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Table of Contents

Reviewed May 4, 2003

Dileep R. Nair, MD

Department
of Neurology

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Definition

Prevalence

Pathophysiology

Signs and
Symptoms

Diagnosis

Therapy

Outcomes

References

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 important. 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 a symptom resembling 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.

Epilepsy can present itself at any age; however, the incidence and prevalence is highest in the very young and the elderly. Depending on age of 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.

Two sets of changes can determine the epileptogenic properties of neuronal tissues. Abnormal neuronal excitability is thought 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:

• cell membrane properties and the microenvironment
  of the neuron
• intracellular processes
• structural features of neuronal elements
• interneuronal connections

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, which may in turn lead to an increase in the excitatory potential of the neuron.⁴ Ca²⁺ currents that occur predominantly at the dendrites cause 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 afterhyperpolarization. These discharges are believed to contribute to the paroxysmal depolarization shifts and afterhyperpolarization 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 neurotransmitter 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 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 analogs 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, a frequent cause of medically intractable focal epilepsy. The first suggests that epileptogenesis results from a change in the synaptic properties of interneurons. The second suggests abnormal intrinsic properties in the neurons, such as a mutation in the ion channel.

The diversity of symptoms that can result from an epileptic seizure arises from the differing brain regions that, when deprived of their function, give 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 relies 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.

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 highlights the main weakness of the ILAE classification.

There is an active effort to improve on the ILAE classification with one that is based primarily on seizure semiology. 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.

The initial evaluation in patients who present with spells or seizures is to determine whether these episodes are epileptic in nature. A false diagnosis can have severe repercussions for the patient, including the expense of medications as well as their potential adverse effects. Other hazards include the loss of driving privileges, loss of income, and the expense of unnecessary visits to the emergency room. Disorders that can be confused with epilepsy include migraine, syncope, transient ischemic attacks, nonepileptic events (pseudoseizures), movement disorders, Meniere's disease, and rage attacks. In pediatric patients, the differential also includes breath-holding spells, pallid infantile syncope, tics, night terrors, somnambulism, and long QT syndrome.⁸

Once epileptic seizures are diagnosed, the next step is to determine the epileptic syndrome and then the seizure type. This is helpful for choosing medications as well as for evaluating a patient for surgical treatment. The epileptic syndrome is determined based on the history, physical examination, EEG findings, and neuroimaging studies. Epileptic syndromes can be divided primarily into two types: generalized epilepsies and focal (or partial) epilepsies. The primary distinction is that the generalized epilepsies have generalized epileptiform abnormalities on EEG, whereas focal epilepsies have focal abnormalities on EEG. Table 1 shows some of the differentiating points between these two types of epilepsies.

The patients with focal epilepsies are candidates for epilepsy surgery if their seizures are intractable to medications. Wilder Penfield in 1956 established the concept of the epileptogenic anatomic lesion and the epileptogenic physiologic lesion.⁹ The physiologic epileptic lesion was the part of the brain that demonstrated abnormalities on EEG that appeared to extend beyond the anatomic boundaries of the identified pathology responsible for the epilepsy. These areas are not always contiguous

There are further subdivisions that one can use to differentiate regions associated with epileptogenicity. For example, the epileptogenic lesion may be mesial temporal sclerosis, which may have a surrounding large region of interictal epileptiform activity (abnormal EEG activity not associated with a clinical seizure) described as the irritative zone. The area representing the detected ictal onset (the EEG findings during an epileptic seizure) is referred to as "the ictal-onset zone." The area which, when removed by surgery and results in rendering the patient seizure-free, is referred to as the "epileptogenic zone." The epileptogenic zone can only be inferred retrospectively after surgery. For epilepsy surgery to be successful, the various defined areas usually need to converge to one particular region
(Figure 1).¹⁰

Figure 1

The EEG helps to confirm the diagnosis of epilepsy and provides information regarding the epileptic syndrome and, in focal epilepsies, the location of the seizure focus. However, the EEG records cerebral activity only during the time of recording, and so its information is thus only a snapshot in time. It therefore cannot confirm the diagnosis of epilepsy in all patients with epilepsy. Certain activation procedures like sleep deprivation, photic stimulation, and hyperventilation can improve the detection of epileptiform activity as can obtaining more-prolonged EEG recordings. In some cases, when the diagnosis is uncertain, video-EEG monitoring can help clarify the epileptic syndrome or identify nonepileptic events. In about 10% of patients with epilepsy, multiple EEG studies could show no abnormalities.⁸

Neuroimaging, especially with magnetic resonance imaging, is likely to show abnormalities in patients with focal epilepsy. These include vascular abnormalities such as strokes, arteriovenous malformations, cavernous angiomas, brain tumors, mesial temporal sclerosis, cortical dysplasia, and encephalomalacias.

The first-line treatment of epilepsy is administration of an antiepileptic drug (AED). The selection of an appropriate AED is based on diagnosis of the epileptic syndrome of the patient (Table 3). First-line therapy for patients with focal seizures includes phenytoin, carbamazepine, and valproate. Drugs for adjunctive therapy for focal seizures include levetiracetam, topiramate, zonisamide, lamotrigine, gabapentin, oxcarbazepine, phenobarbital, and tiagabine. Drugs used in generalized seizures include valproate, lamotrigine, phenytoin, phenobarbital, and ethosuximide (which is specific for absence seizures).

These drugs have initial starting doses, and subsequent titration is based on response to medication and side-effect profile (Table 4). In patients who do not respond to medication, epilepsy surgery is a potential mode of treatment that can offer up to a 70% to 90% chance of seizure freedom (defined as no seizures or auras only, on medication) in some patients. Other novel modes of therapy include the vagal nerve stimulator (VNS), which is usually reserved for those patients with intractable epilepsy who are not surgical candidates. The VNS usually is as effective as a typical AED and usually does not provide a seizure-free state. Its mechanism of action is not known. The benefits of the VNS as opposed to AEDs is that it does not have the neurotoxicities associated with AEDs. Some adverse effects of the VNS include coughing, hoarse voice, bradycardia, and exacerbation of sleep apnea.

Seizures are well controlled with a single anticonvulsant in most patients with epilepsy. However, approximately 20% of patients with primary generalized epilepsy and 35% of patients with focal epilepsy have medically intractable seizures.^11,12 If seizures are not controlled with the initial dose of a first-line AED and there is no evidence of toxicity, the dose of the drug should be systematically increased. If the seizures are still not under control, a second first-line drug should be tried or added to the first drug. The practice of rational polytherapy is the use of two AEDs with differing modes of action, and that do not lead to worsening of adverse effects for the patient. After the third or fourth AED has been tried to appropriate levels and the patient still has seizures, the likelihood of finding an AED that will render that patient seizure-free drops to as low as 5%. These patients who are intractable to medical therapy should be referred to an epilepsy surgery center to determine if they are candidates for surgery.

In those patients who become seizure-free with medications, withdrawal of the AED can be considered after a seizure-free interval has been maintained for 2 years. The risk of recurrent seizures after discontinuation is 25% in those patients without risk factors and 50% in those patients with risk factors (eg, structural lesion, abnormal EEGs, or history of intractable epilepsy). The decision to stop medications should be individualized, and discontinuation should be done gradually, such as by decreasing the daily dose by 25% every 2 or 4 weeks.¹³

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