Published online: 2020-11-11

624

Epilepsy: Workup and Management in Adults

Rebecca O’Dwyer, MD1

1 Department of Neurological Science, Rush University Medical Address for correspondence Rebecca O’Dwyer, MD, Department of
Center, Chicago, Illinois Neurological Science, Rush University Medical Center, 1725 W
Harrison St., Suite 885, Chicago, IL 60612
Semin Neurol 2020;40:624–637. (e-mail: rebecca_odwyer@rush.edu).

Abstract When managing epilepsy, there is a temptation to focus care with respect to the last
and the next seizure. However, epilepsy is a multifaceted chronic condition and should
be treated as such. Epilepsy comes with many physical risks, psychological effects, and
Keywords socioeconomic ramifications, demanding a long-term commitment from the treating
► epilepsy physician. Patients with epilepsy, compared to other chronically ill patient populations,
► medical management have a worse quality of life, family function, and less social support. The majority of
► breakthrough patients are well controlled on antiseizure drugs. However, approximately one-third
seizures will continue to have seizures despite optimized medical management. The primary

Downloaded by: Western University. Copyrighted material.

► women with epilepsy aim of this article is to explore the long-term management of chronic epilepsy, and to
► older adults address some of the particular needs of patients with chronic epilepsy.

Medical Management of Epilepsy an enzyme inducer to an antiseizure drug whose metabolism

The number of antiseizure drugs available has dramatically
increased since the early 1990s, with an additional 17 new
antiseizure drugs approved,1 and it can be daunting as to
which antiseizure drugs to use, whether as initial monother-
apy, replacement therapy, or adjunctive therapy. When con-
sidering which medication to use, the underlying etiology of
the epilepsy should be considered and the patient’s comor-
bidities, in addition to the tolerability, safety profile, pharma-
cokinetics, and efficacy of the antiseizure drug, ensuring the
optimal medication for the particular patient is chosen.
If the first antiseizure drug fails, when deciding what next
step to take, the reason for its failure should be considered. If it
is due to lack of tolerability, it should be replaced with an
alternative monotherapy. If the first antiseizure drug fails due
to lack of efficacy, there is no apparent advantage to either
adding another antiseizure drug or changing to another anti-
seizure drug.2 If it was completely ineffective, substituting it
for an antiseizure drug with a different mechanism of action is
prudent.3 If the initial monotherapy was partially effective and
well tolerated, adding a second antiseizure drug is advised.
When choosing the second antiseizure drug, care should be
taken that the adjunctive agent does not have any negative
effects on the pharmacokinetics of the initial antiseizure drug
or other medications the patient is taking4 (►Table 1). Adding
can be induced will reduce its effectiveness. There has been a
search for synergistic combinations of antiseizure drugs,5 as
there is some evidence that combining two antiseizure drugs
with different mechanisms of action leads to better efficacy
and tolerability.3 While many combinations have been found
synergistic in animal models,5 only the combination of lamo-
trigine and valproate has demonstrated synergy clinically.6
When antiseizure drugs with the same mechanism of action
are used together, an increase in adverse effects is often noted
even if serum concentrations are therapeutic.
It should be noted that these combinations are not listed
in order of effectiveness but, given their synergistic mecha-
nisms of action, are considered favorable or have useful
antagonistic toxicity profiles.
Breakthrough Seizures
A breakthrough seizure is defined as one that occurs despite
the use of an appropriate antiseizure drug that has otherwise
successfully controlled the patient’s seizures in the past.7 The
duration of the seizure remission period is more controver-
sial, with many adopting the International League Against
Epilepsy’s (ILAE’s) “rule of three,” defining seizure-free or
medically responsive epilepsy as seizure freedom for
12 months or three times the longest previous interseizure

published online Issue Theme Seizures and Status Copyright © 2020 by Thieme Medical DOI https://doi.org/
November 11, 2020 Epilepticus; Sebastian Pollandt, MD, and Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0040-1719069.
Thomas Bleck, MD, MCCM New York, NY 10001, USA. ISSN 0271-8235.
Tel: +1(212) 760-0888.

Table 1 Commonly used synergistic antiseizure drug
combinations
LEV þ CBZ
LEV þ TPM
LTG þ TPM
LTG þ VPA
OXC þ GBP
OXC þ LEV
Abbreviations: CBZ, carbamazepine; GBP, gabapentin; LEV, levetirace-
tam; LTG, lamotrigine; OXC, oxcarbazepine.
interval, whichever is longer.8 However, in clinical research,
this seizure-free remission period varies from 6 months9 to
at least 12 months,10 which consequently affects the
reported prevalence and incidence. The SANAD (Standard
And New Antiepileptic Drugs) trial reported a 37% incidence
of breakthrough seizures.11 Breakthrough seizures have
many ramifications beyond the patient’s epilepsy and may
negatively affect their schedules, put their employment at
risk, force them to relinquish their driving privileges and
cause personal injury. Patients with breakthrough seizures
have 2.3 times higher adjusted healthcare costs and 8.1 times
higher adjusted epilepsy-related costs than those without
breakthrough seizures.10 When a patient reports a break-
through seizure, it is important to elucidate the cause before
changing medical management, as the cause for the seizure
may work against any adjustment made (►Table 2). The
neurologist should be vigilant for nonadherence, factors or
interactions that can alter the metabolism of the prescribed
antiseizure drugs, and common seizure precipitants; and, in
particular, if the stereotype of the seizure has changed, the
neurologist should question if the event is epileptic in nature.
Studies have shown that empowerment of the patient in
their long-term care of epilepsy, “self-management,” has led
to improved maintenance of seizure freedom.12
Antiseizure Drug Monitoring
Often, when faced with a breakthrough seizure, a neurologist
will check a serum concentration of the antiseizure drug, and
this can be useful in revealing a cause for the seizure but
should be used with caution. A “normal” serum concentra-
Table 2 Common precipitating factors for breakthrough
seizures
Nonadherence with antiseizure medications
Stress
Sleep deprivation
Fever or Illness
Heat
Menses
Flashing lights
Alcohol withdrawal
Epilepsy: Workup and Management in Adults O’Dwyer 625
tion may be subtherapeutic for a particular patient if it is
lower than their baseline concentration. Indeed, once an
effective antiseizure drug regimen has been established, a
trough antiseizure drug concentration should be obtained,
and this baseline should be used for comparison in the face of
clinical changes.13 Regular, routine serum concentration
monitoring is usually not needed. It can be harmful if an
effective regimen is changed as the result of a concentration
falling below the accepted range. There is a lack of pharma-
covigilance and harmonization of reference ranges between
different laboratories, resulting in sometimes clinically sig-
nificant variability.14 Around certain clinical events such as a
breakthrough seizures, suspected nonadherence, pregnancy,
drug formulation changes, or an anticipated change in phar-
macokinetics, monitoring a serum concentration level is
prudent.13 Ultimately, changes in an antiseizure drug regi-
men should be guided by the patient’s clinical state and not a
long-standing serum concentration.
Medication Nonadherence
Downloaded by: Western University. Copyrighted material.
The leading factor associated with breakthrough seizures is
nonadherence to antiseizure drug.15 Patients in U.S. drug trials
have demonstrated adherence rates varying from 43 to 78%.16 It
has been shown that nonadherence is not strictly binary, but
rather patients tend to fall into four broad categories: high
adherence, moderate adherence, severe early nonadherence,
and variable nonadherence.17 To complicate the clinical picture
further, patients may shift from one group to another over time.
Another phenomenon to remember when checking serum
concentrations is “White coat adherence” that can increase
adherence around the time of office visits from 5 to 15%.18
Frequent daily dosing is known to lead to nonadherence.
Antiseizure drug adherence dropped from 87% with daily
dosing to 81% with twice a day, to 77% with three times a
day, and to 39% with four times a day dosing.19 Antiseizure
drug polytherapy also negatively impacts adherence.20 A 55%
rate of nonadherence was seen in those receiving monother-
apy compared to a 71% rate of nonadherence in those receiving
polytherapy.21 Demographics such as gender and age have no
consistent effects on adherence20,21; however, many clinicians
struggle with achieving optimal adherence with patients in
adolescence and young adulthood.22 Socioeconomic factors
also influence adherence across all ages. In an elderly popula-
tion, adherence as measured from prescription refill counts
paid through Medicare and those who lived in areas of high
poverty (as defined by their zip code) was more likely to be
nonadherent than those living in wealthier areas.23 Psychiatric
factors likewise affect adherence; moderate to severe anxiety
was associated with a threefold risk of nonadherence,24 and
depression also negatively impacted adherence.25
Different methods to increase antiseizure drug adherence
have not been systematically compared, but there are sugges-
tions in the literature.7 A pharmacist-led education session
with patients has been shown to increase adherence in a
sustainable manner from 56 to 74%. 26 However, an embedded
pharmacist in an outpatient clinic is a luxury that is unavail-
able to the majority of practitioners. Simplifying antiseizure
drug regimens can positively impact adherence,19,20 and for
Seminars in Neurology Vol. 40 No. 6/2020
626 Epilepsy: Workup and Management in Adults O’Dwyer

Table 3 Strategies to improve adherence

Optimization of medication regimen

• Address unwanted side effects and change to more tolerable medication
• Decrease number of medications taken (may need to collaborate with primary care physician)
• Change to daily dosing or formulation to extended release
• Schedule administration to fixed time points in patient’s daily schedule, e.g., meals
Reminders
• Encourage setting of alarms
• Use of pill boxes
• Use of medication blister packs
• Use of smartphone apps
Supervision
• Recruitment of family and friends
• In younger patients, recruitment of school administration
• Weekly visits from home health services
Other interventions

Downloaded by: Western University. Copyrighted material.

