MANAGEMENT OF EPILEPSY IN

ADOLESCENTS AND ADULTS

method of
DEAN K. NARITOKU, M.D.
Southern Illinois University School of Medicine
Springfield, Illinois

Epilepsy is one of the most common neurologic

disorders and has an estimated prevalence of 0.6%.
More importantly, the lifetime incidence of seizures is
estimated to be approximately 10%. Thus, seizures
and epilepsy are encountered in every clinical practice.
Furthermore, untreated or uncontrolled epilepsy is
a costly disorder that may result in severe injuries,
morbidity, and death. Therefore, proper identification
and management of seizures are important for all
medical disciplines.
DIAGNOSIS AND CLASSIFICATION
Seizures may be defined as abnormal and uncontrolled hypersynchronous brain activity that results in
a behavioral manifestation. It is a symptom of disordered brain regulation, and therefore it is important
that underlying causes be sought. Interestingly, the
ability to seize is conserved throughout nearly all
animal species that possess a well-organized central
nervous system and therefore must involve brain
mechanisms that are present in normal individuals. In
contrast, epilepsy is a pathologic condition in which
seizures recur under relatively normal conditions,
either spontaneously or after naturally occurring
provocations. Thus, an increased predisposition to
seizures characterizes the epileptic state. This distinction is important because symptomatic seizures, or
seizures that have occurred as a result of transient
conditions, usually do not warrant anticonvulsant
therapy. A common example would be a seizure caused
by insulin-induced hypoglycemia. The estimated
recurrence rate after an unprovoked seizure is 30% to
60%, so treating patients with anticonvulsants after a
first seizure would potentially subject them to unnecessary long-term therapy. Therefore, most clinicians
will wait until seizures recur before starting
antiepileptic drug (AED) therapy.
When approaching a patient with seizures, it is
important to recognize that many conditions are mimickers of seizures, as listed in Table 1. In fact, a large
percentage of patients referred to tertiary care epilepsy
programs are refractory to medications, primarily
TABLE 1. Common Mimickers of Seizures in
Adults and Adolescents
Syncope (with or without seizure)
Cardiogenic
Vasovagal
Panic disorder
Complex migraine
Metabolic encephalopathy
Psychogenic seizures
Rakel and Bope: Conns Current Therapy 2004. Copyright 2004 by Elsevier Inc.

because they have nonepileptic events. One of the most

common differential diagnoses of seizures is syncope.
Syncope can usually be distinguished clinically from
seizures by its prodrome of light-headedness. However,
convulsive seizures may also occur secondary to a syncopal event, thereby making the distinction less clear.
Also commonly confused for seizures is panic disorder,
which may cause symptoms of floating or depersonalization that are mistaken for psychic symptoms of
complex partial seizures.
Because seizures are transient phenomena, the
diagnosis is based initially on a history of the spells
from both the patient and observers. In some valuable
instances seizures occur spontaneously during an electroencephalographic (EEG) study, but unfortunately,
such occurrences are rare unless continuous and
prolonged recordings are performed. Interictal abnormalities (i.e., epileptiform sharp waves or spikes) may
help support the diagnosis of epilepsy, but their presence or absence alone is not diagnostic. Determining
whether the patient has seizures is based on careful
characterization of the prodrome, the actual event,
and the postdrome. A careful history will usually
distinguish between the differential diagnoses of loss
of consciousness.
Syncope, whether caused by cardiac or neurogenic
factors, is usually preceded by light-headedness. The
patient may also complain of graying out or dimming
of vision. During the actual event, the patient appears
pale and sweaty and, in addition, generally becomes
limp. On some occasions, however, the patient may
then have a tonic-clonic seizure. If no seizure occurs,
the patient will generally regain consciousness
quickly.
Panic disorder is a commonly confused differential
diagnosis of complex partial seizures. The feelings of
depersonalization and anxiety and the autonomic
symptoms may resemble seizures. Vasovagal symptoms, syncope, and even secondary seizure may
accompany panic attacks, thereby further confusing
the diagnosis. Although complex migraine, or
migraine with neurologic symptoms and loss of consciousness, is considered a disease of childhood, it may
also occur in adolescents and adults.
Seizures are classified by the International
Classification of Seizures (Table 2) and are broadly
differentiated by whether they begin in part of the
cerebral cortex (partial-onset seizures) or appear to
start over the entire brain (generalized-onset
seizures). Complex partial seizures are often associated
TABLE 2. International Classification of Seizures
Partial Onset

