clinical practice
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.
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?
From the Department of Neurology, New Epilepsy, which is defined as two or more seizures that are not provoked by other
York University School of Medicine (J.A.F.); illnesses or circumstances, affects about 45 million people worldwide. In the United
and the Department of Neurology, Co-
lumbia University Medical Center (T.P.) — States, the prevalence of epilepsy is approximately 6 to 8 per 1000 population, and
both in New York. Address reprint requests the incidence is approximately 26 to 40 per 100,000 person-years, with higher rates
to Dr. French at the NYU Comprehensive among infants and persons older than 60 years of age.1-3 Approximately 70% of
Epilepsy Center, 403 E. 34th St., 4th Fl.,
New York, NY 10016, or at jacqueline. adults with new-onset epilepsy have partial (focal) seizures.3 In the majority of cases
french@nyumc.org. (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%),
N Engl J Med 2008;359:166-76.
Copyright © 2008 Massachusetts Medical Society.
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
S t r ategie s a nd E v idence
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 patient’s 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.
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clinical pr actice
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168
Table 2. Initiation of Antiepileptic Drugs as Initial Monotherapy in the Absence of Special Considerations.
Gabapentin (Neurontin) 300–600 mg; increase daily 900 12–20 Sedation, fatigue, dizzi- None known Gastrointestinal absorp-
dose by 300–600 mg ness, mild weight gain, tion dose-dependent,
each wk‡ ataxia, behavioral ef- reducing bioavailabil-
fects (in children) ity at doses >1200
mg/day
Lamotrigine (Lamictal, 25 mg; initial monotherapy: 100–200 3–14 Dizziness, blurred vision, Rash, Stevens–Johnson syn-
Lamictal XR) 25 mg/day for 2 wk, insomnia, headache drome (in 1–3/1000 pa-
then 50 mg/day for tients); hypersensitivity,
2 wk, followed by in- multiorgan failure, hepatic
creases in the daily dose failure (all rare)
of 25–50 mg each wk
Levetiracetam (Keppra, 250–500 mg; increase daily 1000–2000 10–40 Fatigue, dizziness, irritabil- Psychosis (rare)
n e w e ng l a n d j o u r na l
each wk‡§
Oxcarbazepine (Trileptal) 300–600 mg; increase daily 900–1200 3–40 (10-monohy- Fatigue, dizziness, ataxia, Rash; Stevens–Johnson syn- 10-monohydroxy metab-
dose by 300–600 mg droxy metabolite) diplopia, nausea, vom- drome or toxic epidermal olite is active compo-
each wk iting, headache necrolysis (0.5–6.0 cases nent
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like syndrome sutism may occur
with long-term use;
risk of osteopenia
Phenobarbital (generic only) 30 mg; increase daily dose 60–120 15–45 Fatigue, dizziness, ataxia, Generally rare; blood dyscra-
by 30 mg every 2 wk diplopia, nausea, vom- sias, hepatic failure, rash,
iting, confusion, de- Stevens–Johnson syn-
pression, hyperactivity drome or toxic epidermal
(in children) necrolysis, arthritis
Pregabalin (Lyrica) 75–150 mg; increase daily 150–300 Not established Fatigue, dizziness, ataxia, None reported Schedule V controlled
dose by 75–150 mg diplopia, weight gain, substance
each wk‡ edema
Tiagabine (Gabitril) 4 mg; increase daily dose 16–36 Not useful Fatigue, dizziness, ataxia, Spike-wave status epilepticus
by 4 mg each wk somnolence, nervous-
ness, weakness
Topiramate (Topamax) 25–50 mg; increase daily 100–200 5–25 Drowsiness, ataxia, word- Significant metabolic acidosis
dose by 25–50 mg each finding difficulty and (in 3% of patients), renal
wk slowed speech, diffi calculi (in 1.5% of pa-
culty concentrating, an- tients), acute glaucoma
orexia, weight loss, par- (rare), heatstroke
esthesias, metabolic
acidosis, oligohydrosis
(mostly in children)
Valproate, valproic acid 250–500 mg, or 10–15 mg/ 750–2000 40–100 Drowsiness, ataxia, weight Hepatic failure (in 1/20,000
(Depakene, Depacon), kg orally once a day; in- gain, nausea, vomiting, patients, higher rate
divalproex sodium crease daily dose by thrombocytopenia, among children and with
(Depakote, Depakote 250–500 mg each wk§ tremor, hair loss polytherapy), hyperam-
ER) monemia, aplastic anemia
clinical pr actice
* There is usually no need for intervention unless the neutrophil count is below 1000 cells per cubic millimeter.
