Self-Assessment and CME

Patient Management
ProblemPreferred
Responses
Daniel Friedman, MD, MSc

Following are the preferred responses for the Patient Management Problem
in this Continuum issue. The case, questions, and answer options are
repeated, and the preferred response is given, followed by an explanation
and a reference with which you may seek more specific information. You
are encouraged to review the responses and explanations carefully to evaluate your general understanding of the material. The comment and references
included with each question are intended to encourage independent study.
To obtain CME credits for this activity, subscribers must complete this
Patient Management Problem online at www.aan.com/continuum/cme.
Upon completion of the Patient Management Problem, participants may
earn up to 2 AMA PRA Category 1 Creditsi. Participants have up to 3 years
from the date of publication to earn CME credits. No CME will be awarded
for this issue after February 28, 2019.

Address correspondence to
Dr Daniel Friedman, NYU
Langone Medical Center,
223 East 34th Street, NYU
Comprehensive Epilepsy Center,
New York, NY 10016,
Daniel.Friedman@nyumc.org.
Relationship Disclosure:
Dr Friedman serves on the
physician advisory board of the
Epilepsy Foundation, on the
editorial board of Epilepsy.com,
and as a consultant for
Cyberonics, Inc. Dr Friedman has
received personal compensation
for speaking engagements from
the American College of
Veterinary Internal Medicine
and paid travel accommodations/
meeting expenses from Alexza
Pharmaceuticals. Dr Friedman
receives royalties from Oxford
University Press and research
support from the the Centers for
Disease Control and Prevention,
the Epilepsy Foundation, the
National Institute of
Neurological Disorders and
Stroke, and UCB, Inc.
Unlabeled Use of
Products/Investigational
Use Disclosure:
Dr Friedman reports
no disclosure.
* 2016 American Academy
of Neurology.

Learning Objectives
Upon completion of this activity, the participant will be able to:
& Manage the evaluation of a first unprovoked seizure
& Understand the factors that influence the risk of seizure recurrence
& Manage antiepileptic drugs in women with epilepsy prior to conception
and during pregnancy
& Recognize and evaluate drug-resistant epilepsy

Case
A 24-year-old right-handed woman with a past medical history significant only
for migraine presents for medical attention after experiencing a witnessed
convulsion while at work. Coworkers report that she was sitting in a business
meeting when her eyes rolled back and her arms stiffened. She groaned
loudly as she fell to the floor. The convulsion lasted about 1 minute and was
followed by 10 minutes of confusion. Emergency medical services was called,
and she was taken to the local emergency department, where the patient is
noted to have a normal physical and neurologic examination other than a
lateral tongue laceration and a lack of recall for the events of the afternoon.

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PMPPreferred Responses

b 1. Which of the following investigations is most likely to reveal an underlying

cause for her seizure?
A. basic metabolic panel
B . brain imaging (head CT or MRI)
C. complete blood count
D. lumbar puncture
E . urine toxicology
The preferred response is B (brain imaging [head CT or MRI]). The average
yield of neuroimaging for an adult presenting with a first seizure is
approximately 10%. Urgent brain imaging, typically CT scan, may reveal acute
abnormalities that require intervention, such as intracerebral hemorrhage or
ischemic stroke. Neuroimaging may also uncover other lesions that are
associated with seizures, such as primary or metastatic brain tumors, infections
(eg, neurocysticercosis), or congenital lesions (eg, cortical dysplasia). The
decision of whether to perform an urgent head CT in the emergency department
or wait several days for a high-quality MRI depends on the clinical situation; a
patient who has persistent neurologic impairment following a seizure should
obtain a head CT. The yield of a lumbar puncture in detecting a significant
abnormality in patients presenting with a first seizure has been reported at 8%,
although this figure is likely significantly lower in patients whose postictal
examination in the emergency department is normal. Significant laboratory
abnormalities are uncommon in adults presenting with a first seizure in the
absence of a significant medical comorbidity. Finally, the yield of urine toxicology
for patients presenting with a first seizure is approximately 3%, although it
may be lower in patients who return to baseline following the seizure, such as
this patient.1
1. Krumholz A, Wiebe S, Gronseth G, et al. Practice parameter: evaluating an apparent unprovoked first
seizure in adults (an evidence-based review): report of the Quality Standards Subcommittee of the
American Academy of Neurology and the American Epilepsy Society. Neurology 2007;69(21):1996Y2007.
doi:10.1212/01.wnl.0000285084.93652.43.

