Epilepsy and Seizures

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[edit] Epilepsy and Seizures

R. Mark Sadler

Seizures are a very common manifestation of cerebral cortical dysfunction. Seizures occur when there is an abnormal, excessive, and synchronous electrical discharge of cortical neurons. An important concept to remember is that the central nervous system (CNS) is inherently susceptible to seizures. The fundamental neural circuitry and neurochemistry of the brain are such that there exists a “built in” tendency for seizures to occur that is normally suppressed by a balance of excitatory and inhibitory influences. The basic mechanisms of seizures are incompletely understood and are different for different seizure types and varieties of epilepsy. Simplistically, seizures can be viewed as occurring in circumstances of excessive excitation and/or impaired inhibition.

Epilepsy, as distinct from a seizure, is usually defined as a chronic condition characterized by the occurrence of recurrent, apparently unprovoked seizures. Thus the patient who experiences a generalized tonic-clonic seizure as the result of hypoglycemia is not considered to have epilepsy.

[edit] EPIDEMIOLOGY AND ETIOLOGY OF EPILEPSY

Population-based studies report the prevalence of epilepsy (number of active cases per unit population) at approximately 1%. The incidence (number of new cases per year in a given population) is approximately 40 to 70/100,000. Age-specific incidence rates show the highest figures in the first decade, a decline to a steady level in the 20-to 60-year age range, and a sharp rise again in the last decades of life.^[1] These incidence figures reflect the various etiologies of epilepsy at different ages.

The cumulative incidence of acquiring epilepsy is 2% to 4%. The cumulative incidence of having at least one seizure during one's lifetime is estimated at 8% to 10%.

Virtually any pathologic process that can affect the cerebral cortex may give rise to a seizure or epilepsy. Large population-based studies, however, continue to demonstrate that of patients with epilepsy, up to 60% are of unknown etiology. Genetic varieties of epilepsies are included in the “unknown” group because the precise genetic basis for inherited epileptic disorders is still unknown. Commonly recognized causes of epilepsy include developmental disorders, cerebrovascular disease, trauma, the sequelae of intracranial infection, tumor, and degenerative disorders. The relative proportion of these causes will depend on the age group under study. Thus cerebrovascular disease, degenerative disorders, and tumors are more common in the older population and developmental disorders represent a higher proportion in the pediatric population. The causes of epilepsy are also related to geographic areas. For example, cerebral cysticercosis is an extremely prevalent cause of epilepsy in Africa, South America, Central America, and India.

[edit] CLASSIFICATION

There have been many proposed classification systems of seizures and types of epilepsy. Some systems have used terminology that emphasizes an anatomic basis (e.g., temporal lobe seizures), behavioral aspects (e.g., psychomotor seizures), or etiology (e.g., posttraumatic epilepsy). The most widely used systems in current use are those developed by the International League Against Epilepsy (ILAE). The ILAE has developed a classification of seizures and a separate classification of epilepsies and epileptic syndromes.

[edit] ILAE CLASSIFICATION OF EPILEPTIC SEIZURES

The components of the ILAE seizure classification are listed in Box 159-1.^[2] This system was developed by reviewing the clinical and electroencephalographic (interictal and ictal) features of epileptic seizures demonstrated by simultaneous videotape and electroencephalogram monitoring.

The ILAE system is clinically weighted, and the first important consideration is the distinction of seizures that have the initial clinical and EEG features indicating activation of a restricted portion of one cerebral hemisphere (partial seizures) from those seizures that initially display bilateral cerebral involvement (generalized seizures).

The term partial is used synonymously with focal and does not imply an incomplete variety of seizure.

Within the general category of partial seizures a distinction is made between simple and complex seizures. The term simple indicates that the patient has no impairment of consciousness, whereas complex means that during the seizure consciousness is impaired.

Simple partial seizures have a variety of clinical features that depend on what part of the cortex is involved during the seizure. When motor phenomena occur, clonic movements (jerks) may involve a restricted body part (e.g., the hand or face) and may spread to adjacent body parts (a Jacksonian march). Tonic features refer to relatively pure stiffening (without clonic movements) or sustained postures, such as head and/or eye deviation (version). There may be transient weakness of the body part involved during the seizure after a motor seizure (Todd's paresis). Sensory seizures cause hallucinations or illusions. Somatosensory seizures typically cause numbness or tingling in a body part. Illusions or hallucinations of any of the senses can occur when specialized sensory cortex is involved: olfactory or taste (typically from seizures of mesial temporal lobe structures), visual (occipital cortex), hearing or vestibular (superior temporal gyrus). Autonomic seizures can cause symptoms of sweating, piloerection, palpitations, and, very commonly, an unpleasant, rising epigastic sensation. These autonomic features are usually seen in association with temporal lobe–originating seizures. Psychic phenomena refer to a panoply of sensations, including changes in emotions (fear, depression), déjà vu, depersonalization, memory flashbacks, and a “dreamy” state. These difficult-to-describe experiences most often evolve to partial complex seizures (see below) and probably infer seizure involvement of limbic structures in the temporal lobe.