† HLA-B*1502 testing is now recommended in patients of Asian descent, since this haplotype is associated with a higher risk of Stevens–Johnson syndrome.26
‡ This drug can be initiated at a therapeutic dose.
§ This drug can be administered intravenously.
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169
170
Table 3. Factors Affecting the Choice of Antiepileptic Drugs in Specific Patient Populations.*
known psychiatric
disorder
Oxcarbazepine OCP interaction Caution in patients with Risk of hyponatremia May aggravate general- May aggravate myoclo-
carbamazepine hyper- ized seizures nus, atypical absence
natremia; reduces T4
and free T4 levels
Phenytoin OCP interaction; increased Enzyme induction may Not always well tolerat- Reduces bone density;
risk of fetal anticonvul- lead to interactions ed; more likely to increased risk of gin-
sant syndrome (includ- with other medications; lead to nonlinear ki- gival hyperplasia, hir-
ing hypertelorism, epi- caution in patients with netics‡ sutism, coarsened
canthal folds, digital liver disease; reduces facial features, lym
hyperplasia, and higher T4 and free T4 levels; phadenopathy; rela-
risk of major malforma- may worsen heart block tively inexpensive
tions) in offspring if or arrhythmia; may
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taken during pregnancy mask symptoms of hy-
poglycemia in diabetes;
may cause hypotension
Phenobarbital OCP interaction; possible Enzyme induction may Risk of cognitive dys- Increased risk of behav- May cause exacerbation
teratogen lead to interactions function ioral issues of seizures when
with other medications; withdrawn, hyperac-
caution in patients with tivity in children; least
liver disease; reduce expensive antiepilep-
dose in patients with tic drug
renal impairment
Pregabalin Reduce dose in patients Reduced dose required May aggravate myo Weight gain, peripheral
with renal impairment clonus edema
Tiagabine May aggravate myo May aggravate myoclo-
clonus nus, atypical absence
seizures
Topiramate OCP interaction at doses Renal calculi, may cause Reduced dose may be Weight loss; rarely oligo-
>200 mg metabolic acidosis; re- required hydrosis or hyper-
duce dose in patients thermia
with renal impairment
Valproate, valproic Possible PCO syndrome, Enzyme inhibition may Weight gain, alopecia
acid, divalproex teratogenicity, and de- lead to possible inter-
sodium creased intellectual actions with other
function in offspring if medications; caution
taken during pregnancy in patients with hepatic
dysfunction and in pa-
tients at risk for bleed-
ing; can cause pancrea-
clinical pr actice
titis
Zonisamide Renal calculi; reduce dose May need to reduce Weight loss; rarely oligo-
in patients with renal dose hidrosis or hyper-
impairment; may need thermia
* Dose-related and idiosyncratic reactions are listed only if certain populations are at increased risk for these reactions. OCP denotes oral contraceptive pill or patch, PCO polycystic ovary
syndrome, and T4 thyroxine.
† Limited data are available on the use of newer agents (e.g., gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, and zonisamide) during pregnancy.
‡ When the phenytoin metabolic pathway is saturated, metabolism switches to zero-order kinetics and clearance is substantially reduced; this can lead to toxic levels of the drug.