Generalized Onset

Simple
Complex
Secondary generalized
tonic-clonic

Absence
Primary generalized
tonic-clonic
Myoclonic
Atonic
Clonic
Tonic
Clonic-tonic-clonic

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MANAGEMENT OF EPILEPSY IN ADOLESCENTS AND ADULTS

with an aura, which is actually a simple partial

seizure. This aura represents the start of a seizure and
is perceived by the conscious brain. The symptoms of
the aura reflect the area of brain onset. For example,
temporal-onset seizures often start with psychic or
visceral sensations or recurrent forced memories. Very
often, after a complex partial seizure, patients will
experience postictal confusion. During the event,
patients often display automatisms, such as lip smacking and indiscriminate picking at objects. Absence
seizures are generalized at onset and therefore do not
have a prodrome period. Patients may also exhibit
automatisms, but afterward, post-event confusion is
minimal or absent. Tonic-clonic seizures consist of two
phases, an initial rigid tonic phase followed by jerking
of the extremities. This activity is followed by a
profound postictal state. The post-event confusion and
lethargy are quite distinctive; in patients with an
unwitnessed episode of loss of consciousness followed
by profound post-event obtundation and spontaneous
recovery, a presumptive diagnosis of seizures can
be made.
Complex partial seizures and absence seizures
appear similar, but they differ greatly in their pathophysiology and response to specific AEDs. Complex
partial seizures start with a localized onset within the
cerebral cortex, whereas absence seizures are probably
generated in the diencephalon. Differentiating the two
seizure types may present a diagnostic difficulty. Both
are characterized by staring and automatisms such as
lip smacking and picking at objects. Therefore, they
are easily confused, particularly in childhood, when
both seizure types are commonly expressed. The presence of either an aura or a postictal state may help
clinically identify the staring episode as a partial-onset
seizure. A routine electroencephalogram may be

helpful in classifying the seizure type; partial-onset

seizures are associated with focal spikes (Figure 1),
whereas primary generalized seizures are characterized by generalized high-voltage spike-and-wave
discharges (Figure 2). In many cases, prolonged video
and EEG recording may be necessary to diagnose the
seizure type.
Myoclonic seizures are shock-like jerks. Myoclonus
is commonly seen in normal individuals on falling
asleep, and it is benign. However, when myoclonus
occurs in the waking state, it is abnormal. It is often
described by the patient as clumsiness or a twitch,
especially in the morning or during drowsiness. Atonic
seizures consist of sudden loss of posture and falling.
They often result in injury because the loss of postural
tone causes patients to strike their head.
The initial selection of medications may be made
after a bona fide diagnosis of epilepsy has been made,
as well as after attempts to classify the seizure type.
The seizure medication is then selected according
to the seizure type, as well as other considerations
related to the patient. Coverage of seizure types
may be considered analogous to selection of antibiotics; some of the AEDs are relatively narrow in
spectrum, whereas others are broad spectrum.
Selection of the wrong medication for the seizure type
may lead to ineffective therapy or even worsen the
seizures, especially absence or myoclonic seizures.
It may be useful to select a broad-spectrum drug if
an exact seizure classification cannot be made. A
summary of the spectrum of coverage is presented
in Table 3.
Many of the medications are recognized to be effective against different seizure types. However, the
strength of the clinical evidence varies, particularly
because many of the older AEDs were approved and

Figure 1. Focal epileptiform

spikes on an electroencephalogram. This typical temporal
spike is seen in a person with
complex partial seizures. The
abnormality is highlighted by
the box. Localized spikes and
sharp waves suggest partialonset seizures in persons with
a clinical diagnosis of epilepsy.

Rakel and Bope: Conns Current Therapy 2004. Copyright 2004 by Elsevier Inc.

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MANAGEMENT OF EPILEPSY IN ADOLESCENTS AND ADULTS

Figure 2. Generalized
spike-and-wave discharge.
This typical run of generalized
spike-wave activity is from a
person with absence seizures.
Note the widespread distribution of the spike-and-wave
discharges, which suggests a
generalized-onset seizure.

grandfathered for their indications before the advent

of rigorous clinical trials. Drugs in this category
include phenytoin (Dilantin), phenobarbital, and
primidone (Mysoline). Although carbamazepine
(Tegretol) has not undergone registration trials for
Food and Drug Administration (FDA) indications, it
has been widely used as a standard comparator in
recent clinical trials of new AEDs. To address the
ethical considerations of clinical trials in epilepsy,
most of the newer AEDs were studied and approved

first as add-on therapy for patients with intractable

epilepsy. Only three AEDs (valproate [Depakote],
felbamate [Felbatol], and lamotrigine [Lamictal])
have gained specific FDA approval for monotherapy
use, but it is reasonable to use other AEDs as singledrug therapy, depending on the individual patient
response. Unfortunately, because of financial considerations, it is likely that most of the newer AEDs
will not be tested or approved for FDA monotherapy
indications.

