clinical practice

The new engl and journal o f medicine

n engl j med 359;2 www.nejm.org july 10, 2008
166
Initial Management of Epilepsy
Jacqueline A. French, M.D., and Timothy A. Pedley, M.D.
From the Department of Neurology, New
York University School of Medicine (J.A.F.);
and the Department of Neurology, Co-
lumbia University Medical Center (T.P.)
both in New York. Address reprint requests
to Dr. French at the NYU Comprehensive
Epilepsy Center, 403 E. 34th St., 4th Fl.,
New York, NY 10016, or at jacqueline.
french@nyumc.org.
N Engl J Med 2008;359:166-76.
Copyright 2008 Massachusetts Medical Society.
A 29-year-old woman presents for evaluation. The previous evening, her husband,
who was in the next room, heard unusual sounds and found her lying on the bed look-
ing dazed. She was confused for a few minutes but quickly returned to normal. On
questioning, she recalls an unwitnessed event about 1 month previously; at that time,
she awoke feeling mildly confused, had sore muscles, and discovered she had bitten
her tongue. How should she be evaluated and treated?
The clinical problem
Epilepsy, which is defined as two or more seizures that are not provoked by other
illnesses or circumstances, affects about 45 million people worldwide. In the United
States, the prevalence of epilepsy is approximately 6 to 8 per 1000 population, and
the incidence is approximately 26 to 40 per 100,000 person-years, with higher rates
among infants and persons older than 60 years of age.
1-3
Approximately 70% of
adults with new-onset epilepsy have partial (focal) seizures.
3
In the majority of cases
(62%), the cause is unknown. Stroke (9.0%), head trauma (9.0%), alcohol (6.0%),
neurodegenerative disease (4.0%), static encephalopathy (3.5%), brain tumors (3.0%),
and infection (2.0%) account for most remaining cases.
4
Although cerebrovascular
causes are more common in the elderly, the cause is still unknown in 25 to 40% of
patients who are 65 years of age or older.
5
Strategies and Evidence
Diagnosis
The transient occurrence of altered awareness, abnormal behavior, or involuntary
movements suggests a diagnosis of epilepsy. Because epileptic seizures are rarely ob-
served by a physician, the diagnosis is typically based on historical information
supplemented by selected tests. The first step is to answer the question of whether the
event was a seizure. The second is to determine whether the patient has epilepsy.
A careful history is the single most important element in diagnosis, with a focus
on details of the episode and whether there is any history of previous spells that
may point to a diagnosis of epilepsy. When patients have limited or no recall of
events, witnesses should be queried about details of the episode. The differential di-
agnosis varies according to the patients age and symptoms (Table 1).
Seizures are common in metabolic (e.g., uremia, hypoglycemia, hyperglycemia,
and hepatic failure), toxic (e.g., drug overdose or withdrawal), and infectious (e.g.,
meningitis and encephalitis) conditions.
6
Seizures that occur in patients with these
conditions do not necessarily confer a diagnosis of epilepsy. Although antiepileptic
drugs are sometimes necessary to suppress seizures in the short term in these con-
ditions, medications generally do not need to be continued after the patient has
recovered.
This Journal feature begins with a case vignette highlighting a common clinical problem.
Evidence supporting various strategies is then presented, followed by a review of formal guidelines,
when they exist. The article ends with the authors clinical recommendations.
The New England Journal of Medicine
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Copyright 2008 Massachusetts Medical Society. All rights reserved.
clinical practice
n engl j med 359;2 www.nejm.org july 10, 2008
167
Evaluation
The neurologic examination is normal in most pa-
tients with epilepsy. Findings occasionally point
to an underlying pathologic condition in the brain
or a specific disorder such as skin abnormalities
in neurocutaneous syndromes. According to joint
recommendations of the American Academy of
Neurology and the American Epilepsy Society, pa-
tients with an unprovoked first seizure
7
should un-
dergo electroencephalography (EEG), computed
tomographic (CT) scanning or magnetic resonance
imaging (MRI) of the head, and selected blood tests
according to the clinical circumstances. Epilepti-
form EEG patterns such as spikes and sharp waves
can assist in the diagnosis and in classifying sei-
zures as being either focal or generalized. How-
ever, neither a normal EEG nor interictal abnor-
malities alone refute or confirm a diagnosis of
epilepsy. EEGs are abnormal in about 50% of pa-
tients presenting with a first seizure, and they show
epileptiform discharges in only about half of these
patients.