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171
The n e w e ng l a n d j o u r na l of m e dic i n e
working at heights, and swimming or bathing row-spectrum drugs with regard to efficacy against
alone. In most states, patients who are not seizure- different seizure types and epilepsy syndromes.
free are prohibited from driving; the required dura- Broad-spectrum antiepileptic drugs are particu-
tion of time without seizures varies across states larly useful because they are reasonable initial
and ranges from 3 months to 1 year.11 choices in most adult patients, regardless of the
As many as 55% of patients with uncontrolled type of seizure or syndrome. These drugs include
seizures are depressed.12,13 Even patients with valproate, lamotrigine, topiramate, and levetirac-
well-controlled seizures have rates of depression etam (the efficacy of which [in generalized sei-
that are higher than rates among the general zures] is supported by randomized, controlled
population, and suicide rates are tripled, with the trials), and zonisamide (the efficacy of which [in
highest rates in the 6 months after diagnosis.14‑16 generalized seizures] is based on open studies and
Patients should be observed for signs of depres- clinical experience). In contrast, narrow-spectrum
sion and queried specifically about their mood, drugs, which include carbamazepine, phenytoin,
with attention to the potential need for psychiat- gabapentin, tiagabine, oxcarbazepine, and pregab-
ric referral and treatment. A simple screening tool alin, should be restricted to patients who have lo-
developed specifically for use in people with epi- calization-related (focal) epilepsy with partial and
lepsy may facilitate prompt recognition of major secondarily generalized seizures.22 These drugs are
depression.17,18 less effective than broad-spectrum agents in the
A recent Food and Drug Administration ad- idiopathic generalized epilepsy syndromes (e.g.,
visory indicated an increased risk of suicidal juvenile myoclonic epilepsy and childhood ab-
thoughts among patients who were in the treat- sence epilepsy), and they may even exacerbate
ment group in add-on studies of new antiepilep- some seizure types in these patients.23 About half
tic drugs.19 Over the 2 to 6 months of treatment of patients in whom epilepsy is newly diagnosed
in the various studies, the absolute risk was 0.43% become seizure-free while receiving the first anti-
among patients receiving active treatment as com- epileptic drug. Failure of the first antiepileptic
pared with 0.22% among patients in the placebo drug for reasons other than tolerability increases
group. These findings provide support for the the likelihood of nonresponse to other drugs, but
assessment of mood in patients who are starting nearly two thirds of patients become seizure-free
antiepileptic drug therapy. after receiving the second or third drug.24
Head-to-head trials suggest similar efficacy
Pharmacologic Therapy among the various antiepileptic drugs against par-
Opinion remains divided about treating patients tial seizures.22 However, a recent large, pragmatic,
who have had only a single seizure, since only randomized, controlled trial involving patients
about 25% of patients will have a recurrence with- with generalized epilepsy showed valproic acid to
in 2 years in the absence of factors that predict a be more effective than lamotrigine and topira-
high probability of recurrence (e.g., epileptiform mate. Lamotrigine had almost twice the failure
activity detected on an EEG or a known cause such rate because of inadequate seizure control, where-
as remote major head trauma).20 Even with one or as topiramate was similarly effective in control-
more risk factors, the recurrence rate at 2 years is ling seizures but had a higher failure rate caused
no more than 40%. Furthermore, although ran- by discontinuation because of side effects.25
domized trials have shown that treatment reduces The selection of medication should be informed
the risk of seizure recurrence by 30 to 60%, the by patient characteristics, including sex, age, and
likelihood of being seizure-free at 3 to 5 years coexisting conditions that affect the likelihood of
after a first or second seizure was similar whether adverse events. Table 2 provides useful informa-
treatment was started after the first or second sei- tion regarding the initiation of antiepileptic drugs.
