3311 Seizures and Epilepsy CHAPTER 425

neighboring neurons; (2) accumulation of Ca2+ in presynaptic terminals, leading to enhanced neurotransmitter release; (3) depolarizationinduced activation of the N-methyl-d-aspartate (NMDA) subtype

of the excitatory amino acid receptor, which causes additional Ca2+

influx and neuronal activation; and (4) ephaptic interactions related

to changes in tissue osmolarity and cell swelling. The recruitment of

a sufficient number of neurons leads to the propagation of excitatory

currents into contiguous areas via local cortical connections and to

more distant areas via long commissural pathways such as the corpus

callosum.

Many factors control neuronal excitability, and thus, there are many

potential mechanisms for altering a neuron’s propensity to have bursting activity. Mechanisms intrinsic to the neuron include changes in the

conductance of ion channels, response characteristics of membrane

receptors, cytoplasmic buffering, second-messenger systems, and protein expression as determined by gene transcription, translation, and

posttranslational modification. Mechanisms extrinsic to the neuron

include changes in the amount or type of neurotransmitters present

at the synapse, modulation of receptors by extracellular ions and

other molecules, and temporal and spatial properties of synaptic and

nonsynaptic input. Nonneural cells, such as astrocytes and oligodendrocytes, have an important role in many of these mechanisms as well.

Certain recognized causes of seizures are explained by these mechanisms. For example, accidental ingestion of domoic acid, an analogue

of glutamate (the principal excitatory neurotransmitter in the brain)

produced by naturally occurring microscopic algae, causes profound

seizures via direct activation of excitatory amino acid receptors

throughout the CNS. Penicillin, which can lower the seizure threshold

in humans and is a potent convulsant in experimental models, reduces

inhibition by antagonizing the effects of GABA at its receptor. The

basic mechanisms of other precipitating factors of seizures, such as

sleep deprivation, fever, alcohol withdrawal, hypoxia, and infection,

are not as well understood but presumably involve analogous perturbations in neuronal excitability. Similarly, the endogenous factors

that determine an individual’s seizure threshold may relate to these

properties as well.

Knowledge of the mechanisms responsible for initiation and propagation of most generalized seizures (including tonic-clonic, myoclonic, and atonic types) remains rudimentary and reflects the limited

understanding of the connectivity of the brain at a systems level. Much

more is understood about the origin of generalized spike-and-wave

discharges in absence seizures. These appear to be related to oscillatory

rhythms normally generated during sleep by circuits connecting the

thalamus and cortex. This oscillatory behavior involves an interaction

between GABAB receptors, T-type Ca2+ channels, and K+ channels

located within the thalamus. Pharmacologic studies indicate that modulation of these receptors and channels can induce absence seizures,

and there is good evidence that the genetic forms of absence epilepsy

may be associated with mutations of components of this system.

■ MECHANISMS OF EPILEPTOGENESIS

Epileptogenesis refers to the transformation of a normal neuronal

network into one that is chronically hyperexcitable. There is often a

delay of months to years between an initial CNS injury such as trauma,

stroke, or infection and the first clinically evident seizure. The injury

appears to initiate a process that gradually lowers the seizure threshold

in the affected region until a spontaneous seizure occurs. In many

genetic and idiopathic forms of epilepsy, epileptogenesis is presumably

determined by developmentally regulated events.

Pathologic studies of the hippocampus from patients with temporal

lobe epilepsy suggest that some forms of epileptogenesis are related to

structural changes in neuronal networks. For example, many patients

with MTLE have a highly selective loss of neurons that normally

contribute to inhibition of the main excitatory neurons within the

dentate gyrus. There is also evidence that, in response to the loss of

neurons, there is reorganization of surviving neurons in a way that

affects the excitability of the network. Some of these changes can be

seen in experimental models of prolonged electrical seizures or traumatic brain injury. Thus, an initial injury such as head injury may lead

to a very focal, confined region of structural change that causes local

hyperexcitability. The local hyperexcitability leads to further structural

changes that evolve over time until the focal lesion produces clinically

evident seizures. Similar models have provided strong evidence for

long-term alterations in intrinsic, biochemical properties of cells within

the network such as chronic changes in glutamate or GABA receptor

function. Induction of inflammatory cascades may be a critical factor

in these processes as well.

■ GENETIC CAUSES OF EPILEPSY

The most important recent progress in epilepsy research has been

the identification of genetic mutations associated with a variety of

epilepsy syndromes (Table 425-2). Although most of the mutations

identified to date cause rare forms of epilepsy, their discovery has led

to extremely important conceptual advances. For example, it appears

that many of the inherited epilepsies are due to mutations affecting

ion channel function. These syndromes are therefore part of the larger

group of channelopathies causing paroxysmal disorders such as cardiac

arrhythmias, episodic ataxia, periodic weakness, and familial hemiplegic migraine. Other gene mutations are proving to be associated

TABLE 425-5 Drugs and Other Substances That Can Cause Seizures

Alkylating agents (e.g., busulfan, chlorambucil)

Antimalarials (chloroquine, mefloquine)

Antimicrobials/antivirals

  β-Lactam and related compounds

Quinolones

Acyclovir

Isoniazid

Ganciclovir

Anesthetics and analgesics

Meperidine

Fentanyl

Tramadol

Local anesthetics

Dietary supplements

Ephedra (ma huang)

Gingko

Immunomodulatory drugs

Cyclosporine

OKT3 (monoclonal antibodies to T cells)

Tacrolimus

Interferons

Psychotropics

Antidepressants (e.g., bupropion)

Antipsychotics (e.g., clozapine)

Lithium

Radiographic contrast agents

Drug withdrawal

Alcohol

Baclofen

Barbiturates (short-acting)

Benzodiazepines (short-acting)

Zolpidem

Drugs of abuse

Amphetamine

Cocaine

Phencyclidine

Methylphenidate

Flumazenila

a

In benzodiazepine-dependent patients.

3312 PART 13 Neurologic Disorders

with pathways influencing CNS development, synaptic physiology, or

neuronal homeostasis. De novo mutations may explain a significant

proportion of these syndromes, especially those with onset in early

childhood. A current challenge is to identify the multiple susceptibility

genes that underlie the more common forms of idiopathic epilepsies.

Ion channel mutations and copy number variants may contribute to

causation in a subset of these patients.

