Epilepsy

Epilepsy is a syndrome of central nervous system (CNS) dysfunction that can cause symptoms ranging from momentary sensory disturbances to convulsive seizures. It is the most common chronic neurologic illness, affecting 3 million people in the United States and 50 million people worldwide. It results from excessive electrical activity of neurons (nerve cells) located in the superficial area of the brain known as the cerebral cortex or gray matter. The terms seizure, convulsion, and epilepsy are often used interchangeably, but they do not have the same meaning. A seizure is a brief episode of abnormal electrical activity in the nerve cells of the brain, which may or may not lead to a convulsion. A convulsion is a more severe seizure characterized by involuntary spasmodic contractions of any or all voluntary muscles throughout the body, including skeletal, facial, and ocular muscles. Commonly reported symptoms include abnormal motor function, loss of consciousness, altered sensory awareness, and psychic changes. In contrast, epilepsy is a chronic, recurrent pattern of seizures. Excessive electrical discharges can often be detected by an electroencephalogram (EEG), which is obtained to help diagnose epilepsy. Fluctuations in the brain’s electrical potential are seen in the form of waves. These waves correlate well with different neurologic conditions and are used as diagnostic indicators. In the case of epilepsy, they are used to identify specific seizure subtypes.

Up to 50% of patients with epilepsy have normal EEGs; therefore a careful history is very important for accurate diagnosis. Other applicable diagnostic tests include skull radiography, computed tomography, and magnetic resonance imaging. These procedures help to rule out structural causes of epilepsy, such as brain tumors. In particularly severe cases, patients may be observed in a hospital setting or sleep study laboratory. This allows for continuous EEG and video monitoring to identify detailed patterns of seizure activity and to allow tailoring of an effective treatment.

Epilepsy occurs most commonly in children and the elderly. Epilepsy without an identifiable cause is known as primary epilepsy or idiopathic epilepsy. Primary epilepsy accounts for roughly 50% of cases. Evidence indicates genetic predispositions, but these have yet to be clearly defined. Studies in the field of pharmacogenomics (see Chapter 8) are beginning to clarify genetic factors that can help optimize antiepileptic drug therapy. In other cases, epilepsy has a distinct cause, such as trauma, infection, cerebrovascular disorder, or other illness. This is known as secondary or symptomatic epilepsy. The chief causes of secondary epilepsy in children and infants are developmental defects, metabolic disease, and injury at birth. Febrile seizures occur in children 6 months to 5 years of age, and by definition are caused by fever. Children usually outgrow the tendency to have such seizures, and thus these seizures do not constitute a chronic illness. Antipyretic drugs (e.g., acetaminophen [see Chapter 10]) are normally adequate for acute treatment.

In adults, acquired brain disorder is the major cause of secondary epilepsy. Examples include head injury, disease or infection of the brain and spinal cord, stroke, metabolic disorders, adverse drug reactions (e.g., meperidine [see Chapter 10], theophylline [see Chapter 37]), primary or metastatic brain tumor, or other nonspecific neurologic diseases. The elderly have the highest incidence of new-onset epilepsy. Fortunately, seizures in the elderly are often well controlled with drug therapy.

Generalized onset seizures, formerly called grand mal seizures, are characterized by neuronal activity that originates simultaneously in the gray matter of both hemispheres. There are several subtypes of generalized seizures. Tonic-clonic seizures begin with muscular contraction throughout the body (tonic phase) and progress to alternating contraction and relaxation (clonic phase). Tonic seizures involve spasms of the upper trunk with flexion of the arms. Clonic seizures are the same as tonic-clonic seizures but without the tonic phase. Atonic seizures, also known as drop attacks, involve sudden global muscle weakness and syncope. Myoclonic seizures are characterized by brief muscular jerks, but not as extreme as in other subtypes. Finally, absence seizures involve a brief loss of awareness that commonly occurs with repetitive spasmodic eye blinking for up to 30 seconds. This type occurs primarily in childhood and rarely after 14 years of age.

Partial onset seizures originate in a localized or focal region (e.g., one lobe) of the brain. There are three types of partial onset seizures. Simple partial onset seizure, formerly called petit mal seizure, is characterized by brief loss of awareness (e.g., blank stare) but without loss of consciousness or spasmodic eye blinking as in absence seizures. In complex partial onset seizure, the level of consciousness is reduced but is not completely lost. Partial onset seizures can progress to generalized tonic-clonic seizures in up to 40% of patients. This third type is known as a secondary generalized tonic-clonic seizure. The latter two types are also associated with postictal confusion, a term for the confused mental state that follows seizure activity. Unclassified seizures are those that do not clearly fit into any of the other categories.

Antiepileptic Drugs

Antiepileptic drugs are also called anticonvulsants. Antiepileptic drugs is a more appropriate term, because many of these medications are indicated for the management of all types of epilepsy, and not necessarily just convulsions. Anticonvulsants, on the other hand, are medications that are used to prevent the convulsive seizures typically associated with epilepsy.

The goal of antiepileptic drug therapy is to control or prevent seizures while maintaining a reasonable quality of life. Approximately 70% of patients can expect to become seizure free while taking only one drug. The remaining 30% of cases are more complicated, and often require multiple medications. Antiepileptic drugs have many adverse effects, and it is often difficult to achieve seizure control while avoiding adverse effects. In most cases, the therapeutic goal is not to eliminate seizure activity but rather to maximally reduce the incidence of seizures while minimizing drug-induced toxicity. Many patients must take these drugs for their entire lives. Treatment may eventually be stopped in some, but others will experience repeated seizures if constant levels of antiepileptic drugs are not maintained in the blood. Abrupt discontinuation of these drugs can result in withdrawal seizures. In both children and adults, there is only a 40% chance of recurrence after the first partial or generalized seizure. Therefore, antiepileptic drug therapy is not recommended after a single isolated seizure event.

There are numerous antiepileptic drugs available. To optimize drug selection, neurologists must consider the known efficacy of a drug for a certain type of seizure, the adverse effects and drug interaction profile, the cost, ease of use, and the availability of pediatric dosage forms. Many antiepileptic drugs are also used to treat other types of illnesses, including psychiatric disorders (see Chapter 16), migraine headaches (see Chapter 13), and neuropathic pain syndromes (see Chapter 10).

It is sometimes difficult to control a patient’s seizures using a single drug. Single-drug therapy must fail before multidrug therapy is attempted. Patients are normally started on a single antiepileptic drug, and the dosage is slowly increased until the seizures are controlled or until clinical toxicity occurs. If the first antiepileptic drug is not effective, the drug is tapered slowly while a second drug is introduced. Antiepileptic drugs are never to be stopped abruptly unless a severe adverse effect occurs.

Mechanism of Action and Drug Effects

As with many classes of drugs, the exact mechanism of action of the antiepileptic drugs is not known with certainty. However, evidence indicates that they alter the movement of sodium, potassium, calcium, and magnesium ions. The changes in the movement of these ions result in more stabilized and less excitable cell membranes.

The major pharmacologic effects of antiepileptics are threefold. First, they increase the threshold of activity in the area of the brain called the motor cortex. In other words, they make it more difficult for a nerve to be excited, or they reduce the nerve’s response to incoming electrical or chemical stimulation. Second, they act to limit the spread of a seizure discharge from its origin. They do this by suppressing the transmission of impulses from one nerve to the next. Third, they can decrease the speed of nerve impulse conduction within a given neuron. Less well understood are mechanisms that involve drug effects outside the neuron. For example, some drugs may indirectly affect seizure foci (locations) in the brain by altering the blood supply to these areas. Some drugs