zure or deferred initially and started only if a sei- A common practice in patients who present with
zure recurred.21 Treatment is almost always justi- a first seizure has been to provide a loading dose
fied when a diagnosis of epilepsy has been made. of phenytoin in the emergency department. How-
In the past two decades, nine new antiepilep- ever, clinical trials in newly diagnosed epilepsy
tic drugs have been marketed, making the choice have not shown any advantage associated with
of initial therapy complex. Antiepileptic drugs are phenytoin,27 and it is generally preferable to initi-
classified as being either broad-spectrum or nar- ate whichever antiepileptic drug is considered to
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clinical pr actice
be most appropriate with regard to other patient to be attributable mostly to antiepileptic drugs.39
characteristics. Table 3 lists considerations rele- Studies of the effect of specific drugs during preg-
vant to selecting initial therapy in particular pa- nancy are hampered by confounding factors such
tient populations. as the type and severity of epilepsy and the use
of more than one agent in many patients. No anti-
Adverse Effects epileptic drug can be considered to be absolutely
Table 2 lists dose-related, idiosyncratic, and long- safe. Newer drugs are less well studied, but the
term adverse effects of antiepileptic drugs. Loss of evidence linking valproate to an increased risk of
bone density may occur during treatment with phe- birth defects is most convincing and sufficient
nytoin and possibly with other hepatic enzyme– to advise against its use in women of childbear-
inducing antiepileptic drugs such as carbamazepine ing age unless there is no alternative.40 The risk
and phenobarbital.28,29 Both men and women who of birth defects is likely to be minimized further
take enzyme-inducing drugs should receive sup- by treating with monotherapy and drug dosages
plemental vitamin D (up to 2000 IU daily) and as low as possible during pregnancy, although the
calcium (up to 1200 mg per day), and they should evidence to support these recommendations is
have periodic bone-density measurement.29 limited. Retrospective analyses of school-age chil-
dren have suggested associations between in-
Choice of Antiepileptic Drugs in Women trauterine exposure to valproate (but not other
Antiepileptic drugs, and especially valproate, have antiepileptic drugs) and lower IQ scores and de-
been associated with reproductive endocrine dis- velopmental delay41,42; this finding warrants con-
orders, most notably features of polycystic ovary firmation in prospective studies.
syndrome (e.g., irregular menstrual cycles, weight
gain, and hirsutism).30,31 This association appears Concurrent Medical Conditions
to be related at least in part to the epilepsy itself,32,33 Some patients — particularly many elderly pa-
but in the majority of women, medication seems tients — may be poor candidates for some anti-
to play the major role.34,35 Observational studies epileptic drugs because of coexisting conditions
have shown clinically important associations be- or the use of medications with which a given an-
tween the use of valproate, alone or in combination tiepileptic drug may interact.
with other drugs, and the development of poly- In patients with hepatic dysfunction, dosing
cystic ovaries, anovulatory cycles, and hyperan adjustments of drugs metabolized by the liver may
drogenism.34,36,37 be necessary, although their use is not necessar-
Hepatic enzyme–inducing antiepileptic drugs ily contraindicated; valproate, however, should be
such as phenytoin, carbamazepine, and phenobar- avoided, since it can increase ammonia levels.
bital, as well as topiramate and oxcarbazepine, Many antiepileptic drugs (particularly valproate,
increase the clearance of oral contraceptive pills. phenytoin, phenobarbital, and carbamazepine) can
Thus, women taking these drugs who use oral cause elevations in hepatic enzyme levels, particu-
contraceptive pills are advised to use preparations larly alanine aminotransferase and γ-glutamyl
containing at least 50 µg of ethinyl estradiol in transferase.43 Stable mild elevations (even up to
order to reduce the chance of pregnancy.38 How- two times the normal range) are not a substan-
ever, the contraceptive efficacy of higher-dose oral tive concern, but they may complicate monitor-
contraceptive pills has not been well studied, and ing of patients with underlying hepatic disease.