• Direct patient to epilepsy support groups
• Use educational materials to discuss risks and benefits
• Formal behavioral and educational counseling
• In persistent nonadherence, use cognitive behavioral therapy
• In older patients, formal assessment of ability to live independently

those patients who are less literate, prepackaged “blister
packs” that are clearly marked and contain a single dose
may be helpful. Timing doses with meals or other daily events
can help. A simple strategy of using reminders, whether with
alarms or the use of a medication reminder–specific app for
smartphones, can be effective. Supervision is another strategy
often employed; recruiting family or friends is most common,
but with those living in more isolated circumstances, home
health services can be employed to monitor adherence. Often,
asking a family member to help or monitor how a weekly
pillbox is filled combines both the strategy of reminders
(pillbox) and supervision (family member). Where a patient
is persistently nonadherent and the aforementioned strategies
continue to fail, they may benefit from a form of cognitive
behavioral therapy (CBT),27 involving both education and
exploration of the psychological cause behind the nonadher-
ence (►Table 3). Again, promoting the idea of “self-manage-
ment” and empowering the patient can help adherence.12
Medication Interactions
When faced with a breakthrough seizure, asking the patient
about changes in other medications often yields a cause. There
are innumerable interactions, but some of the more common
will be discussed. Estrogen-containing medications act as
inducers on the enzyme that metabolizes lamotrigine, resulting
in a 50% decrease in its serum concentration.28 A similar effect
is seen with the elevation of estrogen during the menstrual
cycle. Of note, progesterone-containing medications do not
have such an effect.28 Over 50% of patients with epilepsy take
dietary or herbal supplements, and 29% do not report these to
their physician.29 A common herb–antiseizure drug interaction
occurs with ginkgo biloba, often taken to improve mood and
memory. This herb is a known hepatic enzyme inducer and has
been shown to reduce phenytoin and valproate levels.30 There
is also some evidence that it reduces the seizure threshold.31
Asking about over-the-counter medications is important;
something as common as diphenhydramine may lower seizure
threshold.32 Commonly prescribed medications such as carba-
penem antibiotics, in particular imipenem33 and tramadol,34
as well as certain antidepressants, in particular bupropion,35
and varenicline all lower the seizure threshold (►Table 4).
Another change in medication that may be seen in the setting of
a breakthrough seizure is a change in manufacturers of a
generic formulation. Currently, evidence does not support it
as a cause for a breakthrough seizure,36 but this is based only on
one study. There is evidence of adherence decreasing in the
setting of a change in generic formulations.37 Frequent counsel-
ing about possible changes in color and shape of generic
antiseizure drug formulations is now recommended.38
Common Precipitating Factors
When a breakthrough seizure occurs, one should always
inquire about any precipitating factors. Seizure precipitants
are defined as “any endogenous or exogenous factor that
promotes the occurrence of epileptic seizures.”39 The occur-
rence of breakthrough seizures in the setting of precipitating
factors is considered evidence of suboptimal seizure control
and predictive of further seizures.10 The prevalence of sei-
zure precipitants varies across different settings of medical
care. In a community-based practice, the prevalence of

Seminars in Neurology Vol. 40 No. 6/2020


Table 4 Commonly used over-the-counter medications and
supplements, in addition to commonly prescribed medications
that can lower seizure threshold
Bupropion
Ciprofloxacin
Clozapine
Diphenhydramine
Ephedra
Ginkgo biloba
Imipenem
Isoniazid
Sevoflurane
Theophylline
Tramadol
Yohimbine
precipitants was 47%,40 but higher rates of 62 to 97% have
been reported in tertiary epilepsy centers.39,41 The most
common precipitating factors, when reported by patients,
are stress (prevalence 30%), followed by sleep deprivation
and fatigue.39–41 All three factors are likely interrelated, and
it is often difficult to isolate fatigue from stress or sleep
deprivation.39 Anxiety and mood disorders are associated
with higher rates of breakthrough seizures.42 Sleep depriva-
tion is estimated to cause breakthrough seizures in 18 to 25%
of patients.39,40 The precipitating power of sleep deprivation
is often employed in the Epilepsy Monitoring Unit to provoke
a seizure.43 Worse seizure control is associated with sleep
deprivation and insomnia, which are common in patients
with epilepsy, affecting up to 55%.44 It is thought that the
epileptic process might alter circadian regulation and thus
affect sleep distribution.45
Other common precipitating factors include menses (as
seen in catamenial epilepsy), flashing lights, and alcohol
ingestion. Similar to sleep deprivation, flashing lights are often
used in the electroencephalography lab to provoke epileptic
activity and are reported as a precipitant in up to 17% of
patients.39 There are certain types of epilepsy more suscepti-
ble to flashing lights; those with idiopathic generalized epi-
lepsies have three to four times the prevalence of abnormal
responses compared to those with symptomatic focal epilep-
sies.46 Alcohol is another common provoking factor,39 with
higher rates seen in countries where alcohol use is more
acceptable.47 It should be noted that care was not taken during
the withdrawal phase and when the seizure occurred in
relation to the alcohol intake.47 Small amounts of alcohol
neither increase the seizure frequency nor affect antiseizure
drugs,48 while greater use puts patients at risk of alcohol-
withdrawal seizures. Additionally, alcohol ingestion may put
patients at risk for nonadherence and/or sleep deprivation.49
Often, counseling specific to the offending precipitant helps
with seizure control, but a more nuanced approach may be
necessary if the same precipitant continues to cause break-
through seizures. CBT has proved useful in the treatment of
Epilepsy: Workup and Management in Adults O’Dwyer 627
stress, anxiety, and depression, leading to improved mood and
better seizure control.50 Encouraging sleep hygiene and life-
style alterations is the usual first step for sleep deprivation and
insomnia. For more resistant cases of insomnia, CBT is the first-
line treatment.51 Sedative-hypnotic medications should be
avoided, as they can lead to fluctuations in seizure thresholds,
result in habituation, and put the patient at risk for withdrawal
seizures when stopped. Melatonin and gabapentin are pre-
ferred as sleep aids. Educating and empowering the patient to
identify precipitants and learn how to avoid them is often the
most practical and successful solution.
Nonepileptic Events
When faced with breakthrough seizures despite adequate
antiseizure drug levels and in the absence of any precipitants,
a nonepileptic event should be considered. Age, gender, and
other patient comorbidities can guide what type of non-
epileptic event could be occurring. Common neurologic
disorders that can mimic seizures include transient ischemic
attacks (TIA), sleep disorders (parasomnias), movement dis-
Downloaded by: Western University. Copyrighted material.
orders (nonepileptic myoclonus), and panic attacks. Non-
neurologic disorders include toxin ingestion, metabolic
abnormalities, and cardiac arrhythmias. Syncope is com-
monly mistaken for seizures, especially if accompanied by
brief tonic and/or clonic activity.52 On history, prodromal
symptoms consisting of diaphoresis, heart palpitations, or a
feeling of the room “closing in” are suggestive of syncope. It
should be noted that in older patients, cardiac arrhythmias
should always be considered, even in the absence of prodro-
mal symptoms.53 Returning to consciousness quickly with-
out postictal confusion is also suggestive of syncope.52
However, this can also be seen in frontal lobe epilepsy.
Psychogenic nonepileptic spells (PNESs) are paroxysmal
episodes of altered awareness, movement, or sensation that
mimic epileptic seizures but are not associated with concomi-
tant epileptiform activity on EEG.54 Some commonly used
terms, such as “pseudoseizures,” have negative connotations
and should be avoided.55 There are many clinical signs that are
suggestive of PNES, including but are not limited to waxing and
waning movements, asynchronous or distractible movements,
a fluctuating course, gradual onset, prolonged duration, eye
closure, ictal crying, intact memory of the episode of apparent
unresponsiveness, hyperventilation, and pelvic thrusting.56,57
Tongues are more often bitten at the tip or in the middle as
opposed to along the sides, as is seen in epileptic seizures
(►Table 5). PNESs are quite common, with at least one-third of
all patients admitted to epilepsy monitoring units diagnosed
with PNES.58 The gold standard for diagnosis is video-EEG
monitoring59; however, diagnostic guidelines propose a step-
wise and comprehensive assessment of all historical and
clinical data. A “probable” diagnosis can be made if a clinical
event is witnessed and reviewed by an expert who considers
the event suggestive of PNES and is accompanied by a normal
interictal EEG. The diagnosis is considered “documented” if an
event is reviewed and considered suggestive of PNES and also
accompanied by both a normal interictal and ictal EEG during
the event. Although less commonly used but still useful where
access to video-EEG is limited, prolactin levels increase 10 to
Seminars in Neurology Vol. 40 No. 6/2020
628 Epilepsy: Workup and Management in Adults O’Dwyer
Table 5 Common characteristics that distinguish epileptic seizures from PNES
Characteristic Epileptic seizures
Duration Usually brief, 30–120 s
Eyes Usually open
Tongue Bitten on the side(/s)
Head Fixed/moves in unilateral direction
Limbs In phase/move in same direction
Trunk (movement) Usually no rotation
Trunk (axis) Straight
Prolonged ictal atonia Very rare
Incontinence Common in convulsive seizures
Autonomic signs Cyanosis and tachycardia common in convulsive seizures
Evolution Continuous
Postictal symptoms Confused and drowsy
Abbreviation: PNES, psychogenic nonepileptic spells.
20 minutes after a convulsive epileptic seizure. A normal
prolactin level, if collected within the appropriate time frame,
can be suggestive of PNES.60
Neuropsychological testing should be used in conjunction
with clinical assessment and video-EEG to aid diagnosis and
guide treatment. Personality inventories when used within
the context of neuropsychological testing often show
patients with PNES endorse conversion, dissociative, somat-
ic, anxious, and depressive symptoms.61 There are often
delays of several years in the diagnosis and treatment of
these disorders.62 A timely and accurate diagnosis is impor-
tant, as many patients have been misdiagnosed with epilep-
sy, leading to inappropriate and ineffective treatment, worse
quality of life,63 and overuse of healthcare resources.64 At
least 10% of patients with PNES have comorbid epilepsy,
making effective treatment more challenging.65 Educating
the patient and their family on the different clinical presen-
tations of epileptic seizures versus nonepileptic events aids
treatment, not only for nonepileptic events but also for
epilepsy. When delivering the diagnosis, it is important to
emphasize that the patient does not have epilepsy but that
their disease is “real” and derogatory terminology should be
avoided.66 If comorbid psychological disorders, such as PTSD,
are discovered in the assessment, these should be treated
appropriately. CBT is often used for the treatment of PNES,
concentrating on developing a patient’s awareness of their
dysfunctional thoughts and developing new behavioral
responses.67 CBT in several controlled trials in the PNES
population have shown a decrease in event frequency,67
and further studies are underway to provide further evi-
dence-based data for CBT.68 PNES can be refractory to
treatment, with more than 70% of patients continuing to
have events after diagnosis and reporting high rates of
disability.69 Factors associated with better prognosis include
higher level of education, lower scores on assessments of
somatoform and dissociative scales, and shorter time to
diagnosis from symptom onset,69 highlighting the need for
accurate and efficient diagnosis.
Seminars in Neurology Vol. 40 No. 6/2020
PNES
Usually longer than 120 s
Forced closure usually suggests PNES
Bitten at the tip
Side-to-side movements
Asynchronous, out of phase movements
Rotation in bed
Opisthotonus
May occur
Less common
Uncommon
Waxes and wanes
Rapidly awakes and reorients
Downloaded by: Western University. Copyrighted material.
Treatment of Drug-Resistant Epilepsy
If breakthrough seizures continue to persist, the diagnosis of
drug-resistant epilepsy (DRE) should be considered. DRE is
defined as “the failure of adequate trials of two tolerated,
appropriately chosen, and used antiepileptic drug schedules
(whether as monotherapies or in combination) to achieve
sustained seizure freedom,” which was defined earlier as
three times the prior inter-seizure interval or 1 year, which-
ever is longer.8 This definition was borne from a prospective
study that showed only 14% of patients who were already
taking an antiseizure drug became seizure-free after the
failure of an additional antiseizure drug and only 3% of
patients became seizure-free after the addition of a third
antiseizure drug.70 Despite the continuing development of
new antiseizure drugs, the rate of DRE has not significantly
decreased.71 The likelihood that a patient will continue to
have recurring seizures after failing two antiseizure drugs is
high, and they should be referred to a comprehensive epi-
lepsy center for a multidisciplinary assessment, as recom-
mended by current practice guidelines.72 Patients with DRE
are at increased risk of SUDEP,73 and need to be evaluated
promptly.
Despite unified guidelines from the American Epilepsy
Society, the American Academy of Neurology, and the American
Association of Neurological Surgeons, only 1% of patients with
DRE are referred to comprehensive epilepsy centers, and the
referral is often delayed on an average of more than 20 years
after their epilepsy onset.74 The reasons for delayed referrals
vary widely, from family and patient fears to little access to
comprehensive care, health care provider’s lack of knowledge,
or social and cultural issues such as stigma.75 Epilepsy surgery
is relatively safe, despite patients’ fears, with most complica-
tions being only minor and resolving completely within
3 months postoperatively.76 Cognition and memory deficits
are not contraindications for epilepsy surgery. Verbal and visual
memories are known to decline in dominant temporal lobec-
tomies; however, paradoxical gains in verbal and visuospatial

