What is an Epileptic Seizure? Unifying Definitions in Clinical Practice and Animal Research to Develop Novel Treatments

After the great successes of the mid-20th century in the development of drug treatments for epilepsy, subsequent attempts to identify more efficacious therapies have led to incremental improvements but have not had an impact on the problem of medically intractable epilepsy. Indeed, one-third of epilepsy patients still continue to have uncontrolled seizures (1,2), and no method has been found to prevent the development of epilepsy in those at risk (3). Many investigators have proposed that further progress in creating new epilepsy treatments might be made using models with chronic recurrent spontaneous seizures (epilepsy), as opposed to acute evoked seizures. In addition, seizure semiologies and etiologies that approximate those of human epilepsy syndromes better than models currently used for drug discovery, are more likely to involve mechanisms of ictogenesis and epileptogenesis that are relevant to the corresponding human syndrome (4–8). Therefore, substantial efforts have recently been made to introduce into basic and translational research epilepsy models with realistic etiologies that more closely mimic human syndromes, such as stroke (9,10), head injury (11,12), early-life febrile seizures (13), and hypoxia–ischemia (14,15). These new models have a variety of types of spontaneous seizures, including short nonconvulsive partial seizures. Because these seizures differ from the typical motor seizures currently employed in drug development, there could be controversy among investigators as to their significance and whether they are truly seizures. Although there is general agreement that epileptic seizures consists of occasional, sudden, hypersynchronous discharges of gray matter (16), the operational definitions of seizures and the endpoints used to assess treatment results still vary widely in clinical practice and experimental research. Thus, a clarification of the definitions of seizures is needed, because this determines the preclinical endpoints used to test novel therapies for seizure control and epilepsy prevention. This review will first discuss the differences among clinical and experimental definitions of seizures and the detrimental consequences of this disparity to the understanding of mechanisms of epilepsies and the development of better treatments. It will then propose an operational definition of seizures that apply equally well to both humans and animals. Adoption of these definitions could facilitate comparisons of data across laboratories and the translation of new therapies to the bedside.