alternative methods (e.g., barrier contraception) A history of renal calculi is a relative contraindi-
should be discussed. The dosage of lamotrigine cation to the use of topiramate and zonisamide,
requires adjustment when oral contraceptive pills which can predispose to stone formation.44 Both
are started or discontinued, because oral contra- carbamazepine and oxcarbazepine can cause hy-
ceptives enhance the clearance of lamotrigine.38 ponatremia and should generally be avoided in
Serum concentrations of lamotrigine should be patients with preexisting hyponatremia or risk
followed in this setting and in pregnancy,38 which factors for hyponatremia (e.g., older age, history
increases the clearance of many antiepileptic of excess water intake, renal failure, or concur-
drugs, but particularly that of lamotrigine. rent use of other medications associated with
Babies born to women with epilepsy have an hyponatremia).45
increased rate of malformations; this is believed Levels of drugs metabolized by hepatic mi-
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The n e w e ng l a n d j o u r na l of m e dic i n e
Table 4. Common Drugs with Either Increased or Reduced Clearance in the Presence of Antiepileptic Drugs.*
* Data are from Patsalos and Perucca.46 This list is not comprehensive.
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clinical pr actice
for relapse include the onset of epilepsy in ado- formation to classify the seizures definitively as
lescence, partial seizures, abnormal EEG, and spe- being partial or generalized, so a broad-spectrum
cific epilepsy syndromes. The decision to with- antiepileptic drug is preferable. If the patient uses,
draw antiepileptic drugs depends on individual or plans to use, an oral contraceptive pill, it would
circumstance and patient preference. be preferable to avoid antiepileptic drugs that will
increase the clearance of oral contraceptive pills
(see above); oral contraceptive pills with a higher
Guidel ine s from Profe ssiona l
So cie t ie s estrogen content, which are commonly recom-
mended in this setting, may carry increased health
The American Academy of Neurology, the Ameri- risks. Valproate should also be avoided because
can Epilepsy Society, and the International League of the risk of teratogenicity. We would consider
against Epilepsy have issued guidelines for the se- lamotrigine or levetiracetam to be preferred op-
lection of pharmacologic therapy in patients with tions for initial treatment in this patient; as al-
newly diagnosed epilepsy.22,56 As described above, ways, this recommendation should be predicated
the American Academy of Neurology has also re- on individual patient characteristics.
leased guidelines on the evaluation of patients with Dr. French reports receiving consulting fees from Spherics,
an unprovoked first seizure and neuroimaging of Johnson & Johnson, Pfizer, and AstraZeneca, lecture fees from
patients with a seizure who are seen in the emer- Kyowa Pharma, and grant support from Eisai, UCB Pharma, Jazz
Pharmaceuticals, SK Pharmaceuticals, and Intranasal Therapeu-
gency department.7,10 The recommendations in this tics; and serving as director of the nonprofit organizations The
article are consistent with these guidelines. Epilepsy Therapy Development Project and The Epilepsy Study
Consortium. These organizations, which receive payments for Dr.
French’s time spent consulting, lecturing, and providing research
C onclusions a nd services (from Amarin, AstraZeneca, Bial, Cyberonics, Eisai, Endo
R ec om mendat ions Pharmaceuticals, GlaxoSmithKline, Icagen, Intranasal Therapeu-
tics, Jazz Pharmaceuticals, Johnson & Johnson, NeuroVista, Ortho-
McNeil, Ovation Pharmaceuticals, Pfizer, Schwarz Pharma, SK
The patient described in the vignette has had two Pharmaceuticals, Spherics, Supernus Pharmaceuticals, Taro Phar-
probable seizures, one witnessed and the other maceuticals, Teva Pharmaceuticals, UCB Pharma, and Valeant),
suggested by history, and it is therefore appropri- pay a fixed portion of Dr. French’s salary. Dr. French’s academic
employers, previously the Department of Neurology at the Univer-
ate to initiate antiepileptic drug therapy. Evalua- sity of Pennsylvania, and currently the NYU Comprehensive Epi-
tion would include a thorough neurologic exami- lepsy Center, have also received compensation for her work con-
nation, EEG, and brain MRI, but treatment would sulting or speaking from UCB Pharma, GlaxoSmithKline, Valeant,
and Johnson & Johnson. No other potential conflict of interest
not be dependent on abnormal findings. If the relevant to this article was reported.
EEG and MRI are normal, there is insufficient in- An audio version of this article is available at www.nejm.org.
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