7
The incidence of abnormalities increas-
es when EEGs are repeated or performed after the
patient has undergone sleep deprivation.
8
Video
EEG monitoring is necessary if there is concern
about nonepileptic events (Table 1).
MRI of the brain is more sensitive than CT in
identifying structural lesions causally related to
epilepsy.
9
CT, however, is appropriate for emer-
gency situations. Among patients in whom epi-
lepsy has been newly diagnosed, CT of the head is
abnormal in 34 to 56%, and cranial CT findings
affect management in 9 to 17%.
10
Routine blood tests rarely inform the diagno-
sis in otherwise healthy patients. However, a com-
plete blood count, liver-function tests, and mea-
surement of electrolyte levels are useful before
antiepileptic drug treatment is initiated, since dos-
age adjustment may be necessary if hepatic or re-
nal function is abnormal. Albumin levels should
be measured before administering highly protein-
bound drugs such as phenytoin and valproate,
since the fraction of unbound (active) drug is
higher in patients with hypoalbuminemia. In ad-
olescents and adults with unexplained generalized
seizures, screening for substance abuse should
be considered.
A diagnosis of epilepsy can have a considerable
effect on the patients mood, interpersonal rela-
tionships, employability, social functioning, qual-
ity of life, and ability to drive. Early and repeated
discussions of these issues are suggested. Patients
should be discouraged from participating in ac-
tivities for which a history of seizures increases
the risk of injury or death; these activities include
driving, operating high-risk power equipment,
Table 1. Conditions That Can Mimic Epileptic Seizures.
Diagnosis Important Clinical Features
Hyperventilation Anxiety and overbreathing evident; often perioral cyanosis, hand paresthesias, and
carpo pedal spasm are present; environmental trigger may be evident
Migraine Slow progression of neurologic symptoms; visual symptoms prominent; basilar migraine
has unusual features, including confusion, stupor, bilateral blindness; headache
may be minimal or absent
Panic attack Abrupt onset with intense feeling of dread or fear; often sense of impending death or
inability to breathe; prominent autonomic features (e.g., tachycardia, sweating,
nausea); lasts longer (530 min) than typical seizure; no loss of consciousness
Psychogenic seizures Psychiatric history; patient usually motionless with eyes closed at onset; fluttering eye
movements and forceful eye closure common; out-of-phase, thrashing limb move-
ments and pelvic thrusting common; urinary incontinence unusual; refractory to
treatment
Syncope Precipitating circumstances usually identifiable; prodrome of wooziness but no aura or
unilateral symptoms; loss of consciousness brief (<20 sec), with rapid return to nor-
mal; a few muscle jerks (convulsive syncope) can occur at end because of hypoxia
Transient global amnesia Isolated amnesic syndrome; prolonged duration (several hours); no alteration of con-
sciousness; no confusion, weakness, or aphasia; persistent memory gap during
period of attack; recurrence unusual
Transient ischemic attack Sudden onset without progression of symptoms; variable symptoms related to brain
and vascular anatomy; negative features (e.g., weakness, loss of sensation, aphasia)
predominate
The New England Journal of Medicine
Downloaded from nejm.org on August 1, 2013. For personal use only. No other uses without permission.
Copyright 2008 Massachusetts Medical Society. All rights reserved.
The new engl and journal o f medicine
n engl j med 359;2 www.nejm.org july 10, 2008
168
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The New England Journal of Medicine
Downloaded from nejm.org on August 1, 2013. For personal use only. No other uses without permission.
Copyright 2008 Massachusetts Medical Society. All rights reserved.
clinical practice
n engl j med 359;2 www.nejm.org july 10, 2008
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The New England Journal of Medicine
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The new engl and journal o f medicine
n engl j med 359;2 www.nejm.org july 10, 2008
172
working at heights, and swimming or bathing
alone. In most states, patients who are not seizure-
free are prohibited from driving; the required dura-
tion of time without seizures varies across states
and ranges from 3 months to 1 year.