memory are also possible.77 Temporal lobe epilepsy that has
been poorly controlled for many years also leads to a decline in
memory,78 and delay in surgery can affect the postoperative
outcome in terms of lower seizure freedom.79 A lesion on MRI is
not necessary amenable to surgical resection, although out-
comes tend to be better in lesional epilepsies. Histology of the
resected tissue often yields an underlying and causative
pathology.80 While many feel that if eloquent cortex is involved
in the seizure, the patient is not a surgical candidate; this is
simply not true. Careful mapping of the cortical function in
conjunction with a thorough delineation of the epileptogenic
zone (the minimum amount of cortex that must be resected to
produce seizure freedom81) may yield the possibility to per-
form surgery safely and without significant morbidity. If a
resection would result in a functional deficit, the patient could
be offered alternatives, such as neuromodulation in the form of
responsive neurostimulation, vagal nerve stimulation (VNS), or
deep brain stimulation, all of which have been shown to yield
Fig. 1 Pathway to the diagnosis of drug-resistant epilepsy and possible treatments.
Epilepsy: Workup and Management in Adults O’Dwyer 629
meaningful reductions in seizure frequency82 (►Fig. 1). Multi-
focal and generalized epilepsies are not amenable to surgery,
but what seems to be bilateral spikes on scalp EEG might have a
unilateral seizure onset zone. VNS offers a possible treatment in
generalized DRE, with 60% reporting a greater than 50% reduc-
tion in seizures at 1 year.83 Psychiatric comorbidities are also
not a contraindication and often fluctuate perioperatively, but
show little change or a slight improvement in mood in long-
term follow-up.84
Epilepsy centers offer comprehensive care and with this
come opportunities to identify “pseudoresistance” and open
other avenues of treatment, including but not limited to
neurostimulation, ketogenic diet, and epilepsy surgery.
Comprehensive epilepsy centers have resources that are
not usually found in the community, such as social work,
specialized pharmacy, and psychotherapy, allowing a more
complete evaluation of the epilepsy and treatment of comor-
bid conditions.
Downloaded by: Western University. Copyrighted material.
Seminars in Neurology Vol. 40 No. 6/2020
630 Epilepsy: Workup and Management in Adults O’Dwyer
Living with Epilepsy
As with any chronic disease, epilepsy can impact a patient’s
quality of life. Much of the care surrounding epilepsy con-
centrates on seizure control; however, a patient’s quality of
life is determined by many factors beyond seizures.85 Com-
prehensive care of those with epilepsy should address not
only seizure control but also areas of daily living. The total
cost of epilepsy in the United States in 1995 was $12.5 billion,
85% of which was indirect costs.64 Missed days of school or
work, loss of driving privileges, social isolation, coping with
adverse effects from medications, constraints on desired
physical activities, difficulty with mood, and strains on
relationships, both emotional and financial, are all real and
tangible costs that people with epilepsy live with every day.
Optimizing their epilepsy care includes addressing these
problems on an individual basis.
Mood Disorders, Depression, and Anxiety
People with epilepsy have a two- to threefold lifetime risk of
developing depression and/or anxiety.86,87 They are also
twice as likely to report suicidal ideation, and three times
more likely to die of suicide compared to the general popu-
lation.88,89 Worse depression symptoms are associated with
a likelihood of uncontrolled seizures, and has been associat-
ed with lower antiseizure drug adherence.25,90 Depression in
people with epilepsy often presents in an atypical manner,
and its presentation is often complicated by side effects from
antiseizure drugs, leading to the underdiagnosis of depres-
sion in this population.91 Brief screening tools for depression
and anxiety have been validated for people with epilepsy,
allowing mood disorders to be identified more easily. These
include the Neurological Disorders Depression Inventory for
Epilepsy, the Patient Health Questionnaire-9, and the Patient
Health Questionnaire-2.92 The Liverpool Adverse Events
Profile can help distinguish adverse effects from antiseizure
drugs from an underlying mood disorder, informing sensible
therapeutic changes.93
Mood disorders are also undertreated in epilepsy.91 There is
a theoretical fear that antidepressants may exacerbate seiz-
ures,91 but a meta-analysis did not substantiate this,35,94,95
with the exception of bupropion.96 Consensus expert recom-
mendation is to use a selective serotonin reuptake inhibitor as
first-line therapy,97 with Class III and Class IV evidence for the
effectiveness of sertraline, mirtazapine, and citalopram.98–100
Psychotherapy, either alone or in combination with pharma-
cologic management, has been shown to be effective.97 Con-
sultation with a psychiatrist is necessary if the mood disorder
fails to respond to first-line treatment.
The FDA issued a safety alert for increased risk of suicidal
behavior and ideation with antiseizure drugs as a class,
which led to a change in labeling in 2008. This alert was
based on the results of a meta-analysis of placebo-controlled
antiseizure drug trials. However, this analysis was limited by
including trials for all indications of antiseizure drug use,
including psychiatric indications and pain, and the included
trials were not designed to assess psychiatric outcomes and
had short observation times.101 The choice of antiseizure
Seminars in Neurology Vol. 40 No. 6/2020
drug can affect a patient’s mood, either negatively or posi-
tively. Some of the newer antiseizure drugs in a case–control
study were deemed of “high potential to cause depression”
(levetiracetam, tiagabine, vigabatrin), while others have
been deemed of “low potential” (lamotrigine, gabapentin,
pregabalin, oxcarbazepine).102 Awareness of the patient’s
mood is vital when making therapeutic decisions in epilepsy.
Driving
Among people with epilepsy, driving was rated their top
concern for impacting quality of life.103 Maintaining employ-
ment, relationships, and the ability to live independently are
often dependent on the ability to drive. There are contra-
dicting reports on the increased risk for motor vehicle
accidents related to a seizure.104,105 Regardless of the risks,
driving remains highly regulated for people with epilepsy,
despite higher rates of motor vehicle accidents being caused
by cardiovascular disease and alcohol.106 Specific require-
ments and processes vary between states, with some states
making modifications for exclusively nocturnal seizures,
Downloaded by: Western University. Copyrighted material.
seizures provoked by a medication change, or seizure semi-
ology that is unlikely to impair safe driving.107 When the
duration of seizure freedom required to be allowed to drive
in Arizona decreased from 12 to 3 months, no change in the
rate of seizure-related motor vehicle accidents was found.108
In 2007, the AAN released a position statement endorsing a
3-month seizure-free period.109
Physicians are generally poor at counseling their patients
about driving laws110; less than 10% of patients seen in an
emergency department for syncope or seizure were docu-
mented as receiving counseling about driving laws.111 Physi-
cians treating patients with epilepsy must be aware of the
driving laws for their state. Patients need accurate informa-
tion to protect them from both physical and legal harm. For
medicolegal reasons, it is important to document the
counseling and the reasoning behind any individualized
driving recommendations.
Injuries and Falls
People with epilepsy are at increased risk of accidents and
injuries,112 the reasons for which are many. Most are associ-
ated with seizures causing direct and immediate harm,109
but common side effects from antiseizure drugs, including
decreased alertness and dizziness in addition to comorbid
cognitive and physical disabilities, can also put patients at
risk. Generalized tonic–clonic seizures can cause shoulder
dislocations, vertebral compression fractures, and tongue
lacerations.101 Most seizure-related injuries are mild to
moderate in severity, encompassing lacerations, fractures,
dental injuries, and burns.113 Severe injuries occur infre-
quently but include subdural hematomas, drowning, and
those resulting from a serious accident involving heavy
machinery or a car.113 The most important strategy to
prevent injury is to control seizures. Lifestyle modifications
should be discussed with patients on an individual basis that
takes into consideration their specific needs and how to
maximize appropriate independence. There are some broad-
ly applicable strategies that are easy for most patients to