■ MECHANISMS OF ACTION OF

ANTISEIZURE DRUGS

Antiseizure drugs appear to act primarily by blocking the initiation

or spread of seizures. This occurs through a variety of mechanisms

that modify the activity of ion channels or neurotransmitters, and

in most cases, the drugs have pleiotropic effects. The mechanisms

include inhibition of Na+

-dependent action potentials in a frequencydependent manner (e.g., phenytoin, carbamazepine, lamotrigine, topiramate, zonisamide, lacosamide, rufinamide, cenobamate), inhibition

of voltage-gated Ca2+ channels (phenytoin, gabapentin, pregabalin),

facilitating the opening of potassium channels (ezogabine), attenuation of glutamate activity (lamotrigine, topiramate, felbamate, perampanel), potentiation of GABA receptor function (benzodiazepines

and barbiturates), increase in the availability of GABA (valproic acid,

gabapentin, tiagabine), and modulation of release of synaptic vesicles

(levetiracetam, brivaracetam). Two of the effective drugs for absence

seizures, ethosuximide and valproic acid, probably act by inhibiting

T-type Ca2+ channels in thalamic neurons. Cannabidiol (CBD), a derivative of cannabis plants, is effective for reducing seizures in children

with Dravet syndrome and Lennox-Gastaut syndrome but does not

act through endogenous cannabinoid receptors. Rather, CBD has a

multimodal mechanism of action involving modulation of intracellular

calcium via G protein–coupled receptor 55, extracellular calcium influx

via transient receptor potential vanilloid type 1 (TRPV1) channels, and

adenosine-mediated signaling.

In contrast to the relatively large number of antiseizure drugs that

can attenuate seizure activity, there are currently no drugs known to

prevent the formation of a seizure focus following CNS injury. The

eventual development of such “antiepileptogenic” drugs will provide

an important means of preventing the emergence of epilepsy following

injuries such as head trauma, stroke, and CNS infection.

APPROACH TO THE PATIENT

SEIZURE

When a patient presents shortly after a seizure, the first priorities

are attention to vital signs, respiratory and cardiovascular support,

and treatment of seizures if they resume (see “Treatment: Seizures

and Epilepsy”). Life-threatening conditions such as CNS infection,

metabolic derangement, or drug toxicity must be recognized and

managed appropriately.

When the patient is not acutely ill, the evaluation will initially

focus on whether there is a history of earlier seizures (Fig. 425-2).

If this is the first seizure, then the emphasis will be to (1) establish

whether the reported episode was a seizure rather than another

paroxysmal event, (2) determine the cause of the seizure by identifying risk factors and precipitating events, and (3) decide whether

antiseizure drug therapy is required in addition to treatment for any

underlying illness.

In the patient with prior seizures or a known history of epilepsy,

the evaluation is directed toward (1) identification of the underlying cause and precipitating factors, and (2) determination of the

adequacy of the patient’s current therapy.

■ HISTORY AND EXAMINATION

The first goal is to determine whether the event was truly a seizure. An

in-depth history is essential, because in many cases the diagnosis of a

seizure is based solely on clinical grounds—the examination and laboratory studies are often normal. Questions should focus on the symptoms

before, during, and after the episode in order to differentiate a seizure

from other paroxysmal events (see “Differential Diagnosis of Seizures”

below). Seizures frequently occur out-of-hospital, and the patient may

be unaware of the ictal and immediate postictal phases; thus, witnesses

to the event should be interviewed carefully.

The history should also focus on risk factors and predisposing

events. Clues for a predisposition to seizures include a history of febrile

seizures, a family history of seizures, and, of particular importance,

earlier auras or brief seizures not recognized as such. Epileptogenic

factors such as prior head trauma, stroke, tumor, or CNS infection

should be identified. In children, a careful assessment of developmental

milestones may provide evidence for underlying CNS disease. Precipitating factors such as sleep deprivation, systemic diseases, electrolyte or

metabolic derangements, acute infection, drugs that lower the seizure

threshold (Table 425-5), or alcohol or illicit drug use should also be

identified.

The general physical examination includes a search for signs of

infection or systemic illness. Careful examination of the skin may

reveal signs of neurocutaneous disorders, such as tuberous sclerosis

or neurofibromatosis, or chronic liver or renal disease. A finding of

organomegaly may indicate a metabolic storage disease, and limb

asymmetry may provide a clue to brain injury early in development.

Signs of head trauma and use of alcohol or illicit drugs should be

sought. Auscultation of the heart and carotid arteries may identify an

abnormality that predisposes to cerebrovascular disease.

All patients require a complete neurologic examination, with

particular emphasis on eliciting signs of cerebral hemispheric disease

(Chap. 422). Careful assessment of mental status (including memory,

language function, and abstract thinking) may suggest lesions in the

anterior frontal, parietal, or temporal lobes. Testing of visual fields

will help screen for lesions in the optic pathways and occipital lobes.

Screening tests of motor function such as pronator drift, deep tendon

reflexes, gait, and coordination may suggest lesions in motor (frontal)

cortex, and cortical sensory testing (e.g., double simultaneous stimulation) may detect lesions in the parietal cortex.

■ LABORATORY STUDIES

Routine blood studies are indicated to identify the more common metabolic causes of seizures such as abnormalities in electrolytes, glucose,

calcium, or magnesium, and hepatic or renal disease. A screen for

toxins in blood and urine should also be obtained from all patients in

appropriate risk groups, especially when no clear precipitating factor

has been identified. A lumbar puncture is indicated if there is any suspicion of meningitis or encephalitis, and it is mandatory in all patients

infected with HIV, even in the absence of symptoms or signs suggesting

infection. Testing for autoantibodies in the serum and cerebrospinal

fluid (CSF) should be considered in patients presenting with fulminant

onset of epilepsy associated with other abnormalities such as psychiatric symptoms or cognitive disturbances.

■ ELECTROPHYSIOLOGIC STUDIES

The electrical activity of the brain (the EEG) is easily recorded from

electrodes placed on the scalp. The potential difference between pairs

of electrodes on the scalp (bipolar derivation) or between individual

scalp electrodes and a relatively inactive common reference point (referential derivation) is amplified and displayed on a computer monitor,

oscilloscope, or paper. Digital systems allow the EEG to be reconstructed and displayed with any desired format and to be manipulated

for more detailed analysis and also permit computerized techniques to

be used to detect certain abnormalities. The characteristics of the normal EEG depend on the patient’s age and level of arousal. The rhythmic

activity normally recorded represents the postsynaptic potentials of

vertically oriented pyramidal cells of the cerebral cortex and is characterized by its frequency. In normal awake adults lying quietly with the

eyes closed, an 8- to 13-Hz alpha rhythm is seen posteriorly in the EEG,

intermixed with a variable amount of generalized faster (beta) activity

(>13 Hz); the alpha rhythm is attenuated when the eyes are opened

(Fig. 425-3). During drowsiness, the alpha rhythm is also attenuated;

with light sleep, slower activity in the theta (4–7 Hz) and delta (<4 Hz)

ranges becomes more conspicuous.