Partial complex seizures are, by definition, associated with an impairment of consciousness. These seizures start in a restricted part of the brain and spread to other neuroanatomic structures involved with attention and consciousness. Typically the patient will have an arrest of behavior, a blank or “wide-eyed” stare followed by automatisms (e.g., lip smacking or chewing movements), or may continue a complex motor task (such as riding a bicycle). The patient is relatively unresponsive to the environment during a partial complex seizure. The patient will appear “out of touch” for a period of time (usually 30 to 90 seconds). Frequently there is postictal confusion and sleepiness. The postictal confusion can be brief and the patient may be unaware that he or she experienced any type of altered behavior. The patient will be amnestic for the event but may be able to describe some features that occurred at the beginning of the seizure (i.e., the simple partial component before spread of the seizure to contralateral cortical structures). Partial complex seizures often begin in the temporal lobe but may be initiated from any lobe, propagate to temporal lobe structures, and give rise to clinical features indistinguishable from temporal lobe– originating attacks. Therefore a careful inquiry of the initial features of the seizure may give clues to the true origin. An important concept to appreciate is that although a partial complex seizure starts in one area, the seizure may spread very quickly, resulting in impaired consciousness from the outset. Therefore the patient will not be able to give any history of a warning for the attack. Partial complex seizures must be distinguished from absence seizures (see below), with which they are often confused. Partial complex seizures are a focally originating seizure disorder (absence attacks are generalized), they usually last longer than absence seizures, and they commonly have postictal confusion that is lacking with absence attacks. Partial complex seizures are secondary to a variety of focal cortical structural pathologies and have different drugs of choice as initial treatment.

As indicated in Box 159-1, partial seizures may evolve to secondarily generalized seizures. An important concept is that the form of a secondarily generalized seizure is usually a tonic-clonic seizure (convulsion) and not one of the other varieties of generalized seizures (e.g., absence, atonic, or myoclonic). Propagation (spread) of the seizure can occur with such rapidity that there may be no indication of the partial (focal) onset. Seizures that arise focally and spread very rapidly may not be clinically distinguishable from primary generalized tonic-clonic seizures, and an accurate diagnosis will depend on laboratory investigations, including EEG and neuroimaging studies.

Generalized seizures have in common the property of bihemispheric onset from the beginning of the attack. Therefore none of the primary generalized seizures will have a warning.

Absence seizures (formerly called petit mal) are brief (5 to 15 seconds) episodes of impaired awareness that usually consist of an arrest of behavior and a blank stare. There is no postictal confusion. In the untreated patient, these seizures commonly occur multiple times per day and almost always begin in childhood (although they may persist to adulthood). During the seizure a diagnostic, generalized spike-and-wave pattern is seen on the EEG. Approximately 50% of patients will have, or will eventually develop, other primary generalized seizure types, including tonic-clonic (grand mal) seizures and myoclonus. Atypical absence seizures are characterized by a less precise onset and offset, they last longer than typical absence seizures, they may be associated with motor features such as a loss of body tone, and they usually occur in patients with intellectual handicaps and other seizure types.

Myoclonic seizures consist of brief shocklike jerks that in the primary generalized epilepsies consist of bilateral movements of the head, neck, and often the proximal arms and legs. This seizure type can occur alone but more commonly is associated with other primary seizure types and can occur in many different epilepsy syndromes of diverse etiology.

A pure clonic seizure resembles a sequence of myoclonic jerks. Tonic seizures are characterized by brief episodes (usually less than 20 seconds) of bilateral stiffening of the body and extremities. These seizures are characteristic of Lennox-Gastaut syndrome (see Box 159-2), in which tonic seizures occur predominantly during sleep.

Atonic seizures consist of an abrupt, brief (seconds) loss of body tone. Typically the head will droop or the patient will fall to the ground; if consciousness is lost it is very brief. Patients with this seizure type often sustain multiple injuries from their falls. Almost invariably, patients with this seizure type develop their epilepsy in childhood and are cognitively impaired; thus atonic seizures are not usually within the differential diagnosis of drop attacks of a previously neurologically intact adult.

Generalized tonic-clonic seizures (formerly called grand mal) begin with a loss of consciousness and a tonic phase consisting of a generalized stiffening of the body and extremities. A vocal “cry” or “scream” sometimes occurs as the result of air being expelled through the contracted vocal cords. The tonic phase gradually merges with the clonic phase by an evolution from a low-amplitude, high-frequency vibration to bilaterally symmetric clonic jerks of higher amplitude that gradually slow in frequency. The motor component of the seizure typically ends with one to two violent, generalized jerks. The tonic-clonic phase is accompanied by cyanosis and prominent salivation. Tongue biting (on the lateral aspect) and urinary incontinence are common. Musculoskeletal injury (including spinal compression fractures and dislocation of the shoulders) from the force of muscular contraction may occur. Most convulsions last 1 to 2 minutes. The postictal state is characterized by transient stupor, sleepiness, confusion, headache, and muscular soreness later that day or the next. Some patients complain of a postictal memory disturbance lasting hours or, occasionally, a day or two.

The unclassified category of seizures is reserved for any seizure type that does not correspond to one of the other categories and/or whose nature is unclear (e.g., some neonatal seizures).

[edit] THE INTERNATIONAL CLASSIFICATION OF THE EPILEPSIES AND EPILEPTIC SYNDROMES

The ILAE has created a classification of the epilepsies and epileptic syndromes that must be distinguished from the classification of epileptic seizures described earlier. The list of disorders in Box 159-2^[3] is extensive and contains a number of relatively unusual disorders, but it is included because primary care physicians will receive correspondence from consultants using the terminology in this box.

An epileptic syndrome is a disorder characterized by a cluster of signs and symptoms that include factors such as the seizure type, etiology, anatomic onset, precipitating factors, age of onset, severity, chronicity, diurnal cycling, and prognosis.

The major divisions of this classification are those epilepsies with generalized seizures and those characterized by partial (focally originating) seizures. Each of these groups is further subdivided into idiopathic (in which a genetic component is usually assumed) and symptomatic types. Symptomatic refers to the epilepsies and epileptic syndromes that are the result of a known or suspected disorder of the CNS. In Box 159-2 the term cryptogenic is also employed and indicates an epileptic disorder that is symptomatic but the etiology is unknown. It should be appreciated that not all patients are easily classified within this system.