Table 6 Common lifestyle adjustments to prevent seizure-
related injuries
No unsupervised swimming
Take showers rather than baths
Adjust temperature on water heater (lower)
Avoid locking bathroom or bedroom door
Use microwave over stovetop
Avoid high ladders
Place mattress on floor
Wear a helmet when participating in sports
Use an “epilepsy pillow”
Change baby’s diaper on the floor and avoid holding baby
while standing
Potentially dangerous activities must be undertaken with
supervision, e.g., stovetop cooking
implement, for example, avoid high ladders, prevent scalding
by using lukewarm water, use a shower rather than a
bathtub, avoid locking the bathroom or bedroom door, no
unsupervised swimming, use a microwave rather than a
stovetop, and use an epilepsy safety pillow to reduce risk
of suffocation. It is important to encourage healthy habits
such as adherence to medications, sleeping 8 hours every
night, avoiding skipping of meals, and avoiding any other
known triggers. Excessive safety restrictions can be discour-
aging to patients with epilepsy, influencing them to socially
withdraw, which in turn might exacerbate depression and
anxiety (►Table 6).
People with epilepsy have frequent falls, and the rate of
fractures is two to six times higher than in the general popula-
tion.114 The risk of fracture increases with the duration of
antiseizure drug exposure.115 With every decade of antiseizure
drug use, the risk of a fracture increased by 40%, and by 60% for a
seizure-precipitated fracture, and women are at a higher risk for
both falls and fractures compared to men.116 Antiseizure drugs
are known to decrease bone density and quality117 through
alteration of vitamin D metabolism by inducing hepatic cyto-
chrome P450 enzymes and thus reducing calcium absorption.
Over half of those patients on hepatic enzyme-inducing antisei-
zure drugs and one-third on non–enzyme-inducing antiseizure
drugs were found to have vitamin D deficiency in an epilepsy
center.118 Currently, there are no evidence-based guidelines
addressing the prevention, screening, or treatment of low bone
density. As a low-cost intervention, calcium and vitamin D
supplementation is often recommended, with higher doses of
vitamin D (2,000 IU) recommended to patients taking enzyme-
inducing antiseizure drugs.
Mortality of Epilepsy
Population-based studies have shown higher mortality ratios
of 1.6 to 3.0 in adults with epilepsy,119 often related to
complications of the disease underlying their epilepsy or
from causes unrelated to epilepsy.120 Nonadherence to anti-
Epilepsy: Workup and Management in Adults O’Dwyer 631
seizure drugs is linked to increased risk of mortality,121 but
death directly as a result of a seizure is rare and similar to the
general population.120
Sudden unexplained death in an epilepsy patient (SUDEP) is
the most common cause of death associated with a seizure.121
The incidence of SUDEP is 1:1,000 adults with epilepsy in
1 year.122 The strongest risk factor for SUDEP is uncontrolled
generalized tonic–clonic seizures, followed by uncontrolled
seizures and failure to adjust medications for medically refrac-
tory epilepsy.122 One to two generalized seizures per year
increase the risk of SUDEP five-fold, and three or more
generalized seizures increase the risk fifteen-fold.123 There
is evidence that the discussion of SUDEP with patients occurs
rarely,124 and the reasons for this vary.125 It should be noted
that when families who had experienced SUDEP were sur-
veyed, 72% responded that they wished they had been coun-
seled about SUDEP from their physician.126 The AAN released a
practice guideline around SUDEP that included recommenda-
tions about how to counsel patients and families.122 Strategies
to reduce the risk of SUDEP include improving adherence to
Downloaded by: Western University. Copyrighted material.
antiseizure drugs and nocturnal supervision, either directly or
through a listening device.122
Special Populations
Women with Epilepsy
Approximately 1.5 million women of child-bearing age in the
United States live with epilepsy and 24,000 give birth every
year.127 Specific challenges arise in the care of women with
epilepsy throughout their life. Approximately a third of all
women with epilepsy have catamenial epilepsy, defined as
seizures occurring during certain times of the menstrual
cycle.128 The diagnosis is made by keeping seizure diaries in
conjunction with tracking ovulation. Despite much research,
definitive treatments remain elusive.128 Estrogen and proges-
terone have neuroactive properties, with estrogens considered
proconvulsant by increasing the concentration of N-methyl-D-
aspartate (NMDA) receptors, and progesterone (and its me-
tabolite allopregnanolone) considered anticonvulsant through
modulation of gamma-aminobutyric acid (GABA)-A neuro-
transmission.129 While progesterone supplementation is used
as a preferred treatment, a recent placebo-controlled study
failed to show a statistically significant decrease in seizure
frequency in women with catamenial epilepsy who received
adjunctive progesterone supplementation compared to those
who received placebo.130 This could be explained by the fact
that not all catamenial seizures occur around menstruation.
Contraception and preconception counseling are particularly
important in this population due to the potential interactions of
antiseizure drugs with oral contraception and sex hormones,
and their potential teratogenicity.131 Antiseizure drugs are
associated with sexual dysfunction, in particular enzyme-in-
ducing medications such as carbamazepine, phenytoin, pheno-
barbital, and oxcarbazepine.132 Gabapentin and topiramate
have been associated with anorgasmia,132,133 although good
seizure control is associated with improved sexual function-
ing.134 Of note, valproate is associated with hyperandrogenism,
insulin resistance, polycystic ovarian syndrome, significant
Seminars in Neurology Vol. 40 No. 6/2020
632 Epilepsy: Workup and Management in Adults O’Dwyer
Table 7 Common anti seizure drugs and their effects on oral
contraceptives
Contraceptive Contraceptive failure Contraceptive
failure at higher doses effect unknown
Carbamazepine Felbamate Clonazepam
Clobazam Perampanel Ethosuximide
Eslicarbazepine Topiramate Gabapentin
acetate
Oxcarbazepine Lacosamide
Phenobarbital Lamotrigine
Phenytoin Levetiracetam
Primidone Retigabine
Rufinamide Tiagabine
Valproate
Vigabatrin
Zonisamide
weight gain, ovulatory failure, and decreased fertility,135 and
should be avoided in women of childbearing age. It is important
to inform patients that enzyme-inducing antiseizure drugs such
as carbamazepine, clobazam, eslicarbazepine acetate, oxcarba-
zepine, phenobarbital, phenytoin, primidone, and rufinamide
can cause oral contraception failure, and at higher doses,
felbamate, perampanel, and topiramate have the same effect.
Intrauterine devices are highly efficacious and are not affected
by antiseizure drugs, making them a desirable form of contra-
ception for women with epilepsy (►Table 7).
When considering becoming pregnant, women with epilep-
sy have many different factors to consider, including seizure
control and teratogenicity of antiseizure drugs. Thus, precon-
ception counseling is highly recommended,128 although it
appears to be currently suboptimal, with women reporting
inadequate knowledge about pregnancy and birth issues.136
Women with epilepsy are at risk to give birth to children with
congenital malformations for several reasons.137 Although folic
acid supplementation is associated with neurodevelopmental
benefits, data remain inconclusive in this population with
regard to preventing congenital malformations.138,139 There is
debate around optimal dosing, but 400 μg to 5 mg daily is
recommended.140 The majority of women remain seizure free
during pregnancy; 74% of those with genetic generalized
epilepsy remained seizure free in comparison to 60% of those
with focal onset epilepsy.141 Compared to those without epilep-
sy, women with epilepsy have a higher mortality rate in
pregnancy,142 and it is important to optimize seizure control
and provide adequate counseling and support.143 The preva-
lence of preeclampsia is higher in women with epilepsy,144 and
higher rates of spontaneous abortions were associated
with antiseizure drug exposure.145 During pregnancy, concen-
trations of lamotrigine (in particular),146 levetiracetam,146
oxcarbazepine,146 topiramate,147 and zonisamide148 fall precip-
itously, requiring regular and frequent drug monitoring to
ensure adequate dosing.147 Valproate is associated with the
highest risk for congenital malformations, and the lowest risk is
Seminars in Neurology Vol. 40 No. 6/2020
found with lamotrigine and levetiracetam.149–151 The risk asso-
ciated with valproate is dose-dependent, with children exposed
to higher doses having a mean IQ of 9.7 points lower than
unexposed children.152 Valproate exposure is also associated
with increased risk for attention-deficit disorder, autism spec-
trum disorder, and dyspraxia, and valproate should therefore be
avoided in women of childbearing age, if possible.140
Upon giving birth, the physiologic changes of pregnancy
reverse and antiseizure drug concentrations increase. Reduction
in antiseizure drug dosing is necessary to prevent toxicity.153
Fewer women with epilepsy breastfeed due to concerns about
antiseizure drugs contaminating breastmilk.154 Lipid-soluble
antiseizure drugs are present in breastmilk but in insufficient
concentrations to cause side effects.155 It should be noted that
concentrations of lamotrigine, zonisamide, benzodiazepines,
barbiturates, and ethosuximide can be elevated in breastmilk
and cause unwanted side effects, such as lethargy and irritabili-
ty.155 A longitudinal study failed to show any adverse effects of
breastfed children whose mothers were taking carbamazepine,
lamotrigine, or valproate individually or with other antiseizure
Downloaded by: Western University. Copyrighted material.
drugs, compared to children of mothers without epilepsy.156
Breastfeeding was associated with less impairment of develop-
ment at 6 and 18 months compared with children who were
breastfed for less than 6 months or not all in children whose
mothers took antiseizure drugs.156
Women with epilepsy are susceptible to early perimeno-
pause and menopause,128 and should be counseled on the
implications of an early menopause, including a shortened
period of fertility. During perimenopause, seizure frequency
increases due to rapid changes in sex hormones. Exogenous
hormone replacement may also affect seizures in menopaus-
al women, with a dose-associated increase in seizure fre-
quency and severity.157
Older Adults
Epilepsy is often thought of as a disease of youth, but when
compared to other age groups, it has the highest incidence and
is most prevalent in the elderly population.158 Currently, one
in four people with newly diagnosed epilepsy is aged 65 years
or older.53,159 Although it is common, epilepsy in older adults
presents a particular challenge to the clinician and is often mis-
and underdiagnosed.160 Clinically and pathophysiologically, it
presents quite differently, leading to a delay in diagnosis. The
new seizure disorder is often a result of a new underlying
neurologic disorder, such as cerebrovascular disease, a neuro-
degenerative disorder, trauma, or a neoplastic process, while
in a quarter of patients, the underlying cause remains un-
known.158,161,162 Seizure semiology in this population is often
subtle, with few or no motor manifestations, and patients are
less likely to secondarily generalize.163 Postictal periods are
also often prolonged in comparison to younger patients.164
Additionally, other common clinical phenomena can mimic
seizures (e.g. syncope, confusion), and an underlying seizure
disorder can easily be misdiagnosed (e.g., dementia, deliri-
um).165 EEG is known to have its limitations as a diagnostic
test,166 which appears to be more apparent in the elderly.167
EEG used for shorter lengths of time is less sensitive,168 with
longer studies capturing interictal epileptiform discharges in