3313 Seizures and Epilepsy CHAPTER 425

All patients who have a possible seizure disorder should be evaluated with an EEG as soon as possible. In the evaluation of a patient with

suspected epilepsy, the presence of electrographic seizure activity during

the clinically evident event (i.e., abnormal, repetitive, rhythmic activity

having a discrete onset and termination) clearly establishes the diagnosis. The EEG is always abnormal during generalized tonic-clonic seizures. The absence of electrographic seizure activity does not exclude

a seizure disorder, however, because focal seizures may originate from

Normal

Adult Patient with a Seizure

History of epilepsy; currently treated

 with antiseizure drugs

Assess: adequacy of antiseizure drug therapy

 Side effects

  Serum levels

No history of epilepsy

Laboratory studies

 CBC

 Electrolytes, calcium, magnesium

 Serum glucose

 Liver and renal function tests

 Urinalysis

 Toxicology screen

Negative

metabolic screen

Positive metabolic screen

or symptoms/signs

suggesting a metabolic

or infectious disorder

Abnormal or change in

neurologic examination

 Treat identifiable

 metabolic abnormalities

Assess cause of

  neurologic change

  Lumbar puncture

  Cultures

  Endocrine studies

  CT

  MRI if focal

   features present

MRI scan

 and EEG

Subtherapeutic

antiseizure

drug levels

Appropriate

increase or

resumption

of dose

Increase antiseizure

 drug therapy to

 maximum tolerated

 dose; consider

 alternative antiepileptic

 drugs

Therapeutic

antiseizure

drug levels

Focal features of

seizures

Focal abnormalities

on clinical or lab

examination

Other evidence of

neurologic

dysfunction Treat underlying

metabolic abnormality

Idiopathic seizures

Treat underlying disorder

Yes No

Consider: Mass lesion; stroke; CNS infection;

 trauma; degenerative disease

Further workup

Other causes of episodic cerebral dysfunction

Syncope

Transient ischemic attack

Migraine

Acute psychosis

History

Physical examination

Exclude

Consider: Antiseizure drug therapy

Consider: Antiseizure drug therapy

Consider: Antiseizure drug therapy

Consider

 CBC

 Electrolytes, calcium, magnesium

 Serum glucose

 Liver and renal function tests

 Urinalysis

 Toxicology screen

FIGURE 425-2 Evaluation of the adult patient with a seizure. CBC, complete blood count; CNS, central nervous system; CT, computed tomography; EEG, electroencephalogram;

MRI, magnetic resonance imaging.

3314 PART 13 Neurologic Disorders

Eyes open

Fp1-F3

F3-C3

C3-P3

P3-O1

Fp2-F4

F4-C4

C4-P4

P4-O2

F3-A1

C3-A1

P3-A1

O1-A1

F4-A2

C4-A2

P4-A2

O2-A2

F3-C3

C3-P3

P3-O1

F4-C4

C4-P4

P4-O2

T3-CZ

CZ-T4

Fp1-F3

F3-C3

C3-P3

P3-O1

Fp2-F4

F4-C4

C4-P4

P4-O2

A B

C D

FIGURE 425-3 Electroencephalograms. A. Normal electroencephalogram (EEG) showing a posteriorly situated 9-Hz alpha

rhythm that attenuates with eye opening. B. Abnormal EEG showing irregular diffuse slow activity in an obtunded patient

with encephalitis. C. Irregular slow activity in the right central region, on a diffusely slowed background, in a patient with

a right parietal glioma. D. Periodic complexes occurring once every second in a patient with Creutzfeldt-Jakob disease.

Horizontal calibration: 1 s; vertical calibration: 200 μV in A, 300 μV in other panels. In this and the following figure, electrode

placements are indicated at the left of each panel and accord with the international 10–20 system. A, earlobe; C, central;

F, frontal; Fp, frontal polar; O, occipital; P, parietal; T, temporal. Right-sided placements are indicated by even numbers, leftsided placements by odd numbers, and midline placements by Z. (Reproduced with permission from MJ Aminoff: Aminoff’s

Electrodiagnosis in Clinical Neurology, 6th ed. Oxford: Elsevier Saunders, 2012.)

a region of the cortex that cannot be detected by standard scalp electrodes. Because seizures are typically infrequent and unpredictable,

it is often not possible to obtain the EEG during a clinical event. In

such situations, activating procedures are generally undertaken while

the EEG is recorded in an attempt to provoke abnormalities. These

procedures commonly include hyperventilation (for 3 or 4 min),

photic stimulation, sleep, and sleep deprivation on the night prior to

the recording. Continuous monitoring for prolonged periods in videoEEG telemetry units for hospitalized patients or the use of portable

equipment to record the EEG continuously for ≥24 h in ambulatory patients has made it easier to capture the electrophysiologic

correlates of clinical events. In particular, video-EEG telemetry is now

a routine approach for the accurate diagnosis of epilepsy in patients

with poorly characterized events or seizures that are difficult to

control.

The EEG may also be helpful in the interictal period by showing

certain abnormalities that are highly supportive of the diagnosis of

epilepsy. Such epileptiform activity consists of bursts of abnormal discharges containing spikes or sharp waves. The presence of epileptiform

activity is not entirely specific for epilepsy, but it has a much greater

prevalence in patients with epilepsy than in other individuals. However, even in an individual who is known to have epilepsy, the initial

routine interictal EEG may be normal 50–80% of the time. Thus, the

EEG has limited sensitivity and cannot establish the diagnosis of epilepsy in many cases.

The EEG is also used for classifying seizure disorders and aiding in

the selection of anticonvulsant medications (Fig. 425-4). For example,

episodic generalized spike-wave activity is usually seen in patients

with typical absence epilepsy and may be seen with other generalized

epilepsy syndromes. Focal interictal epileptiform discharges would

support the diagnosis of a focal seizure disorder such as temporal lobe

epilepsy or frontal lobe seizures, depending on the location of the

discharges.

The routine scalp-recorded EEG may

also be used to assess the prognosis of

seizure disorders; in general, a normal

EEG implies a better prognosis, whereas

an abnormal background or frequent

epileptiform activity suggests a worse

outcome. Unfortunately, the EEG has

not proved to be useful in predicting

which patients with predisposing conditions such as head injury or brain tumor

will go on to develop epilepsy, because in

such circumstances epileptiform activity

is commonly encountered regardless of

whether seizures occur.

Magnetoencephalography (MEG)

provides another way of looking noninvasively at cortical activity. Instead of

measuring electrical activity of the brain,

it measures the small magnetic fields that

are generated by this activity. The epileptiform activity seen on MEG can be analyzed, and its source in the brain can be

estimated using a variety of mathematical

techniques. These source estimates can

then be plotted on an anatomic image

of the brain such as an MRI (discussed

below) to generate a magnetic source

image (MSI). MSI can be useful to localize potential seizure foci.

■ BRAIN IMAGING

Almost all patients with new-onset

seizures should have a brain imaging

study to determine whether there is an

underlying structural abnormality that

is responsible. The only potential exception to this rule is children

who have an unambiguous history and examination suggestive of a

benign, generalized seizure disorder such as absence epilepsy. MRI

has been shown to be superior to computed tomography (CT) for the

detection of cerebral lesions associated with epilepsy. In some cases,

MRI will identify lesions such as tumors, vascular malformations, or

other pathologies that need urgent therapy. The availability of newer

MRI methods, such as three-dimensional structural imaging at submillimeter resolution, has increased the sensitivity for detection of

abnormalities of cortical architecture, including hippocampal atrophy

associated with mesial temporal sclerosis, as well as abnormalities of

neuronal migration. In such cases, the findings provide an explanation

for the patient’s seizures and point to the need for chronic antiseizure

drug therapy or possible surgical resection.