Admission to the hospital is recommended, but the patient declines this. She
is discharged from the hospital with close follow-up arranged and presents for
a neurologic consultation several days later. During the neurologic history, she
reveals that for the past 2 years she has experienced paroxysmal episodes
in which the voices of the people around her suddenly grow louder, yet she
has difficulty making out the words they are saying. At times, this feeling
grows so intense that she feels she has to stop what she is doing. These episodes
last 20 to 40 seconds. She has experienced five of these episodes, including
one on the day of her convulsion. She states that she sustained a mild head
injury while playing field hockey in high school when she collided with another
player. She was confused for about 5 minutes but did not lose consciousness.
She also reports that her brother had a febrile seizure at age 3. A 1.5-tesla MRI
with and without gadolinium appears normal. A routine awake and asleep
EEG reveals mild right temporal slowing but no other abnormalities.

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b 2. Which of the following clinical features in this patient is most suggestive that
she is at high risk for seizure recurrence?
A. a concussion without loss of consciousness while playing field hockey in
high school
B . family history of febrile seizure
C. her age
D. her history of paroxysmal episodes over the past 2 years
E . right temporal slowing on EEG
The preferred response is D (her history of paroxysmal episodes over the past
2 years). The most predictive risk factor for seizure recurrence is a history of
prior seizures. In a population-based study, the risk of seizure recurrence in the
next 2 years for individuals who have experienced two or more seizures was
more than 70%.1 In a cohort of patients presenting for initial clinical evaluation
of a seizure, having a history of four or more seizures prior to clinical
presentation was associated with a high risk for seizure recurrence, even if
neuroimaging and EEG are normal.2 The episodes described here are suspicious
for focal seizures with sensory symptoms (simple partial seizures). For patients
presenting with a first unprovoked seizure, an abnormal EEG is associated with a
moderate risk of seizure recurrence. Age and a first-degree family member with
febrile seizures have not been shown to be independent predictors of seizure
recurrence. Mild traumatic brain injuries do not appear to be a risk factor for
developing subsequent epilepsy.
1. Hauser WA, Rich SS, Lee JR, et al. Risk of recurrent seizures after two unprovoked seizures. N Engl J
Med 1998;338(7):429Y434. doi:10.1056/NEJM199802123380704.
2. Kim LG, Johnson TL, Marson AG, Chadwick DW. Prediction of risk of seizure recurrence after a
single seizure and early epilepsy: further results from the MESS trial. Lancet Neurol 2006;5(4):
317Y322. doi:10.1016/S1474-4422(06)70383-0.

Treatment with levetiracetam is recommended. The patient is counseled about

teratogenic risks of antiepileptic drugs.

b 3. As part of the discussion of the risks and benefits of levetiracetam, the patient
should be specifically informed about which of the following adverse effects?
A. anorexia and weight loss
B . mood and personality changes
C. pancreatitis
D. renal stones
E . visual field defects

