Peter W. Kaplan
About 2 million people in the United States may have epilepsy. An even larger number seek medical advice for treatment of seizures, generating approximately 5% of visits to physicians and 20% of visits to neurologists (1). This chapter addresses the basic principles that should guide the diagnosis and management of seizures in office practice.
Definition and Classification of Epileptic Seizures
Any paroxysmal disturbance in consciousness, behavior, or motor activity may be called a spell, fit, or seizure, but this chapter addresses primarily epileptic seizures. These may be defined as the clinical manifestations of an abnormal, usually brief, excessive, or hypersynchronous neuronal discharge in the cerebral cortex or deep limbic structures. A seizure has a definite start and finish. Seizures are associated with characteristic electrical abnormalities of the brain. Most patients are normal, and their electroencephalograms (EEGs) are often normal, between seizures (the interictal period).
The term epilepsy refers to a chronic neurologic condition that causes spontaneous, recurrent seizures. Therefore, single or even multiple seizures arising during transient systemic insult such as fever, infection, toxic causes (e.g., alcohol), or metabolic disturbances should not be labeled as epilepsy and are called reactive seizures.
The basic mechanisms underlying epileptic seizures are still uncertain, although much is known about predisposing conditions. The most widely accepted classification is based on behavioral and EEG aspects (Table 88.1) (2).
Clinical Manifestations of Seizure Types
The clinical manifestations of seizures vary according to the degree of maturity of the nervous system, the initial seizure focus, and the pattern of ictal spread. A seizure focus in the motor cortex produces jerking of the corresponding contralateral parts of the body; seizures in sensory regions result in abnormal sensations; and seizures in areas of higher cortical function may produce complex cognitive and behavioral manifestations (Fig. 88.1). Certain types of seizures manifest with sudden changes in vigilance or consciousness rather than with focal motor or sensory signs or symptoms.
Generalized Tonic–Clonic Seizures (Grand Mal)
Generalized tonic–clonic seizures (GTCSs) occur when ictal discharges involve most of the cortex. They may arise
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in the context of primary, idiopathic generalized (genetic) epilepsies, in which seizure activity appears synchronously over both hemispheres, or they may result from secondarily generalized seizure discharges arising from a unilateral focus. GTCSs may be called major motor seizures, although the now-disused term grand mal referred to bilateral generalization of seizure activity.
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TABLE 88.1 Classification of the Epilepsies |
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Idiopathic generalized epilepsies may appear at any age, although onset is rare after 35 years of age. Frequency may range from two seizures in an entire lifetime to several seizures a day. Symptomatic epilepsies giving rise to focal and secondarily generalized tonic–clonic seizures may occur throughout life, caused by developmental abnormalities, perinatal insults, infection and head trauma, and strokes, particularly in the elderly.
GTCSs typically begin with an arrest of activity and sudden loss of consciousness, followed by trembling, tonic extension of the arms and legs, and then clonic rhythmic but progressively slower limb jerking, followed by flaccidity, stupor, and labored, deep breathing. Seizures usually last less than 2 minutes and are followed by lethargy lasting minutes to hours. During the seizures, consciousness is always lost, so a history of the utterance of meaningful speech, the presence of purposeful eye movements, or a memory of the seizure itself excludes the diagnosis. Although malaise may precede GTCSs, a definite sensory, autonomic, psychic, or motor prelude suggests a focal onset with subsequent generalization (secondarily generalized tonic–clonic seizures). Tonic–clonic seizures may be accompanied by incontinence, sweating, tachycardia, elevated blood pressure, minor cardiac arrhythmias, and biting of the lip, cheek, and lateral aspect rather than the tip of the tongue.
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FIGURE 88.1. Relationship of local seizure phenomena to brain topography. |
The EEG that is typical in idiopathic generalized epilepsies shows a pattern of bilateral synchronous spike-and-wave discharges, whereas patients with generalized seizures that arise from a lateralized focus may show focal epileptiform discharges over the affected cortical zone.
Generalized Absence Seizures (Petit Mal)
Typical absence seizures are also generalized seizures; they occur in childhood absence epilepsy (CAE), a type of idiopathic generalized epilepsy (3). Absence seizures may also occur in Lennox–Gastaut syndrome and in juvenile myoclonic epilepsy. Childhood absence epilepsy constitutes approximately 5% of childhood epilepsy. The onset is usually between 4 and 12 years of age. Most affected children (75%) have absence seizures that remit by the age of 20 years, although about half (especially those with atypical absence) may later develop tonic–clonic seizures.
Because of the previous classification of generalized seizures into “petit mal” and “grand mal” types, some patients incorrectly believe that these two entities represent different severities of the same seizure type (although both can occur with idiopathic generalized epilepsy). There is often confusion also between the staring component of absence seizures and the initial staring phase of partial complex seizures (see Complex Partial Seizures). Finally, the term “petit mal” was often incorrectly used by patients to refer to partial seizures with a motor component or to minor motor seizures. Such confusions in classification may lead to incorrect diagnosis, prognosis, and antiepileptic drug (AED) therapy.
Typical absence seizures in childhood absence epilepsy, consisting of lapses of vigilance or awareness, usually last about 3 to 20 seconds. There is no tonic–clonic phase or loss of posture. Slight rhythmic twitching of the mouth and periorbital musculature or upgaze may be observed. With atypical absence seizures, duration may be prolonged, leading to confusion with complex partial seizures
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arising from the temporal or other lobes. In childhood absence epilepsy, there is a rapid recovery of awareness after an absence seizure, but amnesia for events occurring during the seizure persists. Absence seizures typically occur up to 100 times per day. Children who have such frequent seizures may be labeled as being inattentive, daydreamers, or slow learners until the correct diagnosis is made.
Both clinical and EEG findings should be used to secure a diagnosis of childhood absence epilepsy; neither alone is diagnostic. The EEG during an absence seizure shows a characteristic bilateral synchronous three-per-second spike-and-wave pattern; between seizures, the EEG may be normal, but brief 3-second bursts usually persist in the absence of AED therapy. Often, hyperventilation or stimulation with regularly flashing lights (intermittent photic stimulation) induces an absence seizure. Three-per-second spike-and-wave patterns on EEG may be seen in asymptomatic close relatives of patients with childhood absence epilepsy as well as other seizure types (e.g., tonic–clonic seizures).
Myoclonus and Myoclonic Seizures
Myoclonus is the predominantly synchronous, involuntary, nonrhythmic jerking of limbs, trunk, or head. Epileptic myoclonus arises from paroxysmal discharges of the central nervous system (CNS) above the brainstem. Conditions in which nonepileptic myoclonus (segmental myoclonus) may occur are conditions affecting the brainstem and the spinal cord.
Myoclonic seizures are most often seen after severe, diffuse cortical injury resulting from cerebral ischemia and anoxia; these seizures are difficult to suppress and carry a poor prognosis. When myoclonic seizures arise from hypoglycemia, severe renal or hepatic failure, or drug toxicity, they are often self-limited and resolve with correction of the underlying disturbance. Primary neurologic diseases, such as viral encephalitis, Jakob–Creutzfeldt disease, Huntington chorea, Wilson disease, and ceroid lipofuscinoses, may also include myoclonic seizures. Myoclonic seizures are also seen in idiopathic generalized epilepsies, benign myoclonic epilepsy of childhood, juvenile myoclonic epilepsy, the Lennox–Gastaut syndrome (triad of multiple seizure types, psychomotor retardation, and a characteristic EEG pattern, seen mainly in children), progressive myoclonic epilepsies, and a wide variety of seizures from toxic and metabolic causes.
Myoclonic seizures consist of brief and violent muscle contractions, usually bilateral, that do not affect consciousness. Myoclonic contractions may be single or multiple, lasting for seconds to hours. Contractions may be rhythmic or irregular. When the upper limbs are involved, patients may drop or toss objects. When the legs or trunk are involved, the patient may suddenly fall. Myoclonic seizures may be spontaneous, or they may be induced by flashes of light, or more rarely by other triggering stimuli.
The usual EEG correlate of myoclonic seizures is generalized or multifocal spikes, polyspikes, and slow waves. Scalp-recorded EEG discharges may be seen in the case of cortical myoclonus but may not be seen in the case of subcortical myoclonus.
Localization-Related or Partial (Focal) Seizures without Impairment of Consciousness
Focal motor or sensory seizures may manifest at any age. The clinical manifestations depend on the brain region involved in the seizure.
The motor cortex is a common site of origin for focal seizures. Because the seizure discharges spread across the motor strip, clonus (alternating contraction and relaxation) may march up or down a limb and into the trunk or into another limb. Spread into a sensory area of the brain may cause numbness in the face, trunk, or limbs. Sensory seizures can also involve areas of special sensation such as sight or hearing. A focus in or near the visual cortex or its association areas may cause the patient to see spots, lights, or geometric shapes, similar to the experience of patients with classic migraine. Perception of buzzing, clicking, or ringing sounds may be generated from a focus in the superior and mesial temporal lobe. Gustatory and olfactory sensations, usually unpleasant, are components of partial seizures involving mesial temporal lobe structures. Seizures dominated by vestibular symptoms (e.g., dizziness, vertigo) are rare.
Retention of some degree of consciousness is characteristic of focal seizures, so that patients may, for example, walk and talk during a seizure—activities that would be impossible during a generalized seizure. However, a large focus in the dominant hemisphere may generate seizures that blunt awareness.
After a focal motor seizure, there may be focal weakness of a limb, or Todd paralysis, which usually resolves within a few hours or, rarely, after a few days. Distinction between cerebrovascular ischemic events with associated seizures and seizures with Todd paralysis may be difficult without clues from the patient's history. A Todd paralysis has localizing value and is good evidence of the focality of a seizure.
EEG does not necessarily reveal a seizure focus, especially if the seizure is small (e.g., motor seizure involving the leg, in which case the focus lies deep within the interhemispheric fissure), and particularly if the EEG is obtained between seizures. With focal seizures involving the leg, the EEG may be normal in more than 88% of patients even during a seizure.
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Complex Partial Seizures
The category of complex partial seizures (CPSs) is important for several reasons: The condition is common in the adult population, the seizures are often misdiagnosed, and correct diagnosis leads to a search for potentially correctable lesions and effective AED therapy. CPSs are classified with focal or localization-related seizures because of clinical evidence linking these seizures with focal as opposed to generalized epileptiform discharges. CPSs are largely synonymous with the older term psychomotor seizures, but they are not synonymous with temporal lobe seizures because they can arise from any brain region. Although CPSs may begin at any age, the majority begin before age 20 years. An adult onset of CPS carries the same significance as does a new onset of any focal seizure; a treatable structural lesion should be sought. Patients with CPS who come to surgery or to postmortem examination may show either no histologic abnormality of the brain or tumor, infarct, granuloma, or infection; often with temporal lobe origin there is gliosis of the mesial temporal lobe. It is not known whether gliosis causes temporal lobe CPSs or results from them.
CPSs impair attention or consciousness through focal seizure activity. This is why they are called complex. The presentation of these seizures is more varied than that of the other seizure types and may include autonomic, psychic, visceral, sensory, or motor symptoms. Seizures often begin with an aura, which is, in fact, a simple partial seizure. The classic aura, usually consisting of an unpleasant olfactory or gustatory hallucination, is less common than is an aura of poorly described, unpleasant visceral sensations or malaise. Generally, there is no clear boundary between the aura and the seizure itself, particularly when seizures feature distorted visual or auditory sensations, or vertigo or unsteadiness. Arrest of motor activity, rigid posturing of the head and eyes, and slow, repetitive limb movements may occur and are easily distinguished in most cases from the tonic–clonic sequence of convulsive attacks. Autonomic instability, including fluctuating heart rate or blood pressure, flushing, sweating, salivation, or changes in pupillary reactions, may occur in patients with CPSs. Patients often say that they feel strange or as if in a dream, or they experience inappropriate emotions such as intense dread or strange serenity. If they can talk during a CPS, patients may portray what appears to be a psychiatric disturbance. The distinction between CPSs and psychosis may be further obscured in patients who have psychological or psychiatric problems between seizures. Such patients can be misdiagnosed as schizophrenic.
