DEFINITION

Seizures result from paroxysmal and excessive electrical neuronal discharges in the brain that cause a variety of clinical manifestations. The term epilepsy is usually restricted to those cases with a tendency for recurrent seizures. The identification of a seizure as a symptom and not a disease diagnosis is an important distinction. Seizures are the clinical manifestation of epilepsy; the challenge is to identify the disease that explains the symptom. Often the underlying disease is epilepsy, but at other times it may be a nonepileptic disorder that causes symptoms that resemble an epileptic seizure.

The term epilepsy encompasses a group of syndromes that vary in its associated pathology and seizure types. The diagnosis of the epileptic syndrome is one of the primary objectives undertaken when managing a patient with seizures.

PREVALENCE

Epilepsy can manifest itself at any age; however, the incidence and prevalence are highest in the very young and the elderly. Depending on age at manifestation, the causes for epilepsy can differ widely. In the United States, there are approximately 1.6 million people who have epilepsy (roughly 0.6% of the population). Epilepsy has a lifetime prevalence of 3%—that is, 7.2 million persons will become affected by this disorder.¹ Almost 10% of the population will experience at least one epileptic seizure in 80 years of life.

PATHOPHYSIOLOGY

Two sets of changes can determine the epileptogenic properties of neuronal tissues. Abnormal neuronal excitability is believed to occur as a result of disruption of the depolarization and repolarization mechanisms of the cell (this is termed the excitability of neuronal tissue). Aberrant neuronal networks that develop abnormal synchronization of a group of neurons can result in the development and propagation of an epileptic seizure (this is termed the synchronization of neuronal tissue).²

A hyperexcitability of neurons that results in random firing of cells, by itself, may not lead to propagation of an epileptic seizure. Indeed, both normal and abnormal patterns of behavior require a certain degree of synchronization of firing in a population of neurons. Epileptic seizures originate in a setting of both altered excitability and altered synchronization of neurons. The excitability of individual neurons is affected by

The membrane properties and microenvironment of neurons, which maintain potential differences of electrical charge, are determined by selective ion permeability and ionic pumps. Excitatory neurotransmitters usually act by opening Na⁺ or Ca²⁺ channels, whereas inhibitory neurotransmitters usually open K⁺ or Cl⁻ channels. The mechanism of action of certain anticonvulsant medications is by Na⁺ or Ca²⁺ channel blockade, which likely prevents repetitive neuronal firing. Extracellular ionic concentrations also can contribute to neuronal excitability; for example, an increase in extracellular K⁺ concentrations (such as in rapid neuronal firing or dysfunction of glia, which are mainly responsible for K⁺ reuptake) causes membrane depolarization.

Various intracellular processes are controlled by genetic information. Neuronal excitability can be preprogrammed by DNA-controlled effects on cell structure, energy metabolism, receptor functions, transmitter release, and ionic channels. The mechanisms that induce these changes, either phasic or long term, appear to be linked to ionic currents, especially Ca²⁺ influx. Intracellular Ca²⁺ mediates changes in membrane proteins to initiate transmitter release and ion channel opening; it also activates enzymes to allow neurons to cover or uncover receptor sites that alter neuronal sensitivity. Various plastic or persistent changes in excitability can result by influencing the expression of genetic information through Ca²⁺ influx. This may occur by selectively inducing genes to synthesize a protein for a specific reason. One example is the induction of the c-fos gene to produce c-fos protein in neurons involved in an epileptic seizure by the administration of pentylenetetrazol. The exact effects of this coupling are not known, but it provides a means to study the effects of neuronal excitation on cell growth and differentiation as a model for epilepsy, learning, and memory.³

