Novel pharmacological therapies for refractory and super-refractory status epilepticus

Refractory status epilepticus (RSE) is a status epilepticus (SE) that continues despite first- and second-line treatments (i.e., benzodiazepine and intravenous antiseizure medications, respectively). Super-refractory SE (SRSE) is a SE continuing or recurring ۲۴ h or more after the onset of anesthetic therapy, and includes cases of SE recurring on the reduction or withdrawal of anesthesia. Both are associated with high morbidity and mortality. The pharmacological treatment of RSE and SRSE is often regarded as an evidence-free zone, due to the lack of randomized controlled trials. Most data on the treatment of RSE/SRSE are obtained from observational studies, conducted in small and heterogeneous populations, and are therefore not informative, and prone to bias and confounding. The underlying etiology of RSE/SRSE should be promptly identified and adequately treated. Novel antiseizure medications, such as perampanel and topiramate, appear promising; their mechanisms of action and pharmacological properties should be carefully considered to optimize their effectiveness. In some patients with RSE, sequential trial(s) of antiseizure medications could lead to SE resolution; sometimes this strategy might represent an effective alternative to the use of anesthetics, a class of drugs associated with increased risk of infection and death. Ketamine, a noncompetitive NMDA receptor antagonist, could be effective in RSE/SRSE, considering the subcellular maladaptive changes that occur in these conditions. Within the intrinsic clinical heterogeneity of RSE/SRSE, distinct electroclinical phenotypes with different responses to pharmacological interventions were recently identified. This could represent the first step towards a tailored approach in the pharmacological treatment of these conditions