Antiseizure Drugs Roger J.Porter,MD,Brian S.Meldrum,MB,PhD Introduction Approximately 1%of the world's population has epilepsy,the second most common neurologic disorder after stroke.Although standard therapy permits control of seizures in 80%of these patients,millions (500,000 people in the USA alone)have uncontrolled epilepsy.Epilepsy is a heterogeneous symptom complex%a chronic disorder characterized by recurrent seizures.Seizures are finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons.The causes of seizures are many and include the full range of neurologic diseases%from infection to neoplasm and head injury.In some subgroups,heredity has proved to be a predominant factor. The antiseizure drugs described in this chapter are also used in patients with febrile seizures or with seizures occurring as part of an acute illness such as meningitis.The term "epilepsy"is not usually applied to such patients unless chronic seizures develop later.Seizures are occasionally caused by an acute underlying toxic or metabolic disorder,in which case appropriate therapy should be directed toward the specific abnormality,eg,hypocalcemia.In most cases of epilepsy,however,the choice of medication depends on the empiric seizure classification. Drug Development for Epilepsy For a long time it was assumed that a single drug could be developed for the treatment of all forms of epilepsy,but the causes of epilepsy are extremely diverse, encompassing genetic and developmental defects and infective,traumatic,neoplastic, and degenerative disease processes.Drug therapy to date shows little evidence of etiologic specificity.There is,however,some specificity according to seizure type. This is most clearly seen with generalized seizures of the absence type.These are typically seen with 2-3 Hz spike-and-wave discharges on the electroencephalogram, which respond to ethosuximide and valproate but can be exacerbated by phenytoin and carbamazepine.Drugs acting selectively on absence seizures can be identified by animal screens,using either threshold pentylenetetrazol clonic seizures in mice or rats or mutant mice showing absence-like episodes (so-called lethargic,stargazer,or tottering mutants).In contrast,the maximal electroshock(MES)test,with suppression of the tonic extensor phase,identifies drugs such as phenytoin,carbamazepine,and lamotrigine that are active against generalized tonic-clonic seizures and complex partial seizures.Use of the maximal electroshock test as the major initial screen for new drugs has probably led to the identification of drugs with a common mechanism of action involving prolonged inactivation of the voltage-sensitive sodium channel. Limbic seizures induced in rats by the process of electrical kindling (involvingAntiseizure Drugs Roger J. Porter, MD, & Brian S. Meldrum, MB, PhD Introduction Approximately 1% of the world's population has epilepsy, the second most common neurologic disorder after stroke. Although standard therapy permits control of seizures in 80% of these patients, millions (500,000 people in the USA alone) have uncontrolled epilepsy. Epilepsy is a heterogeneous symptom complex¾a chronic disorder characterized by recurrent seizures. Seizures are finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons. The causes of seizures are many and include the full range of neurologic diseases¾from infection to neoplasm and head injury. In some subgroups, heredity has proved to be a predominant factor. The antiseizure drugs described in this chapter are also used in patients with febrile seizures or with seizures occurring as part of an acute illness such as meningitis. The term "epilepsy" is not usually applied to such patients unless chronic seizures develop later. Seizures are occasionally caused by an acute underlying toxic or metabolic disorder, in which case appropriate therapy should be directed toward the specific abnormality, eg, hypocalcemia. In most cases of epilepsy, however, the choice of medication depends on the empiric seizure classification. Drug Development for Epilepsy For a long time it was assumed that a single drug could be developed for the treatment of all forms of epilepsy, but the causes of epilepsy are extremely diverse, encompassing genetic and developmental defects and infective, traumatic, neoplastic, and degenerative disease processes. Drug therapy to date shows little evidence of etiologic specificity. There is, however, some specificity according to seizure type. This is most clearly seen with generalized seizures of the absence type. These are typically seen with 2-3 Hz spike-and-wave discharges on the electroencephalogram, which respond to ethosuximide and valproate but can be exacerbated by phenytoin and carbamazepine. Drugs acting selectively on absence seizures can be identified by animal screens, using either threshold pentylenetetrazol clonic seizures in mice or rats or mutant mice showing absence-like episodes (so-called lethargic, stargazer, or tottering mutants). In contrast, the maximal electroshock (MES) test, with suppression of the tonic extensor phase, identifies drugs such as phenytoin, carbamazepine, and lamotrigine that are active against generalized tonic-clonic seizures and complex partial seizures. Use of the maximal electroshock test as the major initial screen for new drugs has probably led to the identification of drugs with a common mechanism of action involving prolonged inactivation of the voltage-sensitive sodium channel. Limbic seizures induced in rats by the process of electrical kindling (involving