Benzodiazepine-refractory status epilepticus: pathophysiology and principles of treatment

Cholinergic status epilepticus (CSE) quickly becomes self-sustaining, independent of its initial trigger, and resistant to benzodiazepines and other antiepileptic drugs. We review a few of the many physiological changes associated with CSE, with an emphasis on receptor trafficking. Time-dependent internalization of synaptic γ-aminobutyric acid (GABA)_A receptors explains, in part, the loss of inhibition and the loss of response to benzodiazepines in the early stages of CSE. The increase in N-methyl-d-aspartate receptors may contribute to the runaway excitation and excitotoxicity of CSE. These changes have therapeutic implications. The time-dependent increase in maladaptive changes points to the importance of early treatment. The involvement of both inhibitory and excitatory systems challenges current therapeutic guidelines, which recommend treating only one system, and questions the rationale for monotherapy. It suggests that polytherapy may be needed, especially when treatment is delayed, so that drugs can only reach a much reduced number of GABA_A receptors. Finally, it raises the possibility that the current practice of waiting for one treatment to fail before starting the next drug may need to be reevaluated.