11

As many as 55% of patients with uncontrolled
seizures are depressed.
12,13
Even patients with
well-controlled seizures have rates of depression
that are higher than rates among the general
population, and suicide rates are tripled, with the
highest rates in the 6 months after diagnosis.
14-16

Patients should be observed for signs of depres-
sion and queried specifically about their mood,
with attention to the potential need for psychiat-
ric referral and treatment. A simple screening tool
developed specifically for use in people with epi-
lepsy may facilitate prompt recognition of major
depression.
17,18

A recent Food and Drug Administration ad-
visory indicated an increased risk of suicidal
thoughts among patients who were in the treat-
ment group in add-on studies of new antiepilep-
tic drugs.
19
Over the 2 to 6 months of treatment
in the various studies, the absolute risk was 0.43%
among patients receiving active treatment as com-
pared with 0.22% among patients in the placebo
group. These findings provide support for the
assessment of mood in patients who are starting
antiepileptic drug therapy.
Pharmacologic Therapy
Opinion remains divided about treating patients
who have had only a single seizure, since only
about 25% of patients will have a recurrence with-
in 2 years in the absence of factors that predict a
high probability of recurrence (e.g., epileptiform
activity detected on an EEG or a known cause such
as remote major head trauma).
20
Even with one or
more risk factors, the recurrence rate at 2 years is
no more than 40%. Furthermore, although ran-
domized trials have shown that treatment reduces
the risk of seizure recurrence by 30 to 60%, the
likelihood of being seizure-free at 3 to 5 years
after a first or second seizure was similar whether
treatment was started after the first or second sei-
zure or deferred initially and started only if a sei-
zure recurred.
21
Treatment is almost always justi-
fied when a diagnosis of epilepsy has been made.
In the past two decades, nine new antiepilep-
tic drugs have been marketed, making the choice
of initial therapy complex. Antiepileptic drugs are
classified as being either broad-spectrum or nar-
row-spectrum drugs with regard to efficacy against
different seizure types and epilepsy syndromes.
Broad-spectrum antiepileptic drugs are particu-
larly useful because they are reasonable initial
choices in most adult patients, regardless of the
type of seizure or syndrome. These drugs include
valproate, lamotrigine, topiramate, and levetirac-
etam (the efficacy of which [in generalized sei-
zures] is supported by randomized, controlled
trials), and zonisamide (the efficacy of which [in
generalized seizures] is based on open studies and
clinical experience). In contrast, narrow-spectrum
drugs, which include carbamazepine, phenytoin,
gabapentin, tiagabine, oxcarbazepine, and pregab-
alin, should be restricted to patients who have lo-
calization-related (focal) epilepsy with partial and
secondarily generalized seizures.
22
These drugs are
less effective than broad-spectrum agents in the
idiopathic generalized epilepsy syndromes (e.g.,
juvenile myoclonic epilepsy and childhood ab-
sence epilepsy), and they may even exacerbate
some seizure types in these patients.
23
About half
of patients in whom epilepsy is new ly diagnosed
become seizure-free while receiving the first anti-
epileptic drug. Failure of the first antiepileptic
drug for reasons other than tolerability increases
the likelihood of nonresponse to other drugs, but
nearly two thirds of patients become seizure-free
after receiving the second or third drug.
24
Head-to-head trials suggest similar efficacy
among the various antiepileptic drugs against par-
tial seizures.
22
However, a recent large, pragmatic,
randomized, controlled trial involving patients
with generalized epilepsy showed valproic acid to
be more effective than lamotrigine and topira-
mate. Lamotrigine had almost twice the failure
rate because of inadequate seizure control, where-
as topiramate was similarly effective in control-
ling seizures but had a higher failure rate caused
by discontinuation because of side effects.
25
The selection of medication should be informed
by patient characteristics, including sex, age, and
coexisting conditions that affect the likelihood of
adverse events. Table 2 provides useful informa-
tion regarding the initiation of antiepileptic drugs.
