The antiseizure drugs described in this chapter are usually used chronically to prevent the occurrence of seizures in people with epilepsy. These drugs are also, on occasion, used in people who do not have epilepsy—to prevent seizures that may occur as part of an acute illness such as meningitis or in the early period following either neurosurgery or traumatic brain injury. In addition, certain antiseizure drugs are used to terminate ongoing seizures such as in status epilepticus or prolonged febrile seizures or following exposure to seizure-inducing nerve toxins. Seizures are occasionally caused by an acute underlying toxic or metabolic disorder, such as hypocalcemia, in which case appropriate therapy should be directed toward correcting the specific abnormality.
Most antiseizure drugs have been identified by tests in rodent (rat or mouse) models. The maximal electroshock (MES) test, in which animals receive an electrical stimulus, with tonic hindlimb extension as the end point, has been the most productive model. The MES test led to the identification of many of the sodium channel-blocking antiseizure drugs. Another model, the pentylenetetrazol (PTZ) test, in which animals receive a dose of the chemical convulsant PTZ (an antagonist of GABAA receptors) sufficient to cause clonic seizures, has also been widely used. Animals with a genetic susceptibility to absence-like episodes are useful in identifying drugs for the treatment of absence seizures. In the kindling model, mice or rats repeatedly receive a mild electrical stimulus in the amygdala or hippocampus over the course of a number of days, causing them to develop a permanent propensity for limbic seizures when they later are stimulated. The kindling model can be used to assess the ability of a chemical compound to protect against focal seizures. In addition to empirical screening of chemical compounds in such animal models, a few antiseizure drugs have been identified by in vitro screening against a molecular target. Examples of targets that have been used to identify approved antiseizure drugs include γ-aminobutyric acid (GABA) transaminase (vigabatrin), GAT-1 GABA transporter (tiagabine), AMPA receptors (perampanel), or the synaptic vesicle protein SV2A (brivaracetam).
Epileptic seizures are classified into two main categories: (1) focal onset seizures (in the past called “partial” or “partial onset” seizures), which begin in a local cortical site, and (2) generalized onset seizures, which involve both brain hemispheres from the onset (Table 24–1). Focal seizures can transition to bilateral tonic-clonic seizures (formerly called “secondarily generalized”). Focal aware seizures (previously “simple partial seizures”) have preservation of consciousness; focal impaired awareness seizures (formerly “complex partial seizures”) have impaired consciousness. Tonic-clonic convulsions (previously termed “grand mal”) are what most people typically think of as a seizure: the person
TABLE 24–1 International League Against Epilepsy classification of seizure types.
Generalized absence seizure (formerly petit mal seizure; occurs, for example, in absence epilepsy)
Myoclonic seizure (occurs, for example, in juvenile myoclonic epilepsy and Dravet’s syndrome)
Atonic seizure (drop seizure or astatic seizure; occurs, for example, in the Lennox-Gastaut syndrome)
Epileptic spasms (as in infantile spasms also known as West’s syndrome)
Lennox-Gastaut syndrome, Dravet’s syndrome, and juvenile myoclonic epilepsy are epilepsy syndromes in which there are multiple different seizure types.