One of the common syndromes is described here to convey the concept of an epilepsy syndrome. Juvenile myoclonic epilepsy (JME) is one of the common generalized epilepsy disorders. Patients with JME are usually intellectually and neurologically intact. The seizure disorder begins in the preadolescent or adolescent years and is characterized by myoclonic jerks (usually of the head and upper extremities) that typically occur upon awakening. The majority of patients have tonic-clonic seizures that may follow a burst of the myoclonic jerks. Approximately one third of patients have a history of absence attacks during childhood. Myoclonic jerks and generalized tonic-clonic seizures often are precipitated by sleep deprivation. The interictal EEG demonstrates bursts of generalized polyspike and wave discharges at 4 to 6 cycles per second. Many patients also demonstrate photic sensitivity to intermittent strobe light stimulation. The drug of choice for treatment is valproic acid. The majority of patients find their seizures are well controlled with medical therapy. There is a high relapse rate if medication is discontinued, even if the patient has been seizure free for many years.

[edit] DIFFERENTIAL DIAGNOSIS

The diagnosis of a seizure remains a clinically based decision. The most common event that is misconstrued as a generalized seizure is a syncopal attack. Neurocardiogenic (vasovagal) syncope is the most commonly encountered variety among the many causes of syncope.^[4] The distinction of a seizure from syncope can be troublesome if the syncopal attack progresses to a brief tonic phase or includes myoclonic jerks. Clinical features to be sought in the history include a prodrome of nausea, hunger, “feeling hot,” yawning, an erect position (or sudden standing after prolonged recumbency), and a brief loss of consciousness (usually 30 seconds or less). An extremely important component to obtain from a witness is whether the patient was pale (which will not occur in a convulsion). The diagnosis of syncope is secured if the patient returns to consciousness, attempts to stand, but promptly loses consciousness a second time. Patients with neurocardiogenic syncope often give a history of presyncope or complete syncope in association with emotional factors (such as the sight of blood or syringes) or with acute pain. A family history of similar phenomena is frequently obtained.

Disorders with an associated impairment of consciousness that less commonly are confused with seizures include posterior circulation transient ischemic attacks, unwitnessed trauma with retrograde amnesia, episodic metabolic disturbances (such as hypoglycemia), sleep disorders (e.g., narcolepsy), and abrupt elevations of intracranial pressure caused by obstruction of cerebrospinal fluid (CSF) flow.

Psychogenic pseudoseizures commonly have a superficial resemblance to a generalized tonic-clonic seizure but typically lack the relatively stereotypic phases of an epileptic convulsion as described above. A prior psychiatric history is often present and a history of sexual and other physical abuse is typical. Panic attacks with prominent hyperventilation may lead to a transient loss of consciousness. Occasionally, partial complex seizures with bizarre automatisms may be misdiagnosed as a psychiatric disorder and expert assessment will be required. Clues that the spells are epileptic in nature will be the repetitive, stereotypic nature of the attacks and their occasional progression to unequivocal secondarily generalized tonic-clonic seizures. The clinician should also be aware of the possibility of the coexistence of epilepsy and psychogenic pseudoseizures.

A variety of disorders presenting with paroxysmal motor or sensory phenomena may simulate partial motor or partial sensory seizures, respectively. Migraine attacks with prominent visual features may resemble occipital lobe–originating seizures, but generally the visual phenomena last much longer in migraine than those associated with occipital seizures. Similarly, the sensory “numbness and tingling” attacks encountered with migraine tend to be much longer in duration than sensory seizures of parietal lobe origin. Movement disorders (including tics, tremor, and intermittent dystonic posturing) may resemble partial motor seizures, but careful attention to the actual details of the motor phenomena will usually distinguish these events from seizures.

[edit] HISTORY TAKING AND PHYSICAL EXAMINATION

The most common cause of misdiagnosis of a seizure is a failure to obtain an accurate and complete history. It is essential to obtain a history from two sources: the patient and a witness. For patients with “repeated spells” it is most useful to obtain a detailed description of a recent typical event that the patient and a witness can describe in detail.

Frequently the partial (focal) nature of the seizure is overlooked in patients who have rapid secondary generalization to a tonic-clonic seizure. It is important to ask the patient “what happened just before you lost consciousness?” “Do you ever have a warning or a feeling that you are going to have a seizure?” “Do you ever think you are going to have a seizure and it doesn't occur?” An affirmative answer to these questions will often divulge the focal nature of the seizure, with the “aura” representing the simple partial component of the seizure.

The patient's state after the ictus is important. For example, the patient with absence attacks will instantaneously return to awareness, in contrast to most patients with partial complex seizures who gradually awaken. Postictal limb paralysis (Todd's paresis) or dysphasia favors a focal onset.

The neurologic functional inquiry should emphasize potential causes, including a history of head injury and an estimate of its severity, previous intracranial sepsis (meningitis or encephalitis), birth and developmental milestones, and a family history of seizures or other neurologic disorders. A history of febrile convulsions in early childhood should be distinguished from the patient's habitual seizure disorder.

The general medical functional inquiry should be directed toward a search for clues of systemic illnesses that secondarily involve the CNS. Examples of the latter include malignancies with a high predisposition for CNS invasion, such as lung and breast cancers and melanoma.

The purpose of the neurologic examination is to look for clues to etiology and site of seizure onset. A careful assessment of visual fields (as an indicator of occipital lobe pathology) is mandatory if the seizure begins with visual phenomena. Patients with temporal lobe–originating seizures should be examined for a contralateral superior quadrant visual field defect (because the visual pathway subserving this visual field traverses part of the temporal lobe).

[edit] INVESTIGATION

A careful history and physical examination will dictate the appropriate choice of serum tests. Certainly a variety of metabolic and systemic disorders may present with seizures, but extensive tests of blood counts, electrolytes, serum calcium, and hepatic and renal function are not indicated in the otherwise uncomplicated patient.