76% of patients with epileptic events.169 It has been suggested
that foramen ovale electrodes be used to detect seizures in an
older population, in search of a reliable diagnostic test.170,171
Given potential adverse events, this has not been adopted
broadly or often; even with a normal EEG, patients are treated
empirically. Older patients often respond well to medical
treatment.172 It is important to consider changes in drug
metabolism that come with aging and are specific to each
patient when considering which antiseizure drug to use and at
what dose.173 In general, lower dosing is effective and mini-
mizes adverse effects, which in this age group can lead to a
significant reduction in quality of life.174 If epilepsy surgery is
indicated, the patient’s age should not be considered a con-
traindication. When predicting surgical outcome, older
patients perform similarly with younger patients.175
Conclusion
Living with epilepsy presents patients with many challenges
that affect various aspects of their lives, and its chronic
management requires an equally multifaceted approach. Vari-
ous strategies can be employed to not only maximize seizure
control but also to minimize the negative sides of the epilepsy
specific to each patient. Empowerment of the patient has been
shown to increase seizure control,12 and allows the patient to
live a fulfilled life. The basic fundamentals of promoting the
health of these patients should be centered not only on the
basics of medical or surgical treatment but also monitoring for
complications and on counseling and educating the patient
about risks and how to promote their independence.
Conflict of Interest
None declared.
References
1 Abou-Khalil BW. Update on antiepileptic drugs 2019. Continuum
(Minneap Minn) 2019;25(02):508–536
2 Semah F, Thomas P, Coulbaut S, Derambure P. Early add-on
treatment vs alternative monotherapy in patients with partial
epilepsy. Epileptic Disord 2014;16(02):165–174
3 Margolis JM, Chu BC, Wang ZJ, Copher R, Cavazos JE. Effectiveness
of antiepileptic drug combination therapy for partial-onset
seizures based on mechanisms of action. JAMA Neurol 2014;
71(08):985–993
4 Zaccara G, Perucca E. Interactions between antiepileptic drugs,
and between antiepileptic drugs and other drugs. Epileptic
Disord 2014;16(04):409–431
5 Stafstrom CE. Mechanisms of action of antiepileptic drugs: the
search for synergy. Curr Opin Neurol 2010;23(02):157–163
6 Poolos NP, Warner LN, Humphreys SZ, Williams S. Comparative
efficacy of combination drug therapy in refractory epilepsy.
Neurology 2012;78(01):62–68
7 Bauer D, Quigg M. Optimizing management of medically respon-
sive epilepsy. Continuum (Minneap Minn) 2019;25(02):343–361
8 Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug
resistant epilepsy: consensus proposal by the ad hoc Task Force
of the ILAE Commission on Therapeutic Strategies. Epilepsia
2010;51(06):1069–1077
9 Divino V, Petrilla AA, Bollu V, Velez F, Ettinger A, Makin C. Clinical
and economic burden of breakthrough seizures. Epilepsy Behav
2015;51:40–47
Epilepsy: Workup and Management in Adults O’Dwyer 633
10 Bonnett LJ, Powell GA, Tudur Smith C, Marson AG. Breakthrough
seizures-further analysis of the Standard versus New Antiepi-
leptic Drugs (SANAD) study. PLoS One 2017;12(12):e0190035
11 Marson AG, Al-Kharusi AM, Alwaidh MSANAD Study Group.
et al; The SANAD study of effectiveness of carbamazepine,
gabapentin, lamotrigine, oxcarbazepine, or topiramate for treat-
ment of partial epilepsy: an unblinded randomised controlled
trial. Lancet 2007;369(9566):1000–1015
12 Michaelis R, Tang V, Wagner JL, et al. Cochrane systematic review
and meta-analysis of the impact of psychological treatments for
people with epilepsy on health-related quality of life. Epilepsia
2018;59(02):315–332
13 Patsalos PN, Berry DJ, Bourgeois BF, et al. Antiepileptic drugs–best
practice guidelines for therapeutic drug monitoring: a position
paper by the subcommission on therapeutic drug monitoring, ILAE
Commission on Therapeutic Strategies. Epilepsia 2008;49(07):
1239–1276
14 Reimers A, Berg JA, Burns ML, Brodtkorb E, Johannessen SI,
Johannessen Landmark C. Reference ranges for antiepileptic
drugs revisited: a practical approach to establish national guide-
lines. Drug Des Devel Ther 2018;12:271–280
15 Kaddumukasa M, Kaddumukasa M, Matovu S, Katabira E. The
frequency and precipitating factors for breakthrough seizures
among patients with epilepsy in Uganda. BMC Neurol 2013;13:182
Downloaded by: Western University. Copyrighted material.
16 Osterberg L, Blaschke T. Adherence to medication. N Engl J Med
2005;353(05):487–497
17 Modi AC, Rausch JR, Glauser TA. Patterns of nonadherence to
antiepileptic drug therapy in children with newly diagnosed
epilepsy. JAMA 2011;305(16):1669–1676
18 Modi AC, Ingerski LM, Rausch JR, Glauser TA, Drotar D. White
coat adherence over the first year of therapy in pediatric
epilepsy. J Pediatr 2012;161:695–699.e1
19 Cramer JA, Scheyer RD, Mattson RH. Compliance declines between
clinic visits. Arch Intern Med 1990;150(07):1509–1510
20 Cramer J, Vachon L, Desforges C, Sussman NM. Dose frequency
and dose interval compliance with multiple antiepileptic med-
ications during a controlled clinical trial. Epilepsia 1995;36(11):
1111–1117
21 Ferrari CM, de Sousa RM, Castro LH. Factors associated with
treatment non-adherence in patients with epilepsy in Brazil.
Seizure 2013;22(05):384–389
22 Jacob L, Hamer HM, Kostev K. Adherence to antiepileptic drugs in
children and adolescents: a retrospective study in primary care
settings in Germany. Epilepsy Behav 2017;75:36–41
23 Piper K, Richman J, Faught E, et al. Adherence to antiepileptic
drugs among diverse older Americans on Part D Medicare.
Epilepsy Behav 2017;66:68–73
24 Wang S, Chen C, Jin B, et al. The association of psychosocial
variables with adherence to antiepileptic drugs in patients with
temporal lobe epilepsy. Epilepsy Behav 2017;77:39–43
25 Ettinger AB, Good MB, Manjunath R, Edward Faught R, Bancroft T.
The relationship of depression to antiepileptic drug adherence
and quality of life in epilepsy. Epilepsy Behav 2014;36:138–143
26 Ma M, Peng Q, Gu X, et al. Pharmacist impact on adherence of
valproic acid therapy in pediatric patients with epilepsy using
active education techniques. Epilepsy Behav 2019;98(PtA):14–18
27 da Mota Gomes M, NavarroT, Keepanasseril A, Jeffery R, Haynes RB.
Increasing adherence to treatment in epilepsy: what do the
strongest trials show? Acta Neurol Scand 2017;135(03):266–272
28 Reimers A, Helde G, Brodtkorb E. Ethinyl estradiol, not proges-
togens, reduces lamotrigine serum concentrations. Epilepsia
2005;46(09):1414–1417
29 Kaiboriboon K, Guevara M, Alldredge BK. Understanding herb
and dietary supplement use in patients with epilepsy. Epilepsia
2009;50(08):1927–1932
30 Samuels N, Finkelstein Y, Singer SR, Oberbaum M. Herbal medi-
cine and epilepsy: proconvulsive effects and interactions with
antiepileptic drugs. Epilepsia 2008;49(03):373–380
Seminars in Neurology Vol. 40 No. 6/2020
634 Epilepsy: Workup and Management in Adults O’Dwyer
31 Tyagi A, Delanty N. Herbal remedies, dietary supplements, and
seizures. Epilepsia 2003;44(02):228–235
32 Reichert C, Reichert P, Monnet-Tschudi F, Kupferschmidt H,
Ceschi A, Rauber-Lüthy C. Seizures after single-agent overdose
with pharmaceutical drugs: analysis of cases reported to a
poison center. Clin Toxicol (Phila) 2014;52(06):629–634
33 Cannon JP, Lee TA, Clark NM, Setlak P, Grim SA. The risk of
seizures among the carbapenems: a meta-analysis. J Antimicrob
Chemother 2014;69(08):2043–2055
34 Babahajian A, Khomand P, Manouchehri F, et al. Seizure preva-
lence and its related factors in tramadol intoxication; a brief
report. Arch Acad Emerg Med 2019;7(01):e28
35 Johannessen Landmark C, Henning O, Johannessen SI. Procon-
vulsant effects of antidepressants - What is the current evi-
dence? Epilepsy Behav 2016;61:287–291
36 Kesselheim AS, Stedman MR, Bubrick EJ, et al. Seizure outcomes
following the use of generic versus brand-name antiepileptic
drugs: a systematic review and meta-analysis. Drugs 2010;70
(05):605–621
37 Kesselheim AS, Misono AS, Shrank WH, et al. Variations in pill
appearance of antiepileptic drugs and the risk of nonadherence.
JAMA Intern Med 2013;173(03):202–208
38 Vossler DG, Anderson GD, Bainbridge J. AES position statement
on generic substitution of antiepileptic drugs. Epilepsy Curr
2016;16(03):209–211
39 Frucht MM, Quigg M, Schwaner C, Fountain NB. Distribution of
seizure precipitants among epilepsy syndromes. Epilepsia 2000;
41(12):1534–1539
40 Wassenaar M, Kasteleijn-Nolst Trenité DG, de Haan GJ, Carpay JA,
Leijten FS. Seizure precipitants in a community-based epilepsy
cohort. J Neurol 2014;261(04):717–724
41 Ferlisi M, Shorvon S. Seizure precipitants (triggering factors) in
patients with epilepsy. Epilepsy Behav 2014;33:101–105
42 Baldin E, Hauser WA, Pack A, Hesdorffer DC. Stress is associated
with an increased risk of recurrent seizures in adults. Epilepsia
2017;58(06):1037–1046
43 Quigg M, Straume M, Menaker M, Bertram EH III. Temporal
distribution of partial seizures: comparison of an animal model
with human partial epilepsy. Ann Neurol 1998;43(06):748–755
44 Quigg M, Gharai S, Ruland J, et al. Insomnia in epilepsy is
associated with continuing seizures and worse quality of life.
Epilepsy Res 2016;122:91–96
45 Quigg M. Circadian rhythms: interactions with seizures and
epilepsy. Epilepsy Res 2000;42(01):43–55
46 Trenité DG. Photosensitivity, visually sensitive seizures and
epilepsies. Epilepsy Res 2006;70(Suppl 1):S269–S279
47 Kobau R, DiIorio C. Epilepsy self-management: a comparison of
self-efficacy and outcome expectancy for medication adherence
and lifestyle behaviors among people with epilepsy. Epilepsy
Behav 2003;4(03):217–225
48 Gordon E, Devinsky O. Alcohol and marijuana: effects on epilepsy
and use by patients with epilepsy. Epilepsia 2001;42(10):1266–1272
49 Hauser WA, Ng SK, Brust JC. Alcohol, seizures, and epilepsy.
Epilepsia 1988;29(Suppl 2):S66–S78
50 McLaughlin DP, McFarland K. A randomized trial of a group based
cognitive behavior therapy program for older adults with epi-
lepsy: the impact on seizure frequency, depression and psycho-
social well-being. J Behav Med 2011;34(03):201–207
51 Qaseem A, Kansagara D, Forciea MA, Cooke M, Denberg TDClin-
ical Guidelines Committee of the American College of Physicians.
Management of chronic insomnia disorder in adults: a clinical
practice guideline from the American College of Physicians. Ann
Intern Med 2016;165(02):125–133
52 Smith D, Defalla BA, Chadwick DW. The misdiagnosis of epilepsy
and the management of refractory epilepsy in a specialist clinic.
QJM 1999;92(01):15–23
53 Werhahn KJ. [Epileptic seizures in the elderly]. Nervenarzt 2009;
80(04):399–404
Seminars in Neurology Vol. 40 No. 6/2020
54 Hopp JL. Nonepileptic episodic events. Continuum (Minneap
Minn) 2019;25(02):492–507
55 Brigo F, Igwe SC, Ausserer H, et al. Terminology of psychogenic
nonepileptic seizures. Epilepsia 2015;56(03):e21–e25
56 Syed TU, LaFrance WC Jr, Kahriman ES, et al. Can semiology
predict psychogenic nonepileptic seizures? A prospective study.
Ann Neurol 2011;69(06):997–1004
57 Erba G, Giussani G, Juersivich A, et al. The semiology of psycho-
genic nonepileptic seizures revisited: Can video alone predict
the diagnosis? Preliminary data from a prospective feasibility
study. Epilepsia 2016;57(05):777–785
58 Benbadis SR, O’Neill E, Tatum WO, Heriaud L. Outcome of
prolonged video-EEG monitoring at a typical referral epilepsy
center. Epilepsia 2004;45(09):1150–1153
59 LaFrance WC Jr, Baker GA, Duncan R, Goldstein LH, Reuber M.
Minimum requirements for the diagnosis of psychogenic non-
epileptic seizures: a staged approach: a report from the Inter-
national League Against Epilepsy Nonepileptic Seizures Task
Force. Epilepsia 2013;54(11):2005–2018
60 Chen DK, So YT, Fisher RSTherapeutics and Technology Assessment
Subcommittee of the American Academy of Neurology. Use of
serum prolactin in diagnosing epileptic seizures: report of the
Therapeutics and Technology Assessment Subcommittee of the
American Academy of Neurology. Neurology 2005;65(05):668–675
Downloaded by: Western University. Copyrighted material.
61 Thompson AW, Hantke N, Phatak V, Chaytor N. The personality
assessment inventory as a tool for diagnosing psychogenic non-
epileptic seizures. Epilepsia 2010;51(01):161–164
62 Asadi-Pooya AA, Tinker J. Delay in diagnosis of psychogenic
nonepileptic seizures in adults: a post hoc study. Epilepsy Behav
2017;75:143–145
63 Robson C, Myers L, Pretorius C, Lian OS, Reuber M. Health related
quality of life of people with non-epileptic seizures: the role of
socio-demographic characteristics and stigma. Seizure 2018;
55:93–99
64 Begley CE, Famulari M, Annegers JF, et al. The cost of epilepsy in
the United States: an estimate from population-based clinical
and survey data. Epilepsia 2000;41(03):342–351
65 Benbadis SR, Agrawal V, Tatum WO IV. How many patients with
psychogenic nonepileptic seizures also have epilepsy? Neurolo-
gy 2001;57(05):915–917
66 Friedman JH, LaFrance WC Jr. Psychogenic disorders: the need to
speak plainly. Arch Neurol 2010;67(06):753–755
67 Carlson P, Nicholson Perry K. Psychological interventions for
psychogenic non-epileptic seizures: a meta-analysis. Seizure
2017;45:142–150
68 Goldstein LH, Mellers JD, Landau S, et al. COgnitive behavioural
therapy vs standardised medical care for adults with Dissociative
non-Epileptic Seizures (CODES): a multicentre randomised con-
trolled trial protocol. BMC Neurol 2015;15:98
69 Reuber M, Pukrop R, Bauer J, Helmstaedter C, Tessendorf N, Elger
CE. Outcome in psychogenic nonepileptic seizures: 1 to 10-year
follow-up in 164 patients. Ann Neurol 2003;53(03):305–311
70 Kwan P, Brodie MJ. Early identification of refractory epilepsy. N
Engl J Med 2000;342(05):314–319
71 French JA, White HS, Klitgaard H, et al. Development of new
treatment approaches for epilepsy: unmet needs and opportu-
nities. Epilepsia 2013;54(Suppl 4):3–12
72 Engel J Jr, Wiebe S, French JQuality Standards Subcommittee of
the American Academy of Neurology American Epilepsy Society
American Association of Neurological Surgeons. , et al; . Practice
parameter: temporal lobe and localized neocortical resections
for epilepsy: report of the Quality Standards Subcommittee of
the American Academy of Neurology, in association with the
American Epilepsy Society and the American Association of
Neurological Surgeons. Neurology 2003;60(04):538–547
73 Ficker DM, So EL, Shen WK, et al. Population-based study of the
incidence of sudden unexplained death in epilepsy. Neurology
1998;51(05):1270–1274

