Treatment of Seizure Disorders

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Chapter 34 Treatment of Seizure Disorders

Abbreviations
EEG Electroencephalogram
GABA γ-Aminobutyric acid
NMDA N-methyl-D-aspartate

Therapeutic Overview

Epilepsy is a chronic disorder characterized by recurrent, self-limited seizures. Seizures occur when there is abnormal, excessive firing of neurons synchronized throughout a localized or generalized population of neurons. Approximately 0.8% of the population suffers from epilepsy, with most patients having their first seizure before 18 years of age. Recurrent seizures, if frequent, interfere with a patient’s ability to carry out day-to-day activities. However, judicious use of antiepileptic medications allows approximately 75% of patients to remain seizure-free.

Seizures are classified into two major types, partial or focal seizures and generalized seizures. Partial seizures arise in a localized region in one cerebral hemisphere and are accompanied by focal electroencephalographic (EEG) abnormalities. In contrast, generalized seizures involve all, or large parts, of both cerebral hemispheres, with EEG features indicating simultaneous hemispheric involvement.

Partial seizures are further classified as simple, complex, or secondarily generalized tonic-clonic. The seizures are termed simple if consciousness is preserved and complex if consciousness is impaired or lost. In partial complex seizures, motor activity often appears as a complicated and seemingly purposeful movement. If the seizure focus synchronizes and activates neurons in surrounding areas, the partial seizure can secondarily generalize to involve the entire brain and result in tonic-clonic manifestations, which involve rigid extension of the trunk and limbs (tonic phase) and rhythmic contractions of the arms and legs (clonic phase).

In generalized seizures, large areas of the brain are involved at the onset. Generalized seizures are classified by the presence or absence of specific patterns of motor convulsions and include generalized tonic-clonic seizures, in which widespread convulsions occur, absence seizures, characterized by impaired consciousness only, and other types of seizures including myoclonic, clonic, tonic, or atonic, depending on the specific clinical manifestations. The classification of seizures and their characteristics are presented in the Therapeutic Overview Box.

Status epilepticus is a life-threatening neurological disorder characterized by continuous seizures within a short time period. A patient is considered to be in status epilepticus if seizures last at least 30 minutes without recovery of consciousness between seizures. Status epilepticus can lead to systemic hypoxia, acidemia, hyperpyrexia, cardiovascular collapse, and renal shutdown and is a medical emergency.

All people are capable of experiencing seizures. Brain insults such as fever, hypoglycemia, hyponatremia, and extreme acidosis or alkalosis can trigger a seizure, but if the condition is corrected, seizures do not recur. In addition, recent studies have provided evidence for several polymorphisms in genes coding for both ligand-gated and voltage-gated ion channels that are linked to various types

Therapeutic Overview
Partial (Focal) Seizures
Simple seizures
No loss of consciousness, may or may nor be preceded by an aura, includes sensory, motor, autonomic, or psychic features
Complex seizures
Impaired consciousness, dreamy dysaffective state with or without automatisms
Secondarily generalized tonic-clonic seizures
Evolves from simple or complex partial seizure, impaired consciousness with rigid extension of trunk and limbs (tonic phase) and rhythmic contractions of arms and legs (clonic phase)
Generalized Seizures
Tonic-clonic (grand mal) seizures
As above for partial with secondarily generalized tonic-clonic seizures
Absence seizures
Abrupt loss of consciousness with staring and cessation of ongoing activity with or without eye blinks
Other types of seizures
Myoclonic—sporadic, isolated jerking movements
Clonic—repetitive jerking movements
Tonic—muscle stiffness and rigidity
Atonic (atypical)—loss of muscle tone

of familial epilepsy. The causes of isolated seizures and epilepsy (recurrent seizures) are summarized in Box 34-1.

The goal of antiepileptic drug therapy is to prevent seizures while minimizing side effects, by using the simplest drug regimen. If seizures continue after drug therapy begins and dose increases are inadvisable because of side effects, at least one and sometimes another drug should be tried as monotherapy before the use of two drugs simultaneously is considered. Discontinuation of antiepileptic medication after several seizure-free years depends on the diagnosis (type of seizure and epileptic syndrome), cause, and response to therapy. Antiepileptic drugs may be discontinued in patients with certain epileptic syndromes but should be continued for life in patients with others such as recurrent seizures caused by a structural lesion.

Mechanisms of Action

Antiepileptic drugs have been classified and selected for many years based on seizure type (Box 34-2). Although the intricate cellular alterations in the neuronal events mediating the generation of seizures is not totally understood, studies have provided evidence of likely alterations involved in both partial seizures and absence seizures to enable a mechanistic-based approach for treatment.

Partial seizures are thought to develop as a consequence of the loss of surround inhibition, a process that normally prevents the activation of neurons adjacent to a focus (Fig. 34-1). This loss of surround inhibition may result from impaired γ-aminobutyric acid (GABA) transmission, alterations in dendritic structure, changes in voltage-gated ion channel activity or density, or alterations in intracellular ion concentrations. If the seizure generalizes secondarily to involve both hemispheres, tonic-clonic effects are manifest. The tonic phase of muscle contraction is thought to reflect prolonged neuronal depolarization as a consequence of the loss of GABA-mediated inhibition and dominance of excitatory glutamate transmission. As the seizure evolves, neurons repolarize and afterhyperpolarizations are apparent, which reflect the reappearance of GABA-mediated inhibition and diminished glutamate excitation, producing the clonic phase. Thus drugs that increase surround inhibition and prevent the spread of synchronous activity are used for the treatment of partial seizures.

Our understanding of the onset of generalized tonic-clonic seizures is limited. However, there are some clues concerning the cellular mechanisms underlying absence seizures, which are characterized by the sudden appearance of spike-wave discharges synchronized throughout the brain. The EEGs recorded during an absence seizure compared with a generalized tonic-clonic seizure are shown in Figure 34-2. Studies support a major role of thalamocortical circuits in the pathogenesis of absence seizures with abnormal oscillations between cortical and thalamic neurons. The circuit involves excitatory glutamatergic cortical pyramidal and thalamic relay neurons and inhibitory GABAergic thalamic reticular neurons (Fig. 34-3). Thalamic relay neurons exhibit spike-wave discharges that generate normal cortical rhythms and participate in the generation of sleep spindles. The normal bursting pattern of these neurons results from the activation (depolarization) of low voltage-gated T-type (transient inward current) Ca++ channels, followed by hyperpolarization mediated by GABA released from thalamic reticular neurons. Thus drugs that block these T-type Ca++ currents are effective for the treatment of absence seizures.

Agents used for the treatment of epilepsy depress aberrant neuronal firing by primarily altering ion channel activity, enhancing GABA-mediated inhibitory neurotransmission, or dampening glutamate-mediated excitatory neurotransmission. It is important to note that although some drugs have a single mechanism of action, several of these agents have more than one mechanism. Anticonvulsant drugs classified according to mechanisms of action are listed in Box 34-3.