In a condition whose presentation may range from apparent appendicitis to apparent schizophrenia, special efforts should be made to elicit a detailed history of a spell and, if possible, to observe one. CPSs should have a definite start and finish; they should be associated with some impairment in ability to register and process information during the seizure; and they should be stereotyped from episode to episode. Observations of automatic behavior, such as repetitive lip licking or smacking, raising and lowering of the arm, fidgeting or buttoning and unbuttoning of clothing, stroking or rubbing movements, or pacing in circles, may secure the diagnosis of a CPS, because such automatisms are common in CPS but uncommon in other seizure types.
The routine EEG is abnormal in fewer than half of patients with partial seizures, but positive tracings may be found in 80% to 90% of patients by recording multiple EEGs that should include sleep and, in the case of temporal lobe origin, by using special electrodes positioned closer to temporal lobe structures.
Complex electrophysiologic mechanisms determine whether seizure discharges remain localized, spread along particular anatomic pathways, or involve much of the brain. AEDs can limit the spread of a focal seizure and prevent generalization, but generally do not obscure the EEG diagnosis of focal epilepsies. It is unknown how often tonic–clonic seizures are caused by spread from occult primary foci.
Unclassifiable Seizures
With an adequate history, most seizures should be classifiable by the scheme described. Often, however, the history is lacking. The event may not have been witnessed, or observers may report the patient's falling down and shaking but be unable to describe the full sequence of events. In these instances, it is best to list the seizure as unclassifiable or to use descriptive terms that are not otherwise used to classify seizure types, such as jerks, convulsions, or staring spells, until a specific seizure type can be identified.
Classifications of Epilepsy Syndromes
Seizures are observable phenomena with symptoms or signs that last a finite time. An epilepsy syndrome is a cluster of signs and symptoms that occur together and constitute a chronic condition of recurrent seizures. There is no single known cause or pathology for epilepsy. Features of a particular epilepsy syndrome include cause, family history, age at onset, seizure frequency, typical course, precipitating factors, imaging studies, and the EEG. For example, damage to the temporal lobe may result in a condition of recurrent seizures characterized by an aura, unresponsiveness with automatisms, and tonic–clonic movements. This would represent a syndrome in which there is a progression of seizure types from simple partial to complex partial
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to secondarily generalized tonic–clonic seizures. If clinical data point to damage in the temporal lobe (EEG focus, imaging findings), the epilepsy syndrome is that of symptomatic temporal lobe epilepsy. This is also true with idiopathic generalized epilepsies (previously called primary generalized epilepsies). For example, absence seizures may be seen in a number of epilepsy syndromes (e.g., childhood absence epilepsy), each of which may have a different constellation of signs and symptoms and carry a different prognosis.
The importance of establishing a syndromic classification of epilepsy is that the particular prognosis in this chronic condition is tied to the epilepsy syndrome rather than the seizure type. Furthermore, success in the use of AEDs or even seizure surgery is also predicated more on the epilepsy syndrome classification than just on the seizure type (4).
Epidemiology
The annual incidence rate of epilepsy is approximately 40 to 70 per 100,000 population, and the reported prevalence rates are between 1.5 and 57 per 1,000 (5). Partial epilepsies constitute about two thirds of the cases, one fifth are generalized, and the remainder are unclassified (6). In adults, CPSs constitute approximately 40%; GTCSs, about 40%; and simple partial (focal motor or sensory) seizures, approximately 15% (6). For younger age groups, partial seizures are less prevalent and generalized absence seizures are correspondingly more common.
Natural History and Prognosis
The natural course of epilepsy is difficult to determine because modern studies include a mixture of treated and untreated patients. Comparison of prevalence and incidence ratios suggests a crude mean for the duration of epilepsy of approximately 12 to 13 years (7), not taking into consideration the age at onset of epilepsy, the clinical type, or the response to treatment. After a first unprovoked seizure, the cumulative risk of recurrence at 3 to 5 years has been estimated to be 40% (8,9). Until further data are available, a 40% crude risk for recurrence within a few years after a spontaneous tonic–clonic seizure is a reasonable estimate. Of adults who have a recurrence of tonic–clonic seizures, approximately 60% have recurrence in the first year and 70% by 3 years (10). Risk factors that increase the risk of recurrence and decisions about treatment are discussed in a later section (see The Patient with a First Seizure). If a person has a second, unprovoked seizure, the risk for further seizures is higher, and after several unprovoked seizures it exceeds 75%.
Once two spontaneous seizures have occurred, epilepsy is considered to exist, and the epidemiologic focus switches to the possibility for remission. Before the development of AEDs, the spontaneous remission rate for all types of epilepsy was approximately 10% to 32%. Reported remission rates for epilepsy with or without treatment vary between 10% and 82% (11,12), according to when the study was done, retrospective versus prospective methodology, and the length of followup. Studies on prognosis have not yet clarified the role of treatment in the long-term outcome. The probability of going 5 years without a seizure is approximately 40% at 1 year and 50% at 2 years after diagnosis of epilepsy (11). From 50% to 82% of patients are in remission after 2 to 5 years (13,14). The probability of remission at 20 years is 80% to 85% for idiopathic generalized epilepsies but only 65% for localization-related epilepsies. After being free from seizures for 5 years, almost 50% of patients relapse after tapering AEDs, usually in the first year and particularly in the first 6 months (15).
Prognostic factors include age at onset, severity of epilepsy, number of seizures before treatment, number of types of seizures, history of status epilepticus, number of medications required to control the disease, and length of time before attainment of seizure control. CPSs without secondary generalization are the most difficult seizure type to control (16,17).
Epilepsy that has not been controlled after 2 years of treatment represents a significant risk for chronic epilepsy. Some authorities believe that the long-term risk may be decreased by early treatment of seizures; however, this concept remains controversial. An abnormal EEG during AED withdrawal increases the chance of relapse in patients with CPSs (18), but a normal EEG does not exclude a relapse (83% versus 54%) (19). The presence of neurologic or psychiatric problems worsens the prognosis.
It is generally possible to reassure a person with epilepsy that the long-term prognosis for remission is good; however, except for childhood absence epilepsy, which usually remits before young adulthood, the attainment of remission can be expected to require many years.
Causes of Seizures
Classification of seizures requires clinical observation, and classification of an epilepsy syndrome often requires clinical, EEG, and imaging data. Because a seizure represents a symptom of cerebral dysfunction, a primary cause should be sought.
Epilepsy that arises from definable causes has also been called symptomatic, as opposed to essential or idiopathic. Symptomatic epilepsies often arise from identifiable brain lesions, as from infection, trauma, tumor, or stroke. With idiopathic generalized epilepsies, however, patients have a normal examination, normal screening laboratory tests
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(see Laboratory Tests), an EEG often showing a generalized spike-and-wave pattern, and a family history of similar seizures. Such patients would not be exhaustively studied for underlying causes.
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TABLE 88.2 Causes of Seizures with Onset at Various Ages |
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Table 88.2 lists specific causes that should be considered for different types of seizures at various ages; the causes are listed from top to bottom in approximate order of frequency. It is worth emphasizing that many of the
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partial epilepsies display secondarily generalized seizures and that the focal onset may be obscured. Therefore, causes of focal seizures should be sought even in apparently generalized seizures.
Special issues are raised by seizures that are manifested for the first time in the elderly. First, most seizure disorders have onset in the first three decades of life, and onset of the idiopathic generalized epilepsy is unusual after this age. Second, cerebrovascular disease accounts for 30% to 60% of all new seizures in the elderly population. Tumors, the major cause of focal seizures in middle-age persons, have been found to be the cause of 2% to 30% of seizures in elderly patients (20); brain tumors in this age group are likely to be malignant. No cause is found in about half of elderly patients with seizures. When an elderly patient presents with seizures, a special effort should be made to find treatable conditions such as carotid artery stenosis, cardiac arrhythmias, infection, and toxic–metabolic derangements.
Posttraumatic Seizures
New-onset seizures after head trauma are usually partial (focal) in onset, and often secondarily generalized seizures occur after serious head injuries. There is little risk of seizures after mild head trauma with brief unconsciousness or amnesia, whereas severe injuries with intracranial hematomas, focal neurologic signs, and unconsciousness for longer than 24 hours result in epilepsy in about 10% of patients. Moderately severe injuries (skull fractures or unconsciousness for 30 minutes to 24 hours) impose an intermediate risk. Injuries over the vertex are more epileptogenic.
The value of prophylactic therapy to prevent the onset of posttraumatic seizures has not been firmly established. Until more data are available, the following approaches are recommended. Patients with minor scalp lacerations or brief loss of consciousness should not be considered to have a significantly increased risk of epilepsy. A single seizure occurring early (during the first 2 weeks after head injury), or while the patient is still experiencing the acute effects of injury, should not be an indication for long-term therapy; a second seizure in this setting might be grounds for treatment. Some patients with brain injuries might be considered for a 2- to 4-year course of prophylactic AED, especially with severe, penetrating, or vertex injuries. A patient with a seizure occurring more than 2 weeks after a head injury should be evaluated and managed as one would any other patient with new-onset seizures, and the seizure should not be attributed to a recent or remote episode of head trauma until other treatable causes have been excluded.
Alcohol-Related Seizures
Alcohol withdrawal is a common cause of seizures; almost all of them occur within the first 48 hours of abstinence or after marked reduction in alcohol intake, and most of them are generalized. In some series, up to 25% of withdrawal seizures have been focal, presumably because of an old cortical scar from trauma, infection, or vascular disease. The risk of epilepsy in the alcohol abuser is related to the amount of alcohol that was consumed (no longer being consumed at time of seizure) (21), but it may be increased by the higher likelihood of head trauma and intracranial infection in this population. If a known alcohol abuser has had a prior withdrawal seizure, presents a typical picture of a generalized seizure without focal features, and has a normal examination and no complications, then investigations may be limited. More often, the history is imprecise and findings are equivocal, or the patient has a fever or an elevated leukocyte count. In these instances, lumbar puncture, EEG, and continued observation are indicated. A computed tomography (CT) scan may be indicated with new-onset focal seizures, focal neurologic deficits, fever, neck stiffness, or signs of acute head trauma.
The use of AEDs to prevent alcohol withdrawal seizures is controversial. Some investigators recommend the use of AEDs for recent seizures or clusters of seizures during alcohol withdrawal (22), but others argue that alcohol withdrawal seizures are self-limited (23), and some studies show that treatment is usually ineffective (24). Long-term therapy with AEDs is not recommended.
Alcohol abusers may abuse other drugs. Concurrent benzodiazepine or barbiturate withdrawal can cause fulminant seizures. Occasionally, seizures occur during periods of alcohol consumption, as distinct from the period of alcohol withdrawal (25).
Seizures and Brain Tumors
Brain tumor is an uncommon cause of epilepsy, but epilepsy is a common symptom of brain tumors. About one third of intracranial and one half of intrahemispheric tumors are associated with seizures. Our present understanding of epilepsy secondary to tumor has been completely changed with the advent of CT and magnetic resonance imaging (MRI) head scanning (26). More and more often, tumors manifest with a single seizure, leading to early investigation and diagnosis with CT head scan or MRI. Between 1% and 16% of patients with epilepsy are found to have tumors. The probability varies according to age group: In adolescents it is approximately 1%; in young adults, 12% to 16%; and in older people, approximately 10% (27,28). Young and middle-age adults with new onset of focal seizures have the greatest chance of having a tumor (35%) (6). Nonetheless, CT or MRI scanning is not indicated in the investigation of patients with idiopathic generalized epilepsies who have diagnostic EEG patterns and in previously investigated patients who present with repeated seizures of unchanged character.