In the patient with a suspected CNS infection or mass lesion, CT

scanning should be performed emergently when MRI is not immediately available. Otherwise, it is usually appropriate to obtain an MRI

study within a few days of the initial evaluation. Functional imaging

procedures such as positron emission tomography (PET) and singlephoton emission computed tomography (SPECT) are also used to

evaluate certain patients with medically refractory seizures (discussed

below).

■ GENETIC TESTING

With the increasing recognition of specific gene mutations causing

epilepsy, genetic testing is beginning to emerge as part of the diagnostic

evaluation of patients with epilepsy. In addition to providing a definitive diagnosis (which may be of great benefit to the patient and family

members and curtail the pursuit of additional, unrevealing laboratory

testing), genetic testing may offer a guide for therapeutic options (see

section “Selection of Antiseizure Drugs” below). Genetic testing is

currently being done mainly in infants and children with epilepsy syndromes thought to have a genetic cause but should also be considered

3315 Seizures and Epilepsy CHAPTER 425

F3-C3

C3-P3

P3-O1

F4-C4

C4-P4

P4-O2

T3-CZ

CZ-T4

Fp1-F7

F7-T3

T3-T5

T5-O1

Fp2-F8

F8-T4

T4-T6

T6-O2

Fp1-A1

F7-A1

T3-A1

T5-A1

Fp2-A2

F8-A2

T4-A2

T6-A2

A

B

C

FIGURE 425-4 Electrographic seizures. A. Onset of a tonic seizure showing

generalized repetitive sharp activity with synchronous onset over both

hemispheres. B. Burst of repetitive spikes occurring with sudden onset in the

right temporal region during a clinical spell characterized by transient impairment

of awareness. C. Generalized 3-Hz spike-wave activity occurring synchronously

over both hemispheres during an absence seizure. Horizontal calibration: 1 s;

vertical calibration: 400 μV in A, 200 μV in B, and 750 μV in C. (Reproduced with

permission from MJ Aminoff: Aminoff’s Electrodiagnosis in Clinical Neurology,

6th ed. Oxford: Elsevier Saunders, 2012.)

in older patients with a history suggesting an undiagnosed genetic

epilepsy syndrome that began early in life.

DIFFERENTIAL DIAGNOSIS OF SEIZURES

Disorders that may mimic seizures are listed in Table 425-6. In most

cases, seizures can be distinguished from other conditions by meticulous attention to the history and relevant laboratory studies. On occasion, additional studies such as video-EEG monitoring, sleep studies,

tilt-table analysis, or cardiac electrophysiology may be required to

reach a correct diagnosis. Two of the more common nonepileptic syndromes in the differential diagnosis are discussed below.

■ SYNCOPE

(See also Chap. 21) The diagnostic dilemma encountered most frequently is the distinction between a generalized seizure and syncope.

Observations by the patient and bystanders that can help differentiate

between the two are listed in Table 425-7. Characteristics of a seizure

include the presence of an aura, cyanosis, unconsciousness, motor

manifestations lasting >15 s, postictal disorientation, muscle soreness,

and sleepiness. In contrast, a syncopal episode is more likely if the

event was provoked by acute pain or emotional stress or occurred

immediately after arising from the lying or sitting position. Patients

with syncope often describe a stereotyped transition from consciousness to unconsciousness that includes tiredness, sweating, nausea,

and tunneling of vision, and they experience a relatively brief loss of

consciousness. Headache or incontinence usually suggests a seizure but

may on occasion also occur with syncope. A brief period (i.e., 1–10 s)

of convulsive motor activity is frequently seen immediately at the onset

of a syncopal episode, especially if the patient remains in an upright

posture after fainting (e.g., in a dentist’s chair) and therefore has a sustained decrease in cerebral perfusion. Rarely, a syncopal episode can

TABLE 425-6 Differential Diagnosis of Seizures

Syncope

Vasovagal syncope

Cardiac arrhythmia

Valvular heart disease

Cardiac failure

Orthostatic hypotension

Psychological disorders

Psychogenic seizure

Hyperventilation

Panic attack

Metabolic disturbances

Alcoholic blackouts

Delirium tremens

Hypoglycemia

Hypoxia

Psychoactive drugs (e.g.,

hallucinogens)

Migraine

Confusional migraine

Basilar migraine

Transient ischemic attack (TIA)

Basilar artery TIA

Sleep disorders

Narcolepsy/cataplexy

Benign sleep myoclonus

Movement disorders

Tics

Nonepileptic myoclonus

Paroxysmal choreoathetosis

Special considerations in children

Breath-holding spells

Migraine with recurrent abdominal

pain and cyclic vomiting

Benign paroxysmal vertigo

Apnea

Night terrors

Sleepwalking

TABLE 425-7 Features That Distinguish Generalized Tonic-Clonic

Seizure from Syncope

FEATURES SEIZURE SYNCOPE

Immediate precipitating

factors

Usually none Emotional stress,

Valsalva, orthostatic

hypotension, cardiac

etiologies

Premonitory symptoms None or aura (e.g., odd

odor)

Tiredness, nausea,

diaphoresis, tunneling

of vision

Posture at onset Variable Usually erect

Transition to

unconsciousness

Often immediate Gradual over secondsa

Duration of

unconsciousness

Minutes Seconds

Duration of tonic or clonic

movements

30–60 s Never >15 s

Facial appearance during

event

Cyanosis, frothing at

mouth

Pallor

Disorientation and

sleepiness after event

Many minutes to hours <5 min

Aching of muscles after

event

Often Sometimes

Biting of tongue Sometimes Rarely

Incontinence Sometimes Sometimes

Headache Sometimes Rarely

a

May be sudden with certain cardiac arrhythmias.

3316 PART 13 Neurologic Disorders

induce a full tonic-clonic seizure. In such cases, the evaluation must

focus on both the cause of the syncopal event as well as the possibility that the patient has a propensity for recurrent seizures. Postictal

symptoms can be very helpful when differentiating convulsive syncope

from seizure, as confusion and disorientation are typically much less

prominent following syncope.

■ PSYCHOGENIC SEIZURES

Psychogenic seizures are nonepileptic behaviors that resemble seizures.

They are often part of a conversion reaction precipitated by underlying

psychological distress. Certain behaviors such as side-to-side turning

of the head, ictal eye closure, asymmetric and large-amplitude shaking

movements of the limbs, twitching of all four extremities without loss

of consciousness, and pelvic thrusting are more commonly associated

with psychogenic rather than epileptic seizures. Psychogenic seizures

often last longer than epileptic seizures and may wax and wane over

minutes to hours. However, the distinction is sometimes difficult on

clinical grounds alone, and there are many examples of diagnostic

errors made by experienced epileptologists. This is especially true for

psychogenic seizures that resemble focal seizures, because the behavioral manifestations of focal seizures (especially of frontal lobe origin)

can be extremely unusual, and in both cases, the routine surface EEG

may be normal. Video-EEG monitoring is very useful when historic

features are nondiagnostic. Generalized tonic-clonic seizures always

produce marked EEG abnormalities during and after the seizure. For

suspected focal seizures, the use of additional electrodes may help to

localize a seizure focus. Measurement of serum prolactin levels may

also help to distinguish between epileptic and psychogenic seizures.

