Pathophysiology of Status Epilepticus

Status epilepticus is refractory to initial intravenous anticonvulsants in every third patient and at least the generalised convulsive form is commonly associated with neuronal long-term consequences. The understanding of pathophysiological mechanisms underlying development and maintenance of status epilepticus and its sequelae is therefore of uttermost importance. Spontaneous seizure termination seems to be an active energy-demanding inhibitory process aiming at restoration of impaired Na-K-pump function. Lack of sufficient energy supply by mitochondrial ATP synthesis may result in ongoing seizure activity and the development of status epilepticus. Continuing epileptic activity itself induces a cascade of pathological alterations in the brain that contribute to maintenance of the condition. Decrease of inhibitory GABAA receptors and increase of excitatory NMDA receptors at the postsynaptic membrane facilitate sustained epileptic activity. Furthermore, these key adaptions impact pharmacology of status epilepticus with progressive pharmacoresistance to GABAergic anticonvulsants and an increased anticonvulsant effect of NMDA receptor antagonists in advanced stages of status epilepticus. Long-term consequences such as development of chronic epilepsy have been studied extensively in experimental animals but in patients status epilepticus is epileptogenic as well. Neuronal circuit modifications such as mossy fiber sprouting and loss of GABAergic interneurons may contribute to epileptogenesis, other mechanisms comprise long-term changes in gene expression and disruption of the blood-brain-barrier. The proper identification of molecular targets is the prerequisite todevelop effective antiepileptogenic treatment strategies in conditions such as status epilepticus and other severe brain injuries.