of our group did not indicate that Pgp plays any important role in drug resistance of SE. Improved understanding the molecular mechanisms underlying AED resistance in SE will ultimately provide new treatment options for RSE.