A common practice in patients who present with
a first seizure has been to provide a loading dose
of phenytoin in the emergency department. How-
ever, clinical trials in newly diagnosed epilepsy
have not shown any advantage associated with
phenytoin,
27
and it is generally preferable to initi-
ate whichever antiepileptic drug is considered to
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Copyright 2008 Massachusetts Medical Society. All rights reserved.
clinical practice
n engl j med 359;2 www.nejm.org july 10, 2008
173
be most appropriate with regard to other patient
characteristics. Table 3 lists considerations rele-
vant to selecting initial therapy in particular pa-
tient populations.
Adverse Effects
Table 2 lists dose-related, idiosyncratic, and long-
term adverse effects of antiepileptic drugs. Loss of
bone density may occur during treatment with phe-
nytoin and possibly with other hepatic enzyme
inducing antiepileptic drugs such as carbamazepine
and phenobarbital.
28,29
Both men and women who
take enzyme-inducing drugs should receive sup-
plemental vitamin D (up to 2000 IU daily) and
calcium (up to 1200 mg per day), and they should
have periodic bone-density measurement.
29
Choice of Antiepileptic Drugs in Women
Antiepileptic drugs, and especially valproate, have
been associated with reproductive endocrine dis-
orders, most notably features of polycystic ovary
syndrome (e.g., irregular menstrual cycles, weight
gain, and hirsutism).
30,31
This association appears
to be related at least in part to the epilepsy itself,
32,33

but in the majority of women, medication seems
to play the major role.
34,35
Observational studies
have shown clinically important associations be-
tween the use of valproate, alone or in combination
with other drugs, and the development of poly-
cystic ovaries, anovulatory cycles, and hyperan-
drogenism.
34,36,37
Hepatic enzymeinducing antiepileptic drugs
such as phenytoin, carbamazepine, and phenobar-
bital, as well as topiramate and oxcarbazepine,
increase the clearance of oral contraceptive pills.
Thus, women taking these drugs who use oral
contraceptive pills are advised to use preparations
containing at least 50 g of ethinyl estradiol in
order to reduce the chance of pregnancy.
38
How-
ever, the contraceptive efficacy of higher-dose oral
contraceptive pills has not been well studied, and
alternative methods (e.g., barrier contraception)
should be discussed. The dosage of lamotrigine
requires adjustment when oral contraceptive pills
are started or discontinued, because oral contra-
ceptives enhance the clearance of lamotrigine.
38

Serum concentrations of lamotrigine should be
followed in this setting and in pregnancy,
38
which
increases the clearance of many antiepileptic
drugs, but particularly that of lamotrigine.
Babies born to women with epilepsy have an
increased rate of malformations; this is believed
to be attributable mostly to antiepileptic drugs.
39

Studies of the effect of specific drugs during preg-
nancy are hampered by confounding factors such
as the type and severity of epilepsy and the use
of more than one agent in many patients. No anti-
epileptic drug can be considered to be absolutely
safe. Newer drugs are less well studied, but the
evidence linking valproate to an increased risk of
birth defects is most convincing and sufficient
to advise against its use in women of childbear-
ing age unless there is no alternative.
40
The risk
of birth defects is likely to be minimized further
by treating with monotherapy and drug dosages
as low as possible during pregnancy, although the
evidence to support these recommendations is
limited. Retrospective analyses of school-age chil-
dren have suggested associations between in-
trauterine exposure to valproate (but not other
antiepileptic drugs) and lower IQ scores and de-
velopmental delay
41,42
; this finding warrants con-
firmation in prospective studies.
Concurrent Medical Conditions
Some patients particularly many elderly pa-
tients may be poor candidates for some anti-
epileptic drugs because of coexisting conditions
or the use of medications with which a given an-
tiepileptic drug may interact.
In patients with hepatic dysfunction, dosing
adjustments of drugs metabolized by the liver may
be necessary, although their use is not necessar-
ily contraindicated; valproate, however, should be
avoided, since it can increase ammonia levels.
Many antiepileptic drugs (particularly valproate,
phenytoin, phenobarbital, and carbamazepine) can
cause elevations in hepatic enzyme levels, particu-
larly alanine aminotransferase and -glutamyl-
transferase.
