How do seizures stop?

Although often overshadowed by factors influencing seizure initiation, seizure termination is a critical step in the return to the interictal state. Understanding the mechanisms contributing to seizure termination could potentially identify novel targets for anticonvulsant drug development and may also highlight the pathophysiological processes contributing to seizure initiation. In this article, we review known physiological mechanisms contributing to seizure termination and discuss additional mechanisms that are likely to be relevant even though specific data are not yet available. This review is organized according to successively increasing "size scales"-from membranes to synapses to networks to circuits. We first discuss mechanisms of seizure termination acting at the shortest distances and affecting the excitable membranes of neurons in the seizure onset zone. Next we consider the contributions of ensembles of neurons and glia interacting at intermediate distances within the region of the seizure onset zone. Lastly, we consider the contribution of brain nuclei, such as the substantia nigra pars reticulata (SNR), that are capable of modulating seizures and exert their influence over the seizure onset zone (and neighboring areas) from a relatively great-in neuroanatomical terms-distance. It is our hope that the attention to the mechanisms contributing to seizure termination will stimulate novel avenues of epilepsy research and will contribute to improved patient care.