Seizures may be generalized tonic–clonic or partial. Diverse and changing clinical features are highly indicative
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of neoplasia. The following features suggest that seizures may be associated with a brain tumor: onset after 20 years of age, presence of persistent focal neurologic signs, signs of increased intracranial pressure, and focal unilateral slow waves on the EEG. Seizure frequency varies according to tumor location and histology: Frequent seizures are seen with supratentorial tumors, especially in the rolandic, temporal, or parietal cortical regions. Slow-growing tumors appear to be more epileptogenic.
Seizures and Cerebrovascular Disease
Cerebrovascular disease and epilepsy are the two most common causes of serious neurologic illnesses, and they often occur in the same patient. Ischemia damages brain and can lead to an epileptic focus. The incidence of early seizures (within the first 2 weeks after stroke onset) is approximately 5% in patients with nonembolic stroke (29). The seizures are more likely to be focal (80%) than generalized, and the distribution depends on stroke location. Only a small proportion of stroke patients develop recurrent seizures, i.e., epilepsy: 2.5% of those with intracranial hemorrhage and 3% of those with ischemic stroke (29). In ischemic stroke, although the highest incidence of seizures is shortly after stroke onset (30), epilepsy is most common (90%) in patients with late-onset seizures (more than 2 weeks after stroke) than in those with early-onset seizures (35%). Consequently, early seizures after stroke do not mandate AEDs; late recurrent seizures should be treated as epilepsy.
As previously mentioned, seizures in the elderly should raise the suspicion of cerebrovascular disease and may herald transient ischemia or impending stroke (31). In young patients, cerebral vascular disease is uncommon, but a seizure may lead to a diagnosis of an arteriovenous malformation, an aneurysm, collagen vascular disease, or a rare case of cortical thrombophlebitis.
Seizures and Infections
A seizure may be an early sign of bacterial meningitis, particularly in the very young and in the very old patient in whom the classic signs of meningitis may be lacking. Less fulminant forms of meningitis, such as cryptococcal or tuberculous meningitis, produce seizures that recur over weeks or months. Viral encephalitides, including herpes simplex encephalitis, the childhood exanthems, and the equine viruses, may also produce seizures. Human immunodeficiency virus (HIV) infection (see Chapter 39) is increasingly of concern as a cause of neurologic and systemic disease; most seizures associated with acquired immunodeficiency syndrome (AIDS) result from secondary complications such as cerebral toxoplasmosis, other atypical infections, or CNS lymphoma (32). Any meningoencephalitis can scar the cerebral cortex, resulting in an epileptic focus that can persist after resolution of the infection.
For reasons that are poorly understood, systemic infections may trigger seizures in susceptible patients, even if the infection does not directly involve the CNS (CNS). However, when a patient presents with a seizure and signs of infection, especially if the seizure is focal or if focal signs are detected on neurologic examination, the possibility of brain abscess must be explored with the use of head CT scanning or MRI, often with contrast.
Evaluation of a Patient with Seizures
In the evaluation of a patient with a history of one or more episodes of self-limited disturbance of consciousness or behavior, three questions must be addressed: First, were the events epileptic seizures? Second, if so, what type of seizures were they (Table 88.1)? Third, are there clues in the history, physical examination, or laboratory tests that point to a cause for the epileptic seizures (Table 88.2) or toward another cause?
Differential Diagnosis of Seizure-Like Behavior
Determination of the nature of a seizure-like episode is often difficult (Table 88.3). Unless the physician has observed an attack, the patient or witnesses must be asked for information about the sequence of behavioral events with attention to specific signs of neurologic dysfunction. Inquiry should be directed at establishing whether there were tonic–clonic features, with or without biting of tongue, lip, or cheek; head and eye deviation; urinary or fecal incontinence; rhythmic face or limb jerking; or speech and motor arrest followed by automatisms. Syncope not caused by a seizure is characteristically associated with prodromal
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malaise, dizziness, and light-headedness, often with pallor, sweating, palpitations, and upright posture (see Chapter 89); if an observer notes sudden loss of consciousness and tone without convulsions and with brief postictal confusion, syncope is a much more likely diagnosis than is seizure. However, syncopal events can include some arrhythmic limb jerking, occasionally accompanied by incontinence and brief confusion. Transient numbness, weakness, speech or vision problems, or dizziness may occur with cerebrovascular events (see Chapter 91), including transient ischemic attacks, stroke, bleeding from an arteriovenous malformation or from an aneurysm, or a classic migraine (seeChapter 87). Precipitating factors such as postural changes, changes in antihypertensive medication, and the sequence of seizure characteristics may help distinguish epileptic seizures from cerebrovascular insufficiency. Particularly in the elderly, where the two conditions may be linked, a firm diagnosis may have to be deferred.
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TABLE 88.3 Differential Diagnosis of Seizure-Like Behavior |
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Hypoglycemia (see Chapter 81) is most commonly seen in alcoholics, diabetics, and patients who have had gastrointestinal (GI) surgery and often manifests with presyncopal symptoms.
Narcolepsy (see Chapter 7) is a rare disorder characterized by the sudden lapse into rapid eye movement (REM) sleep by episodes, when alert, of brief inhibition of muscle tone (cataplexy). These patients can be aroused from their sleep, often report that they dreamed during the attack, and deny postictal confusion.
In the elderly, a waxing and waning delirium with fluctuating agitation, lethargy, and occasional motor manifestations (see Chapter 26) occurring with intercurrent illness (e.g., renal failure, drug intoxication, infection) may superficially resemble a seizure but usually lacks both the stereotypical aspects of a seizure and a clear start and finish.
Vertigo, caused by disease of the inner ear, can present paroxysmally and may be confused with epilepsy (see Chapter 89).
Certain adults have face or limb tics, which, unlike most epileptic seizures, can be partially controlled by volition and often occur at predictable times.
Psychogenic Nonepileptic Seizures
In some patients, the greatest challenge is to distinguish between epileptic and psychogenic nonepileptic events. Misdiagnosis of an epileptic seizure may result in incorrect treatment of the actual underlying condition and the possible social stigma and consequences of being labeled an epileptic. Panic attacks can produce recurrent, fulminant, and moderately stereotyped symptoms, all of which may be seen in patients with partial complex seizures (see Chapter 22). Because epileptic seizures may have emotional concomitants (e.g., an aura of extreme fear) and may be triggered by stressful situations, the distinction can be difficult. If a diagnosis of psychogenic illness can be supported on other grounds, if the attacks are strongly linked to preceding anxiety, and if automatisms are lacking, a panic attack becomes a more likely diagnosis.
Patients with seizures caused by a conversion disorder may exhibit inattention, staring, deep unresponsiveness, and tonic and clonic movements that closely resemble epileptic events. These psychogenic seizures are involuntary events and must be differentiated frommalingering and factitious seizures, which are produced deliberately by the patient. However, patients with nonepileptic events often also have epilepsy, and the management of epileptic events may be complicated by nonepileptic ones. Thrashing, asynchronous limb movements, crying, screaming, pelvic thrusting, and rapid side-to-side head turning have traditionally been ascribed to nonepileptic events but may also be seen with epileptic seizures. Observation of a generalized attack may reveal features that are atypical of an epileptic event, such as retention of protective reflexes (e.g., the blink reflex), a breathing effort when the airway is briefly occluded, coherent speech, or directed eye movements. Other features include the variability and nonstereotypy of each event, emotional precipitants, the usual presence of witnesses, recall after the event, biting of the tip of the tongue, forced eye closure, and the absence of postictal confusion (33). The motor activity may lack the organized tonic–clonic stages seen with generalized seizures, unless the patient is sophisticated and has observed seizures before. Psychogenic partial complex seizures may be the most difficult to diagnose.
As a general rule, purposeful, goal-directed behavior such as driving, shopping, talking in full sentences, or coordinated acts of violence should not be considered to be part of an epileptic seizure unless there is strong supporting evidence. Some of these features may be seen in the postictal state. Other features typical of a conversion disorder—presence of secondary gain, la belle indifference, inappropriate reactions to stress—may contribute to a correct diagnosis. Consultation among primary physician, neurologist, and psychiatrist may be required for proper diagnosis and management (see also Chapter 21).
Initial Determination of Seizure Type and Cause
The identification of seizure type (Table 88.1) should be made at the time of diagnosis of epilepsy. Features of the clinical onset should be especially addressed, because a brief focal onset or an aura may be the only indication that a seizure was secondarily rather than primarily generalized.
The history usually provides the main clues to the cause of the seizure. Contributory factors may include birth trauma or perinatal illness, head trauma, previous cerebral infarction or intracranial hemorrhage, encephalitis or
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meningitis, malignancies, and prior seizures. A family history of seizures may be pertinent because there is increased risk, particularly with idiopathic generalized epilepsies, for seizures in relatives of people with epilepsy. There should be inquiry into the use of alcohol, benzodiazepines, barbiturates, and other proconvulsants such as cocaine, amphetamine, neuroleptic medications, tricyclic antidepressants, bupropion, and theophylline. Patients may volunteer accounts of precipitating events such as flashing lights or hyperventilation. In some epilepsies, patients identify particular stimuli such as games, music, eating, laughing, or the touching of certain regions of skin. Thesereflex seizures may be avoided by avoiding the offending stimulus.
A general physical examination and neurologic examination (see Chapter 86) may reveal asymmetries or provide evidence for a structural, metabolic, or other cause of the seizure disorder. Some findings (e.g., focal paralysis) may be postictal, indicating focal onset (Todd paralysis), or they conversely may be suppressed, warranting reexamination in a few hours or days.
Investigations in a Patient with Seizures
Laboratory tests are usually not very helpful in determining whether a seizure has taken place, but they may be useful in establishing an underlying cause, in epilepsy classification, and in patient management.
Laboratory Tests
Depending on one's diagnostic hypotheses, investigations may include a full blood count, blood urea nitrogen or serum creatinine concentration, serum glucose, and serum electrolytes. In evaluating test results, it should be remembered that striking abnormalities may appear transiently immediately after a seizure (e.g., metabolic acidosis, marked leukocytosis). If clinically indicated, blood gases, liver function tests, and a screen for proconvulsive drugs should be obtained. A baseline electrocardiogram (ECG) may show arrhythmias or ischemia, although immediately after a seizure, these changes also may be results, rather than causes, of the seizure.
At times, measurement of a serum prolactin level helps in the evaluation of a patient with a suspected psychogenic seizure (see Kaplan,http://www.hopkinsbayview.org/PAMreferences). Commonly, the prolactin level rises two- to threefold after an epileptic but not after a psychogenic tonic–clonic event. In a lesser percentage of patients (45%), CPSs may cause serum prolactin increases, as may syncope (34), but 85% of simple partial (epileptic) seizures cause no rise (35). Partial complex seizures of temporal lobe origin are more likely to cause prolactin increases than those from the frontal lobe (36). Because this transient rise is present for 10 to 60 minutes after the event, positive findings are helpful, but negative findings, especially if measured more than 1 hour after the event, are inconclusive.
Electroencephalography
The electroencephalography (EEG) is the most useful laboratory study in the diagnosis of seizure disorders. An EEG may show generalized or focal epileptiform activity, or, even in the absence of such activity, it may demonstrate asymmetries of basic rhythms, focal slow waves, or diffuse slowing, all of which may give direction to further investigation. The appearance of epileptiform discharges on an EEG performed within 1 week after a first seizure predicts an 83% recurrence rate within 2 years, compared with a 41% recurrence rate in patients without such findings (37). Usually, the EEG is obtained more than 48 hours after the seizure. About 50% of patients with epilepsy have a normal EEG first. In about 10% of patients with epileptic seizures, multiple EEGs are all normal (38). Generally, the EEG should be relied on not to make a diagnosis of a seizure but to confirm a clinical impression derived from the history. When the history and EEG results are at variance, primacy should go to the history. Patients should not be treated for epilepsy because of an abnormal EEG alone, because interictal epileptiform discharges may be seen in 0.4% of the healthy population, in 2.2% of patients with nonepileptic neurologic disease, and in 3.5% of asymptomatic relatives of people with epilepsy (39). Conversely, one should not be dissuaded from a clinical impression of a seizure disorder just because of a normal EEG.