43
Stable mild elevations (even up to
two times the normal range) are not a substan-
tive concern, but they may complicate monitor-
ing of patients with underlying hepatic disease.
A history of renal calculi is a relative contraindi-
cation to the use of topiramate and zonisamide,
which can predispose to stone formation.
44
Both
carbamazepine and oxcarbazepine can cause hy-
ponatremia and should generally be avoided in
patients with preexisting hyponatremia or risk
factors for hyponatremia (e.g., older age, history
of excess water intake, renal failure, or concur-
rent use of other medications associated with
hyponatremia).
45
Levels of drugs metabolized by hepatic mi-
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n engl j med 359;2 www.nejm.org july 10, 2008
174
crosomal enzymes (e.g., cytochrome P-450 and
glucuronyl transferases) can be altered consider-
ably by concurrent antiepileptic drug use (Table 4).
Enzyme-inducing antiepileptic drugs should be
avoided, whenever possible, in patients receiving
antiretroviral therapy for human immunodefi-
ciency virus infection, in organ-transplant recipi-
ents, and in patients with cancer being treated
with chemotherapy.
Other medical conditions may also influence
the choice of antiepileptic drugs. Carbamazepine
can cause partial or complete heart block and
aggravate sick sinus syndrome.
47
Carbamazepine
may reduce the white-cell count and should prob-
ably be avoided in patients with blood dyscrasias,
because a change in the white-cell count may be
difficult to interpret. Valproate causes a dose-
related thrombocytopenia in up to 17% of patients
and should be avoided in patients who are at risk
for bleeding.
48,49

Carbamazepine and gabapentin are associated
with modest weight gain (5 to 10 lb [2.3 to 4.5 kg]),
and valproate and pregabalin are associated with
more substantial weight gain (10 to 50 lb [4.5 to
23.0 kg]) in about one third of patients. These
drugs should be avoided, if possible, in patients
with diabetes or eating disorders. Felbamate, topi-
ramate, and zonisamide can result in variable
weight loss.
50,51
Weight should be recorded be-
fore starting antiepileptic drugs and at follow-up
visits.
Monitoring
Routine follow-up EEG is not usually indicated,
but reassessment can be useful when deciding
whether to discontinue antiepileptic drugs, since
patients with abnormal EEGs have a modestly
higher risk of recurrence.
52
There is controversy
about how often to monitor levels of antiepileptic
drugs and perform routine laboratory tests (e.g.,
complete blood count, measurement of electro-
lyte levels, and liver-function tests).
53
With older
antiepileptic drugs (e.g., phenytoin, carbamazepine,
valproate, and phenobarbital), yearly monitoring
is sufficient in stable patients in whom more fre-
quent monitoring in the first 6 to 12 months af-
ter treatment initiation has been normal. Table 2
summarizes recommendations for the monitor-
ing of newer antiepileptic drugs. The target-dose
range (listed in Table 2) corresponds to the aver-
age blood levels required for tolerability and sei-
zure control. Many patients do well with levels
above or below those values; thus, dosages should
be adjusted primarily on the basis of seizure con-
trol and side effects.
53
Areas of Uncertainty
There is considerable uncertainty as to when an-
tiepileptic drugs can be discontinued. In various
studies, the incidence of seizure recurrence after
withdrawal of the drug after a 2-year seizure-free
period ranges from 12 to 66%.
54,55
Risk factors
The new engl and journal o f medicine
Table 4. Common Drugs with Either Increased or Reduced Clearance in the Presence of Antiepileptic Drugs.*
Type of Medication
Increased Clearance
(and Need for Higher Doses) with Phenytoin,
Phenobarbital, Carbamazepine
Decreased Clearance
(and Need for Lower Doses)
with Valproic Acid
Cardiac Mexiletine, quinidine, amiodarone, propranolol, meto-
prolol, nifedipine, felodipine, nimodipine, digoxin,
lovastatin, simvastatin, dicoumarol, warfarin
Nimodipine
Psychiatric Amitriptyline, nortriptyline, imipramine, desipramine,
clomipramine, citalopram, paroxetine, buproprion,
haloperidol, chlorpromazine, clozapine, olanzapine,
risperidone, quetiapine
Amitriptyline, nortriptyline, clomip-
ramine, paroxetine
Antineoplastic Cyclophosphamide, busulfan, etoposide, methotrexate,
teniposide, some vinca alkaloids
Antiinfective Praziquantel, albendazole, doxycycline, nevirapine,
efavirenz, delavirdine, indinavir, ritonavir, saquinavir
Zidovudine, possibly others
Other Cyclosporine, tacrolimus, diazepam, alprazolam,
prednisone, oral contraceptive pills, theophylline,
methadone
Lorazepam, diazepam
* Data are from Patsalos and Perucca.
