Annals of Internal Medicine䊛

In the Clinic® Diagnosis

Epilepsy Prevention

Treatment

A
n epileptic seizure is defined by the Inter-
national League Against Epilepsy (ILAE)
as “a transient occurrence of signs and/or
symptoms due to abnormal excessive or syn- Further Considerations
chronous neuronal activity in the brain” (1). In
2014, the ILAE provided an operational (practi-
cal) clinical definition of epilepsy as a disease of
the brain defined as any of the following condi-
tions: at least 2 unprovoked [or reflex] seizures
occurring more than 24 hours apart; 1 unpro-
voked [or reflex] seizure and a probability of
further seizures similar to the general recur-
rence risk [at least 60%] after 2 unprovoked sei-
zures, occurring over the next 10 years; [and/or]
a diagnosis of an epilepsy syndrome (2).

The CME quiz is available at www.annals.org/intheclinic.aspx. Complete the quiz to earn up to 1.5 CME credits.

Physician Writer doi:10.7326/AITC201602020

Kaarkuzhali B.
Krishnamurthy, MD CME Objective: To review current evidence for diagnosis, prevention, treatment, and
further considerations of epilepsy.
Funding Source: American College of Physicians.
Disclosures: Dr. Krishnamurthy, ACP Contributing Author, has disclosed no conflicts of
interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterest
Forms.do?msNum=M15-2484.
With the assistance of additional physician writers, the editors of Annals of Internal
Medicine develop In the Clinic using MKSAP and other resources of the American
College of Physicians.
In the Clinic does not necessarily represent official ACP clinical policy. For ACP clinical
guidelines, please go to https://www.acponline.org/clinical_information/guidelines/.
© 2016 American College of Physicians

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 A seizure can cause isolated or fection (6). Because a first seizure
combined sensory, motor, cogni- can lead to other events, an elec-
tive, or emotional symptoms. The troencephalogram (EEG) is also
ILAE defines reflex seizures as recommended at the time of initial
those “that are objectively and presentation as identification of
consistently demonstrated to be interictal abnormalities increases
evoked by a specific afferent the risk for a second seizure, which
1. Fisher RS, van Emde Boas
stimulus or by activity of the pa- may or may not lead to a diagnosis
W, Blume W, Elger C, tient” (3). Epilepsy is a chronic of epilepsy (4).
Genton P, Lee P, et al.
Epileptic seizures and disorder that can have long-
epilepsy: definitions pro- standing medical, psychological, The causes of epilepsy vary and
posed by the International
and social sequelae. are identified in only about 30%
League Against Epilepsy
(ILAE) and the Interna- of people with the disorder (see
tional Bureau for Epilepsy
(IBE). Epilepsia. 2005;46:
Isolated seizures are common; the Box: Seizure Evaluation).
470-2. [PMID: 15816939] they are believed to occur in 1 in Common risk factors include pre-
2. Fisher RS, Acevedo C,
Arzimanoglou A, Bogacz A,
10 persons over a lifetime. An iso- mature birth; complicated febrile
Cross JH, Elger CE, et al. lated seizure should not be con- seizures; infections, such as men-
ILAE official report: a prac-
tical clinical definition of fused with epilepsy. The preva- ingitis or encephalitis, at any age;
epilepsy. Epilepsia. 2014;
55:475-82. [PMID:
lence of recurrent, unprovoked head trauma, which may be mi-
24730690] seizures, or epilepsy, is believed to nor, particularly if it is recurrent;
3. Illingworth JL, Ring H.
Conceptual distinctions
be 5– 8 per 1000 persons in devel- and/or a family history of epi-
between reflex and nonre- oped countries; higher (10/1000 lepsy or neurologic illnesses.
flex precipitated seizures
in the epilepsies: a sys- persons) in developing countries; Causes of epilepsy may include
tematic review of defini-
tions employed in the
and higher still in rural areas, due structural lesions related to dis-
research literature. Epilep- in part to infectious and traumatic turbances in intrauterine devel-
sia. 2013;54:2036-47.
[PMID: 24032405]
causes (4). In low- and middle- opment, such as TORCH (toxo-
4. Moshé SL, Perucca E, income countries, other factors, plasmosis, other [syphilis,
Ryvlin P, Tomson T. Epi-
lepsy: new advances. including age and sex, can influ- varicella-zoster, parvovirus B19],
Lancet. 2015;385:884-98.
[PMID: 25260236]
ence morbidity and mortality re- rubella, cytomegalovirus, and
5. Wagner RG, Bottomley C, lated to epilepsy (5). herpes) infections, abnormalities
Ngugi AK, Ibinda F,
Gómez-Olivé FX, Kahn K,
Causes of isolated seizures can of neuronal migration, and fetal
et al; SEEDS Writing
Group. Incidence, remis- include such toxic, metabolic, intracranial hemorrhage. Prema-
sion and mortality of con-
structural, and infectious factors ture birth can lead to white mat-
vulsive epilepsy in rural
northeast South Africa. as alcohol intoxication and with- ter and cortical damage in the
PLoS One. 2015;10:
e0129097. [PMID: drawal, hypoglycemia and hyper- developing brain, producing an
26053071]
glycemia, acute stroke, and me- environment that is conducive to
6. Krumholz A, Wiebe S,
Gronseth G, Shinnar S, ningoencephalitis. Thus, the the initiation and propagation of
Levisohn P, Ting T, et al;
Quality Standards Sub- algorithm for evaluation of a first seizures (7). Other acquired le-
committee of the Ameri- seizure includes a thorough his- sions can serve as seizure foci,
can Academy of Neurol-
ogy. Practice parameter: tory and physical examination, a including benign and malignant
evaluating an apparent
blood glucose test, electrolyte intracranial or extra-axial tumors,
unprovoked first seizure in
adults (an evidence-based panels, a blood count, toxicology abscesses, cysts, hemorrhagic
review): report of the
Quality Standards Sub- screening, brain imaging (com- lesions, or strokes. Genetic causes
committee of the Ameri- puted tomography [CT] or mag- have been identified for some id-
can Academy of Neurology
and the American Epilepsy netic resonance imaging [MRI]), iopathic epilepsy syndromes, and
Society. Neurology. 2007; systemic illnesses, such as HIV in-
69:1996-2007. [PMID:
and spinal fluid analysis in pa-
18025394] tients with fever or other symp- fection and malaria, can also lead
7. Robinson S. Systemic
prenatal insults disrupt toms or signs of intracranial in- to chronic epilepsy (8).
telencephalon develop-
ment: implications for
potential interventions.
Epilepsy Behav. 2005;7:
345-63. [PMID:
Diagnosis
16061421]
8. Bhalla D, Godet B, Druet-
What are the symptoms of tingling, pain, or isolated motor
Cabanac M, Preux PM. epilepsy? symptoms) or twitching, jerking,
Etiologies of epilepsy: a
comprehensive review. Symptoms of seizures vary or rhythmic or semirhythmic un-
Expert Rev Neurother. widely. They can be isolated controlled movements. They can
2011;11:861-76. [PMID:
21651333] sensory symptoms (numbness, be purely psychic symptoms,