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PMPPreferred Responses

The preferred response is B (mood and personality changes). Levetiracetam

is associated with an approximately 10% to 15% risk of mood changes. Most
commonly, this manifests as irritability or mood lability. Significant psychiatric
side effects, such as depression and psychosis, are less common, occurring in
about 2.5% and 1.2% of patients, respectively.1,2 While a black box warning
regarding suicidality exists for antiseizure medications as a class, in clinical practice,
levetiracetam, topiramate, vigabatrin, and tiagabine were found to be the most
likely to be associated with suicidal thoughts or behavior.3 Renal stones and
anorexia are side effects seen with topiramate and zonisamide. Pancreatitis is
an idiosyncratic side effect of valproic acid and its derivatives. Visual field
abnormalities can be seen with vigabatrin use.
1. Mula M, Trimble MR, Yuen A, et al. Psychiatric adverse events during levetiracetam therapy.
Neurology 2003;61(5):704Y706. doi:10.1212/01.WNL.0000078031.32904.0D.
2. Weintraub D, Buchsbaum R, Resor SR Jr, Hirsch LJ. Psychiatric and behavioral side effects of the
newer antiepileptic drugs in adults with epilepsy. Epilepsy Behav 2007;10(1):105Y110.
doi:10.1016/j.yebeh.2006.08.008.
3. Andersohn F, Schade R, Willich SN, Garbe E. Use of antiepileptic drugs in epilepsy and the risk of
self-harm or suicidal behavior. Neurology 2010;75(4):335Y340. doi:10.1212/WNL.0b013e3181ea157e.

The patient is started on levetiracetam and titrated to an initial dose of

500 mg 2 times a day. She is also prescribed folic acid 2 mg daily.

b 4. What is the approximate likelihood that this medication will completely

prevent recurrent seizures?
A. 5%
B . 15%
C. 25%
D. 50%
E . 80%
The preferred response is D (50%). Approximately 50% of patients will become
seizure free on the first antiseizure drug chosen as long as they tolerate the
medication and the medication is appropriate for their epilepsy syndrome.1
1. Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia 2001;42(10):1255Y1260.
doi:10.1046/j.1528-1157.2001.04501.x.

Despite the levetiracetam, the patient continues to have focal seizures

about once per month, at times with brief loss of awareness. The dose of
levetiracetam is increased gradually to 3000 mg/d without significant
improvement in her seizures, and she reports that she is often tired during
the day. After a discussion with her on a follow-up visit, she is
cross-tapered to lamotrigine over the next 2 months.

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b 5. Having failed to achieve seizure freedom with levetiracetam, what is the

approximate likelihood that the second medication will fully control her seizures?
A. 1%
B . 11%
C. 33%
D. 66%
E . 88%
The preferred response is B (11%). While 47% of patients will achieve complete
seizure control on the first appropriately selected antiseizure medication, with
each successive medication, used either as monotherapy or in polytherapy, the
likelihood of becoming seizure free diminishes significantly. The likelihood that
a second medication will lead to seizure control is approximately 11%. Only 5%
of patients will achieve seizure freedom with a third medication. The likelihood
of sustained seizure freedom with additional medication trials is less than 5%
per medication.1
1. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342(5):314Y319.
doi:10.1056/NEJM200002033420503.

On lamotrigine monotherapy, the patients seizure frequency and fatigue

improve. She still continues to have a focal seizure approximately every
3 months. She recently married, and she and her husband are interested in
starting a family. She continues to take folic acid 2 mg daily.

b 6. How should this patient and her husband be counseled regarding specific
known teratogenic risks of lamotrigine?
A. lamotrigine has been associated with an elevated risk of cleft lip and
palate in one study
B . lamotrigine has been associated with an increased risk of autism in offspring
C. lamotrigine has been associated with congenital heart defects in offspring
D. lamotrigine has been associated with neural tube defects
E . lamotrigine is not associated with any congenital malformations or
neurodevelopmental abnormalities