Most generalized seizures and some focal seizures are accompanied

by a rise in serum prolactin during the immediate 30-min postictal

period, whereas psychogenic seizures are not, though this is not always

reliable because baseline prolactin levels are rarely available and certain

medications can elevate prolactin levels. The diagnosis of psychogenic

seizures also does not exclude a concurrent diagnosis of epilepsy,

because the two may coexist.

TREATMENT

Seizures and Epilepsy

Therapy for a patient with a seizure disorder is almost always

multimodal and includes treatment of underlying conditions that

cause or contribute to the seizures, avoidance of precipitating

factors, suppression of recurrent seizures by prophylactic therapy

with antiseizure medications or surgery, and addressing a variety of

psychological and social issues. Treatment plans must be individualized, given the many different types and causes of seizures as well

as the differences in efficacy and toxicity of antiseizure medications

for each patient. In almost all cases, a neurologist with experience

in the treatment of epilepsy should design and oversee implementation of the treatment strategy. Furthermore, patients with refractory

epilepsy or those who require polypharmacy with antiseizure drugs

should remain under the regular care of a neurologist.

TREATMENT OF UNDERLYING CONDITIONS

If the sole cause of a seizure is a metabolic disturbance such as

an abnormality of serum electrolytes or glucose, then treatment

is aimed at reversing the metabolic problem and preventing its

recurrence. Therapy with antiseizure drugs is usually unnecessary

unless the metabolic disorder cannot be corrected promptly and the

patient is at risk of having further seizures. If the apparent cause of a

seizure was a medication (e.g., theophylline) or illicit drug use (e.g.,

cocaine), then appropriate therapy is avoidance of the drug; there

is usually no need for antiseizure medications unless subsequent

seizures occur in the absence of these precipitants.

Seizures caused by a structural CNS lesion such as a brain tumor,

vascular malformation, or brain abscess may not recur after appropriate treatment of the underlying lesion. However, despite removal

of the structural lesion, there is a risk that the seizure focus will

remain in the surrounding tissue or develop de novo as a result of

gliosis and other processes induced by surgery, radiation, or other

therapies. Most patients are therefore maintained on an antiseizure

medication for at least 1 year, and an attempt is made to withdraw

medications only if the patient has been completely seizure free.

If seizures are refractory to medication, the patient may benefit

from surgical removal of the seizure-producing brain tissue

(see below).

AVOIDANCE OF PRECIPITATING FACTORS

Unfortunately, little is known about the specific factors that determine precisely when a seizure will occur in a patient with epilepsy.

An almost universal precipitating factor for seizures is sleep deprivation, so patients should do everything possible to optimize their

sleep quality. Many patients can identify other particular situations

that appear to lower their seizure threshold; these situations should

be avoided. For example, patients may note an association between

alcohol intake and seizures, and they should be encouraged to modify their drinking habits accordingly. There are also relatively rare

cases of patients with seizures that are induced by highly specific

stimuli such as a video game monitor, music, or an individual’s

voice (“reflex epilepsy”). Because there is often an association

between stress and seizures, stress reduction techniques such as

physical exercise, meditation, or counseling may be helpful.

ANTISEIZURE DRUG THERAPY

Antiseizure drug therapy is the mainstay of treatment for most people with epilepsy. The overall goal is to completely prevent seizures

without causing any untoward side effects, preferably with a single

medication and a dosing schedule that is easy for the patient to

follow. Seizure classification is an important element in designing

the treatment plan, because some antiseizure drugs have different

activities against various seizure types. However, there is considerable overlap between many antiseizure drugs such that the choice

of therapy is often determined more by anticipated side effects,

drug-drug interactions, medical comorbidities, dosing frequency,

and cost.

When to Initiate Antiseizure Drug Therapy Antiseizure drug

therapy should be started in any patient with recurrent seizures

of unknown etiology or a known cause that cannot be reversed.

Whether to initiate therapy in a patient with a single seizure is controversial. Patients with a single seizure due to an identified lesion

such as a CNS tumor, infection, or trauma, in which there is strong

evidence that the lesion is epileptogenic, should be treated. The risk

of seizure recurrence in a patient with an apparently unprovoked or

idiopathic seizure is uncertain, with estimates ranging from 31 to

71% in the first 12 months after the initial seizure. This uncertainty

arises from differences in the underlying seizure types and etiologies in various published epidemiologic studies. Generally accepted

risk factors associated with recurrent seizures include the following:

(1) prior brain insult such as a stroke or trauma, (2) an EEG with

epileptiform abnormalities, (3) a significant brain imaging abnormality, or (4) a nocturnal seizure. Most patients with one or more

of these risk factors should be treated. Issues such as employment

or driving may influence the decision regarding whether to start

medications as well. For example, a patient with a single, idiopathic

seizure whose job depends on driving may prefer taking an antiseizure drug rather than risk a seizure recurrence and the potential

loss of driving privileges.

Selection of Antiseizure Drugs Antiseizure drugs available in

the United States are shown in Table 425-8, and the main pharmacologic characteristics of commonly used drugs are listed in

Table 425-9. Worldwide, older medications such as phenytoin,

valproic acid, carbamazepine, phenobarbital, and ethosuximide

are generally used as first-line therapy for most seizure disorders

because, overall, they are as effective as recently marketed drugs

and significantly less expensive overall. Most of the new drugs

that have become available in the past decade are used as add-on

or alternative therapy, although many are now also being used as

first-line monotherapy.

3317 Seizures and Epilepsy CHAPTER 425

In addition to efficacy, factors influencing the choice of an initial

medication include the convenience of dosing (e.g., once daily vs

three or four times daily) and potential side effects. In this regard,

a number of the newer drugs have the advantage of reduced drugdrug interactions and easier dosing. Almost all of the commonly

used antiseizure drugs can cause similar, dose-related side effects

such as sedation, ataxia, and diplopia. Long-term use of some

agents in adults, especially the elderly, can lead to osteoporosis.

Close follow-up is required to ensure these side effects are promptly

recognized and reversed. Most of the older drugs and some of the

newer ones can also cause idiosyncratic toxicity such as rash, bone

marrow suppression, or hepatotoxicity. Although rare, these side

effects should be considered during drug selection, and patients

must be instructed about symptoms or signs that should signal

the need to alert their health care provider. For some drugs, laboratory tests (e.g., complete blood count and liver function tests)

are recommended prior to the institution of therapy (to establish

baseline values) and during initial dosing and titration of the agent.

Monitoring serum concentrations of antiseizure medications can

help determine when a therapeutic dose has been reached, though

clinical response is paramount (see below).