TABLE 3. Spectrum of Coverage of Antiepileptic Drugs

Primary Generalized-Onset Seizures
Spectrum

Drug

Absence

Narrow
Limited

Ethosuximide
Carbamazepine
Gabapentin
Phenobarbital
Phenytoin
Primidone
Tiagabine
Lamotrigine
Levetiracetam
Felbamate
Topiramate
Valproate
Zonisamide

*N

Expanded

Broad

Myoclonic

Tonic-Clonic
*
*
*N
*

*A

A
*

Partial-Onset Seizures

Epilepsy Syndrome

Complex
Partial

Secondary
Tonic-Clonic

LennoxGastaut

*N

A
*
*
*N

A, M

A, M

A, M

*
*
*
*
*

A
A
*

*Comparative trials or extensive clinical experience.

Randomized, double-blind placebo or active controlled trials.

Case series or clinical experience.

A, FDA indication for add-on therapy; M, FDA indication for monotherapy; N, FDA indication, no reference to monotherapy or add-on therapy
(grandfathered).
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MANAGEMENT OF EPILEPSY IN ADOLESCENTS AND ADULTS

CHARACTERISTICS OF COMMONLY
USED ANTIEPILEPTIC DRUGS
Carbamazepine
Carbamazepine is one of the most widely used medications for treatment of partial-onset seizures. Its
main attributes include relatively low expense and
long-standing clinical experience. Although titration
rates have never been formally assessed, it is clear
that in at least some patients, titration should be performed slowly, with a starting dose of 200 mg twice
daily (bid) titrated up to doses of 400 mg/d three times
daily (tid). Carbamazepine may cause a condition
similar to the syndrome of inappropriate secretion of
antidiuretic hormone (SIADH), which can result in
troublesome hyponatremia, especially in the elderly.
Carbamazepine commonly causes a symptomatic
leukopenia that should not be confused with the very
rare condition fatal aplastic anemia. It is a potent
inducer of the cytochrome P-450IIIA4 system, which
may increase the metabolism of other medications
using this pathway. Carbamazepine may autoinduce
its own metabolism, thereby lowering levels a month
after initial titration of therapy.
Phenytoin
Although phenytoin is one of the most commonly
used medications by primary care physicians, its use
has fallen out of favor with neurologists and epilepsy
specialists. It is notoriously nonlinear and saturates
its metabolic sites at therapeutic levels. Because of
this nonlinearity, even small increases may result in
large increases in its blood level (see Figure 3). As a
result, phenytoin has been one of the leading causes of
hospitalization for adverse drug affects. The nonlinearity of phenytoin may result in the need to draw
multiple blood samples to determine levels during
drug monitoring. The cost of drug monitoring may
more than exceed the perceived inexpensive cost of
phenytoin, and any hospitalization would nullify the
savings of the medication. Phenytoin may also cause

Nonlinear: phenytoin

Linear
Level

Dose of drug
Figure 3. Nonlinear behavior of phenytoin. This figure shows
hypothetical phenytoin levels as a function of dose. Note that most
antiepileptic drugs follow a linear dose proportionality; that is,
doubling a dose roughly doubles the resulting blood level.
Phenytoin typically saturates its metabolic sites at therapeutic
levels, so small increases or reductions in dose may result in
large changes in levels, which may complicate therapy.