74 Berg AT, Langfitt J, Shinnar S, et al. How long does it take for
partial epilepsy to become intractable? Neurology 2003;60(02):
186–190
75 Jetté N, Sander JW, Keezer MR. Surgical treatment for epilepsy:
the potential gap between evidence and practice. Lancet Neurol
2016;15(09):982–994
76 Hader WJ, Tellez-Zenteno J, Metcalfe A, et al. Complications of
epilepsy surgery: a systematic review of focal surgical resections
and invasive EEG monitoring. Epilepsia 2013;54(05):840–847
77 Sherman EM, Wiebe S, Fay-McClymont TB, et al. Neuropsycho-
logical outcomes after epilepsy surgery: systematic review and
pooled estimates. Epilepsia 2011;52(05):857–869
78 Grewe P, Schulz R, Woermann FG, et al. Very long-term outcome
in resected and non-resected patients with temporal lobe epi-
lepsy with medial temporal lobe sclerosis: a multiple case-study.
Seizure 2019;67:30–37
79 Bjellvi J, Olsson I, Malmgren K, Wilbe Ramsay K. Epilepsy
duration and seizure outcome in epilepsy surgery: a systematic
review and meta-analysis. Neurology 2019;93(02):e159–e166
80 Rastogi S, Lee C, Salamon N. Neuroimaging in pediatric epilepsy: a
multimodality approach. Radiographics 2008;28(04):1079–1095
81 Lüders HO, Najm I, Nair D, Widdess-Walsh P, Bingman W. The
epileptogenic zone: general principles. Epileptic Disord 2006;8
(Suppl 2):S1–S9
82 Kwon CS, Ripa V, Al-Awar O, Panov F, Ghatan S, Jetté N. Epilepsy
and neuromodulation-randomized controlled trials. Brain Sci
2018;8(04):8
83 Englot DJ, Rolston JD, Wright CW, Hassnain KH, Chang EF. Rates
and predictors of seizure freedom with vagus nerve stimulation
for intractable epilepsy. Neurosurgery 2016;79(03):345–353
84 Macrodimitris S, Sherman EM, Forde S, et al. Psychiatric out-
comes of epilepsy surgery: a systematic review. Epilepsia 2011;
52(05):880–890
85 England MJ, Liverman CT, Schultz AM, Strawbridge LM. Epilepsy
across the spectrum: promoting health and understanding. A
summary of the Institute of Medicine report. Epilepsy Behav
2012;25(02):266–276
86 Fiest KM, Dykeman J, Patten SB, et al. Depression in epilepsy: a
systematic review and meta-analysis. Neurology 2013;80(06):
590–599
87 Scott AJ, Sharpe L, Hunt C, Gandy M. Anxiety and depressive
disorders in people with epilepsy: a meta-analysis. Epilepsia
2017;58(06):973–982
88 Christensen J, Vestergaard M, Mortensen PB, Sidenius P, Agerbo
E. Epilepsy and risk of suicide: a population-based case-control
study. Lancet Neurol 2007;6(08):693–698
89 Tian N, Cui W, Zack M, Kobau R, Fowler KA, Hesdorffer DC.
Suicide among people with epilepsy: a population-based analy-
sis of data from the U.S. National Violent Death Reporting
System, 17 states, 2003-2011. Epilepsy Behav 2016;61:210–217
90 Josephson CB, Lowerison M, Vallerand I, et al. Association of
depression and treated depression with epilepsy and seizure
outcomes: a multicohort analysis. JAMA Neurol 2017;74(05):
533–539
91 Barry JJ, Ettinger AB, Friel PAdvisory Group of the Epilepsy
Foundation as part of its Mood Disorder. , et al. Consensus
statement: the evaluation and treatment of people with epilepsy
and affective disorders. Epilepsy Behav 2008;13(Suppl 1):S1–S29
92 Gill SJ, Lukmanji S, Fiest KM, Patten SB, Wiebe S, Jetté N.
Depression screening tools in persons with epilepsy: a system-
atic review of validated tools. Epilepsia 2017;58(05):695–705
93 Stern JM, Labiner DM, Gilliam FG, et al. More effective assess-
ment of adverse effects and comorbidities in epilepsy: results of
a Phase II communication study. Epilepsy Behav 2011;22(03):
552–556
94 Fiest KM, Patten SB, Altura KC, et al. Patterns and frequency of the
treatment of depression in persons with epilepsy. Epilepsy
Behav 2014;39:59–64
Epilepsy: Workup and Management in Adults O’Dwyer 635
95 Alper K, Schwartz KA, Kolts RL, Khan A. Seizure incidence in
psychopharmacological clinical trials: an analysis of Food and
Drug Administration (FDA) summary basis of approval reports.
Biol Psychiatry 2007;62(04):345–354
96 Johnston JA, Lineberry CG, Ascher JA, et al. A 102-center pro-
spective study of seizure in association with bupropion. J Clin
Psychiatry 1991;52(11):450–456
97 Kerr MP, Mensah S, Besag FInternational League of Epilepsy
(ILAE) Commission on the Neuropsychiatric Aspects of Epilepsy,
et al; International consensus clinical practice statements for the
treatment of neuropsychiatric conditions associated with epi-
lepsy. Epilepsia 2011;52(11):2133–2138
98 Kanner AM, Kozak AM, Frey M. The use of sertraline in patients
with epilepsy: Is it safe? Epilepsy Behav 2000;1(02):100–105
99 Kühn KU, Quednow BB, Thiel M, Falkai P, Maier W, Elger CE.
Antidepressive treatment in patients with temporal lobe epilep-
sy and major depression: a prospective study with three differ-
ent antidepressants. Epilepsy Behav 2003;4(06):674–679
100 Hovorka J, Herman E, Nemcová I. Treatment of interictal depres-
sion with citalopram in patients with epilepsy. Epilepsy Behav
2000;1(06):444–447
101 Noe K. Counseling and management of the risks of living with
epilepsy. Continuum (Minneap Minn) 2019;25(02):477–491
Andersohn F, Schade R, Willich SN, Garbe E. Use of antiepileptic
Downloaded by: Western University. Copyrighted material.
102
drugs in epilepsy and the risk of self-harm or suicidal behavior.
Neurology 2010;75(04):335–340
103 Gilliam F, Kuzniecky R, Faught E, Black L, Carpenter G, Schrodt R.
Patient-validated content of epilepsy-specific quality-of-life
measurement. Epilepsia 1997;38(02):233–236
104 Kwon C, Liu M, Quan H, Thoo V, Wiebe S, Jetté N. Motor vehicle
accidents, suicides, and assaults in epilepsy: a population-based
study. Neurology 2011;76(09):801–806
105 Ma BB, Bloch J, Krumholz A, et al. Regulating drivers with
epilepsy in Maryland: results of the application of a United
States consensus guideline. Epilepsia 2017;58(08):1389–1397
106 Sauber-Schatz EK, Ederer DJ, Dellinger AM, Baldwin GT. Vital
signs: motor vehicle injury prevention - United States and 19
comparison countries. MMWR Morb Mortal Wkly Rep 2016;65
(26):672–677
107 Krumholz A, Hopp JL, Sanchez AM. Counseling epilepsy patients on
driving and employment. Neurol Clin 2016;34(02):427–442, ix
108 Drazkowski JF, Fisher RS, Sirven JI, et al. Seizure-related motor
vehicle crashes in Arizona before and after reducing the driving
restriction from 12 to 3 months. Mayo Clin Proc 2003;78(07):
819–825
109 Bacon D, Fisher RS, Morris JC, Rizzo M, Spanaki MV. American
Academy of Neurology position statement on physician report-
ing of medical conditions that may affect driving competence.
Neurology 2007;68(15):1174–1177
110 Drazkowski JF, Neiman ES, Sirven JI, McAbee GN, Noe KH.
Frequency of physician counseling and attitudes toward driving
motor vehicles in people with epilepsy: comparing a mandatory-
reporting with a voluntary-reporting state. Epilepsy Behav
2010;19(01):52–54
111 Shareef YS, McKinnon JH, Gauthier SM, Noe KH, Sirven JI,
Drazkowski JF. Counseling for driving restrictions in epilepsy
and other causes of temporary impairment of consciousness:
how are we doing? Epilepsy Behav 2009;14(03):550–552
112 Beghi E, Cornaggia CRESt-1 Group. Morbidity and accidents in
patients with epilepsy: results of a European cohort study.
Epilepsia 2002;43(09):1076–1083
113 Camfield C, Camfield P. Injuries from seizures are a serious,
persistent problem in childhood onset epilepsy: a population-
based study. Seizure 2015;27:80–83
114 Souverein PC, Webb DJ, Petri H, Weil J, Van Staa TP, Egberts T.
Incidence of fractures among epilepsy patients: a population-
based retrospective cohort study in the General Practice Re-
search Database. Epilepsia 2005;46(02):304–310
Seminars in Neurology Vol. 40 No. 6/2020