An important advance in the care of people with epilepsy has

been the application of genetic testing to help guide the choice of

therapy (as well as establishing the underlying cause of a patient’s

syndrome). For example, the identification of a mutation in the

SLC2A1 gene, which encodes the glucose type 1 transporter (GLUT-1)

and is a cause of GLUT-1 deficiency, should prompt immediate

treatment with the ketogenic diet. Mutations of the ALDH7A1

gene, which encodes antiquitin, can cause alterations in pyridoxine

metabolism that are reversed by treatment with pyridoxine. There

is also mounting evidence that certain gene mutations may indicate

better or worse response to specific antiseizure drugs. For example,

patients with mutations in the sodium channel subunit SCN1A

should generally avoid taking phenytoin or lamotrigine, whereas

patients with mutations in the SCN2A or SCN8A sodium channel

subunits appear to respond favorably to high-dose phenytoin.

Genetic testing may also help predict antiseizure drug toxicity.

Studies have shown that Asian individuals carrying the human

leukocyte antigen (HLA) allele HLA-B*1502 are at particularly

high risk of developing serious skin reactions from carbamazepine,

phenytoin, oxcarbazepine, and lamotrigine. HLA-A*31:01 has also

been found to be associated with carbamazepine-induced hypersensitivity reactions in patients of European or Japanese ancestry.

As a result, racial background and genotype are additional factors

to consider in drug selection.

Antiseizure Drug Selection for Focal Seizures Carbamazepine (or related drugs, oxcarbazepine and eslicarbazepine),

lamotrigine, phenytoin, and levetiracetam are currently the drugs

of choice approved for the initial treatment of focal seizures,

including those that evolve into generalized seizures. Overall, they

have very similar efficacy, but differences in pharmacokinetics and

toxicity are the main determinants for use in a given patient. For

example, an advantage of carbamazepine (which is also available in

an extended-release form) is that its metabolism follows first-order

pharmacokinetics, which allows for a linear relationship between

drug dose, serum levels, and toxicity. Carbamazepine can cause leukopenia, aplastic anemia, or hepatotoxicity and would therefore be

contraindicated in patients with predispositions to these problems.

Oxcarbazepine has the advantage of being metabolized in a way

that avoids an intermediate metabolite associated with some of the

side effects of carbamazepine. Oxcarbazepine also has fewer drug

interactions than carbamazepine. Eslicarbazepine has a long serum

half-life and is dosed once daily.

Lamotrigine tends to be well tolerated in terms of side effects and

has mood-stabilizing properties that can be beneficial. However,

patients need to be particularly vigilant about the possibility of a

skin rash during the initiation of therapy. This can be extremely

severe and lead to Stevens-Johnson syndrome if unrecognized and

if the medication is not discontinued immediately. This risk can be

reduced by the use of low initial doses and slow titration. Lamotrigine must be started at even lower initial doses when used as add-on

therapy with valproic acid, because valproic acid inhibits lamotrigine metabolism and results in a substantially prolonged half-life.

Phenytoin has a relatively long half-life and offers the advantage

of once- or twice-daily dosing compared to twice- or thrice-daily

dosing for many of the other drugs. However, phenytoin shows

properties of nonlinear kinetics, such that small increases in phenytoin doses above a standard maintenance dose can precipitate

marked side effects. This is one of the main causes of acute phenytoin toxicity (dizziness, diplopia, ataxia). Long-term use of phenytoin is associated with untoward cosmetic effects (e.g., hirsutism,

coarsening of facial features, gingival hypertrophy) and effects on

bone metabolism. Due to these side effects, phenytoin is often

avoided in young patients who are likely to require the drug for

many years.

Levetiracetam has the advantage of having no known clinically

relevant drug-drug interactions, making it especially useful in the

elderly and patients on other medications. However, a significant

number of patients taking levetiracetam complain of irritability,

anxiety, and other psychiatric symptoms.

Topiramate can be used for both focal and generalized seizures.

Similar to some of the other antiseizure drugs, topiramate can cause

significant psychomotor slowing and other cognitive problems.

Additionally, it should not be used in patients at risk for the development of glaucoma or renal stones.

Valproic acid is an effective alternative for some patients with

focal seizures, especially when the seizures generalize. Gastrointestinal side effects are fewer when using the delayed-release formulation (Depakote). Laboratory testing is required to monitor toxicity

because valproic acid can rarely cause reversible bone marrow suppression and hepatotoxicity. This drug should generally be avoided

in patients with preexisting bone marrow or liver disease. Valproic

acid also has relatively high risks of unacceptable adverse effects

for women of childbearing age, including hyperandrogenism, that

may affect fertility and teratogenesis (e.g., neural tube defects) in

offspring. Irreversible, fatal hepatic failure appearing as an idiosyncratic rather than dose-related side effect is a relatively rare

TABLE 425-8 Selection of Antiepileptic Drugs

GENERALIZEDONSET

TONIC-CLONIC FOCAL TYPICAL ABSENCE

ATYPICAL

ABSENCE,

MYOCLONIC,

ATONIC

First-Line

Lamotrigine

Valproic acid

Lamotrigine

Carbamazepine

Oxcarbazepine

Eslicarbazepine

Phenytoin

Levetiracetam

Valproic acid

Ethosuximide

Lamotrigine

Valproic acid

Lamotrigine

Topiramate

Alternatives

Zonisamidea

Phenytoin

Levetiracetam

Carbamazepine

Oxcarbazepine

Topiramate

Phenobarbital

Primidone

Felbamate

Perampanel

Zonisamidea

Brivaracetam

Topiramate

Valproic acid

Tiagabinea

Gabapentina

Lacosamidea

Phenobarbital

Primidone

Felbamate

Perampanel

Clonazepam

Zonisamide

Levetiracetam

Clonazepam

Felbamate

Clobazam

Rufinamide

a

As adjunctive therapy.

3318 PART 13 Neurologic Disorders

TABLE 425-9 Dosage and Adverse Effects of Commonly Used Antiepileptic Drugs

ADVERSE EFFECTS

GENERIC NAME

TRADE

NAME PRINCIPAL USES

TYPICAL DOSE;

DOSE INTERVAL HALF-LIFE

THERAPEUTIC

RANGE NEUROLOGIC SYSTEMIC

DRUG

INTERACTIONSa

Brivaracetam Briviact Focal onset 100–200 mg/d;

bid

7–10 h Not established Fatigue

Dizziness

Weakness

Ataxia

Mood changes

Gastrointestinal

irritation

May increase

carbamazepineepoxide causing

decreased

tolerability

May increase

phenytoin

Cannabidiol Epidiolex Dravet and

Lennox-Gastaut

syndromes

10–20 mg/kg per

d; bid

18–32 h Not established Sedation Elevated

transaminases

Anorexia

Weight loss

Diarrhea

Increases

clobazam causing

somnolence

Tuberous sclerosis

complexassociated seizures

Carbamazepine Tegretolc Tonic-clonic

Focal onset

600–1800 mg/d

(15–35 mg/

kg, child); bid

(capsules

or tablets),

tid-qid (oral

suspension)