Most patients with a suspected seizure disorder will have an EEG as part of their investigation. Unfortunately, many physicians expect the EEG to answer the question as to whether the patient has epilepsy or not. Epilepsy is a clinical diagnosis, and the EEG cannot produce a diagnosis with certainty unless the patient has a seizure during the recording. This occurrence is relatively unusual except for patients with very frequent seizures, such as absence attacks. The predominant role of the outpatient EEG is to provide laboratory support for a clinical impression. The interictal (between seizure) EEG abnormality of generalized spike waves or focal spikes may provide clues to the mechanism of the seizures (generalized or partial, respectively).

The frequency of interictal spikes is highly variable and therefore a single normal EEG does not rule out the possibility of a seizure disorder. Some patients require multiple recordings (including recording during sleep) before definitive interictal spikes are noted. At least 80% of patients with undoubted epilepsy will eventually demonstrate EEG interictal spikes. The specificity of definite interictal spikes is relatively high because less than 2% of the population will have spikes without an accompanying seizure disorder. However, it must be emphasized that accurate identification of EEG abnormalities is very dependent on the experience and skills of the electroencephalographer. There is no indication for repeated EEGs after a diagnosis of epilepsy is established (e.g., on a yearly basis as a checkup or follow-up).

The EEG is useful for guiding further studies. For example, an adolescent or young adult who presents with generalized tonic-clonic seizures, lacks risk factors for focally originating seizures, has a normal physical examination, and whose EEG demonstrates generalized spike wave discharges has a diagnosis of one of the primary generalized epilepsy syndromes (Fig. 159-1). No neuroimaging tests are required. Conversely, the presence of focal EEG spikes (Fig. 159-2) suggests the presence of focal pathology (note the exception of the childhood benign localization-related syndromes listed in Box 159-2) and neuroimaging studies are indicated. A computed tomography (CT) scan is a minimal neuroimaging study for focally originating seizure disorders. A CT scan may be the only imaging study required for patients who have a history of a brain insult that could explain the etiology of the seizure disorder (e.g., ischemic cerebral infarction, trauma). However, a magnetic resonance imaging (MRI) scan is the neuroimaging study of choice for focally originating seizures, particularly for those patients with seizures of unknown etiology and whose CT scans are normal. Examples of epileptogenic lesions well seen with MRI that are poorly imaged during a CT scan include mesial temporal sclerosis (the most common neuropathology of patients with temporal lobe epilepsy), low-grade primary brain tumors, vascular lesions (such as cavernous angiomas), and neuronal migration disorders (Figs. 159-3 and 159-4).

Figure 159-1 Ten channels from a 32-channel EEG recording are shown. The top five channels are from scalp electrodes over the left hemisphere; the bottom five channels are from the homologous electrode positions overlying the right hemisphere. The recording is from a 20-year-old female with a history of two generalized tonic-clonic seizures. The demonstrated interictal abnormality is a generalized spike-and-wave discharge; note the bilaterally synchronous nature of the EEG abnormality. This finding would support a clinical impression that the patient has one of the primary generalized epilepsies.

Figure 159-2 Eight channels from a 32-channel EEG are shown. The top four channels are derived from scalp electrodes overlying the left temporal lobe; the bottom four channels are from the homologous electrodes overlying the right temporal lobe. Several left temporal interictal spikes are shown (black circles). This recording is from an 18-year-old male who came to medical attention after a convulsion in sleep. Further history revealed a several-month history of partial complex seizures. Further neuroimaging studies with particular attention to the left temporal lobe are indicated.

Figure 159-3 Axial MRI scan showing a collection of abnormal blood vessels (cavernous angioma) in the temporal lobe (arrow). This scan is from a 25-year-old male with longstanding partial complex seizures; the CT scan was normal. Neurosurgical excision of this lesion rendered the patient seizure free.

Figure 159-4 Coronal MRI scans from a 24-year-old female with medically resistant partial complex seizures that began 6 years after an episode of febrile status epilepticus in early childhood. The T1 weighted image (A) shows atrophy of the right medial temporal structures (arrow). The T2 weighted image (B) shows increased signal (as indicated by the brighter white area, arrow) in the right medial temporal area. These MRI scan abnormalities are characteristic of the pathology known as mesial temporal sclerosis. This is the most common pathologic finding in patients undergoing epilepsy surgery for refractory temporal lobe epilepsy. The precise mechanism of temporal lobe damage in these patients is debated but may be related to neuronally mediated cell death during status epilepticus.

Continuous video–EEG telemetry has become increasingly available in specialized centers. This technique involves the acquisition of EEG signals that are synchronized with simultaneous videotaping of the patient's behavior. Patients are typically recorded for long periods (days) in an attempt to capture their paroxysmal events. This technique may be very useful in clarifying the diagnosis in patients with frequent spells of an unknown nature (e.g., distinguishing epileptic seizures from psychiatrically based pseudoseizures). Video– EEG telemetry is an obligatory part of the investigation of patients with medically resistant epilepsy who may be candidates for epilepsy surgery.

[edit] GENERAL MEASURES IN THE MANAGEMENT OF EPILEPSY

Patients with a diagnosis of epilepsy face a number of burdens that are relatively unique in medicine. Patients continue to encounter remarkable prejudices from society because of a number of misperceptions and preconceived notions about the nature of epilepsy. When initially informed of the diagnosis, many patients need to be reassured that they do not have a mental illness and that a progressive decline in cognitive function is not the typical course for the vast majority of patients with seizure disorders.

Friends and relatives of the patient should be instructed in the first aid management of generalized tonic-clonic seizures, including admonitions to avoid placing objects in the mouth of the patient to prevent them from swallowing their tongue.

The physician should be aware of local regulations governing the operation of motor vehicles by persons who experience seizures. There are considerable worldwide differences in the obligations of the physician (mandatory vs. nonmandatory reporting) and the length of time required for a patient to be seizure free before operating a motor vehicle. Additional attention should be given to local regulations concerning professional drivers.