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PMPPreferred Responses

The preferred response is A (lamotrigine has been associated with an elevated

risk of cleft lip and palate in one study). In multiple large pregnancy registries,
lamotrigine has been associated with low rates of major congenital malformations,
approximately 2% to 3% compared to 1.6% to 2.1% in the general population.
In one study, lamotrigine was associated with a higher rate of cleft lip and palate
in offspring born to mothers taking the medication (occurring in 0.73% of births,
a relative risk of 10 compared to the rate in the general population), but this
association was not seen in other pregnancy registries.1 In several studies
examining neurodevelopmental outcomes in offspring born to mothers taking
common antiseizure medications, lamotrigine was not associated with
decreased IQ at 6 years of age.2 Valproate exposure in utero has been
associated with decreased IQ and increased rates of autism.2,3 Neural tube
defects are associated with valproate and carbamazepine exposure.
1. Pennell PB. Antiepileptic drugs during pregnancy: what is known and which AEDs seem to be
safest? Epilepsia 2008;49(suppl 9):43Y55. doi:10.1111/j.1528-1167.2008.01926.x.
2. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes
at age 6 years (NEAD study): a prospective observational study. Lancet Neurol 2013;12(3):244Y252.
doi:10.1016/S1474-4422(12)70323-X.
3. Christensen J, Grnborg T, Srensen M, et al. Prenatal valproate exposure and risk of autism spectrum
disorders and childhood autism. JAMA 2013;309(16):1696Y1703. doi:10.1001/jama.2013.2270.

b 7. Six months later, the patient returns and states that she is 10 weeks pregnant.
What is the most appropriate course of action regarding her lamotrigine?
A. check serum levels regularly and adjust the dose to maintain stable levels
B . discontinue lamotrigine
C. lower the dose
D. maintain the preconception dose throughout the pregnancy
E . switch to carbamazepine
The preferred response is A (check serum levels regularly and adjust the dose
to maintain stable levels). Lamotrigine is metabolized by the liver through the
glucuronidation pathway; its activity is influenced by gonadal steroids. Lamotrigine
clearance increases throughout pregnancy, peaking at almost twice baseline in
the third trimester. Clearance decreases late in pregnancy and drops to preconception
levels within a few weeks after delivery.1 Changing medications or lowering
the dose at this point in the pregnancy is unlikely to reduce teratogenic risks as
fetal organogenesis is nearly complete. Stopping lamotrigine will also be
unlikely to reduce risk of birth defects and exposes the mother and fetus to
risks of seizures.
1. Pennell PB, Peng L, Newport DJ, et al. Lamotrigine in pregnancy: clearance, therapeutic drug
monitoring, and seizure frequency. Neurology 2008;70(22 pt 2):2130Y2136. doi:10.1212/01.wnl.
0000289511.20864.2a.

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The patient has an uncomplicated pregnancy. Serum lamotrigine levels are

checked monthly, and her lamotrigine dose is adjusted to maintain her
prepregnancy serum level of 6.0 mg/dL to 7.0 mg/dL. Her total daily dose is
increased by 250% over the course of her pregnancy. She delivers a healthy
baby girl, and her lamotrigine dose is slowly lowered to the prepregnancy
amount over the course of 3 weeks. However, about 6 months later, her
seizure frequency increases to monthly, with more episodes including a loss
of awareness. Her lamotrigine dose is increased without a significant impact
on her seizures. Her most recent level was 8.7 mg/dL (laboratory reference
range 3.0 mg/dL to 12.0 mg/dL), and she reports occasional dizziness.

b 8. What is the next appropriate course of action?

A.
B.
C.
D.
E.

increase the dose of lamotrigine

initiate therapy with valproate
obtain a positron emission tomography (PET) scan of the brain
refer for placement of a vagus nerve stimulator
refer to an epilepsy monitoring unit for characterization of her seizures

The preferred response is E (refer to an epilepsy monitoring unit for

characterization of her seizures). The patient continues to have seizures despite
a trial of two antiseizure medications at maximally tolerated doses. Admission to
an epilepsy monitoring unit for video-EEG monitoring can confirm that the
ongoing seizures are epileptic or nonepileptic (including psychogenic nonepileptic
seizures or physiologic nonepileptic events such as arrhythmias).1 Identification
of a nonepileptic cause of her spells would spare her trials of additional antiseizure
medications and could lead to definitive treatment. Video-EEG recording of her
seizures would also be helpful to determine if her seizures have a single focal onset,
making her a potential candidate for epilepsy surgery. The patient is already
experiencing dizziness, a sign of lamotrigine toxicity, and she would likely be unable
to tolerate higher doses. A vagus nerve stimulator is a treatment for refractory
epilepsy in patients who are not candidates for resective/ablative epilepsy surgery.
While other medication trials may be appropriate, valproate is likely not the
preferred next agent to prescribe for this woman of childbearing age with probable
focal epilepsy. A brain PET scan is typically helpful in identifying an epileptic
focus in patients who have normal MRIs as part of the evaluation for epilepsy
surgery but would not be indicated at this time.
1. Nordli DR Jr. Usefulness of video-EEG monitoring. Epilepsia 2006;47(suppl 1):26Y30. doi:10.1111/
j.1528-1167.2006.00656.x.