636 Epilepsy: Workup and Management in Adults O’Dwyer
115 Souverein PC, Webb DJ, Weil JG, Van Staa TP, Egberts AC. Use of
antiepileptic drugs and risk of fractures: case-control study
among patients with epilepsy. Neurology 2006;66(09):
1318–1324
116 Shiek Ahmad B, Hill KD, O’Brien TJ, Gorelik A, Habib N, Wark JD.
Falls and fractures in patients chronically treated with antiepi-
leptic drugs. Neurology 2012;79(02):145–151
117 Nicholas JM, Ridsdale L, Richardson MP, Grieve AP, Gulliford MC.
Fracture risk with use of liver enzyme inducing antiepileptic
drugs in people with active epilepsy: cohort study using the
general practice research database. Seizure 2013;22(01):37–42
118 Teagarden DL, Meador KJ, Loring DW. Low vitamin D levels are
common in patients with epilepsy. Epilepsy Res 2014;108(08):
1352–1356
119 Faught E, Duh MS, Weiner JR, Guérin A, Cunnington MC. Non-
adherence to antiepileptic drugs and increased mortality: find-
ings from the RANSOM Study. Neurology 2008;71(20):
1572–1578
120 Nickels KC, Grossardt BR, Wirrell EC. Epilepsy-related mortality
is low in children: a 30-year population-based study in Olmsted
County, MN. Epilepsia 2012;53(12):2164–2171
121 Tomson T, Beghi E, Sundqvist A, Johannessen SI. Medical risks in
epilepsy: a review with focus on physical injuries, mortality,
traffic accidents and their prevention. Epilepsy Res 2004;60(01):
1–16
122 Harden C, Tomson T, Gloss D, et al. Practice guideline summary:
sudden unexpected death in epilepsy incidence rates and risk
factors: Report of the Guideline Development, Dissemination,
and Implementation Subcommittee of the American Academy of
Neurology and the American Epilepsy Society. Neurology 2017;
88(17):1674–1680
123 Hesdorffer DC, Tomson T, Benn EILAE Commission on Epidemi-
ology; Subcommission on Mortality. , et al; . Combined analysis
of risk factors for SUDEP. Epilepsia 2011;52(06):1150–1159
124 Waddell B, McColl K, Turner C, et al. Are we discussing SUDEP?–A
retrospective case note analysis Seizure 2013;22(01):74–76
125 Miller WR, Young N, Friedman D, Buelow JM, Devinsky O.
Discussing sudden unexpected death in epilepsy (SUDEP) with
patients: practices of health-care providers. Epilepsy Behav
2014;32:38–41
126 Louik J, Doumlele K, Hussain F, et al. Experiences with premorbid
SUDEP discussion among participants in the North American
SUDEP Registry (NASR). Epilepsy Behav 2017;70(PtA):131–134
127 Ngugi AK, Kariuki SM, Bottomley C, Kleinschmidt I, Sander JW,
Newton CR. Incidence of epilepsy: a systematic review and meta-
analysis. Neurology 2011;77(10):1005–1012
128 Vélez-Ruiz NJ, Pennell PB. Issues for women with epilepsy.
Neurol Clin 2016;34(02):411–425, ix
129 Reddy DS, Kim HY, Rogawski MA. Neurosteroid withdrawal
model of perimenstrual catamenial epilepsy. Epilepsia 2001;
42(03):328–336
130 Herzog AG, Fowler KM, Smithson SDProgesterone Trial Study Group.
, et al; . Progesterone vs placebo therapy for women with epilepsy: a
randomized clinical trial. Neurology 2012;78(24):1959–1966
131 Brodie MJ, Mintzer S, Pack AM, Gidal BE, Vecht CJ, Schmidt D.
Enzyme induction with antiepileptic drugs: cause for concern?
Epilepsia 2013;54(01):11–27
132 Svalheim S, Sveberg L, Mochol M, Taubøll E. Interactions between
antiepileptic drugs and hormones. Seizure 2015;28:12–17
133 Chen LW, Chen MY, Chen KY, Lin HS, Chien CC, Yin HL. Top-
iramate-associated sexual dysfunction: a systematic review.
Epilepsy Behav 2017;73:10–17
134 Lin CY, Burri A, Fridlund B, Pakpour AH. Female sexual function
mediates the effects of medication adherence on quality of life in
people with epilepsy. Epilepsy Behav 2017;67:60–65
135 Verrotti A, Mencaroni E, Cofini M, et al. Valproic acid metabolism
and its consequences on sexual functions. Curr Drug Metab
2016;17(06):573–581
Seminars in Neurology Vol. 40 No. 6/2020
136 McGrath A, Sharpe L, Lah S, Parratt K. Pregnancy-related knowl-
edge and information needs of women with epilepsy: a system-
atic review. Epilepsy Behav 2014;31:246–255
137 Tomson T, Xue H, Battino D. Major congenital malformations in
children of women with epilepsy. Seizure 2015;28:46–50
138 Bjørk M, Riedel B, Spigset O, et al. Association of folic acid
supplementation during pregnancy with the risk of autistic
traits in children exposed to antiepileptic drugs in utero. JAMA
Neurol 2018;75(02):160–168
139 Meador KJ, Baker GA, Browning NNEAD Study Group. , et al; .
Fetal antiepileptic drug exposure and cognitive outcomes at age
6 years (NEAD study): a prospective observational study. Lancet
Neurol 2013;12(03):244–252
140 Stephen LJ, Harden C, Tomson T, Brodie MJ. Management of
epilepsy in women. Lancet Neurol 2019;18(05):481–491
141 Battino D, Tomson T, Bonizzoni EEURAP Study Group. , et al; .
Seizure control and treatment changes in pregnancy: observa-
tions from the EURAP epilepsy pregnancy registry. Epilepsia
2013;54(09):1621–1627
142 MacDonald SC, Bateman BT, McElrath TF, Hernández-Díaz S.
Mortality and morbidity during delivery hospitalization among
pregnant women with epilepsy in the United States. JAMA
Neurol 2015;72(09):981–988
143 The Epilepsies: The Diagnosis and Management of the Epilepsies
Downloaded by: Western University. Copyrighted material.
in Adults and Children in Primary and Secondary Care: Pharma-
cological Update of Clinical Guideline 20.
;:624–637.London2012
144 Danielsson KC, Borthen I, Morken NH, Gilhus NE. Hypertensive
pregnancy complications in women with epilepsy and antiepi-
leptic drugs: a population-based cohort study of first pregnan-
cies in Norway. BMJ Open 2018;8(04):e020998
145 Hernández-Díaz S, McElrath TF, Pennell PB, Hauser WA, Yerby M,
Holmes LBNorth American Antiepileptic Drug Pregnancy Regis-
try. Fetal growth and premature delivery in pregnant women on
antiepileptic drugs. Ann Neurol 2017;82(03):457–465
146 Tomson T, Landmark CJ, Battino D. Antiepileptic drug treatment
in pregnancy: changes in drug disposition and their clinical
implications. Epilepsia 2013;54(03):405–414
147 Voinescu PE, Park S, Chen LQ, et al. Antiepileptic drug clearances
during pregnancy and clinical implications for women with
epilepsy. Neurology 2018;91(13):e1228–e1236
148 Reimers A, Helde G, Becser Andersen N, et al. Zonisamide serum
concentrations during pregnancy. Epilepsy Res 2018;144:25–29
149 Hernández-Díaz S, Smith CR, Shen ANorth American AED Preg-
nancy Registry North American AED Pregnancy Registry. , et al; .
Comparative safety of antiepileptic drugs during pregnancy.
Neurology 2012;78(21):1692–1699
150 Campbell E, Kennedy F, Russell A, et al. Malformation risks of
antiepileptic drug monotherapies in pregnancy: updated results
from the UK and Ireland Epilepsy and Pregnancy Registers.
J Neurol Neurosurg Psychiatry 2014;85(09):1029–1034
151 Tomson T, Battino D, Bonizzoni EEURAP Study Group. , et al; .
Comparative risk of major congenital malformations with eight
different antiepileptic drugs: a prospective cohort study of the
EURAP registry. Lancet Neurol 2018;17(06):530–538
152 Baker GA, Bromley RL, Briggs MLiverpool and Manchester Neu-
rodevelopment Group. , et al; . IQ at 6 years after in utero
exposure to antiepileptic drugs: a controlled cohort study.
Neurology 2015;84(04):382–390
153 Richards N, Reith D, Stitely M, Smith A. Are doses of lamotrigine
or levetiracetam adjusted during pregnancy? Epilepsia Open
2017;3(01):86–90
154 Meador KJ, Baker GA, Browning NNeurodevelopmental Effects of
Antiepileptic Drugs (NEAD) Study Group. , et al; . Breastfeeding
in children of women taking antiepileptic drugs: cognitive out-
comes at age 6 years. JAMA Pediatr 2014;168(08):729–736
155 Veiby G, Bjørk M, Engelsen BA, Gilhus NE. Epilepsy and recom-
mendations for breastfeeding. Seizure 2015;28:57–65