If EEG confirmation of seizure activity is needed (e.g., the history is equivocal, seizures occur during sleep or drowsiness), a repeat study with sleep deprivation or sleep induction, hyperventilation or intermittent photic stimulation, use of other scalp or semi-invasive electrodes (nasopharyngeal or sphenoidal leads), or eventually the use of prolonged video monitoring with EEG recording may be indicated. Many hospitals have epilepsy monitoring units specializing in the diagnosis and treatment of epilepsy. Referral to such units is sometimes the most effective way to elucidate the nature of spells not delineated by more routine maneuvers.
Epileptiform EEG discharges can usually be observed in the presence of AEDs, although some generalized discharges may be suppressed. Therefore, medications should not be altered for the first EEG. If tracings are repeatedly negative and the diagnosis of epilepsy is suspect, then the patient can be admitted to a hospital for rapid tapering of AEDs and concurrent EEG and video monitoring to look for epileptic activity. However, abrupt withdrawal of barbiturates or benzodiazepines may precipitate seizures even in normal subjects. Among patients
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with epilepsy, the pattern of generalized EEG slowing without seizure discharges is fairly common, usually resulting from underlying diffuse cortical dysfunction, medication effects, or a postictal state.
Because EEGs can stay abnormal for several weeks after a tonic–clonic seizure, any findings should be re-evaluated with repeated studies. An EEG is without risk (see Chapter 86), barring an injudicious interpretation.
Cerebrospinal Fluid Examination
Certain illnesses that lead to seizures may require examination of cerebrospinal fluid (CSF) to secure a diagnosis; examples are suspected acute or chronic meningitis or subarachnoid hemorrhage. The yield of CSF studies in patients with various seizure types is unknown, and the indication for these studies should be considered on a case-by-case basis. The CSF examination is not indicated in a normal child with classic absence epilepsy or with EEG evidence of focal rolandic spikes, and it is contraindicated in a patient in whom a mass lesion is strongly suspected. Most other patients with focal or generalized seizures of uncertain cause should undergo spinal fluid analysis (seeChapter 86).
After prolonged generalized seizures, the CSF may show a pleocytosis of up to 100 cells, presumably from a transient breakdown of the blood–brain barrier. Clearly, however, infection must be excluded or temporarily considered in this setting.
Cerebral Imaging
CT head scans (see Chapter 86) of patients with primary generalized seizures are abnormal (excluding nonspecific atrophy) in approximately 10% of instances. Scans of patients with focal motor or secondarily generalized seizures show a focal abnormality in 65%. Patients with CPSs show abnormalities about one third of the time. An abnormal and asymmetric neurologic examination has a high correlation with focal abnormalities on the head CT scan. Studies of patients with seizures show that MRI of the head (see Chapter 86) has a higher diagnostic yield than CT scanning and may show specific changes of mesial temporal sclerosis, various angiomas, neuronal migration disorders, or perisylvian polymicrogyria but is not a procedure needed for all patients (40).
Adults with new-onset focal or secondarily generalized seizures should have an MRI or CT scan with contrast if possible, unless the EEG shows a pattern of a genetic disorder. Patients with an abnormal neurologic examination should also be imaged. In patients with a normal examination and in children, this decision should be individualized. Subsequent imaging may also be indicated if there is a change in seizure pattern or neurologic examination.
Other Diagnostic Tests
Skull radiographs, radionuclide brain scans, pneumoencephalography, and arteriography have largely been replaced by newer imaging studies. Several techniques show promise for definition of seizure foci: imaging of brain metabolism and chemistry by positron emission tomographic (PET) scanning; single-photon emission computed tomography (SPECT), which examines cerebral blood flow at particular time points; functional magnetic resonance imaging (fMRI); and magnetoencephalography (MEG), which records brain activity.
Treatment of Epilepsy
Except in unusual instances, epilepsy cannot be cured. In about three of four patients, it can be controlled so that the patient experiences few or no seizures. Much attention has been focused on the pharmacologic management of seizures, but the importance of a comprehensive approach cannot be overemphasized: A patient who is seizure free but so intoxicated by medicines that employment is impossible represents at best a dubious success. Employment problems and other social aspects of the management of epilepsy are considered in the following sections. General measures of therapy should not be neglected. Removal of precipitating factors for seizures, reduction of stress, and provision for adequate amounts of rest can all be important in the control of epilepsy and are also discussed here. Patients should be advised to wear medical alert bracelets or medallions.
The Patient with a First Seizure
In deciding whether to treat a first seizure, one should recall that a single seizure does not constitute epilepsy nor necessarily require treatment. In patients with “provoked” or acute symptomatic seizures such as those that occur after alcohol withdrawal, cocaine intake, or overdose of tricyclics, identification and removal of the precipitating cause usually prevents further seizures, and AEDs are rarely indicated. Additionally, single or early seizures, i.e., within 2 weeks after closed head trauma or stroke do not require chronic AED therapy.
In about one third of patients with first seizures, the seizures are unprovoked. Such patients may be so frightened by the possibility of having another seizure, with potential repercussions on employment, social relations, and license to drive, that they are willing to accept the inconvenience and morbidity of chronic medication. Most patients first present to a physician after having had several unprovoked seizures. Of this group, more than three-fourths may be expected to have further seizures. This contrasts with
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the finding from prospective studies that approximately 16% to 36% of patients who present after their first unprovoked seizure have a recurrence within 1 year, and that in the aggregate 27% to 50% have recurrent seizures within 3 years (8,9). Retrospective studies suggest higher recurrence rates.
Because for a given patient the probability of further seizures over a 5-year period may vary from 30% to 80%, it is important to consider the following risk factors that increase the probability of additional seizures: an identifiable cause for the first seizure, such as CNS infection or recent stroke or head injury; the presence of EEG epileptiform abnormalities; occurrence of the initial seizure at night; previous febrile seizures; status epilepticus or multiple seizures in the same day; Todd paralysis; and partial seizures (9,16). With genetic epilepsies, typically with childhood onset, in which the EEG shows epileptiform activity, there is an increased risk of seizure recurrence in the short term. Many of these epilepsy syndromes are age dependent and remit after several years.
In one prospective study, addressing the issue of treatment after a first unprovoked tonic–clonic seizure, the rate of recurrence at 1 year in patients randomly assigned to AED treatment was 18%, compared with 38% for those who were not started immediately on treatment (41). Depending on the AED used, the incidence of side effects severe enough to warrant discontinuation of treatment ranges from less than 1% to approximately 6%. These figures usually are not used in deciding whether a patient should be offered a specific AED. Rather, the efficacy profile, the overall side effect profile, and the frequency with which the medication must be taken govern the institution of the drug.
General Principles of Drug Therapy
Patients who have monthly or more frequent generalized seizures are usually undertreated; and the goal of therapy is zero seizures. In contrast, other patients may be taking an unnecessary polypharmacy or incorrect regimens of AEDs. Table 88.4 summarizes general principles for the planning of drug therapy. Prospective observations show that, with adequate AED treatment, the prognosis for seizure control during the first 12 months varies according to seizure type: GTCS, 60% to 70%; mixed (predominately GTCS), 50% to 53%; CPS, 21% to 28% (16).
Selection of Drugs
To select the appropriate AED, it is important to know the type of epilepsy under consideration. Table 88.5 represents a general but not unanimous consensus on drugs of choice and alternatives for the principal types of seizures and epilepsy (42). Selection of preferred drugs takes into consideration efficacy in suppressing seizures, tolerability, and favorable side effect profiles. Two large controlled clinical trials compared the effectiveness of several AEDs (carbamazepine, phenobarbital, phenytoin, and primidone) and valproic acid versus carbamazepine for the treatment of partial seizures or secondarily generalized tonic–clonic seizures (43,44). Both carbamazepine and phenytoin were highly effective and were recommended as drugs of choice for these two common types of seizures (44). For complex partial seizures with or without secondarily generalized tonic-clonic seizures, carbamazepine, phenytoin, oxcarbazepine, lamotrigine, and valproate are recommended as first line. Levetiracetam, topiramate, zonisamide, or gabapentin are recommended as second line (42). For efficacy, valproate has been generally recommended as the drug of first choice for idiopathic generalized epilepsies. Newer drugs such as lamotrigine, topiramate, zonisamide, and levetiracetam as well as phenytoin have been favored by an expert consensus committee. Childhood absence epilepsy may be treated with either ethosuximide or valproate or lamotrigine, although the former does not always prevent concurrent myoclonic seizures. Myoclonic seizures are best treated with valproate, lamotrigine, topiramate, zonisamide, clonazepam, or levetiracetam. A certain percentage of idiopathic generalized epilepsies with GTCSs respond to monotherapy with carbamazepine (although absence seizures may worsen), and a certain percentage of partial seizures respond to valproic acid monotherapy. In several instances, more than one drug may be considered the drug of choice in terms of efficacy, in which case the selection can be made on the basis of personal familiarity with the drug, convenience of dose scheduling, or the relative risk and spectrum of side effects. For example, some practitioners prefer carbamazepine to phenytoin to avoid possible gum hyperplasia and hirsutism, even though these side effects are seen in only approximately 10% of patients.
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With phenytoin, the convenience of a simpler dosage regimen, lower cost, and availability of a parenteral preparation may offset these considerations. Several reviews and meta-analyses compared controlled trials of AEDs and revealed no significant differences in efficacy among AEDs in current use (45). Table 88.6 gives dosages, half-lives, serum levels, and principal side effects of the drugs.
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TABLE 88.4 Principles of Antiepileptic Drug Therapy |
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TABLE 88.5 Drugs of Choicea According to Seizure Type |
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Dose Adjustment
The AED dosage should be increased over several weeks to avoid early side effects that might discourage the patient from continuing with treatment. Because some AEDs remain in the blood for some time, it may take several days to weeks before the effects of a dosage adjustment are manifested.
Although initial treatment with more than one AED, typically phenytoin and phenobarbital, was once common, there is little evidence that two drugs at subtherapeutic dosages are better tolerated or more effective than one drug at higher dosages. In fact, 90% of new-onset seizures that are controlled can be controlled with one drug. If one drug is unsuccessful, addition of a second helps in only approximately 36% of patients (46).
Compliance is a major factor in the success of drug therapy for epilepsy (see Chapter 4). Every effort should be made to simplify the dosage regimen and choose the best-tolerated drug. Phenobarbital and zonisamide can be given in a once-daily dose. The complexity of providing carbamazepine, valproate, Trileptal, lamotrigine, or levetiracetam which must be given in divided doses, should be offset by a better-suited profile of side effects for the individual patient. At each visit the patient (or other responsible person) should be asked to report on the exact medication regimen and encouraged to bring the most recent medicine bottles with them. All too often, inquiry indicates a need for clearer oral and written communication with the patient. If necessary, the drug regimen should be written out for the patient's use.
Familiarity with cost of medicines is important, because patients may be hesitant to buy an expensive medicine unless the need is clearly explained. Generic brands are less expensive, but for several AEDs, such as carbamazepine, primidone, phenytoin, and valproic acid, bioavailability is variable (47). Generally, generic brands should be avoided in patients with seizures that are difficult to control. If generic brands are prescribed, use of the same brand should be encouraged; drug levels may have to be checked more often if toxicity or seizures appear.
The optimal dosage of an AED may vary several-fold among different patients. Determination of serum levels (Table 88.6) is a reliable way to measure how much medication is circulating, but such measurements should not be ordered routinely. If a patient's seizures are controlled on the regimen that is initiated and there is no toxicity from that drug regimen, measurement of a drug serum level might lead one to alter a successful regimen inappropriately. If control is not optimal, drug levels can help
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detect inadequate compliance or absorption. They may also provide guidance for patients with symptoms that might be caused by drug intoxication. Ideally, blood specimens obtained to monitor side effects should be taken at times of peak serum concentrations, and specimens obtained to monitor drug efficacy should be taken at times of trough serum levels. It is important to know that for some AEDs, particularly phenytoin, drug dosage and drug level are not linearly related: A saturation point is reached above which small increments in daily dosage (e.g., increasing from 400 to 500 mg of phenytoin per day) may lead to marked increases in serum level and side effects. A serum level is most informative if measured in the steady state (Table 88.6), which requires a stable dosage for approximately five half-lives or longer before measurement.