cosmetic difficulties, including gingival hyperplasia,

hirsutism, and collagen abnormalities, which may
result in coarsening of facial features and Dupuytrens
contractures. The initial starting dose for adults is
300 mg/d, but only about a third of patients achieve
levels within the therapeutic range. When the level
exceeds 10 mg/L, the dose increase should preferably
be small, with no more than 30- to 60-mg increments.
Valproate
Valproate is a broad-spectrum medication that has
efficacy against all seizure types, which makes it particularly useful when the exact seizure classification is
unknown or multiple seizure types exist. It is a fairly
linear drug, although it exhibits reduced protein binding at high concentrations. Valproate inhibits a less
commonly used subset of the P-450 system for drug
metabolism and therefore tends to cause fewer interactions than the other older AEDs do. Valproate
potently inhibits lamotrigine metabolism, probably by
inhibiting glucuronidation, and it may raise phenobarbital levels. Overall, it is one of the most flexible
drugs in that it is available in every formulation,
including tablet, time-release, suspension, sprinkles,
and intravenous preparations. Valproate may be
loaded rapidly intravenously and is well tolerated at
a rate of 3 mg/kg/min, thereby allowing the fastest
initiation of any AED. At high doses it is associated
with weight gain, and therefore weight monitoring
and diet counseling should be provided as needed.
Valproate may also increase physiologic tremor and
cause temporary hair thinning. The starting daily
dose of valproate is 7 to 15 mg/kg/d given either bid or
tid, with an initial target dose of 15 mg/kg/d, and it
may be titrated to doses up to 60 mg/kg/d.
Lamotrigine
Lamotrigine is an expanded-spectrum AED. In addition to partial and tonic-clonic seizures, it appears to
be effective against absence seizures. However, it may
be ineffective against myoclonic seizures and in some
individuals may exacerbate or precipitate myoclonus.
Lamotrigine is metabolized primarily through glucuronidation and does not inhibit or induce the P-450
system. Its metabolism, however, is strongly inhibited
by valproate, and therefore special care must be exercised when adding to drug regimens with valproate.
Its metabolism is also increased by inducers of the
P-450 system. At the recommended rates of dose escalation, lamotrigine has an overall 0.8% risk of rash; if
introduced rapidly, the rate may be as high as 10% to
15%. Because of inhibition of lamotrigine metabolism
by valproate, special care must be taken to introduce
lamotrigine slowly when the patient is taking
valproate. The initial starting dose of lamotrigine is
25 mg/d, with increments of 25 to 50 mg weekly to
reach an initial target dose of 100 mg bid., and it is
titrated according to clinical response up to 150 to
250 mg bid, if needed. If valproate is used, the initial
dose and rate of increase should be halved.
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MANAGEMENT OF EPILEPSY IN ADOLESCENTS AND ADULTS

939

Topiramate

Zonisamide

Topiramate (Topamax) is an expanded-spectrum

drug that is useful against partial-onset, tonic-clonic,
and myoclonic seizures. It does not appear to be effective against absence seizures. Topiramate is cleared by
both the P-450 and renal systems. In general, it does
not induce P-450 metabolism, but at higher doses
(>200 mg/d), it may induce the metabolism of birth
control medications. In some individuals, phenytoin
metabolism may be inhibited by topiramate, thereby
resulting in unexpectedly higher levels. When escalated too quickly, especially during AED polytherapy,
it can result in significant cognitive impairment,
which is generally transient. Because topiramate possesses carbonic anhydrase inhibitory properties, its
use is associated with a slightly higher risk for the
development of renal stones (estimated at 1.4%).
The carbonic anhydrase inhibition may also result in
tingling paresthesias. Topiramate is associated with
weight loss, but the mechanism is unknown. The
initial starting dose of topiramate is 25 to 50 mg/d,
with increases of 25 to 50 mg each week to an initial
target dose of 100 mg bid and titration to clinical
response up to 200 to 300 mg bid.

Zonisamide (Zonegran) is a broad-spectrum drug

that is probably effective against all seizure types,
although formal trial data are lacking for many of the
primary generalized seizure types. Its main attribute
is an extremely long half-life of approximately 60
hours, which allows it to be taken once daily or bid.
Zonisamide is metabolized by the P-450 system, but it
does not have significant interactions with other medications. It also must be titrated slowly for tolerability
considerations. Zonisamide is a weak carbonic anhydrase inhibitor and is associated with an estimated
1.4% risk for kidney stones. Zonisamide is associated
with weight loss, but the mechanism is unknown. The
initial starting dose of 100 mg/d is clinically effective,
with increases of 100 mg every 1 to 2 weeks to a daily
dose of 100 to 600 mg.