Patients may find that certain employment situations are unsuitable or may be prohibited, though not necessarily with validity. Career counseling, particularly for adolescents, may be required. For example, an individual considering a career in the military is well advised to determine if he or she may be disqualified because of a history of seizures. A common-sense approach should be used pertaining to recreational activities. Most sports are acceptable, but activities in which an abrupt loss of consciousness could lead to major physical injury (such as hang gliding or scuba diving) and those sports carrying a substantial risk of head injury (such as boxing) should be discouraged.

Patients should be encouraged to take showers, as opposed to tub baths. An unattended seizure in a bathtub can lead to a catastrophe.

Excessive alcohol intake should be discouraged, but small amounts of alcohol usually can be consumed without adverse effects. Recreational drug use of substances with potent proconvulsant properties (notably cocaine) must be forbidden.

Sleep deprivation is a potent activating effect for some seizures and therefore adequate sleep should be encouraged.

Patients should be made aware of the potential for drug interactions of their antiepileptic medications with other prescription medications. Antiepileptic medication compliance must be emphasized. Strategies include the simplest possible dosing schedules, linking the taking of medication to other regular daily activities (e.g., tooth brushing), and pill reminder containers.

Caregivers with active epilepsy who supervise very young children should be instructed to change and feed babies on the floor and never to bathe a baby alone.

[edit] MEDICAL MANAGEMENT

Antiepileptic drug (AED) treatment should be considered after a confident diagnosis of epilepsy (recurrent, unprovoked seizures) is made. In general, treatment should not be initiated until a diagnosis is reasonably established. A therapeutic trial should not be undertaken with an AED to prove if a patient does or does not have epilepsy.

The goals of therapy should be made clear to the patient and may include complete control of seizures with minimal adverse effects from the AEDs. It is important to recognize that some seizure types and epilepsy syndromes are notoriously difficult to bring under complete control. It may be preferable to accept, for example, occasional simple partial seizures rather than complete seizure control at the expense of medication toxicity. Conversely, simple partial seizures that occur exclusively in sleep may not require any AED treatment at all. In general, patients with normal cognition and without neurologic deficits require complete seizure control and no or few adverse effects from AEDs to obtain optimal quality of life and psychosocial development.

The patient should understand that AEDs treat symptoms and do not remove the underlying cause of epilepsy. Similarly, there is no compelling evidence that any of the currently available AEDs prevent the development of epilepsy in patients who are destined to do so (i.e., prophylactic AED treatment is not indicated after head injury in an attempt to prevent the development of epilepsy).

Prospective randomized trials have failed to demonstrate major differences in AED efficacy for most seizure types. Differences in successful treatment of epilepsy have been accounted for predominantly by differences in toxicity among AEDs.

Additional considerations in the initial selection of an AED include the presence of other medical conditions that could interfere with the metabolism of AEDs (e.g., hepatic and renal disease) and the presence of concomitant medication (of which there are multiple potential interactions with AEDs). Cost of medication is a consideration in AED selection because there are marked differences in price among the AEDs, particularly when comparing the traditional AEDs (phenobarbital, phenytoin, carbamazepine, valproic acid) to the new AEDs (gabapentin, lamotrigine, vigabatrin, and topiramate).

Suggestions for initial AED selection for specific seizure types are listed in Table 159-1. A detailed discussion of doses, adverse effects, and drug interactions is beyond the scope of this chapter, but selected aspects are listed in Table 159-2. The product monograph for each medication should be carefully consulted before initiating treatment. The recent published reviews of AEDs cited at the end of this chapter are highly recommended.^[5][6]

Table 159-1 Suggested Choices for AEDs✢

✢AEDs are listed alphabetically; the order in the list does not imply a rank order.

†Clobazam is not available in the United States; felbamate is not available in Canada.

Table 159-2 Some Characteristics of Antiepileptic Drugs✢

✢Consult product monograph for details of dosing, preparations, titration schedules, drug interactions, and a complete list of adverse effects; felbamate is not listed because it is not available in Canada and the lack of experience with this drug by the author.

†Virtually all AEDs can produce sedation, fatigue, cognitive impairment, dizziness, and ataxia in a dose-dependent fashion.

Virtually all modern AED treatment is initiated as monotherapy (single drug). With the exceptions of phenytoin and phenobarbital, which may be started at their maintenance dose, AEDs are started at a fraction of the ultimate maintenance dose and slowly titrated upward. The patient should be assessed after achieving the initial desired maintenance dose to monitor efficacy and toxicity. If seizures continue but the drug has been well tolerated, the dose should be slowly increased to the maximally tolerated amount before abandoning treatment with that drug. One of the alternate monotherapy choices should be introduced if seizure control cannot be achieved with the maximally tolerated dose of the first-choice medication. The first drug should be slowly withdrawn if seizure control is achieved with the second drug. Although commonly practiced, there are very few clinical data to support polytherapy for most patients with epilepsy. Polytherapy combinations are probably best used after consultation with a physician experienced in epilepsy management.

[edit] DRUG LEVELS: HEMATOLOGY AND LIVER FUNCTION MONITORING

Most laboratories can monitor the serum levels of the traditional AEDs. The ability to measure AED levels has demonstrated that there are substantial differences in dose and the resultant serum level from patient to patient. These variations can be attributed to individual differences in absorption, metabolism, and excretion. Serum AED levels may also be altered considerably by the presence of some other AEDs and other concomitant medications.

Serum AED levels are reported by most laboratories in the context of a therapeutic range. This range implies that there is a minimal drug concentration required for the antiepileptic effect and an upper limit that indicates the presence of dose-related (serum level) toxicity. However, in reality, there are relatively few studies that have substantiated the therapeutic ranges for any of the AEDs. There are considerable difficulties in conducting clinical trials that would establish minimal drug concentrations for seizure control because of the considerable spectrum of epilepsy severity. Consequently, patients with relatively mild epilepsy may have seizure control with drug concentrations below the usually quoted therapeutic range. Some patients with moderate to severe epilepsy may require AED serum levels above the usually quoted therapeutic range (provided there is no clinical toxicity) to obtain satisfactory seizure control.

