Epilepsia, 44(Suppl.
3):41–44, 2003
Blackwell Publishing, Inc.

C International League Against Epilepsy
Case Reports of Women with Epilepsy
∗ Deborah T. Combs-Cantrell and †Mark S. Yerby
∗ North Texas Epilepsy Center, and Epilepsy Monitoring Unit, Baylor Hospital, Irving, Texas; and †North Pacific Epilepsy Research,
Portland, Oregon, U.S.A.
Women with epilepsy are faced with many unique is-
sues regarding their reproductive health. Pregnancies in
women with epilepsy are considered high risk because of
the increased risk for seizures, maternal complications,
and adverse outcomes in the newborn. Infants of women
with epilepsy have a two- to threefold increase in the rate
of fetal malformations. Investigators have hypothesized
that the increased risks are secondary to genetic predis-
position, exposure of the fetus to seizures, and in utero
exposure to antiepileptic drugs (AEDs). However, the rel-
ative contribution of each factor is undetermined.
Two similar cases of women with epilepsy involving
pregnancy and the risk of neural tube defects (NTDs) are
presented. Although the cases are similar, they illustrate
the diverse challenges faced in the care of women with
epilepsy and their unborn children.
CASE REPORT 1
A 36-year-old right-handed woman presented with a
history of seizures that began at age 16. She was the prod-
uct of a normal pregnancy, birth, and delivery. She had
normal developmental milestones. She denied any history
of febrile seizures, central nervous system infections, head
injury, status epilepticus, or skin lesions and reported no
family history of seizures.
Her seizures were described as generalized tonic-clonic.
She had been seizure free for 2 years. Originally, she re-
ceived phenobarbital. The tonic-clonic seizures were con-
trolled, but she began to have episodes of nonresponsive
staring. Her medication was changed to phenytoin (PHT).
PHT controlled both the staring episodes and the tonic-
clonic seizures, but severe gum hypertrophy occurred. She
was changed to carbamazepine, but the episodes of star-
ing became more frequent and she developed involuntary
jerking of her upper extremities. For the past 2 years, she
had received 500 mg of valproate (VPA) three times per
Address correspondence and reprint requests to Dr. D. T. Combs-
Cantrell at Epilepsy Monitoring Unit, North Texas Neuroscience Center,
440 West Interstate 635, Plaza Two, Suite 225, Irving, TX 75063, U.S.A.
E-mail: debbiec@ntnc.net
41
day. She reported no side effects, seizures, or other related
events.
Findings of computed tomography of the brain and mul-
tiple electroencephalograms (EEGs) were reported as nor-
mal. The patient’s menstrual cycles were normal. At age
30, she suffered a miscarriage at 13 weeks of gestation
while taking PHT. She had a 3.5-year-old son. During the
pregnancy, she remained seizure free. There was no ma-
ternal or paternal history of birth defects. She was taking
an oral contraceptive and had no other medical conditions.
She wished to conceive in the future. She was referred by
her gynecologist because of the increased risk for NTDs
associated with VPA.
Findings of neurological and general physical examina-
tions were normal. Magnetic resonance imaging (MRI) of
the brain, routine sleep-deprived EEG, 72-h ambulatory
EEG, complete blood count, and comprehensive chem-
istry panel yielded normal results. The peak VPA level
was 98 mg/dl and the trough level was 76 mg/dl. The pa-
tient was given folic acid 1 mg per day, calcium citrate
400 mg three times per day, selenium 30 µg per day, and
zinc 30 mg per day.
She was admitted for closed-circuit TV–EEG monitor-
ing. VPA was discontinued at the time of admission. The
interictal EEG was abnormal because of the presence of
4.5-Hz polyspike-and-wave formations in a generalized
distribution. Three myoclonic seizures and two atypical
absence seizures were recorded. She was given the di-
agnosis of juvenile myoclonic epilepsy. Before discharge,
she was given intravenous VPA, oral VPA, and lamotrigine
(LTG). She was eventually converted to LTG monother-
apy in the outpatient setting. She remained seizure free
without side effects while taking LTG 250 mg per day.
The LTG trough level was 6 mg/dl.
After 6 months of LTG monotherapy, the patient be-
came pregnant. At 9 weeks of gestation, she began to
have myoclonic jerks, and her trough LTG level was 3.5
µg/dl. LTG was increased to 300 mg per day with trough
levels of 5.8 µg/dl, and she remained seizure free. The
alpha-fetoprotein level and findings of level II ultrasonog-
raphy were normal. At 39 weeks of gestation, a healthy
male infant was born by spontaneous vaginal delivery. The
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42 D. T. COMBS-CANTRELL AND M. S. YERBY

infant was breastfed without complications. Three weeks
postpartum, the patient complained of frequent “dizzi-
ness” after the administration of LTG, and her trough LTG
levels were 8.8 µg/dl. The dose of LTG was decreased to
250 mg/day. She has remained seizure free and without
side effects since that time.
successful pregnancies and healthy children. AED selec-
tion in women with epilepsy of reproductive age should
be based on efficacy, tolerability, drug interactions, and
teratogenicity. Available data should be used to formulate
clinical care plans for women with epilepsy that are unique
and specific to each individual.