Oxcarbazepine
Oxcarbazepine (Trileptal) is a derivative of carbamazepine that does not form an epoxide metabolite,
which is believed to be more toxic than the parent
compound. However, its advantages over carbamazepine for initial therapy may be more theoretic
than practical, especially given the cost differential.
Similar to carbamazepine, it is a limited-spectrum
drug that is effective against partial-onset seizures
and tonic-clonic seizures. It may also cause an SIADHlike syndrome resulting in significant hyponatremia,
especially in the elderly. However, unlike carbamazepine, it does not strongly induce the P-450
system, nor does it induce asymptomatic leukopenia.
The initial starting dose of oxcarbazepine is 300 mg
bid, with weekly 300-mg increases to an initial target
dose of 450 to 600 mg bid and titratation according to
response up to 1200 mg bid.
Gabapentin
Gabapentin (Neurontin) is a limited-spectrum drug
that is effective against partial-onset seizures. It is
water soluble and cleared exclusively by the renal
system. It has relatively low potency, and its limited
absorption from the gut potentially limits its efficacy.
Gabapentin has no known pharmacokinetic interactions
with other medications, which may make it useful in
patients with compromised hepatic function. However,
caution must be taken in the elderly or other patients
who may have reduced renal function, and lower doses
should be used. The initial starting dose of gabapentin is
300 mg tid; in elderly and renally compromised patients,
it should be reduced to 100 to 200 mg tid. The dose may
be titrated upward to 1200 mg tid per clinical response.
Rakel and Bope: Conns Current Therapy 2004. Copyright 2004 by Elsevier Inc.

Levetiracetam
Levetiracetam (Keppra) is a limited- to expandedspectrum AED that is effective against partial-onset
and tonic-clonic seizures. Early open-label data
suggest that it may also be effective against some of
the primary generalized seizure types, including
myoclonic seizures. Levetiracetam is water soluble
and predominantly cleared by the kidneys. It does not
have known interactions with the P-450 system. The
starting dose of levetiracetam is 500 mg bid, which is
clinically effective for intractable epilepsy, and it may
be titrated upward to 1500 mg bid.
Tiagabine
Tiagabine (Gabitril) is an interesting compound in
that it is one of the few AEDs developed as a
rational therapy based on its mechanism of action.
It is a derivative of nipecotic acid, which blocks
-aminobutyric acid (GABA) reuptake into neurons
and glia. It is effective against partial-onset seizures.
Tiagabine has a very short half-life, but clinical trials
have shown no significant difference in efficacy with
bid or tid dosing, and therefore the drug may be given
bid. Tiagabine should be taken with food to blunt the
peak effect of the medication, which may cause dizziness or drowsiness at peak doses. It is metabolized
by the P-450IIIA4 system but does not induce or
inhibit the metabolism of other medications.
Tiagabine must be introduced slowly, with 4 mg at
bedtime and 4-mg/wk increases to an initial target
dose of 6 to 12 mg tid, and it may be increased further
up to 56 mg/d as needed.
Barbiturates
Barbiturates, including phenobarbital and primidone, should not be routinely used in practice.
Although they are inexpensive, they very frequently
cause problems with sedation or cognitive impairment.
They are strong inducers of the P-450 system, and
phenobarbital is partially cleared by the renal system.

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MANAGEMENT OF EPILEPSY IN ADOLESCENTS AND ADULTS

Barbiturates are effective against partial-onset and

tonic-clonic seizures. However, given the plethora of
AEDs with better tolerability profiles, this category
should be considered one of the last choices for seizure
therapy. The initial dose of phenobarbital is 30 mg tid
with titration upward according to response.
Felbamate
Felbamate, a derivative of meprobamate, is an
expanded-spectrum anticonvulsant. It has been particularly useful for childhood epilepsies, but its association with aplastic anemia and hepatotoxicity has
been a source of major concern. It is a major inhibitor
of the P-450 system and can cause concomitant medication levels to increase greatly, thereby resulting in
toxicity. Felbamate is also associated with weight loss.
Although withdrawal from the market was considered
by the FDA, it continues to be available, in recognition
of its value to many patients with severe epilepsy.
However, it should be used only when other alternatives have failed. The initial dose of felbamate is 300 to
400 mg tid, and this dose may be titrated upward to a
maximum of 1200 mg tid as needed for seizure control.
Vigabatrin
Vigabatrin is an irreversible inhibitor of the GABA
transaminase enzyme, which normally inactivates
GABA. It is also the result of rational drug development. Vigabatrin is effective in a wide variety of
seizures, including many of the severe epilepsies of
infancy and early childhood. It is currently available
in several countries and used on a limited basis.
However, vigabatrin is associated with irreversible
visual field loss, which has prevented it from being
approved in the United States.
PRINCIPLES OF ANTIEPILEPTIC
DRUG THERAPY
Before initiating therapy, it is important to establish whether the patient has a bona fide diagnosis
of epilepsy (i.e., has episodes of recurrent seizures).
Information from the history and electroencephalogram should be used to classify the seizure type to
ensure appropriate drug selection. If the classification
is uncertain, it may be helpful to use a broad-spectrum
agent, as listed earlier. In general, most anticonvulsant drugs need to be introduced at a low dose and
titrated upward slowly to the target dose. Exceptions
to this guideline include fosphenytoin (Cerebyx) and
valproate (Depacon), which may be loaded intravenously and are well tolerated under loading conditions. It should be noted that the suggested starting
dose for some AEDs, such as levetiracetam and zonisamide, is clinically effective, although the further
adjustment may be needed for optimal response. The
remaining drugs require slow titration for tolerability
and/or safety reasons.
*Not available in the United States.