The clinical data describing the relationship of drug level to toxicity are somewhat better than those supporting the antiepileptic effect, but they are still imperfect. The upper end of the therapeutic range is a statistical measure indicating that at this upper limit most patients will have some manifestations of toxicity. However, because this is only a statistical probability, there will be patients who display unequivocal toxicity at relatively low serum levels and patients who can tolerate higher levels without difficulties. Dose-related toxicity can take many forms, and not all toxic manifestations occur at the same serum level. When using AEDs it is prudent to adhere to the adage that “there are no toxic drug levels, only toxic patients.”

Measurement of serum AED levels may be useful in certain circumstances. Some experts will check the AED level after sufficient time has elapsed for the drug to achieve steady-state pharmacokinetics to determine if a “reasonable” serum level has been achieved. AED levels can be used as a measure of patient compliance, although an open patient-physician relationship and direct questioning of the patient will probably be as effective. AED levels may be useful in guiding therapy when a patient continues to have a substantial number of seizures despite relatively high serum levels. In this situation, change to a different medication should be considered because it is unlikely that a marginal increase in serum levels will abruptly transform the patient to a seizure-free state. AED levels can be used as a guide to which medication is likely to be responsible for toxic symptoms when the patient is taking multiple AEDs. Drug levels may be helpful in guiding initial dose requirements and subsequent dose adjustments in complex metabolic situations (e.g., hepatic or renal failure and pregnancy).

An area of controversy is the required frequency of checking hematologic and hepatic function studies in patients taking AEDs. Among the traditional AEDs, this issue relates to treatment with carbamazepine, valproic acid, and to some extent, phenytoin. Virtually all of the older AEDs have been associated with idiosyncratic hematologic toxicity (e.g., aplastic anemia, thrombocytopenia, neutropenia) and hepatic dysfunction (hypersensitivity reactions and possibly direct toxic effects by an AED or its metabolites). Some manufacturers have recommended that complete blood counts (CBCs) and hepatic function studies be performed on a regular basis throughout the period of treatment with the drug. This position has been challenged on the basis that testing of asymptomatic patients will create unnecessary medical costs, some patients may be withdrawn from effective therapy on the basis of trivial laboratory abnormalities, and there may not be a presymptomatic phase before the adverse effect can be detected by laboratory tests.^[7] One suggested approach is to provide informed consent of the major adverse effects, baseline CBC and liver function studies, a follow-up of these investigations in 4 to 12 weeks (since most of the major idiosyncratic effects develop in the first several weeks of therapy), and only investigate patients further if they are symptomatic. Minor elevations of hepatic transaminase levels (e.g., less than twice the baseline level) and modest reductions of blood counts are common with AED treatment, but they do not predict impending catastrophe and are not indications to stop otherwise successful therapy.

With the notable exception of felbamate, the most recently marketed AEDs appear to be relatively safe with respect to hepatic and hematologic difficulties.

[edit] TREATMENT OF MEDICALLY RESISTANT EPILEPSY

Approximately 30% of all patients with epilepsy will be resistant to treatment with a single drug. Polytherapy (the addition of one or more AEDs) may improve seizure control in approximately 10% of these patients.

Surgery for epilepsy has become increasingly available at specialized centers. Prerequisites for epilepsy surgery generally include an unequivocal failure of reasonable AED therapy, demonstration of a surgically accessible focus that can be removed without substantial risk, and a motivated patient.

Patients considered for epilepsy surgery will be admitted to a specialized monitoring unit for video–EEG telemetry monitoring. The epileptogenic zone is delineated by assessment of the interictal and ictal EEG abnormalities and recording the patient's behavior during seizures. Detailed neuropsychology testing is performed to identify language areas and to assess cognitive functions. High-quality MRI scans are used to search for structural lesions. Optimum surgical results are obtained when there is congruence of information from the various investigations (i.e., structural and functional studies demonstrate abnormalities in the same brain region and this region can be resected without creating a major neurologic deficit).

The most common type of epilepsy surgery performed is a temporal lobe resection. A resection may result in a seizure-free or markedly improved outcome in at least 60% to 80% of patients with disease confined to one temporal lobe. The results for epilepsy surgery outside the temporal lobe are not as impressive but are still worthy of consideration in individual circumstances.

Epilepsy surgery need not be deferred until all possible AEDs and AED combination therapies have been explored. Optimal psychosocial outcome, employability, and contribution to society are more likely to be achieved with early eradication of the seizures.

Patients with multifocal epilepsy, and particularly those with akinetic (drop) attacks, may receive palliative benefits from other surgical procedures, including a corpus callosum section.

Other nonsurgical and nonpharmacologic therapies have attracted recent attention. A unique ketogenic diet may be successful for severe forms of epilepsy that are resistant to conventional AEDs. This therapy has been most widely used in children; it is a very difficult diet to initiate and maintain in adults. Vagal nerve stimulation (with a device similar to a cardiac pacemaker implanted in the chest wall) delivers intermittent electrical stimulation to the vagus nerve. This therapy may be considered for those patients with medically resistant epilepsy who are not candidates for other forms of surgical therapy.

[edit] SPECIAL SITUATIONS

[edit] The First Seizure

An area of some controversy is the management of the patient who presents with the first seizure.^[8] This situation will usually arise in the setting of a convulsion (either primary generalized or secondarily generalized). An important factor to ascertain is whether the presentation is truly the first seizure. A careful inquiry for features of prior unrecognized nocturnal seizures (e.g., awakening in the morning with a chewed tongue, unexplained episodes of incontinence, musculoskeletal injury) or partial complex seizures and simple partial seizures is mandatory. Similarly, in the child and adolescent, a careful line of inquiry should be conducted to determine if there have been absence attacks or myoclonic jerks. Patients rarely come to medical attention after their first partial complex seizure and virtually never with the first absence seizure.

