Simultaneous triple therapy for the treatment of status epilepticus

Early maladaptive internalization of synaptic GABA_A receptors (GABA_AR) and externalization of NMDA receptors (NMDAR) may explain the time-dependent loss of potency of standard anti-epileptic drugs (AED) in refractory status epilepticus (SE). We hypothesized that correcting the effects of changes in GABA_AR and NMDAR would terminate SE, even when treatment is delayed 40 minutes. SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABA_AR agonist midazolam, the NMDAR antagonist ketamine and the AED valproate were injected 40 min after SE onset in combination or as monotherapy. The midazolam-ketamine-valproate combination was more efficient than triple-dose midazolam, ketamine or valproate monotherapy or higher-dose dual therapy in reducing several parameters of SE severity. Triple therapy also reduced SE-induced acute neuronal injury and spatial memory deficits. In addition, simultaneous triple therapy was more efficient than sequential triple therapy: giving the three drugs simultaneously was more efficient at stopping seizures than the standard practice of giving them sequentially. Furthermore, midazolam-ketamine-valproate therapy suppressed seizures far better than the midazolam-fosphenytoin-valproate therapy, which follows evidence-based AES guidelines. These results show that a treatment aimed at correcting maladaptive GABA_AR and NMDAR trafficking can reduce the severity of SE and its long-term consequences.