The ultimate goal of AED therapy is freedom from

seizures with no side effects. Although this goal
cannot always be achieved, the clinician should continue to strive for such results. Therapy should be
guided by individual patient response, as measured
clinically by seizure frequency and adverse effects. A
seizure diary is essential for determining the outcome
of therapeutic changes. Because seizure frequency
fluctuates, it is helpful to calculate a seizure index
(number of seizures/duration of the interval in days
from the last visit) to examine seizure trends. The
patient should be questioned at each visit for signs of
neurotoxicity, as outlined in the next section. AED
levels are only a surrogate for clinical outcome.
Although they provide feedback for rough dosing,
monitoring of compliance, and evaluation of pharmacokinetic changes, they are not a substitute for the
clinical endpoints of seizure frequency and side
effects. In general, the lowest dose that achieves freedom from seizures will provide the most desirable
results. AEDs should be titrated upward until either
the best response is achieved or side effects occur.
Management of Toxicities
The most common adverse effects encountered with
AED therapy are neurotoxic symptoms, including
dizziness, drowsiness, blurred vision, cognitive
impairment, behavioral changes, and gait unsteadiness. These effects may be related to the initial introduction of medication or be dose related. Slowing the
titration rate may reduce the introduction-related toxicities, which abate as the patient builds tolerance to
the adverse effects. As the dose is increased further,
the patient may encounter nontransient dose-related
toxicities as higher levels are achieved. It is important
to remember that AED toxicity is a function of the
total drug load and that the incidence of adverse
effects increases with each successive anticonvulsant
drug added. Recent case series have shown that the
incidence of drug toxicity approaches 100% in patients
taking four or more AEDs. Drug reduction should
always be considered whenever the patient is receiving AED polytherapy and is having adverse effects.
Similarly, reduction of concomitant medications
during the introduction of a new AED improves its
tolerability.
Idiosyncratic reactions are rare but often dangerous. Both aplastic anemia and fatal hepatotoxicity
have been reported with all the older-generation
AEDs. Although laboratory monitoring of some
medications with a complete blood count and liver
function studies is recommended by the FDA, it is
unclear whether such studies are of value in detecting
dangerous idiosyncratic reactions. Clinical vigilance is
crucial to avert these rare problems. The patient and
family should be instructed to contact the physician
immediately should any rash, bruises, or petechiae
appear, which may signal a blood dyscrasia. The hepatotoxic syndrome is a Reye-like syndrome with ataxia,
drowsiness, and potential paradoxic increases in
seizures. The symptoms should alert the physician to
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MANAGEMENT OF EPILEPSY IN ADOLESCENTS AND ADULTS

immediately reassess the condition and stop AED

therapy if necessary.
Long-Term Outcome and Prognosis
Several open-label and long-term studies have
looked at the prognosis of newly treated epilepsy.
Interestingly, they show very similar results and
suggest that about 47% of patients will respond to the
initial therapy. Of the remaining patients, approximately 47% will respond to a second agent, which
means that overall, approximately 30% of the population will remain resistant to two-drug trials. At
this point, a patient may be considered medically
intractable because only a small percentage of patients
become seizure free after subsequent trials of AEDs,
although many are considerably improved. Studies of
patients enrolled in randomized controlled trials
investigating new AEDs suggest that the rate of freedom from seizures is no higher than 5% to 7% for each
successive AED. It is worthwhile noting that patients
who respond to a second drug tend to be those who
have failed the initial therapy as a result of adverse
effects rather than efficacy. Thus, even failure to
respond to the first medication predicts a poor outcome for such subsequent treatment, if the failure
is due to lack of efficacy. Failure of two AEDs may
earmark the patient for alternative approaches, such
as epilepsy surgery. Certain pathologies are also associated with a poorer prognosis for freedom from
seizures. Most notably, patients with more than one
seizure focus or brain pathology are the most difficult
to control.