CASE REPORT 2
ADDENDUM
A 37-year-old right-handed woman presented with a
These cases have important lessons for us. Fundamen-
history of seizures that began at age 14. She was the prod-
tal understanding of the pathophysiology, epidemiology,
uct of a normal pregnancy, birth, and delivery. She had
and genetics of NTDs, as well as comorbid conditions,
normal developmental milestones. She denied any history
allows for the planning of specific interventions and risk
of febrile seizures, central nervous system infections, head
reduction. However, patients should be treated individ-
injury, skin lesions, or status epilepticus. Her maternal
ually, considering that the number of variables (such as
grandmother and brother had seizure disorders. The de-
race, age, gender, weight, and body mass index) is large.
scription of her seizures was consistent with myoclonic,
In these two cases, both patients are women with juve-
generalized tonic-clonic, and absence seizures. Findings
nile myoclonic epilepsy. However, they are quite different
of general physical and neurological examinations and an
clinically.
MRI scan of the brain were normal. Routine EEG was
The first woman had myoclonic, generalized tonic-
abnormal because of 4-Hz polyspike-and-wave forma-
clonic, and absence seizures. Her diagnosis was con-
tions. The patient was diagnosed with juvenile myoclonic
firmed by EEG, which demonstrated generalized 4.5-Hz
epilepsy.
polyspike-and-wave discharges. All of these seizure types
Originally, when her seizures began at age 14, she was
responded well to LTG. This permitted her physician to
given VPA sprinkles 250 mg three times per day, folic
reduce the potential risk for NTDs by using LTG as an
acid 1 mg per day, zinc 30 mg per day, selenium 30 µg
alternative to VPA. The other patient was historically
per day, and calcium 400 mg twice per day. VPA peak
and clinically similar in terms of seizure types. She also
levels were 80 µg/dl and a trough level was 68 µg/dl.
had “classic” generalized 4.0-Hz polyspike-and-wave dis-
She remained seizure free and without side effects for
charges. Unlike the first woman, she did not respond to
>12 years. Menstrual cycles were normal. She was tak-
LTG and in fact had a significant worsening of her my-
ing an oral contraceptive and had no other medical con-
oclonus. Exacerbations of myoclonic seizures have been
ditions. She had suffered two spontaneous miscarriages
described with LTG (1,2). It was therefore appropriate for
within the first 8 weeks of gestation. There was no ma-
her to be returned to her original VPA regimen to have her
ternal history of defects, but her husband had spina bifida
seizures controlled.
occulta. She wished to change her AED regimen before
Congenital malformations are unfortunate pregnancy
conception.
outcomes. Modern technology permits us to diagnose
She made the informed decision to change to LTG
the vast majority relatively early in gestation. It is esti-
monotherapy. Crossover to LTG monotherapy was suc-
mated that anatomic ultrasonography is >95% accurate at
cessful. However, despite increasing dosages of LTG,
16 weeks of gestational age. This may still leave parents
she had frequent myoclonic seizures. Alternative AEDs
with the uncomfortable decision of whether to terminate
were discussed, but she asked to return to her previ-
a pregnancy. This is always a difficult choice, one that
ous regimen of VPA. She was converted to her origi-
we would like our patients to be able to avoid. Although
nal VPA regimen and, in addition, was given folic acid
the risk for NTDs is only 1–2% with VPA exposure, it
4 mg per day, zinc 30 mg per day, selenium 80 µg
is clear that alternative AEDs with the broad spectrum
per day, and calcium 400 mg three times per day. She
and clinical efficacy of VPA but without this risk are
had three pregnancies with normal-term infants born by
needed.
spontaneous vaginal delivery. Each child was breastfed
Several newer AEDs, including LTG, levetiracetam,
successfully. She has remained seizure free without side
topiramate, and zonisamide, appear to be effective in a
effects.
variety of epilepsy types, although their impact on my-
oclonus and absence has yet to be clearly established.
CONCLUSION
Our experience with their safety in pregnancy is unfortu-
These cases highlight that, despite the increased risks of nately limited; however, the data are greatest for LTG. The
pregnancy in women with epilepsy, with appropriate clin- International Lamotrigine Pregnancy Registry has iden-
ical management >90% of women with epilepsy can have tified 334 first-trimester pregnancy outcomes in women