Most epilepsy experts do not recommend treatment after a single convulsion, particularly if the patient has an otherwise unremarkable history, normal neurologic examination, and negative investigations. The risks of treatment must be weighed against the likelihood of seizure recurrence. It has been estimated that a patient with an idiopathic seizure and normal EEG has a recurrence risk of 24% by 2 years. A significantly increased risk of seizure recurrence has been noted in patients who have a clear, remote, known cause for a seizure. Some studies have suggested an increased risk of recurrence if one or more of the following features are present: (1) a focally originating seizure, (2) presence of an abnormal neurologic examination, and (3) an abnormal EEG, particularly if the EEG demonstrates epileptiform discharges.

It should be noted that most studies that have evaluated recurrence rates after a first seizure do not include patients with “active” intracranial disease such as acute stroke and brain tumor. Therefore, the decision to treat patients with AEDs after a single seizure must be individualized.

[edit] Epilepsy and Women^[9]

It has long been recognized that some women have an exacerbation of seizures in relationship to their menstrual cycles. Close scrutiny of seizure calendars with recording of menstrual cycles does not always corroborate the impression of a tight linkage of these phenomena. However, there is a relatively small subset of women who have an increased tendency for seizures in the days immediately preceding and after the onset of menstrual flow. The precise mechanisms of this so-called catamenial epilepsy have not been determined but likely relate to the ratio of the proepileptic effects of estrogen and the antiepileptic effects of progesterone. Specific treatment with hormonal manipulation (such as exogenous progesterone) has been suggested for catamenial epilepsy but does not appear to be widely used.

There are no contraindications to women with epilepsy receiving estrogen in the form of oral contraceptives or as postmenopausal therapy from the perspective of these hormones exacerbating epilepsy. It is important to appreciate that the hepatic enzyme–enhancing AEDs (phenobarbital, primidone, carbamazepine, phenytoin, and topiramate) confer an increased risk of “pill failure” in women taking oral contraceptives. The failure rate has been estimated to increase from 0.7 per 100 women years to 3.1 when enzyme-enhancing AEDs are used. Experts have recommended that women taking enzyme-enhancing AEDs should use an oral contraceptive containing a minimum of 50 μg of estrogen. Women concurrently taking oral contraceptives and enzyme-enhancing AEDs and who experience midcycle breakthrough bleeding may be at risk of ovulation and require an increase in their estrogen dose.

Epilepsy in pregnancy is a complex topic, and the ideal time to discuss the various issues surrounding epilepsy and pregnancy is before conception occurs. In women whose epilepsy has been well controlled for several years it may be advisable to discontinue AED therapy before embarking on a planned pregnancy. The rationale of this approach relates to the potential teratogenic effect of AEDs on the developing fetus (see below).

Some authorities recommend continuous folic acid supplementation (a minimum dose of 0.4 mg daily) for all women taking AEDs who are of childbearing potential.^[9] Folate may reduce the incidence of major malformation in the offspring in this population.

Recent studies suggest that a relatively minor increase in seizure frequency may occur during pregnancy. Most authors have attributed the seizure exacerbations to changes in the pharmacokinetics of the AEDs (including increased metabolism and volume of distribution) but contributions from the sex hormones, other metabolic changes in pregnancy, sleep deprivation, and psychologic stress have all been implicated. Several authors recommend following AED serum levels throughout the pregnancy, with dose adjustment accordingly.

Studies of the outcome of pregnancy in women with epilepsy who are taking antiepileptic drugs have demonstrated a number of adverse outcomes. There is a twofold to fourfold increase in complications, including preeclampsia, placenta previa, and abruptio placentae. Some studies have demonstrated a twofold to fourfold increase in prematurity and low birth weight.

A major concern of prospective parents is the potential for teratogenic effects of the AEDs. In general, the overall risk of malformations in the offspring of women with epilepsy taking AEDs is 4% to 6%. Some studies have found an increased risk of malformations in women with untreated epilepsy. This finding, if confirmed, would suggest that genetic factors also play a role in teratogenesis. There are probably few specific malformations that are directly related to an individual AED. Examples of minor malformations associated with AED use include digital nail hypoplasia, hypertelorism, and abnormally shaped ears. The most common “major” malformations associated with AED use include congenital heart disease (including cardiac septal defects) and a variety of clefting disorders of the face and palate. Valproic acid appears to confer a 1% to 2% risk of producing spina bifida. Carbamazepine may also be associated with a small risk of a similar malformation. The major malformations take place very early in embryogenesis (even before the woman may know she is pregnant), thus the recommendation for folic acid supplementation to all women of childbearing potential. The majority of spinal closure defects and many cardiac abnormalities can be very reliably detected early in pregnancy with modern ultrasound techniques. The diagnostic algorithm for detecting these defects may vary from center to center; expert consultation is recommended for appropriate timing and type of ultrasound.

Among the commonly used AEDs, there is no overwhelming evidence that any particular AED is safer in pregnancy than another. Most authorities do not recommend changing one AED to another in women whose seizures are well controlled and are planning a pregnancy. However, some physicians discontinue valproic acid if there is a positive family history of spinal closure defects. In general, it is best to use the AED that is most suitable for the patient's seizure disorder. Monotherapy should be achieved before conception if at all possible.

The experience with the new generation of AEDs is insufficient to make any recommendations pertaining to their safety in pregnancy. Most of the traditional AEDs have the potential to reduce vitamin K levels, and it is recommended that oral vitamin K supplementation (20 mg/day) be given during the 4 weeks before the expected delivery date.

There is no strict contraindication to breastfeeding, although babies born to mothers taking barbiturates may be somewhat sedated.