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TABLE 88.6 Major Antiepileptic Drugs |
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Many patients with severe and long-standing epilepsy have endured a gradual increase in AED dosage. Excessive polypharmacy may be ineffective, may produce marked side effects, and may even limit the ability to increase a single potentially effective AED to the maximum dosage. In this circumstance, one should consider reduction in AED dosage or number of medications over several months. Other side effects may prompt discontinuation of AEDs.
Although several AEDs can cause modest rises in liver enzyme levels, only moderate to marked abnormalities (more than two to three times baseline) necessitate stopping the drug. Conversely, serious hepatotoxicity may not be heralded by changes in liver function tests. Symptoms may include anorexia, malaise, tiredness, and jaundice, usually appearing 2 to 16 weeks after starting treatment. Carbamazepine can cause mild leukopenia and thrombocytopenia, but a rapid, progressive leukocyte decline, typically to lower than 3,000 cells/mm3 with a total neutrophil count of less than 1,000 cells/mm3, would warrant concern (33). Nystagmus should not be used as an indication of toxicity but rather as a marker of AED therapy. Conversely, ataxia, unacceptable somnolence, cognitive impairment, and malaise may indicate the need for modification of therapy.
Duration of Treatment
The determination of how long to maintain treatment with AEDs may be difficult, because seizures remit over time, and therefore freedom from seizures may not be the result of medication. About one half to two thirds of patients are entirely seizure free for 2 years with therapy. If an adult patient is seizure free for about 5 years on medication and then stops treatment by gradual taper, there is a 30% to 50% chance of relapse during the next 5 years (45,15). Approximately 80% of relapses occur within 4 months after starting the taper, and 90% within the first year (48,49).
As with the decision to initiate therapy, the decision to terminate AED therapy must be individualized. A patient with seizures that were initially very difficult to control who has an underlying structural lesion or a persistently abnormal EEG may benefit from lifelong therapy. In contrast, a patient with idiopathic epilepsy who has been seizure free for 2 to 5 years and is willing to accept an increased risk of having a seizure may be a candidate for drug withdrawal. Certain patients who have attained seizure control over a long period do not wish to stop treatment. In these instances, potential benefits and risks of medication reduction should be discussed, but patients should not be forced off medications for the sake of principle. If more than one drug has been prescribed, the medications should be tapered one at a time, each over a period of several months, and reinstated rapidly if seizures recur. The least effective medication or the most toxic may be chosen as the candidate for initial reduction.
An example of a cautious tapering schedule for a patient who has been taking carbamazepine 400 mg (two 200-mg tablets) three times daily would be reduction by one tablet per day every 2 weeks. During tapering and in the first few months after the tapering of all AEDs, it is prudent for the patient to refrain from driving.
Ambulatory Followup
Seizure frequency, medication side effects, and social factors determine the pattern for outpatient followup. Patients who are free from seizures for longer than 1 year and who have no intercurrent problems may be seen yearly. Conversely, patients with frequent seizures, significant side effects, or social problems may need to be seen every few weeks during problem periods. Visits may be necessary every 2 to 4 weeks during adjustment of the drug regimen. For appropriate management and monitoring of therapeutic changes, a patient should be evaluated no sooner than five AED half-lives after the change is initiated.
Specific Antiepileptic Drugs
Carbamazepine (Tegretol, Carbatrol)
Carbamazepine has been used for more than two decades for the treatment of seizures and chronic neuropathic pains. Carbamazepine is one of the drugs of choice for CPSs, but it may worsen absence seizures. Studies comparing carbamazepine with other AEDs for the treatment of partial seizures showed that carbamazepine resulted in the highest rate of complete remission (although mean seizure frequency was similar for patients taking carbamazepine, phenytoin, or phenobarbital) (43). Table 88.6 gives the adult dosage of carbamazepine, which is 400 to 1,600 mg/day, along with dosing guidelines for Carbatrol and Tegretol. It is advisable to initiate therapy with no more than 200 to 400 milligrams per day, increasing to the full dosage over 1 or 2 weeks.
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The half-life is about 10 to 25 hours. A newer long-acting preparation, Tegretol XR, is available in 100-mg, 200-mg, and 400-mg tablets, with ports that allow slow release. There is also a suspension of 100 mg/5 mL. This form can be taken twice daily. Total daily dosage remains the same, meaning that conversion to the more convenient form is simple, but more even blood levels are obtained. Patients should be warned that the tablet shell may appear in the stool, but this does not represent inadequate release of contents. Patients must be instructed not to chew XR tablets but to swallow them whole. Another long-acting preparation, Carbatrol, also has a long half-life and produces more constant blood levels. Recommended target serum levels with all preparations of carbamazepine are around 4 to 12 mg/dL. Because of erratic absorption of the generic preparation, it should not be continued in any patient who takes it and continues to have seizures.
Because carbamazepine in tablet form may lose one third or more of its effectiveness if stored in humid conditions, patients should be advised to keep their tablet containers in a dry location, away from the bathroom. Recently, manufacturers have been asked by the U.S. Food and Drug Administration (FDA) to package carbamazepine in moisture-proof containers.
The side effects of carbamazepine include fatigue, nystagmus, diplopia, dizziness, ataxia, dysarthria, rash (including, rarely, Stevens–Johnson syndrome), inappropriate secretion of antidiuretic hormone, occasionally abnormal liver function tests, and an infrequent lupus-like syndrome. Gastrointestinal distress is the most common side effect, particularly if the medication is initiated too rapidly. Reversible leukopenia or thrombocytopenia is seen in 5% to 10% of patients, so blood counts may be monitored weekly for the first few weeks after the start of therapy. This drug has had a reputation for causing aplastic anemia, based largely on six cases of this complication that were reported in the 1960s (even though a causal relationship to carbamazepine was not established). The actual incidence of aplastic anemia is unknown, but it is thought to be very small (the warning provided by the manufacturer reports a general population incidence of potentially fatal blood dyscrasia of 8 per 1,000,000 and an incidence associated with carbamazepine of about 40 per 1,000,000). Carbamazepine along with phenytoin and the barbiturates are cytochrome-P450 hepatic enzyme inducers and may decrease the efficacy of oral contraceptive pills (OCPs), cholesterol-lowering agents, and Coumadin, among others.
Phenytoin (Diphenylhydantoin, DPH, PHT, Dilantin)
Since its introduction in 1938, phenytoin has been one of the major drugs used to treat seizures. It is most useful in epilepsies with simple and complex partial seizures, with or without secondary generalization. Phenytoin may make absence seizures worse.
Without a loading dose, a full week is required to reach therapeutic levels, but a load given on the first day, achieves immediate therapeutic levels. This rapid dosing scheme is likely to induce transient side effects and is useful chiefly for initiating treatment in a patient who has seized repeatedly (e.g., in an emergency department) and remains unconscious.
The mean half-life of phenytoin is 22 hours, with a range from 7 to 42 hours. It is 90% protein bound, so low serum albumin can lead to an increased concentration of the free agent and consequently to increased toxicity. The drug is metabolized in the liver and is not excreted by the kidney. In renal failure, drug-binding proteins may be deficient, resulting in a low measured total serum level with an adequate free drug serum level. Dosage should be lowered only in renal failure to compensate for a decrease in serum protein, and then a reduction of approximately 25% usually suffices. Phenytoin is partially removed by hemodialysis.
The usual starting dosage of phenytoin is 100 mg/day for 3 to 5 days, increasing by 100 mg at similar intervals to 300 mg/day. If seizures are not controlled at this dosage, it is prudent to increase by increments of 50 mg/day, because small increases in dosage may cause large increases in serum levels. Phenytoin (as Dilantin) comes in 30- and 100-mg capsules, suspension (300 mg and 125 mg/5 mL), and chewable 50-mg tablets. This medication can be given once a day if it is given as Dilantin Kapseals, because this preparation is manufactured as a slow-release form. Other forms of phenytoin preparations (e.g., Phenytek) may be less expensive and comes in a 200-mg or 300-mg dosage (Phenytek). A parenteral formulation of phenytoin is fosphenytoin sodium injection (Cerebyx), which can be given intramuscularly or intravenously. It is dosed in phenytoin equivalents and can be given more rapidly intravenously at up to 150 mg/minute. A target range for phenytoin is generally between 10 and 20 mg/L (toxicity usually occurs at levels greater than 20 mg/L, but patients show fairly wide individual susceptibility to side effects). The lethal dose may range from 2 to 20 g.
A number of drugs elevate phenytoin plasma levels—disulfiram and isoniazid commonly. Amiodarone increases phenytoin 1.5 times, while fluconazole and miconazole increase phenytoin 2 to 4 times. Warfarin, chloramphenicol, methylphenidate, phenothiazines, benzodiazepines, propoxyphene, fluoxetine, omeprazole, propoxyphene, thioridazine, haloperidol, cimetidine, and erythromycin less often increase phenytoin plasma levels and OCPs leading to decreased efficacy. Other drugs may lead to decreased phenytoin levels: alcohol, folic acid, pyridoxine, theophylline, and occasionally carbamazepine, oral contraceptives, sulfonamides, ticlopidine, trazodone, ciprofloxacin, and antacids. Phenytoin may decrease cyclosporin
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levels and OCPs, leading to decreased efficacy. These potential drug interactions may be managed best by patient and physician awareness and by observation of serum drug levels during times of medication changes.
There are many potential undesirable effects of phenytoin. Dose-related acute effects include ataxia (usually beyond 25 to 30 mg/L), lethargy, depression, paradoxical tendency to increase seizures at higher toxic levels (usually greater than 10 mg/L), and allergic reactions.Chronic side effects of phenytoin are generally manifested after a few months to several years of daily ingestion. Chronically progressive cosmetic changes can be vexing in young women. Gum hyperplasia occurs in approximately 10%; it may in some be forestalled by good oral hygiene, but once established it may regress only partially. Hirsutism is seen in 5% overall but in 30% of young women. Even more disconcerting are facial changes caused by thickening of subcutaneous tissue about the nose and eyes, the so-called leonine facies. Skin rash occurs in 2% to 10% of users of phenytoin, with a peak incidence about 2 to 8 weeks into the course. Stevens–Johnson syndrome occurs rarely. Lymphadenopathy develops in 2% to 5%, sometimes in association with fever, arthralgia, eosinophilia, and hepatosplenomegaly, presenting a picture of pseudolymphoma and, rarely, true lymphoma. Hepatitis and a variety of blood dyscrasias have been reported. Megaloblastic anemia may occur, which responds to folate. Many patients develop measurable antinuclear antibodies in the serum; a tiny minority of this group progress to symptomatic systemic lupus erythematosus, which remits entirely within days to weeks after discontinuation of phenytoin. The rare instances of pulmonary infiltrates and fibrosis have given rise to the term, Dilantin lung.Phenytoin can induce liver enzymes, thereby secondarily affecting metabolism of numerous hormones and drugs. Induced inactivation of vitamin D leads to radiologic or biochemical evidence of bone disease in one of every three chronically treated patients. Teratogenic effects of phenytoin are strongly suspected (see Juvenile Absence Epilepsy section).
Sodium Valproate (Depakote)
The antiseizure effect of valproic acid was discovered in 1963. Its effectiveness is broad, but it is thought to be particularly valuable for absence seizures and childhood absence epilepsy, for idiopathic (JAE and juvenile myoclonic epilepsy [JME]) and symptomatic generalized epilepsies (e.g., Lennox-Gastaut Syndrome), and as a first- or second-line agent for partial epilepsies (49).