46
This list is not comprehensive.
The New England Journal of Medicine
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clinical practice
n engl j med 359;2 www.nejm.org july 10, 2008
175
for relapse include the onset of epilepsy in ado-
lescence, partial seizures, abnormal EEG, and spe-
cific epilepsy syndromes. The decision to with-
draw antiepileptic drugs depends on individual
circumstance and patient preference.
Guidelines from Professional
Societies
The American Academy of Neurology, the Ameri-
can Epilepsy Society, and the International League
against Epilepsy have issued guidelines for the se-
lection of pharmacologic therapy in patients with
newly diagnosed epilepsy.
22,56
As described above,
the American Academy of Neurology has also re-
leased guidelines on the evaluation of patients with
an unprovoked first seizure and neuroimaging of
patients with a seizure who are seen in the emer-
gency department.
7,10
The recommendations in this
article are consistent with these guidelines.
Conclusions and
Recommendations
The patient described in the vignette has had two
probable seizures, one witnessed and the other
suggested by history, and it is therefore appropri-
ate to initiate antiepileptic drug therapy. Evalua-
tion would include a thorough neurologic exami-
nation, EEG, and brain MRI, but treatment would
not be dependent on abnormal findings. If the
EEG and MRI are normal, there is insufficient in-
formation to classify the seizures definitively as
being partial or generalized, so a broad-spectrum
antiepileptic drug is preferable. If the patient uses,
or plans to use, an oral contraceptive pill, it would
be preferable to avoid antiepileptic drugs that will
increase the clearance of oral contraceptive pills
(see above); oral contraceptive pills with a higher
estrogen content, which are commonly recom-
mended in this setting, may carry increased health
risks. Valproate should also be avoided because
of the risk of teratogenicity. We would consider
lamotrigine or levetiracetam to be preferred op-
tions for initial treatment in this patient; as al-
ways, this recommendation should be predicated
on individual patient characteristics.
Dr. French reports receiving consulting fees from Spherics,
Johnson & Johnson, Pfizer, and AstraZeneca, lecture fees from
Kyowa Pharma, and grant support from Eisai, UCB Pharma, Jazz
Pharmaceuticals, SK Pharmaceuticals, and Intranasal Therapeu-
tics; and serving as director of the nonprofit organizations The
Epilepsy Therapy Development Project and The Epilepsy Study
Consortium. These organizations, which receive payments for Dr.
Frenchs time spent consulting, lecturing, and providing research
services (from Amarin, AstraZeneca, Bial, Cyberonics, Eisai, Endo
Pharmaceuticals, GlaxoSmithKline, Icagen, Intranasal Therapeu-
tics, Jazz Pharmaceuticals, Johnson & Johnson, NeuroVista, Ortho-
McNeil, Ovation Pharmaceuticals, Pfizer, Schwarz Pharma, SK
Pharmaceuticals, Spherics, Supernus Pharmaceuticals, Taro Phar-
maceuticals, Teva Pharmaceuticals, UCB Pharma, and Valeant),
pay a fixed portion of Dr. Frenchs salary. Dr. Frenchs academic
employers, previously the Department of Neurology at the Univer-
sity of Pennsylvania, and currently the NYU Comprehensive Epi-
lepsy Center, have also received compensation for her work con-
sulting or speaking from UCB Pharma, GlaxoSmithKline, Valeant,
and Johnson & Johnson. No other potential conflict of interest
relevant to this article was reported.
An audio version of this article is available at www.nejm.org.
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