TABLE 4. Stages of Intravenous Pharmacologic

Therapy for Status Epilepticus
Stage
I
II
III
IV

Standard
(Initial Dose)

Alternative
(Initial Dose)

Lorazepam (Ativan), 0.1 mg/kg

(maximum, 4 mg)
Fosphenytoin (Cerebyx),
20 mg/kg
Phenobarbital,
*20 mg/kg
Midazolam (Versed)*,
Pentobarbital (Nembutal)
Propofol (Diprivan)*,

Valproate (Depacon),
*25 mg/kg
Valproate,
*25 mg/kg

*Not FDA approved for this indication.

Use continuous electroencephalography to titrate to cessation of

electrographic seizures.

STATUS EPILEPTICUS
Status epilepticus has traditionally been defined as
either 30 minutes of continuous convulsive activity or
multiple seizures without regaining consciousness.
Because most seizures typically last 2 minutes or less,
many centers have adopted a more rigorous definition
of status epilepticus: 10 minutes of continuous
seizures. This definition reflects the recognition that
the prognosis for control of status epilepticus is
related to how quickly therapy is instituted. Status
epilepticus is a life-threatening emergency, and delay
in therapy increases the risk for morbidity and mortality. The goals of therapy are to stabilize the patient
and terminate the status epilepticus as quickly as possible. As with all emergencies, it is most important to

A
Figure 4. Electroencephalographic (EEG) monitoring during status epilepticus. Sequential electroencephalograms from a patient in
convulsive status epilepticus are shown. Each line represents 1-second intervals. A, The EEG changes correlate with behavioral seizure
episodes early in treatment.
Continued
Rakel and Bope: Conns Current Therapy 2004. Copyright 2004 by Elsevier Inc.

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MANAGEMENT OF EPILEPSY IN ADOLESCENTS AND ADULTS

Figure 4, contd.
B, The behavioral changes
during seizures are minimal,
but electrographic seizures
persist. Without EEG monitoring, the continuation of seizure
activity may not have been
identified and treated properly.
Later, in C, no behavioral
seizures are observed; the
electrographic seizure activity
has slowed but requires further aggressive treatment. All
electrographic seizure activity
was eventually arrested, thus
underscoring the importance of
continuous EEG monitoring
for proper management of
status epilepticus.

first stabilize the airway, breathing, and circulation

before proceeding with other therapies and studies.
An intravenous line with saline is recommended in
case resuscitation is necessary and for administration
of anticonvulsants. When the state of the patient is
in doubt, a glucose bolus and thiamine should be
administered.
Pharmacologic treatment of status epilepticus may
be divided into therapeutic stages as outlined in
Table 4. It is crucial that electrographic seizures be
completely eradicated because AED therapy may initially stop behavioral, but not electrographic seizures.
Accordingly, the use of continuous EEG monitoring is

mandated to verify the cessation of seizure activity

(Figure 4). Failure to control electrographic seizures
may allow the development of intractable status
epilepticus and excitotoxic brain damage. In analogy
to the use of electrocardiograms during cardiac
emergencies, a continuous EEG monitor should now
be considered the standard of care for management of
status epilepticus.
Initiation of pharmacologic therapy should begin
with a benzodiazepine. Lorazepam (Ativan) is currently the preferred benzodiazepine because of its long
duration of action. Approximately 0.1 mg/kg (maximum of 4 mg) may be given intravenously. If this drug
Rakel and Bope: Conns Current Therapy 2004. Copyright 2004 by Elsevier Inc.