10–17 h

(variable

due to

autoinduction:

complete

3–5 wk after

initiation)

4–12 μg/mL Ataxia

Dizziness

Diplopia

Vertigo

Aplastic anemia

Leukopenia

Gastrointestinal

irritation

Hepatotoxicity

Hyponatremia

Rash

Level decreased by

enzyme-inducing

drugsb

Level increased

by erythromycin,

propoxyphene,

isoniazid, cimetidine,

fluoxetine

Clobazam Onfi Lennox-Gastaut

syndrome

10–40 mg/d

(5–20 mg/d for

patients <30 kg

body weight); bid

36–42 h

(71–82 h for

less active

metabolite)

Not established Fatigue

Sedation

Ataxia

Aggression

Insomnia

Constipation

Anorexia

Skin rash

Level increased by

CYP2C19 inhibitors

Clonazepam Klonopin Absence

Atypical absence

Myoclonic

1–12 mg/d; qd-tid 24–48 h 10–70 ng/mL Ataxia

Sedation

Lethargy

Anorexia Level decreased by

enzyme-inducing

drugsb

Eslicarbazepine Aptiom Focal onset 400–1600 mg/d;

qd

20–24 h 10–35 μg/mL (as

oxcarbazepine

mono-hydroxy

derivative)

Sedation

Ataxia

Dizziness

Diplopia

Vertigo

See carbamazepine Level decreased by

enzyme-inducing

drugsb

Ethosuximide Zarontin Absence 750–1250 mg/d

(20–40 mg/kg);

qd-bid

60 h, adult

30 h, child

40–100 μg/mL Ataxia

Lethargy

Headache

Gastrointestinal

irritation

Skin rash

Bone marrow

suppression

Level decreased by

enzyme-inducing

drugsb

Level increased by

valproic acid

Felbamate Felbatol Focal onset

Lennox-Gastaut

syndrome

Tonic-clonic

2400–3600 mg/d,

tid-qid

16–22 h 30–60 μg/mL Insomnia

Dizziness

Sedation

Headache

Aplastic anemia

Hepatic failure

Weight loss

Gastrointestinal

irritation

Increases

phenytoin, valproic

acid, active

carbamazepine

metabolite

Gabapentin Neurontin Focal onset 900–2400 mg/d;

tid-qid

5–9 h 2–20 μg/mL Sedation

Dizziness

Ataxia

Fatigue

Gastrointestinal

irritation

Weight gain

Edema

No known

significant

interactions

Lacosamide Vimpat Focal onset 200–400 mg/d;

bid

13 h Not established Dizziness

Ataxia

Diplopia

Vertigo

Gastrointestinal

irritation

Cardiac conduction

(PR interval

prolongation)

Level decreased by

enzyme-inducing

drugsb

Lamotrigine Lamictalc Focal onset

Tonic-clonic

Atypical absence

Myoclonic

Lennox-Gastaut

syndrome

150–500 mg/d;

bid (immediate

release), daily

(extended

release) (lower

daily dose

for regimens

with valproic

acid; higher

daily dose for

regimens with

an enzyme

inducer)

25 h

14 h (with

enzyme

inducers), 59 h

(with valproic

acid)

2.5–20 μg/mL Dizziness

Diplopia

Sedation

Ataxia

Headache

Skin rash

Stevens-Johnson

syndrome

Level decreased by

enzyme-inducing

drugsb

 and oral

contraceptives

Level increased by

valproic acid

(Continued)

3319 Seizures and Epilepsy CHAPTER 425

TABLE 425-9 Dosage and Adverse Effects of Commonly Used Antiepileptic Drugs

ADVERSE EFFECTS

GENERIC NAME

TRADE

NAME PRINCIPAL USES

TYPICAL DOSE;

DOSE INTERVAL HALF-LIFE

THERAPEUTIC

RANGE NEUROLOGIC SYSTEMIC

DRUG

INTERACTIONSa

Levetiracetam Keppra Focal onset 1000–3000 mg/d;

bid (immediate

release), daily

(extended

release)

6–8 h 5–45 μg/mL Sedation

Fatigue

Incoordination

Mood changes

Anemia

Leukopenia

No known

significant

interactions

Oxcarbazepinec Trileptal Focal onset

Tonic-clonic

900–2400 mg/d

(30–45 mg/kg,

child); bid

10–17 h

(for active

metabolite)

10–35 μg/mL Fatigue

Ataxia

Dizziness

Diplopia

Vertigo

Headache

See carbamazepine Level decreased

by enzymeinducing drugsb

May increase

phenytoin

Perampanel Fycompa Focal onset

Tonic-clonic

4–12 mg; qd 105 h Not established Dizziness

Somnolence

Aggression

Ataxia

Anxiety

Paranoia

Headache

Nausea

Level decreased

by enzymeinducing drugsb

Phenobarbital Luminal Tonic-clonic

Focal onset

60–180 mg/d;

qd-tid

90 h 10–40 μg/mL Sedation

Ataxia

Confusion

Dizziness

Decreased

libido

Depression

Skin rash Level increased

by valproic acid,

phenytoin

Phenytoinc

(diphenylhydantoin)

Dilantin Tonic-clonic

Focal onset

300–400 mg/d

(3–6 mg/kg,

adult; 4–8 mg/kg,

child); qd-tid

24 h (wide

variation,

dosedependent)

10–20 μg/mL Dizziness

Diplopia

Ataxia

Incoordination

Confusion

Gingival

hyperplasia

Lymphadenopathy

Hirsutism

Osteomalacia

Facial coarsening

Skin rash

Level increased

by isoniazid,

sulfonamides,

fluoxetine

Level decreased

by enzymeinducing drugsb

Altered folate

metabolism

Primidone Mysoline Tonic-clonic

Focal onset

750–1000 mg/d;

bid-tid

Primidone,

8–15 h

Phenobarbital,

90 h

Primidone,

4–12 μg/mL

Phenobarbital,

10–40 μg/mL

Same as

phenobarbital

Level increased by

valproic acid

Level decreased

by phenytoin

(increased

conversion to

phenobarbital)

Rufinamide Banzel Lennox-Gastaut

syndrome

3200 mg/d

(45 mg/kg, child);

bid

6–10 h Not established Sedation

Fatigue

Dizziness

Ataxia

Headache

Diplopia

Gastrointestinal

irritation

Leukopenia

Cardiac conduction

(QT interval

shortening)

Level decreased

by enzymeinducing drugsb

Level increased by

valproic acid

May increase

phenytoin

Tiagabine Gabitril Focal onset 32–56 mg/d; bidqid (as adjunct

to enzymeinducing

antiepileptic

drug regimen)

2–5 h (with

enzyme

inducer),

7–9 h (without

enzyme

inducer)

Not established Confusion

Sedation

Depression

Dizziness

Speech or

language

problems

Paresthesias

Psychosis

Gastrointestinal

irritation

Level decreased

by enzymeinducing drugsb

Topiramatec Topamax Focal onset

Tonic-clonic

Lennox-Gastaut

syndrome

200–400 mg/d;

bid (immediate

release), daily

(extended

release)

20 h

(immediate

release), 30

h (extended

release)

2–20 μg/mL Psychomotor

slowing

Sedation

Speech or

language

problems

Fatigue

Paresthesias

Renal stones (avoid

use with other

carbonic anhydrase

inhibitors)

Glaucoma

Weight loss

Hypohidrosis

Level decreased

by enzymeinducing drugsb

(Continued)

(Continued)

3320 PART 13 Neurologic Disorders

complication; its risk is highest in children <2 years old, especially

those taking other antiseizure drugs or with inborn errors of

metabolism.