The patient is referred to a comprehensive epilepsy center and admitted to

the epilepsy monitoring unit for characterization of her seizures. During the
4-day admission, she has four focal seizures characterized by quiet staring,
automatic movements of her right hand, and dystonic posturing of her left
hand that last for 30 to 75 seconds. The EEG shows a 2-Hz to 3-Hz ictal
rhythm with onset in the right temporal region. She is amnestic for three of
her seizures but reports an aura of distorted sound for one of the seizures.

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PMPPreferred Responses
b 9. Which of the following tests would be most useful in determining the likelihood
that she would benefit from epilepsy surgery?
A. ictal single photon emission computed tomography (SPECT)
B . intraarterial amobarbital procedure
C. magnetoencephalography (MEG)
D. neuropsychological testing
E . 3-tesla epilepsy protocol MRI
The preferred response is E (3-tesla epilepsy protocol MRI). While all of the
above tests are commonly used in the presurgical evaluation of patients with
drug-resistant focal epilepsy, identification of a structural abnormality that
corresponds to the seizure symptomatology and EEG findings is the strongest
predictor of successful epilepsy surgery. A high-field MRI with thin cuts
through the suspected seizure focus or an isovolumetric study can identify
subtle abnormalities, such as gray matter heterotopias or cortical dysplasia,
that may be missed by a routine MRI.1
1. Jackson GD, Badawy RA. Selecting patients for epilepsy surgery: identifying a structural lesion.
Epilepsy Behav 2011;20(2):182Y189. doi:10.1016/j.yebeh.2010.09.019.

A 3-tesla MRI with a dedicated epilepsy protocol reveals a linear band of

increased T2 signal in the white matter of the right temporal lobe and blurring
of the right hippocampal architecture, consistent with a malformation of
cortical development in the right temporal lobe (PMP Figure 1).

3-Tesla MRI with a dedicated epilepsy protocol

reveals a linear band of increased T2 signal in
the white matter of the right temporal lobe
(red arrow) and blurring of the right hippocampal architecture
(yellow arrow), consistent with a malformation of cortical
development in the right temporal lobe.

FIGURE 1

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b 10. What should this patient be told in regard to epilepsy surgery?

A.
B.
C.
D.
E.

epilepsy surgery can decrease her life expectancy

epilepsy surgery can improve her quality of life
epilepsy surgery is not a reasonable treatment option
she is at risk for left inferior quadrantanopia if she has surgery
she should try another medication prior to considering epilepsy surgery

The preferred response is B (epilepsy surgery can improve her quality of life).
Successful epilepsy surgery has been associated with improved patient-reported
quality of life.1 This patient is a reasonable candidate for epilepsy surgery as
she meets the criteria for drug-resistant epilepsy and is unlikely to achieve seizure
control through medications alone.2 Successful epilepsy surgery is associated
with reduced mortality in people with epilepsy because it lowers the rate of sudden
unexpected death in epilepsy (SUDEP).1 The lesion is in the right temporal
neocortex, and she should be counseled about the risks of a left superior
quadrantanopia following epilepsy surgery.
1. Tllez-Zenteno JF, Dhar R, Hernandez-Ronquillo L, Wiebe S. Long-term outcomes in epilepsy surgery:
antiepileptic drugs, mortality, cognitive and psychosocial aspects. Brain 2007;130(pt 2):334Y345.
doi:10.1093/brain/awl316.
2. Wiebe S, Jette N. Epilepsy surgery utilization: who, when, where, and why? Curr Opin Neurol 2012;
25(2):187Y193. doi:10.1097/WCO.0b013e328350baa6.