943

EPILEPSY IN INFANCY AND CHILDHOOD

is unsuccessful, fosphenytoin should be given in a dose

of approximately 20 mg/kg at a rate of 150 mg/min
in adults. Clinical experience with intravenous valproate* suggests that it an important alternative
choice for the treatment of status epilepticus because
it is well tolerated and causes little hypertension. The
exact place of valproate in the sequence of therapy for
status epilepticus has not been determined, but it
should be considered an alternative before the use
of barbiturates, especially in cases of pre-existing
cardiovascular instability, because of the cardiotoxicity of rapid barbiturate infusion. It may be loaded at
a dose of 25 mg/kg with maintenance doses of 15 to
60 mg/kg/d in four divided doses. Valproate may be
infused very rapidly at a rate of 3 mg/kg/min. Because
of its short half-life, the first maintenance dose should
be given approximately 1 hour after the loading dose
to ensure that adequate trough levels are obtained.
If control of status epilepticus is not achieved
with the aforementioned three agents, phenobarbital*
therapy should be instituted with a loading dose of
20 mg/kg at a rate of 100 mg/min. Care must be taken
to avoid hypotension and respiratory compromise;
intubation and ventilator support are necessary.
Should phenobarbital fail, anesthesia is required with
either midazolam (Versed),* pentobarbital (Nembutal),
or propofol (Diprivan)* under constant EEG monitoring. In the past, it was suggested that anesthesia
should be titrated to a burst suppression coma pattern
on the electroencephalogram. However recent case
series suggest that burst suppression may increase
morbidity and mortality, and it is now recommended
that the dosage be titrated to cessation of electrographic seizures only. Clinical experience also suggests
that midazolam may be safer than pentobarbital or
propofol.
Additional studies such as brain imaging and
lumbar puncture should be strongly considered. A
lumbar puncture is especially necessary in patients
with any suggestion of central nervous system infection or nonlocalized fever. Serum chemistry panels
and infection studies may also help establish a
systemic cause as a precipitant. In addition, AED
levels may identify noncompliance with medications.
WHEN TO REFER
Timely referral for neurologic evaluation may be of
great assistance in making an accurate diagnosis and
ensuring optimal patient management. Neurologic
consultation is important for a new onset of seizures
because seizures are a symptom of disordered brain
regulation and may be a manifestation of a latent
disease process. Patients should also be referred after
failure of two medications or lack of control after
6 months because such responses identify the patient
as intractable. The high incidence of nonepileptic
events in patients referred to tertiary care epilepsy
centers underscores the importance of detailed investigation of medically intractable patients. Surgical
*Not FDA approved for this indication.
Rakel and Bope: Conns Current Therapy 2004. Copyright 2004 by Elsevier Inc.

alternatives such as lobectomy and brain stimulation

may offer substantial improvement in seizure control
and freedom from seizures.
In summary, seizures are commonly encountered in
clinical practice. Careful and timely evaluations are
crucial to achieving freedom from seizures and the
best quality of life.
ACKNOWLEDGMENT
I would like to thank Judy Taylor for her assistance
in preparing the manuscript.

EPILEPSY IN INFANCY AND

CHILDHOOD
method of
JOHN N. GAITANIS, M.D.
Childrens Hospital Boston
Boston, Massachusetts

DEFINITIONS
Seizures are self-limited clinical events resulting
from abnormal and excessive firing of cortical neurons. The clinical manifestations are transient and
involve motor, sensory, autonomic, or psychic changes
with or without an alteration in consciousness.
Epilepsy, on the other hand, is a condition characterized by recurrent, unprovoked epileptic seizures
(Table 1).
It is important to note that epilepsy does not constitute a single entity and is instead a heterogeneous
group of disorders with a multitude of etiologies and
clinical manifestations. Subdivisions of epilepsy and
epileptic seizures are based upon the etiology or the
clinical features (Table 2). The effect of seizures on
quality of life, the optimal treatment, and the prognosis
TABLE 1. Seizure Terminology
Seizure: A clinical event, displaying signs or symptoms, resulting
from an abnormal and excessive discharge of cortical neurons.
Epilepsy: Recurrent, unprovoked seizures.
Generalized: The initial seizure discharge involves a large number
of neurons throughout both hemispheres and the clinical
manifestations indicate bilateral onset.
Partial: The initial seizure discharge involves a limited number of
neurons in just one hemisphere.
Simple: A seizure that does not cause alteration in consciousness.
Complex: A seizure involving alteration in consciousness.
Idiopathic: Epilepsy with a genetic cause.
Cryptogenic: Nonidiopathic epilepsy without a known cause.
Symptomatic: Nonidiopathic epilepsy with a known cause (usually
a brain insult or other lesion).
Tonic: Sustained posturing of a body part.
Clonic: Rhythmic jerking of a body part.
Myoclonic: Brief, irregular contractions of a body part.
Atonic: An abrupt loss of muscle tone.
Tonic-clonic: Tonic activity alternating with clonic movements.
Absence: A transient discontinuation of activity with loss of
awareness.