Zonisamide, brivaracetam, tiagabine, gabapentin, perampanel,

and lacosamide are additional drugs currently used for the treatment of focal seizures with or without evolution into generalized

seizures. Phenobarbital and other barbiturate compounds were

commonly used in the past as first-line therapy for many forms

of epilepsy. However, the barbiturates frequently cause sedation in

adults, hyperactivity in children, and other more subtle cognitive

changes; thus, their use should be limited to situations in which no

other suitable treatment alternatives exist.

Antiseizure Drug Selection for Generalized Seizures

Lamotrigine, valproic acid, and levetiracetam are currently considered the best initial choice for the treatment of primary generalized,

tonic-clonic seizures. Topiramate, zonisamide, perampanel, phenytoin, carbamazepine, and oxcarbazepine are suitable alternatives,

although carbamazepine, oxcarbazepine, and phenytoin can worsen

certain types of generalized seizures. Valproic acid is particularly

effective in absence, myoclonic, and atonic seizures. It is therefore

commonly used in patients with generalized epilepsy syndromes

having mixed seizure types. However, levetiracetam, rather than

valproic acid, is increasingly considered the initial drug of choice

for women with epilepsies having mixed seizure types given the

adverse effects of valproic acid for women of childbearing age.

Lamotrigine is also an alternative to valproate, especially for absence

epilepsies. Ethosuximide is a particularly effective drug for the

treatment of uncomplicated absence seizures, but it is not useful

for tonic-clonic or focal seizures. Periodic monitoring of blood cell

counts is required since ethosuximide rarely causes bone marrow

suppression.

INITIATION AND MONITORING OF THERAPY

Because the response to any antiseizure drug is unpredictable,

patients should be carefully educated about the approach to therapy. The goal is to prevent seizures and minimize the side effects

of treatment; determination of the optimal medication and the

optimal dose typically involves trial and error. This process may

take months or longer if the baseline seizure frequency is low. Most

antiseizure drugs need to be introduced relatively slowly to minimize side effects. Patients should expect that minor side effects such

as mild sedation, slight changes in cognition, or imbalance will typically resolve within a few days. Starting doses are usually the lowest

value listed under the dosage column in Table 425-9. Subsequent

increases should be made only after achieving a steady state with

the previous dose (i.e., after an interval of five or more half-lives).

Monitoring of serum antiseizure drug levels can be very useful

for establishing the initial dosing schedule. However, the published therapeutic ranges of serum drug concentrations are only

an approximate guide for determining the proper dose for a given

patient. The key determinants are the clinical measures of seizure

frequency and presence of side effects, not the laboratory values.

Conventional assays of serum drug levels measure the total drug

(i.e., both free and protein bound). However, it is the concentration of free drug that reflects extracellular levels in the brain and

correlates best with efficacy. Thus, patients with decreased levels

of serum proteins (e.g., decreased serum albumin due to impaired

liver or renal function) may have an increased ratio of free to bound

drug, yet the concentration of free drug may be adequate for seizure

control. These patients may have a “subtherapeutic” drug level, but

the dose should be changed only if seizures remain uncontrolled,

not just to achieve a “therapeutic” level. It is also useful to monitor

free drug levels in such patients. In practice, other than during the

initiation or modification of therapy, monitoring of antiseizure

drug levels is most useful for documenting adherence, assessing

clinical suspicion of toxicity, or establishing baseline serum concentrations prior to pregnancy, when clearance of many antiseizure

drugs increases significantly.

If seizures continue despite gradual increases to the maximum

tolerated dose and documented compliance, then it becomes necessary to switch to another antiseizure drug. This is usually done

by maintaining the patient on the first drug while a second drug is

added. The dose of the second drug should be adjusted to decrease

seizure frequency without causing toxicity. Once this is achieved,

the first drug can be gradually withdrawn (usually over weeks

unless there is significant toxicity). The dose of the second drug is

then further optimized based on seizure response and side effects.

Monotherapy should be the goal whenever possible.

WHEN TO DISCONTINUE THERAPY

Overall, ~50–60% of patients who have their seizures completely

controlled with antiseizure drugs can eventually discontinue therapy. The following patient profile yields the greatest chance of

remaining seizure free after drug withdrawal: (1) complete medical control of seizures for 1–5 years; (2) single seizure type, with

generalized seizures having a better prognosis than focal seizures;

(3) normal neurologic examination, including intelligence; (4) no

family history of epilepsy; and (5) normal EEG. The appropriate

seizure-free interval is unknown and undoubtedly depends on the

form of epilepsy and whether or not the causal factor is still present

(e.g., resection of a brain tumor causing seizures). However, it seems

reasonable to attempt withdrawal of therapy after 2 years in a patient

who meets all of the above criteria, is motivated to discontinue the

TABLE 425-9 Dosage and Adverse Effects of Commonly Used Antiepileptic Drugs

ADVERSE EFFECTS

GENERIC NAME

TRADE

NAME PRINCIPAL USES

TYPICAL DOSE;

DOSE INTERVAL HALF-LIFE

THERAPEUTIC

RANGE NEUROLOGIC SYSTEMIC

DRUG

INTERACTIONSa

Valproic acid

(valproate sodium,

divalproex sodium)

Depakene

Depakote

Tonic-clonic

Absence

Atypical absence

Myoclonic

Focal onset

Atonic

750–2000 mg/d

(20–60 mg/

kg); bid-qid

(immediate

and delayed

release), daily

(extended

release)

15 h 50–125 μg/mL Ataxia

Sedation

Tremor

Hepatotoxicity

Thrombocytopenia

Gastrointestinal

irritation

Weight gain

Transient alopecia

Hyperammonemia

Level decreased

by enzymeinducing drugsb

Zonisamide Zonegran Focal onset

Tonic-clonic

200–400 mg/d;

qd-bid

50–68 h 10–40 μg/mL Sedation

Dizziness

Confusion

Headache

Psychosis

Anorexia

Renal stones

Hypohidrosis

Level decreased

by enzymeinducing drugsb

a

Examples only; please refer to other sources for comprehensive listings of all potential drug-drug interactions. b

Phenytoin, carbamazepine, phenobarbital. c

Extendedrelease product available.

(Continued)