Chapter 21: Pharmacotherapy of the Epilepsies

INTRODUCTION

The epilepsies are common and frequently devastating disorders, affecting ~2.5 million people in the U.S. alone. More than 40 distinct forms of epilepsy have been identified. Epileptic seizures often cause transient impairment of consciousness, leaving the individual at risk of bodily harm and often interfering with education and employment. Therapy is symptomatic in that available drugs inhibit seizures, but neither effective prophylaxis nor cure is available. Compliance with medication is a major problem because of the need for long-term therapy together with unwanted effects of many drugs.

The mechanisms of action of anti-seizure drugs fall into three major categories.

1. The first mechanism is to limit the sustained, repetitive firing of neurons, an effect mediated by promoting the inactivated state of voltage-activated Na⁺ channels.

2. A second mechanism appears to involve enhanced γ-aminobutyric acid (GABA)–mediated synaptic inhibition, an effect mediated either by a presynaptic or postsynaptic action. Drugs effective against the most common forms of epileptic seizures, partial and secondarily generalized tonic-clonic seizures, appear to work by one of these two mechanisms.

3. Drugs effective against absence seizure, a less common form of epileptic seizure, work by a third mechanism, inhibition of voltage-activated Ca²⁺ channels responsible for T-type Ca²⁺ currents.

Although many treatments are available, much effort is being devoted to elucidating the genetic causes and the cellular and molecular mechanisms by which a normal brain becomes epileptic, insights that promise to provide molecular targets for both symptomatic and preventive therapies.

TERMINOLOGY AND EPILEPTIC SEIZURE CLASSIFICATION

The term seizure refers to a transient alteration of behavior due to the disordered, synchronous, and rhythmic firing of populations of brain neurons. The term epilepsy refers to a disorder of brain function characterized by the periodic and unpredictable occurrence of seizures. Seizures can be "non-epileptic" when evoked in a normal brain by treatments such as electroshock or chemical convulsants, or "epileptic" when occurring without evident provocation. Pharmacological agents in current clinical use inhibit seizures, and thus are referred to as anti-seizure drugs. Whether any of these prevent the development of epilepsy (epileptogenesis) is uncertain.

Seizures are thought to arise from the cerebral cortex, and not from other central nervous system (CNS) structures such as the thalamus, brainstem, or cerebellum. Epileptic seizures have been classified into partial seizures, those beginning focally in a cortical site, and generalized seizures, those that involve both hemispheres widely from the outset (Commission on Classification and Terminology, 1981). The behavioral manifestations of a seizure are determined by the functions normally served by the cortical site at which the seizure arises. For example, a seizure involving motor cortex is associated with clonic jerking of the body part controlled by this region of cortex. A simple partial seizure is associated with preservation of consciousness. A complex partial seizure is associated with impairment of consciousness. The majority of complex partial seizures ...