Women whose AED dose has been increased during the pregnancy are at risk of rather precipitously developing AED dose-related toxicity in the first 2 to 4 weeks postdelivery as enzymatic deinduction occurs. The dose of the AED should be reduced to the prepregnancy level soon after delivery.

It should be emphasized to prospective mothers that over 90% of pregnancies in women with epilepsy who are taking AEDs have a satisfactory outcome and that a number of steps can be taken to maximize the probability of a healthy baby and mother.

[edit] Status Epilepticus

Status epilepticus (SE) is a state of continuous or rapidly repeating seizures. Recent publications have suggested a working definition of SE as a state of continuous seizures lasting at least 20 minutes; a more conservative definition has been proposed suggesting that SE consists of more than two seizures between which there is an incomplete return to consciousness. Most review papers discuss predominantly the management of “convulsive” SE, although it should be appreciated that all of the seizure types listed in Box 159-1 may manifest as a form of a status.

Myoclonic SE is a relatively unusual form of primary generalized seizure disorder. A number of rare neurologic degenerative disorders and some toxic-metabolic disorders may produce myoclonic SE. Notable among the latter is myoclonic SE occurring in association with anoxic-ischemic encephalopathy (particularly after cardiac arrest). This form of SE is extremely difficult to treat, is often associated with a very poor prognosis for neurologic recovery, and is viewed by some authorities as an agonal brain event.

The two major forms of nonconvulsive SE are partial complex SE and absence SE. Patients with these disorders present with an alteration of consciousness that ranges from subtle confusion to an unresponsive state. Absence SE may last for hours or occasionally days to weeks; the diagnosis is confirmed by an EEG that discloses abundant or continuous runs of generalized spike and wave discharges. Absence SE should be in the differential diagnosis of any patient who presents with an acute onset confusional state, particularly when he or she has a history of one of the primary generalized epilepsy syndromes. The SE may be spectacularly terminated with intravenous benzodiazepines that are best administered during simultaneous EEG recording. In its classic form, partial complex SE consists of a continuous twilight state alternating with episodes of more typical partial complex seizures. The distinction of absence SE from partial complex SE usually will require an EEG.

Emotionally based pseudoseizures may occur as “status” with recurrent attacks that superficially resemble generalized tonic-clonic seizures that are unresponsive to the usual initial treatments. Conversely, patients with absence SE and partial complex SE are easily misdiagnosed as having “hysteria” or a “conversion disorder.”

The remainder of this section on SE will concentrate on convulsive SE. At least 80% of cases of convulsive SE are of the secondarily generalized variety; close clinical observation at the onset of the attack may disclose the focal onset (e.g., head and eye deviation to one side, clonic jerks beginning in one limb). In other patients, particularly those with a frontal lobe focus, the propagation may be of such rapidity that an EEG is required to recognize the focal onset.

Virtually any process that affects the CNS can lead to SE. In the pediatric age group the most common causes are secondary to congenital structural lesions, infections (including febrile SE), trauma, and consequences of anoxia. In adults the most common causes are cerebrovascular disease, anoxic injury, trauma, decrease in AEDs, and ethanol and other recreational drug use. Additional causes of SE common to both adults and children include toxic-metabolic disturbances (e.g., disorders of fluid and electrolytes, glucose, and calcium) and neoplasm.

The overall mortality rate of convulsive SE is approximately 20%. The major determinants of mortality relate to the etiology and duration of SE. Animal models of SE and some data from human studies suggest that brain damage occurs with SE lasting more than 30 to 45 minutes. Some studies suggest that the longer status is allowed to continue, the more difficult it is to terminate. The injury to brain (especially the hippocampus) is separate from the underlying process that initiated the SE and appears to be mediated by excitotoxic neurotransmitters. Therefore prompt termination of the seizures and correction of the underlying cause offer the best hope to diminish mortality and morbidity.

The initial care of patients with convulsive SE consists of attention to the airway (patients require an oral airway and often intubation and ventilation), administration of oxygen, electrocardiographic monitoring, and blood work as noted in Table 159-3. All patients should receive 50 ml of 50% dextrose and 50 to 100 mg of thiamine. A large-bore intravenous catheter should be inserted in each arm (one for the administration of a rapidly acting benzodiazepine, the other to begin an infusion of phenytoin or phenobarbital). A benzodiazepine alone may be sufficient if the underlying cause of the status is quickly correctable.^[10][11] Most published protocols for treating SE recommend using diazepam or lorazepam as initial therapy. These benzodiazepines are potent and have a rapid onset of action. Lorazepam has become increasingly popular and a recent prospective randomized trial attests to its efficacy.^[11]

Table 159-3 Initial Management of Convulsive Status Epilepticus

Simultaneous to the administration of a benzodiazepine, either phenytoin or phenobarbital is started in the second intravenous line. An adequate loading dose of either of these AEDs must be given. Phenytoin cannot be given in glucose-containing solutions; it should be given at a dose of 17 to 18 mg/kg at a rate not exceeding 50 mg/minute. The infusion rate should be slowed if hypertension or cardiac arrhythmias develop. A water-soluble prodrug of phenytoin (fosphenytoin) and a parenteral preparation of valproic acid have recently been released for use; the precise roles for these agents are yet to be determined. If phenytoin fails, phenobarbital (20 mg/kg at 50 to 75 mg/minute) should be infused while careful monitoring of respiratory function and blood pressure is maintained. Most episodes of convulsive SE can be terminated with adequate doses of benzodiazepines, phenytoin, and/or phenobarbital (see summary in Table 159-3). Expert consultation should be sought urgently if these therapies are unsuccessful, with consideration of treatment with propofol, midazolam, pentobarbital, or thiopental. Further details of the management of therapy-resistant SE can be obtained in the literature cited at the end of this chapter.

[edit] REFERENCES