Valproic acid is a fatty acid, structurally dissimilar from all other common AEDs. It is usually prescribed as sodium valproate/valproic acid (Depakote), purported by the manufacturer to cause less GI upset than pure valproic acid (Depakene). It is available in 125-mg, 250-mg, and 500-mg tablets delayed release and in 125-mg sprinkle capsules; also available in 250-mg extended-release tablets. Valproic acid is also available in generic form (Depakene), which comes in 250-mg capsules and 250 mg/5 mL syrup. Peak serum levels are reached in 1 to 4 hours after ingestion, and the half-life is about 8 to 12 hours. The drug is metabolized in the liver and excreted in the urine in modified form. The approximate target range is 50 to 100 mg/L. The manufacturer suggests initiation of therapy with a dosage of about 10 to 15 mg/kg/day, to be increased at weekly intervals by about 5 to 10 mg/kg per day to a maximal dosage of 60 mg/kg/day. A common final regimen is 250 to 500 mg orally, two to four times per day.
About one in five patients taking valproate has significant side effects, commonly GI upset, drowsiness, rash, reversible hair loss, weight loss (or more frequently gain), ataxia, tremor, or hyperactivity. A limited number of studies suggest that valproate inhibits platelet aggregation and may prolong the bleeding time, but this effect is poorly documented. There may be a dose-dependent fall in platelets. The health risk from use of valproate that has received the greatest attention is hepatic toxicity. Thirty-seven fatalities from hepatic failure associated with use of valproate were reported in the United States between 1978 and 1984 (50). Among patients receiving valproate as monotherapy, the calculated rate of fatality from hepatic injury was 1 per 37,000. This rate was much higher for children younger than 2 years of age and for children receiving polytherapy. These two risk factors together resulted in a fatality rate from hepatic injury of 1 per 500 children. In contrast, no fatalities from hepatic injury were reported in patients older than 10 years of age who were receiving monotherapy. Several patients have developed serious episodes of pancreatitis while taking valproate. Valproate has not yet replaced ethosuximide as the drug of choice for absence epilepsy unless there are concurrent atypical absence attacks or tonic–clonic seizures. There may be drug interactions with aspirin, warfarin, cimetidine, phenothiazines, antacids, the benzodiazepines, and other AEDs such as phenytoin, carbamazepine, and lamotrigine.
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Phenobarbital
In past decades, phenobarbital was a drug of choice for GTCSs. It is now a drug of last resort for a variety of seizure types. Phenobarbital has been used in the pediatric age group, where it may be better tolerated than phenytoin because it does not cause cosmetic side effects; however, it can cause significant behavioral side effects (hyperactivity in up to 40% of children).
Phenobarbital is a long-lasting drug. The GI absorption is slow, so it takes 10 to 12 hours for levels to reach their peak after an oral dose, compared with 20 minutes after an intravenous dose. The drug is detoxified by the liver and excreted by the kidney, but the dosage need be only slightly reduced in renal failure. The serum half-life is about 72 hours, ranging from 37 to 96 hours. Therapeutic levels are 15 to 40 mg/L. Phenobarbital is a potent inducer of liver enzymes and leads to rapid tolerance, as well as to alteration of kinetics of numerous other medications. The dosage of phenobarbital is 1 to 3 mg/kg/day, or about 100 mg/day for the average adult. Little justification can be made for giving it in divided doses. Available tablet strengths are 15, 30, 60, and 100 mg; elixir of 15 mg/5 mL and 20 mg/5 mL.
The main acute side effect of phenobarbital in adults is sedation. After a few weeks, partial tolerance to the sedation usually develops. In elderly patients, phenobarbital can cause confusion and respiratory depression. Subtle or overt personality changes caused by phenobarbital probably occur more often than is generally recognized, especially in the elderly. Ataxia and nystagmus are common in all patients at high dosages. Occasionally, there is idiosyncratic allergy, with accompanying dermatitis or GI symptoms. Connective tissue problems may occur. Phenobarbital must be administered with caution to potential drug or alcohol abusers or to unreliable patients who might precipitously discontinue their medicine. There are drug interactions with warfarin, β-blockers, and corticosteroids, and possible interactions with acetaminophen, chloramphenicol, chlorpromazine, cimetidine, cyclosporine, desipramine, furosemide, haloperidol, meperidine, methadone, methyldopa, phenacemide, prochlorperazine, propoxyphene, rifampicin, thioridazine, tricyclic antidepressants, verapamil, and other AEDs.
Primidone (Mysoline)
Primidone is a barbiturate used for treatment of CPSs and other partial epilepsies (usually as a drug of last resort). It has also been used in place of phenobarbital for treatment of GTCSs or focal seizures and epilepsies, when the latter drug has failed, but it should not be a drug of first choice for these conditions. Primidone is in part excreted unchanged and in part metabolized to phenobarbital and to phenylethylmalonamide (PEMA). Serum levels of primidone and PEMA can be ascertained, but it often suffices just to confirm that a therapeutic steady-state level of phenobarbital is present. To benefit from the short-lived primidone and PEMA, each of which has some antiepileptic action, primidone must be given in three or four divided doses. A therapeutic dosage is usually about 250 mg orally three or four times a day, but the initial dosages should be much lower to avoid inducing extreme sedation. It is reasonable to start with 125 to 250 mg daily, with increments each week, until therapeutic effect, therapeutic levels, unacceptable sedation, or the maximal dosage of 2 grams per day is reached. If patients are taking other AEDs, it is better to start with a dosage of 100 to 125 milligrams per day. The dosage should be reduced by about half in patients with significant renal failure. Strengths available are 50- and 250-mg tablets and suspension.
Side effects and drug interactions of primidone parallel those of phenobarbital, except that primidone tends to be more sedating.
Ethosuximide (Zarontin)
Ethosuximide is the drug of choice for treatment of absence epilepsy in children when there are concerns for potential hepatotoxicity from valproic acid, and absence seizures are the only seizure type. It is as effective as valproate in controlling absence seizures. It has little efficacy in other types of seizures, and patients with mixed seizure types may respond better to valproate. Peak plasma levels are reached 3 to 7 hours after oral ingestion in children and 2 to 4 hours after ingestion in adults. It is only minimally protein bound, with a volume of distribution of 70% of body weight; it has minimal interaction with other AEDs. The half-life is about 30 hours in children, rising to 60 hours in adults, and 6 to 12 days, respectively, is required to reach steady state. Elimination is primarily by metabolism, with urinary excretion of the metabolites. Absence seizures appear to be controlled by blood levels of about 25 to 165 milligrams per liter, with an average of about 60 mg/L. Levels of 150 mg/L may be needed and tolerated. Dose-related side effects include anxiety, depression, behavioral and psychiatric disturbances, nausea, vomiting, anorexia, fatigue, headache, lethargy, and dizziness. Liver function tests and complete blood counts are recommended monthly for 6 months by the manufacturer and occasionally thereafter. Ethosuximide is supplied as syrup (250 mg/5 mL) and as capsules (250 mg).
Clonazepam (Klonopin)
Clonazepam is a benzodiazepine, closely related to diazepam, that is used principally for treatment of myoclonus. It is not approved for treatment of partial seizures but has been used effectively for these conditions in Europe. Clonazepam is an oral medicine, with a serum half-life of 20 to 40 hours. Serum levels vary from 0.05 to 0.7 mg/L and correlate only very roughly with clinical effect. Because of the sedative effect of the medicine, therapy is usually initiated very gradually, beginning with 0.01 to 0.15 mg/kg, and increased every third day to clinical effect or to maintenance at 0.1 to 0.2 mg/kg/day. In adults the daily maximal dosage is 20 mg. Clonazepam commonly produces drowsiness, ataxia, and behavioral changes and can also cause dizziness and decreased muscle tone. Strengths available are 0.5-, 1-, and 2-mg tablets.
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AED Formulations for Rapid Administration
In the acute treatment of seizures, fosphenytoin (Cerebyx) and intravenous valproate (Depakon) (both mentioned previously) are used when rapid intravenous AED supplementation is indicated or a patient cannot take oral preparations. A new rectal diazepam gel (Diastat) has been formulated in prefilled, unit-dose, rectal delivery systems containing 2.5, 5, 10, 15, or 20 mg of diazepam with specialized applicators for children and adults. This product overcomes many of the problems associated with rectal administration by non–health professional caregivers. Rapid plasma concentrations are reached within 15 minutes, and multicenter studies have shown the safety and efficacy of this formulation for reducing seizure frequency in children and adults with acute repetitive seizures, thus forestalling the otherwise necessary admission of the patient to an emergency department.
Newer Antiepileptic Drugs
Newer agents are becoming increasingly available in the United States. Experience with these medications has been gained predominantly in European and American trials. These drugs are often FDA approved for add-on therapy, but they are gaining popularity for use earlier in the treatment of epilepsy because of their lower side-effect profiles. They are usually more expensive.
Felbamate (Felbatol)
Felbamate (FDA-approved in 1993) is a drug that has been tested as add-on therapy for drug-resistant CPSs with or without secondary generalization and in patients with Lennox–Gastaut syndrome in several European and American trials.
An oral dose has a half-life of about 20 hours as monotherapy, or 14 hours in patients receiving poly pharmacy, and a volume of distribution of 0.8 L/kg.
Typical dosing regimens vary from 2,400 to 3,600 mg/day. Felbamate may increase phenytoin levels but decrease carbamazepine levels. Little effect has been noted on valproate levels. Felbamate (Felbatol) is available in 400-mg and 600-mg tablets and in suspension.
Side effects include mild problems such as weight loss, nausea, blurred vision, diplopia, headache, and ataxia, as well as severe problems including aplastic anemia (more than 30 reported cases, with 10 deaths) and primary hepatotoxicity (liver failure reported in about 20 cases, with some deaths). At present the drug is largely restricted to use for patients who have epilepsy that cannot be controlled by other AEDs, and in whom the morbidity from epilepsy is believed to outweigh the morbidity risk from felbamate. The patient must sign an informed consent form.
Gabapentin (Neurontin)
This GABA analog (FDA-approved in 1994) was developed and used as an AED based on the GABAergic theory of epileptogenesis; however, it probably does not directly enhance GABA, although whole-brain GABA levels may be increased. Gabapentin is not protein bound, does not alter other AED levels, and is not metabolized. The half-life is 5 to 7 hours. Capsules of 100, 300, and 400 mg as well as tablets of 600 and 800 mg are made.
Clinical trials so far have been as an add-on AED in refractory partial epilepsies with or without secondary generalization. There are usually few if any side effects (Table 88.6), although limb edema has been reported. It is now available in generic form (gabapentin) with dosing at 100-mg, 300-mg, and 400-mg capsules.
Lamotrigine (Lamictal)
Lamotrigine is structurally unrelated to any other AED in current use. Its antiepileptic action is probably related to its inhibitory effect on glutamate release and stabilization of neuronal membrane voltage-sensitive sodium channels. There are over 4.8 million patient exposures.
It appears to be effective in patients with intractable CPSs with or without secondary generalization; patients with primary GTCSs, atypical absences, or nonconvulsive status epilepticus; and some patients with Lennox–Gastaut syndrome. It has also been approved for monotherapy when a patient who is already on an enzyme-inducing AED such as phenytoin or carbamazepine or an enzyme-inhabiting drug such as valproate is then weaned off that medication and maintained on lamotrigine.
The pharmacokinetics in normal human subjects show complete bioavailability, a very long plasma half-life (24 ± 5 to 7 hours), linear kinetics, and approximately 60% protein binding when used as monotherapy.
Enzyme-inducing AEDs reduce its half-life, necessitating b.i.d. dosing while valproate increases it, often to 24 hours. Lamotrigine does not appear to alter other AED levels, but will decrease OCP levels. The drug is well tolerated and side effects are few particularly modest or minimal lethargy in many. Skin rashes, sometimes severe but reversible, occur in about the same percentage of patients as for those starting phenytoin or carbamazepine, if drug escalation is gradual, following new labeling guidelines. The incidence of skin rashes falls the more gradually the drug is started. Diplopia, dizziness, nausea and vomiting, drowsiness, and headache also occur in a small percentage of users.