In regard to the structural features of neuronal elements in relation to epilepsy, the two primary regions of the brain that are involved in epilepsy are the cerebral neocortex and the hippocampus. In the neocortex, excitatory synapses are made primarily on the dendritic spines and shaft. The release of neurotransmitters at these sites gives rise to excitatory postsynaptic potentials. The inhibitory synapses are more prominent on the soma or proximal dendrites, and give rise to inhibitory postsynaptic potentials. The placement of these synapses effectively prevents distal excitatory events from reaching the axon hillock. Alterations of neuronal morphology, either spontaneously or as a response to injury, could enhance excitability with either an actual increase in the number of excitatory synapses or a decrease in the number of inhibitory synapses. Such alterations could consist of reduced dendritic branching with excitatory synapses placed closer to the axon hillock, or loss of spines, allowing more excitatory synapses to occur directly on the shaft. Lesions in the neuronal cell body or tracts lead to degeneration of the axon terminal and a new terminal may sprout to make contact with the vacated postsynaptic membrane. This may in turn lead to an increase in the excitatory potential of the neuron.⁴ Ca²⁺ currents that occur predominantly at the dendrites causing a high-amplitude prolonged depolarization that can evoke a rapid train of Na⁺ action potentials (burst-firing of Na⁺), which is followed by a prolonged after-hyperpolarization. These discharges are believed to contribute to the paroxysmal depolarization shifts and after-hyperpolarization in experimental epileptic foci.⁵

Neurons are influenced by synaptic and nonsynaptic interconnections. Neurochemical transmission between neurons involves a number of steps that can be selectively altered to affect neuronal excitability. These steps result in the release of neurotransmitters into the synaptic cleft and the postsynaptic membrane, resulting in excitatory or inhibitory postsynaptic potentials via Ca²⁺ and other second messengers. The transmitters are deactivated by enzymes, by reuptake into axon terminals, or by uptake by glia. The primary excitatory neurotransmitters in the central nervous system are the amino acids glutamate and aspartate. The primary inhibitory neurotransmitters in the central nervous system are gamma-aminobutyric acid (GABA) and glycine. Neurotransmitters and neuromodulators exert their effects by acting on receptors. Specific properties of receptors have been identified on the basis of the effects of certain agonist and antagonist agents, some of which are anticonvulsant drugs. GABA_A receptor drugs, which activate Cl⁻, appear to be more effective as anticonvulsants than GABA_B receptor agents, which activate K⁺. The GABA_A receptor is of primary importance in absence epilepsy due to its role in the synchronization and desynchronization of thalamocortical pathways. The oscillatory and burst-firing of these circuits is attributed to neurons in the reticular nucleus of the thalamus and leads to synchronization and desynchronization of the electroencephalogram (EEG). Alterations of this mechanism produce absence seizures. Kainic acid, quisqualic acid, and N-methyl-D-aspartate (NMDA) are excitatory amino acid analogues used to define the classes of receptors responsive to glutamate and aspartate. NMDA antagonists are one potential mechanism for some of the anticonvulsants.

Two hypotheses are associated with cortical dysplasia, which is a frequent cause of medically intractable focal epilepsy. The first hypothesis suggests that epileptogenesis results from a change in the synaptic properties of interneurons. The second hypothesis suggests abnormal intrinsic properties in the neurons, such as a mutation in the ion channel.

SIGNS AND SYMPTOMS

The diversity of symptoms that can result from an epileptic seizure arises from the differing brain regions that gives rise to the particular features of an individual seizure. The determination of seizure types can often help in the identification of the epileptic syndrome (Table 1). In spite of the technologic advances that have contributed to the understanding and treatment of epilepsy, the initiation and selection of treatment rely on the observed details of the seizure phenomenology. In this regard, obtaining an accurate seizure history from the patient as well as from observers who have witnessed the patient’s seizures is extremely important.

Table 1 Features of Primary Generalized and Partial Epilepsies

There have been many attempts at a classification system for epileptic seizures. The most widely used classification system is the one developed by the International League Against Epilepsy (ILAE), which is an electroclinical classification system (Table 2).⁶ This classification assumes that there is a one-to-one correlation between the phenomenology of the actual seizures and electrical abnormalities on the EEG seen with the seizure. This, however, is not always the case and these exceptions highlight the main weakness of the ILAE classification.

Table 2 International League Against Epilepsy Classification of Epileptic Seizures

* EEG, encephalogram.

† SWC, spike-wave complex.

There is an active effort to improve the ILAE classification. One such classification system is already in use in many centers that perform evaluations for epilepsy surgery.⁷ The advantage of such a semiologic classification is that it does not rely on knowledge of the electrical abnormalities in a patient, which are frequently unavailable. The classification of seizures can be either vague or more specific with this type of classification, depending on the accuracy of the information available.