b 11. What is the approximate likelihood that the patient will have long-term
(5-year) freedom from disabling seizures following epilepsy surgery?
A. 10%
B . 25%
C. 30%
D. 65%
E . 90%
The preferred response is D (65%). In a pooled analysis of long-term outcomes
following epilepsy surgery, approximately 66% of patients were seizure free at
5 years following temporal lobe epilepsy surgery.1 Resection of cortical dysplasia
is associated with an approximate 55% change of seizure freedom, although
temporal location and an MRI-apparent lesion improve the chances of success.2
1. Tllez-Zenteno JF, Dhar R, Wiebe S. Long-term seizure outcomes following epilepsy surgery: a
systematic review and meta-analysis. Brain 2005;128(pt 5):1188Y1198. doi:10.1093/brain/awh449.
2. Rowland NC, Englot DJ, Cage TA, et al. A meta-analysis of predictors of seizure freedom in the
surgical management of focal cortical dysplasia. J Neurosurg 2012;116(5):1035Y1041. doi:10.3171/
2012.1.JNS111105.

The patient undergoes a right temporal lobectomy and is seizure free following
surgery for the next 2 years. On a follow-up visit 2 years after surgery, she is
interested in coming off her antiseizure medications.

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PMPPreferred Responses
b 12. What is the most accurate statement about seizure recurrence with tapering
medications following successful epilepsy surgery?
A. antiseizure medications should never be stopped entirely following surgery
B . her short duration of epilepsy prior to resection makes recurrence after
tapering more likely
C. lamotrigine use is associated with a lower risk of postoperative seizure
recurrence after tapering
D. a majority of patients who have seizure recurrence after stopping antiseizure
medication will be able to regain control once they restart medications
E . patients who have temporal lobe resections are more likely to have seizure
recurrence
The preferred response is D (a majority of patients who have seizure recurrence
after stopping antiseizure medication will be able to regain control once they
restart medications). In several prospective and retrospective observational
studies, about 15% to 20% of patients who achieved prolonged (more than
2 years) seizure freedom following surgery had seizure recurrence when they
discontinued medications. Approximately two-thirds of these patients regained
seizure control with resuming medications.1,2 Patients who have seizures after all
of their seizure medications are stopped are more likely to regain seizure
control than patients who have seizures during medication reduction.3 Factors
that may be predictive of successful discontinuation of medications include
short duration of epilepsy prior to surgery and temporal lobe location.1 In one
study, it was suggested that levetiracetam use at the time of surgery, not
lamotrigine, was associated with a low risk of seizure recurrence after surgery,
although it was unknown what proportion of these patients tapered off
all medications.4
1. Schmidt D, Baumgartner C, Lscher W. Seizure recurrence after planned discontinuation of
antiepileptic drugs in seizure-free patients after epilepsy surgery: a review of current clinical experience.
Epilepsia 2004;45(2):179Y186. doi:10.1111/j.0013-9580.2004.37803.x.
2. Berg AT, Vickrey BG, Langfitt JT, et al. Reduction of AEDs in postsurgical patients who attain
remission. Epilepsia 2006;47(1):64Y71. doi:10.1111/j.1528-1167.2006.00371.x.
3. Yardi R, Irwin A, Kayyali H, et al. Reducing versus stopping antiepileptic medications after temporal
lobe surgery. Ann Clin Transl Neurol 2014;1(2):115Y123. doi:10.1002/acn3.35.
4. Jehi LE, Irwin AI, Kayyali H, et al. Levetiracetam may favorably affect seizure outcome after
temporal lobectomy. Epilepsia 2012;53(6):979Y986. doi:10.1111/j.1528-1167.2012.03453.x.

An EEG demonstrates no residual epileptiform activity. The patient decides

to taper off lamotrigine after discussing the risks and benefits with her
epileptologist. Two years later, she experiences a brief episode of auditory
distortion similar to her prior simple partial seizures. She is restarted on
lamotrigine at a lower dose than she was previously taking and does not
have any further episodes.

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