The drug may be started at 50 mg each night for 2 weeks, 50 mg twice daily for 2 weeks, then 100 mg twice daily, increasing in steps of 50 mg every 2 weeks until seizure control, clinical toxicity, or a maximum dosage of 600 to 700 mg/day is encountered. It may be started as low as 15 mg/day. Initial target levels may be 150 to 200 mg/day
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on monotherapy or 300 mg to 500 mg as adjunctive therapy. In patients who are also taking valproate, lamotrigine should be started at 25 mg every other day, increasing by 25 mg every 2 weeks so as to minimize the incidence of rash. Lamotrigine serum levels may be used as markers of patient compliance. Lamictal is available in 25-mg, 100-mg, 150-mg and 200-mg tablets with 2-mg, 5-mg, and 25-mg chewable (dispersible tablets).
Topiramate (Topamax)
Topiramate was approved in early 1997 for use as adjunctive therapy in adults with partial seizures. It probably has multiple mechanisms of action, including modulating sodium channels, enhancing the effect of gamma-aminobutyric acid (GABA), and decreasing the excitability of brain cells. More than 3 million patients have taken it, with a greater than 50% reduction in seizures in 35% to 44% of patients taking 400 mg/day in early clinical trials. Topiramate has a time to maximum concentration of about 2 hours, a bioavailability of approximately 88% unaffected by food, and little plasma protein binding (13% to 17%). It has linear pharmacokinetics, is not extensively metabolized, and is predominantly excreted by the kidneys. It has limited pharmacokinetic interactions, and its half-life makes it suitable for twice-daily dosing. Clinical studies show that it has no effect on carbamazepine but may increase phenytoin levels in some patients. The side-effect profile is similar to those of most other AEDs, and most side effects are not serious. They occur in the first weeks of therapy and usually resolve by the fourth month. Side effects are predominantly CNS related, including dizziness, drowsiness, and problems with coordination. There is a 1.5% incidence of kidney stones and rare reports in patients with acute myopia of angle closure glaucoma under 40 years of age. Tingling of the tongue, mouth, and digits is frequent. Word finding and other cognitive problems are reported in 10% to 20%, some of which can be moderated by lower ascension rates and lower target levels. Oral contraceptive effectiveness may be affected. The medication is available in 25-mg, 100-mg, and 200-mg tablets with 15-mg and 25-mg sprinkle capsules. Therapy should be initiated at a dosage of 25 mg/day and gradually increased over several weeks to a recommended dosage of 200 mg to 400 mg/day in two divided doses. At doses greater than 200 mg, liver enzyme induction can occur and affect, among others, OCPs.
Tiagabine (Gabitril)
Tiagabine was approved in late 1997 for adjunctive therapy for partial-onset seizures in adults and children 12 years and older. Tiagabine was specifically designed to inhibit the uptake of GABA and prolong its action after synaptic release. Clinical trials have shown it to be effective as an add-on drug for patients with intractable focal seizures; 26% of patients have a 50% or greater reduction in focal seizures (51). A reduction of 50% or more of CPSs was seen in 20% to 30% of patients. Tiagabine should be started at 4 mg once daily and increased by 4 mg the first week and 8 mg weekly thereafter to 32 to 56 mg/day. It should be taken with food, in divided doses (two to four times per day), with the largest dose at bedtime. Tablets are available in 2-mg, 4-mg, 12-mg, 16-mg, and 20-mg strengths; side effects include dizziness, confusion, tiredness, GI upset, encephalopathy, and nonconvulsive status epilepticus.
Oxcarbazepine (Trileptal)
Oxcarbazepine is a 10-keto analog of carbamazepine and is active as a prodrug, having similar efficacy but purportedly lower side effects than carbamazepine. It is effective against partial seizures.
Oxcarbazepine is metabolized to the pharmacologically active 10-monohydroxy metabolite. Protein binding is relatively low. The drug does not autoinduce and does not produce an epoxide that normally accounts for most side effects seen with carbamazepine. It is a less potent cytochrome P-450 enzyme inducer, and when patients are switched from carbamazepine to oxcarbazepine, levels of phenytoin, lamotrigine, and topiramate may rise.
In trials at the highest dose of 2,400 mg/day, 50% of patients had a 50% reduction in seizures, compared with 13% in the placebo group. Lower does may be better tolerated as adjunctive therapy. There are more than 1.8 million patient exposures.
Oxcarbazepine has been approved for initial monotherapy in adults and children with partial seizures. The side-effect profile is the same as for carbamazepine, but side effects reportedly occur less frequently and neutropenia is not seen. However, hyponatremia not infrequently occurs. Hypersensitivity and rash reactions are less common than with carbamazepine.
Initial doses are 150 to 300 mg/day in monotherapy, increasing to clinical effect, usually at about 900 to 2,400 mg/day. As adjunctive therapy, initiation is recommended at 150 mg twice daily, with weekly increments of 600 mg/day or less for better tolerability. Serum levels of monohydroxy derivative are available with a target range of 50 to 200 mmol/mL. Oxcarbazepine is available in 150-mg, 300-mg, and 600-mg tablets with a 300-mg/5 mL suspension.
Levetiracetam (Keppra)
This drug has a unique preclinical profile with an efficacy in various animal models of seizures. Mechanic levetiracetam absorption is not affected by food. It has very low protein binding and is not hepatically metabolized. Two thirds of the drug is excreted renally, unchanged. There are
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no known drug interactions, and levetiracetam is neither an inducer nor an inhibitor of cytochrome P-450 enzymes. It has no effect on oral contraceptives, digoxin, warfarin, or other AEDs. No dosage adjustment is needed for hepatic impairment, but adjustments are needed for renal impairment with creatinine clearance less than 50 mL/minute. Therefore, the dosage may need to be adjusted in elderly patients. Trials have shown a 50% reduction in 23% to 42% of patients with levetiracetam dosages of 1,000 to 3,000 mg/day, compared with 10% to 17% for placebo. At the higher dosage, 8% of patients became seizure free.
The drug is well-tolerated with few adverse events, including somnolence, dizziness, anorexia, which are usually mild to moderate. Of the about one million individuals exposed to date, few serious hepatic, renal, or cardiovascular adverse events have been found. Rash is rare, but fatigue, irritability or personality changes are not.
Levetiracetam is started at 500 mg twice daily, or more gradually, and increased as tolerated to 1,000 mg or 1,500 mg orally twice daily. Levetiracetam is available in 250-mg, 500-mg, and 750-mg tablets and 100 mg/mL oral solution. Target levels typically are 3 mg/L to 20 mg/L.
Zonisamide (Zonegran)
Preclinical studies have suggested a similar profile to phenytoin, but with some action at other channels. The drug is reduced via a cytochrome P-450 (CYP 3A4) and by N-acetylene, with about one third excreted unchanged in the urine. The half-life is about 60 hours, and therefore steady state is reached in about 2 weeks. Hepatic metabolism of zonisamide is increased by enzyme-inducing drugs, but protein binding is relatively moderate (40%). Zonisamide neither induces nor inhibits hepatic enzymes; does not affect levels of phenytoin, carbamazepine, or valproate; and does not autoinduce. However, phenytoin and carbamazepine decrease the half-life of zonisamide to about 27 and 38 hours, respectively. Therefore, after enzyme-inducing AEDs are withdrawn, zonisamide levels may increase. Because of its renal excretion, adjustments should be made in renally compromised and elderly patients. With dosages between 100 and 600 mg/day, seizure reductions in up to about one third of patients were seen after exclusion of a placebo response. Zonisamide may be particularly effective in progressive myoclonus epilepsies. Side effects include dizziness, somnolence, headache, anorexia, nausea, and irritability, particularly with more rapid up titration.
Zonisamide is a sulfonamide and may exhibit similar hypersensitivity reactions, occasionally with Stevens–Johnson syndrome. Rash may occur early in treatment. Aplastic anemia and agranulocytosis have been reported. About 1% of patients have renal stones, possibly because of the drug's effect as a carbonic anhydrase inhibitor. Similarly, mouth and digit tingling are not rare. Initial dosing is 100 mg/day, with up titration by 100 mg/day every 2 weeks as tolerated. Treatment may be once or twice daily, and dosages as low as 100 mg/day have been reported to be effective. Optimal plasma zonisamide levels for seizure therapy are reported to be 10 to 40 mg/mL, but evidence is scant. Zonegran is available in 25-mg, 50-mg, and 100-mg capsules.
Other Antiepileptic Drugs
Practitioners often use diazepam, clorazepate, or chlordiazepoxide to treat seizures under certain circumstances. Benzodiazepines (other than clonazepam and clorazepate) have drawbacks for long-term therapy; AED effects tend to diminish as sedative effects accumulate.
Vagal Nerve Stimulation for Refractory Seizures
Vagus nerve stimulation (VNS) is a recent treatment for refractory seizures; it provides a programmed, regular stimulus via coiled electrodes from a chest-implanted generator to the left cervical vagal nerve. The pulse generator is powered by a lithium battery connected to a helical bipolar lead, which is, in turn, attached to the midcervical portion of the left vagal nerve, delivering a biphasic current continuously cycling between on and off periods. Animal data suggest that VNS stimulates small unmyelinated C fibers, with the locus ceruleus playing a crucial role in the mechanism of VNS, because chemical lesioning reduces the anticonvulsant effect of stimulation. VNS inhibits seizures in multiple animal models, including maximum electroshock, penicillin, and pentylenetetrazol models. It also measurably alters cerebral blood flow in the thalamus, cerebellum, and cortex and activates inhibitory structures in the brain.
Several clinical studies using active-control, parallel-blinded formats revealed a substantial reduction in seizure frequency. Long-term studies have shown a sustained reduction of 50% or more in 37% of patients, with a 43% responder rate at 2 and 3 years. Common side effects include voice change and hoarseness. Reductions compared to baseline were about 35% at 1 year, increasing to 44% at 2 and 3 years. Other side effects included paresthesias, headache, and shortness of breath.
Careful patient selection and evaluation by epilepsy centers are optimal techniques for the choice of VNS for refractory epilepsy.
Referral to a Neurologist
The role of a consulting neurologist to help with the evaluation and management of epilepsy depends on the experience of the primary physician. Table 88.7 lists common problems for which referral may be helpful.
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TABLE 88.7 When to Refer or Hospitalize the Patient with Seizures |
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Hospitalization
Few general statements can be made about the need for hospital admission for seizure patients, because the availability of monitoring systems, emergency room holding rooms, and inpatient beds varies from locale to locale. Table 88.7 shows a set of reasonable guidelines. Patients brought to offices or emergency rooms after a first seizure are usually admitted to facilitate the diagnostic workup and to observe the patient in case a serious underlying cause (e.g., meningitis, subdural hematoma) is present. This principle has exceptions. A young patient with a normal examination and a reliable family may be evaluated in an ambulatory setting. Any patient with new focal signs on examination should be admitted, as should obtunded patients, febrile patients, and those whose postictal lethargy persists for longer than 30 minutes. A patient with a crescendo pattern of seizures, with several in one day, especially if they are tonic–clonic seizures, should be admitted to a hospital immediately. Status epilepticus, a condition in which continuous or back-to-back seizures occur without intervening return of consciousness for at least 30 minutes, is a medical emergency and requires immediate hospitalization. Barbiturate withdrawal seizures may become fulminant; therefore, patients having seizures in this setting should be admitted. If the possibility exists of a rapidly expanding mass lesion, such as tumor, abscess, or possible hematoma after head trauma, then admission should not be delayed. Reasons for elective admission include a need for special inpatient studies (arteriography, continuous monitoring), evaluation for possible neurosurgical procedures for intractable epilepsy, and, lastly, trials of supervised drug management to check for noncompliance as a factor in treatment failure.
Admission usually is not needed for patients who are known to have chronically recurrent seizures, whose pattern of seizures is stable, whose cause is established or is thought to be idiopathic on the basis of a prior thorough workup, who have fully recovered from recent seizures, who have normal examinations (or static documented old deficits), and who are reliable enough to return for followup.