Epilepsia, Vol. 44, Suppl. 3, 2003


WOMEN WITH EPILEPSY
exposed to LTG monotherapy or polytherapy. The malfor-
mation rates when LTG is used as monotherapy, as poly-
therapy without VPA, and as polytherapy with VPA are
1.8, 4.3, and 10.0%, respectively (3). These results suggest
that LTG is relatively safe, but with low-frequency out-
comes such as NTDs, even these sample sizes have modest
power. In general, there is an inherent potential for sample
bias in registries, and this registry cannot be considered
a random sample of women taking LTG. Nevertheless, it
is a very positive thing that we have this information for
LTG: data for the other medications are extremely limited,
so much so that no estimate of the risk of those agents in
pregnancy can be made.
Another useful observation from these case reports is
the demonstration of the sharp decline in plasma concen-
tration that occurs in pregnancy. While this phenomenon
has been well documented for most “older” AEDs, it is
useful to remember that newer agents are not immune to
increased clearance and decreased plasma levels. Careful
monitoring is required to ensure that the drug levels re-
main in the therapeutic range and that the patient is thus
protected from seizures.
Folic acid supplementation is clearly appropriate for all
women. However, its protective effect is not absolute, and
thus careful planning and pregnancy management are still
critical if outcomes are to be optimized.
The American Academy of Neurology has developed
guidelines (4) to assist clinicians in treating patients: these
guidelines have great utility but require flexibility. The
American Academy of Neurology’s Guidelines for preg-
nant women with epilepsy are summarized below.
GENERAL GUIDELINES FOR MANAGEMENT
OF PREGNANT WOMEN WITH EPILEPSY
In view of the risks of epilepsy and pregnancy for
mother and fetus, the fact that no single AED is safer
than any other for use in pregnancy (with the exception of
trimethadione), and the fact that both seizures and AEDs
have the potential for harm, the following guidelines are
recommended:
Preconception guidelines
1. Women of childbearing age should be counseled
early and educated about the risks of pregnancy
and adverse pregnancy outcomes. Included in the
educational counseling of the patient should be in-
formation regarding the increased risk of seizures
during pregnancy, as well as the increased risk of
adverse pregnancy outcomes.
2. The importance of monotherapy should be empha-
sized with the patient and attempts to switch to
monotherapy made if withdrawal from the patient’s
AED is not recommended.
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43
3. Preconceptional supplementation has been recom-
mended by the Centers for Disease Control for
all women of childbearing age. The recommended
dosage is 0.4 mg/day. This should be encouraged
for women with epilepsy.
Postconception guidelines
1. The patient, her family, and the obstetrician should
be educated about the risks of AED use during
pregnancy.
2. The patient should ideally have AED concentra-
tions monitored monthly. The measurement of un-
bound levels may be necessary to adequately mon-
itor the patient.
3. The patient should continue folate supplementa-
tion during pregnancy. Supplemental vitamin K
(10 mg/day) should be given during the last 2 weeks
of pregnancy. The patient and fetus should be mon-
itored for evidence of malformations and growth
retardation, ideally with ultrasound.
4. AEDs should be changed only if it is necessary to
do so to improve seizure control.
Postdelivery guidelines
1. AED concentrations should be monitored through
the eighth postpartum week.
2. The patient should be counseled on how to deal
with seizures while managing child care. Breast-
feeding can generally be performed safely in term
infants.
These cases illustrate the importance of precise diag-
nosis, without which one has no foundation on which to
develop a treatment plan. Second, they illustrate that even
when patients appear similar clinically (both had juvenile
myoclonic epilepsy), they may still be divergent in their
response to AEDs. We report outcomes in terms of relative
risk. Relative risk is just that, relative. There is no study to
date with enough statistical power to give clear and accu-
rate rates for individual AED exposure. This, coupled with
the variables of race, occupation, geography, and pharma-
cogenetics, makes individual case prediction extremely
difficult.
We can lower but not eliminate risks. One must be will-
ing to modify one’s approach to meet the needs of in-
dividual patients. The large body of collective medical
information allows us to generalize about patients and
their conditions, but we care for them as individuals, one
at a time.
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2000;55:1758.
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44 D. T. COMBS-CANTRELL AND M. S. YERBY

2. Carrazana EJ, Wheeler SD. Exacerbation of juvenile myoclonic outcomes in women using lamotrigine. Epilepsia 2002;43:1161–7.
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Epilepsia, Vol. 44, Suppl. 3, 2003