156 Veiby G, Engelsen BA, Gilhus NE. Early child development and
exposure to antiepileptic drugs prenatally and through breast-
feeding: a prospective cohort study on children of women with
epilepsy. JAMA Neurol 2013;70(11):1367–1374
157 Koppel BS, Harden CL. Gender issues in the neurobiology of
epilepsy: a clinical perspective. Neurobiol Dis 2014;72(Pt
B):193–197
158 Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and
unprovoked seizures in Rochester, Minnesota: 1935-1984. Epi-
lepsia 1993;34(03):453–468
159 Ghosh S, Jehi LE. New-onset epilepsy in the elderly: challenges
for the internist. Cleve Clin J Med 2014;81(08):490–498
160 Sander JW, Hart YM, Johnson AL, Shorvon SD. National general
practice study of epilepsy: newly diagnosed epileptic seizures in
a general population. Lancet 1990;336(8726):1267–1271
161 Brodie MJ, Elder AT, Kwan P. Epilepsy in later life. Lancet Neurol
2009;8(11):1019–1030
162 Ramsay RE, Rowan AJ, Pryor FM. Special considerations in
treating the elderly patient with epilepsy. Neurology 2004;62
(05, Suppl 2):S24–S29
163 Silveira DC, Jehi L, Chapin J, et al. Seizure semiology and aging.
Epilepsy Behav 2011;20(02):375–377
164 Oono M, Uno H, Umesaki A, Nagatsuka K, Kinoshita M, Naritomi
H. Severe and prolonged ictal paresis in an elderly patient.
Epilepsy Behav Case Rep 2014;2:105–107
165 Werhahn KJ. Epilepsy in the elderly. Dtsch Arztebl Int 2009;106
(09):135–142
Epilepsy: Workup and Management in Adults O’Dwyer 637
166 Smith SJ. EEG in the diagnosis, classification, and management of
patients with epilepsy. J Neurol Neurosurg Psychiatry 2005;76
(Suppl 2):ii2–ii7
167 Watson P, Conroy A, Moran G, Duncan S. Retrospective study of
sensitivity and specificity of EEG in the elderly compared with
younger age groups. Epilepsy Behav 2012;25(03):408–411
168 Chochoi M, Tyvaert L, Derambure P, Szurhaj W. Is long-term electro-
encephalogram more appropriate than standard electroencephalo-
gram in the elderly? Clin Neurophysiol 2017;128(01):270–274
169 McBride AE, Shih TT, Hirsch LJ. Video-EEG monitoring in the
elderly: a review of 94 patients. Epilepsia 2002;43(02):165–169
170 Lam AD, Deck G, Goldman A, Eskandar EN, Noebels J, Cole AJ. Silent
hippocampal seizures and spikes identified by foramen ovale
electrodes in Alzheimer’s disease. Nat Med 2017;23(06):678–680
171 Sheth SA, Aronson JP, Shafi MM, et al. Utility of foramen ovale
electrodes in mesial temporal lobe epilepsy. Epilepsia 2014;55
(05):713–724
172 Cheng JY, French JA. Intelligent use of antiepileptic drugs is
beneficial to patients. Curr Opin Neurol 2018;31(02):169–175
173 Perucca E, Berlowitz D, Birnbaum A, et al. Pharmacological and
clinical aspects of antiepileptic drug use in the elderly. Epilepsy
Res 2006;68(Suppl 1):S49–S63
174 Poza JJ. Management of epilepsy in the elderly. Neuropsychiatr
Dis Treat 2007;3(06):723–728
Downloaded by: Western University. Copyrighted material.
175 O’Dwyer R, Byrne R, Lynn F, et al. Age is but a number when
considering epilepsy surgery in older adults. Epilepsy Behav
2019;91:9–12
Seminars in Neurology Vol. 40 No. 6/2020