Social Issues and Patient Education
Once a serious underlying cause has been ruled out, there is a tendency for physicians to view epilepsy as a benign disease. From the viewpoint of the patient, this is often far from the case. Seizures are distressing for every patient and for the patient's family. Fear of having a seizure can cause people with epilepsy to withdraw from society, and those who are willing to compete may be faced with nearly insurmountable discrimination.
The Commission for the Control of Epilepsy and Its Consequences (1977) found that the unemployment rate among people with epilepsy is twice the national average, and the underemployment rate is even higher. Suspension of a driver's license (discussed later) may make it almost impossible to get to work. Children may be denied participation in sports or moved unnecessarily to special sections in school. Persons with epilepsy marry less often than matched subjects without epilepsy. A significant fraction of the public believe that people with epilepsy are likely to be physically unattractive. Because of these and other social stigmata associated with epilepsy, it is important to focus on the patient's overall functioning rather than simply on seizure control. The patient and family should be counseled regularly to help them address the concerns that limit full participation in society.
Patients should be told that epilepsy is a medical illness, because too many believe that it is a punishment for some past abuse. Whereas a single or even multiple reactive seizures (e.g., to alcohol) should not be labeled as epilepsy, definite epilepsy should not be mislabeled as something else in an attempt to avoid facing the diagnosis. The patient should know that individual seizures usually do not cause measurable brain damage and that the
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condition does not lead to mental deterioration. Unfortunately, sudden unexpected death in epilepsy does occur. The prognosis for most patients with epilepsy is good.
Restrictions of Activity
Patients often ask for guidelines about what they can and cannot do. Clearly, if identifiable precipitants such as sleep deprivation, flashing lights, alcohol, or particular medicines can be avoided, the patient should be so advised. Maximal activity consistent with avoidance of risk of personal injury should be the goal. The specifics must be formulated by a physician familiar with the individual patient and the patient's pattern of seizures. Patients with nocturnal seizures need not be restricted during the day. Contact sports are safe for people with infrequent seizures. Common sense dictates limits on activities during which a seizure could be fatal—for example, piloting an airplane, rock climbing, or scuba diving. Some potentially hazardous activities, such as swimming, may be acceptable if provisions can be made for proper supervision. Seizures are not contraindications to strenuous activities, including sex. Alcohol consumption (in moderation) can be enjoyed by most patients with impunity (5,19,52).
Driving a Motor Vehicle
Overall, motor vehicle accident rates for people with epilepsy are about twice the rates in control subjects. The actual proportion of all traffic accidents caused by people with epilepsy has been estimated at 1/10,000 accidents (5,19,53). It is estimated that 6/10,000 of all deaths at the wheel are from natural causes, including epilepsy, and that 5,000/10,000 are caused by alcohol use. Approximately 12% to 20% of accidents involving people with epilepsy occur with the patient's first seizure. As indicated by these statistics, seizures at the wheel do occur and can represent both personal and public dangers. The key element of increased risk is blunting or loss of consciousness. Seizures without this element (e.g., partial simple motor seizures) do not affect the risk of driving, and affected patients are usually exempted from restrictions, although in some, determining momentary loss of consciousness is problematic.
Some states require that physicians directly report occurrence of seizures to the Department of Motor Vehicles (DMV); others require only documentation in the medical record that the patient has been informed of the risks for traffic accidents and has been instructed to contact the DMV for a hearing (see Epilepsy Foundation, http://www.hopkinsbayview.org/PAMreferences). Patients and physicians should be honest in their communications; both are potentially liable for consequences of inaccurate or incomplete information. Generally, the physician should address the medical facts of a case and leave the final determination of licensing to the state authorities. Often, if an applicant has regular lapses of consciousness, the license will be suspended until a period of 3 months to 2 years without seizures has elapsed (depending on the state); the recent national trend has been to consider shorter periods of suspension.
Employment
It is illegal to discriminate against handicapped people, including people with epilepsy, in the job market. If a person with seizures is unemployed or dissatisfied with work, one should consider prompt referral to a vocational rehabilitation agency for possible retraining, patient and employer education, or advice on legal action. The Epilepsy Foundation (4351 Garden City Drive #500, Landover, MD 20774, telephone 301-459-3700; http://www.efa.org) is a central nonprofit organization that can serve as a source for information and action on social and occupational aspects of epilepsy; at least one chapter exists in each state. Their training and placement service has been effective in training people with epilepsy for work and in finding them employment, either in the general work pool or in sheltered workshops. The same local organizations may further aid patients with regular group counseling for those who cannot live independently, or by providing for regular home visits by visiting nurses and other medical personnel.
Some patients with difficult-to-control seizures should be advised to apply for Social Security medical disability compensation (see criteria inChapter 9).
Pregnancy
Special problems are raised by a woman with epilepsy who is, or wishes to become, pregnant (54). Approximately 0.4% of all pregnancies occur in mothers with seizures. In women with epilepsy, child-bearing carries an above-average risk for eclampsia, vaginal hemorrhage, and complicated labor. The rates of premature birth and perinatal death are increased. Seizures become more difficult to control during pregnancy in approximately 30% to 50% of cases, easier to control in approximately 10% to 30%, and unchanged in the rest. Rarely, pregnancy can induce a new onset of recurring idiopathic seizures. AEDs—phenytoin, carbamazepine, valproate, and, to a lesser extent, most of the other agents—are teratogenic. The teratogenic effects of most of the newer AEDs are unknown. Studies suggest that the incidence of congenital abnormalities, particularly cleft lip, cleft palate, and cardiac defects, is two to six times higher in offspring of drug-treated mothers with epilepsy. Valproate has specifically been associated with a 1% to 2% risk of neural tube closure defects and 6% to 9% of major malformations. A minimum of almost 400 first trimester monotherapy exposures is needed to establish with 80%
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power, twofold increase in major malformation rate, assuming an expected 3% background incidence. A number of pregnancy registries has provided data, in aggregate, to suggest that the background rate of major malformations in women with epilepsy is 2.1%. For the older AEDs, the North American Registry has shown a major malformation rate of 6.5% (5/77) for phenobarbital and 8.8% for valproate. The UK Registry revealed 2.4% for women with epilepsy on no AED; 2.3% major malformation rate of 700 pregnancies for carbamazepine, and 2.1% in 390 pregnancies for lamotrigine.
Authorities agree that tonic–clonic seizures can produce anoxic, ischemic, or traumatic damage to a fetus and that this risk must be balanced against the teratogenic potential of medication. The best solution to this dilemma is careful planning. Physicians should ask their patients not only to plan pregnancies but also to alert the physician to the plan months in advance. Before pregnancy, special efforts can be made to taper medications or to switch to phenobarbital or carbamazepine, which may be less teratogenic than phenytoin or valproate. However, most authorities agree that the AED to be used in pregnancy should be the one best suited for the patient and her epilepsy. Switching drugs after conception, i.e., when the patient discovers that she is pregnant, usually is not recommended, partly because the greatest vulnerability of the developing fetus is early in the pregnancy. Brief CPSs or absence seizures pose no known risk to a fetus, and a decision may be made by the patient to tolerate them during pregnancy rather than take medication. If pregnancy is unexpected, an ongoing successful regimen of AEDs should probably be continued, to avoid the possibility of fulminant withdrawal seizures during a critical obstetric stage. Ultimately, all of these relative risks must be discussed among primary and specialist physicians, the patient, and her partner, so that a mutually satisfactory plan can be derived. The problems of child-bearing are increased for mothers with epilepsy, but not greatly, and only the severely disabled epileptic woman should be flatly discouraged from having children.
Counseling should also include advice on prenatal vitamins, folate, postnatal help with the baby, and further followup in case AEDs need to be adjusted in the postpartum period. No clearly established optimal dosage of folate acid or folate has been established, but dosages recommended usually range between 1 and 4 mg/day, the latter if there is a history of neural tube defects.
Mothers taking AEDs who wish to breast-feed may do so, because the amount of AEDs excreted in breast milk is generally relatively low, and the developing baby was exposed often to even higher doses while in utero. Data on the newer AEDs are scarce, but breast milk exposure would be low for topiramate and medium to high for clonazepam, oxcarbazepine, zonisamide, levetiracetam, and tiagabine.
Potential parents wonder about the likelihood that their child will have epilepsy if they or one of their children have epilepsy. Although there are methodologic problems in performing studies to answer this question, it can generally be said that there is a risk of about 1 in 40 of transmitting idiopathic generalized epilepsy from the mother. When seizures result from head trauma, tumor, drug withdrawal, or other identified causes, then the risk of heritability is not increased.
There is an increasing body of evidence of long-term effects of antiepileptic drugs. Several studies on enzyme-inducing AEDs, have suggested that chronic usage extending beyond 5 years (in both men and women), particularly after the age of 50, an increasing incidence of osteopenia and osteoporosis. These latter conditions predispose to fractures and their consequent morbidity. With prolonged, chronic enzyme-inducing AED usage and particularly with an unexpected fracture, dual-energy x-ray absorptiometry (DEXA) scans are recommended. Optimal calcium and vitamin D therapy has not been determined, but many practitioners advocate 500 mg twice daily of calcium and 600 international units (IUs) of vitamin D for patients at risk. Higher dosages, or the use of bisphosphonates may be recommended for worse bone disease.
Valproate has been implicated in increase in body mass index often carrying with it, a tendency toward insulin resistance, hyperandrogenism, hirsutism, and a polycystic ovarian syndrome (PCOS) (see Chapter 101). Initial studies showed a high prevalence of PCOS in valproate-treated women when valproate is started before or after the age of 20 years. Further studies to investigate these findings are ongoing in the United States and the United Kingdom. Characteristically, women with PCOS have anovulatory cycles. In affected patients, improvement in anovulatory cycles and other aspects of this syndrome has been obtained by choosing an alternate AED.
Family Education
Families must be told how to behave during a seizure; too often, frantic efforts to treat the seizure result in extreme anxiety and broken teeth. Seizures should be allowed to run their course; unless convulsions become continuous or nearly continuous (status epilepticus) they are not dangerous, and no first aid can shorten them. The mouth should not be forced open so that spoons, fingers, towels, pencils, or other objects can be pushed in. The family should be informed that it is impossible to “swallow the tongue.” The person undergoing a seizure should be moved away from sharp corners and heights and turned on his or her side to decrease the risk of aspiration. Forcible restraint during a tonic–clonic phase is of no value, and during the automatisms of CPSs restraints may increase agitation. There is little need to fear behavior during automatisms, because directed violence is extremely rare.
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Concerned family members may be very helpful in promoting improved seizure control. They should be encouraged to discuss compliance, the cost of a pharmaceutical regimen, and how the seizures or drug toxicities affect school, work, and social relations. Patients should be encouraged to keep a log of their seizures, medication times, side effects, and possible precipitating stresses. Perfect control of epilepsy with no toxicity is an ideal attained in only a minority of cases; in the remainder, patient, family, and physician can decide in concert how to balance the inconvenience of seizures against the unpleasant side effects of medication and thereby achieve the best possible results.
Medicolegal Issues
In addition to conducting discussions of the diagnosis, management, prognosis of epilepsy, and potential adverse effects of treatment, it is important to document in the patient's record the principal points that have been addressed with the patient and the family. One should offer patients written information advising them of driving laws, notify them of their obligation to alert the DMV, and warning them to avoid dangerous activities and occupations. They should also have full written records of medications and their side effects, in lay terms, and instructions to contact the physician for any worrisome side effects. In addition, all women of child-bearing age should be counseled regarding fetal teratogenicity effects on fetal and subsequent postnatal cognitive development, possible change in maternal seizure frequency, and the need or lack of need for AED therapy (see Pregnancy). Many of these essential facts are covered well in patient education literature available from the Epilepsy Foundation (see Employment).
Attention to these aspects of patient and family education and a close, compassionate, and open doctor–patient relationship are sound ways to limit malpractice exposure.
Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
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