姝 2016 American College of Physicians ITC18 In the Clinic Annals of Internal Medicine 2 February 2016

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 such as fear, sadness, elation, or
laughing. Awareness may be al-
tered, leading to an inability to
interact normally. Although pa-
tients may seem to be conscious,
difficulty responding verbally to
questions and difficulty integrating
new memories, as well as auto-
matic behaviors such as lip smack-
ing, chewing, or swallowing, can
be signs of a seizure. Patients with
focal-onset epilepsy (in which the
electrical disturbance spreads to
involve wider areas of the cerebral
cortex) may have other visible mo-
tor manifestations, including stiff-
ening, jerking, or twitching on one
or both sides of the body. Loss of
tone, incontinence, and tongue
biting may occur. Confusion and
disorientation may be seen for sev-
eral minutes afterward and, con-
cordant with the duration of the
seizure, resolution to normal cog-
nitive function may take hours or
days. Patients with absence sei-
zures may stare or blink repeti-
tively with little else in the way of
motor manifestations, and they
may not be aware that a seizure
has occurred unless they are told.
However, lack of recall does not
distinguish absence seizures from
complex partial seizures because
some patients with the latter also
may be unaware that an event has
occurred.
In patients with epilepsy, in addi-
tion to obtaining a detailed history
with special emphasis on the pa-
tient's description of seizure onset
(“How do you know that a seizure
is going to occur? What's the first
thing that happens? Then what?
Do you have any other intermittent
movements or feelings that occur
without an apparent cause?”), a
thorough physical examination
should be performed to look for
focal findings that indicate the
presence of an intracranial struc-
tural disturbance. A finding of
blurred disc margins on an ocular
examination could indicate an in-
tracranial mass lesion causing in-
2 February 2016 Annals of Internal Medicine
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creased intracranial pressure.
Hemiatrophy of a limb or digit Seizure Evaluation
suggests incomplete contralateral
First seizure:
cerebral development, such as
can be seen in patients who may Thorough history and physical
have had intrauterine insults. examination
Bloodwork: Serum glucose
Several causes of altered behav- level, chemistry panel (so-
ior should be considered in the dium, calcium, phosphorus,
differential diagnosis of pre- magnesium,) liver function
sumed epilepsy (9). Syncope is a tests, blood urea nitrogen/
commonly misidentified event that creatinine, pregnancy test for
can occur with vascular insuffi- women, complete blood
count, toxicology, alcohol
ciency, cardiac dysrhythmias, hy-
level
povolemia, anemia, and auto-
nomic dysfunction. Sleep Lumbar puncture if febrile,
disturbances; metabolic derange- nuchal rigidity, immune
ments, such as hypoglycemia; compromise
movement disorders; and mi- Electroencephalogram
graine can also lead to repetitive Computed tomography or
or stereotyped movements, al- magnetic resonance imaging
tered awareness, and impaired
Consider HIV test
cognitive function. Altered aware-
ness in the context of delirium or Breakthrough seizure:
dementia can also be mistaken for History and examination
seizure activity, although the coin-
Bloodwork: As above, add in
cidence of seizures in these medi- trough anticonvulsant levels
cal conditions can be high. Finally,
No need for neuroimaging
psychiatric and psychological con-
unless new seizure type,
ditions, including panic attacks, change in seizure semiology
posttraumatic stress disorder, and
or frequency
nonepileptic events (also known as
Electroencephalogram if
pseudoseizures), may be difficult
patient does not return to
to distinguish from epileptic sei-
baseline
zures and may require further
testing.
What tests should be done to
diagnose epilepsy?
In addition to the bloodwork
noted earlier, more specific test-
ing in patients with epilepsy
should focus on identifying 2 fac-
tors: confirmation that the events
are epileptic, and identification
of the cause. For confirmation, an
EEG should be offered. In a rou-
tine EEG, a short period (typically
20 – 60 minutes) of brain wave
activity is recorded. Although the
likelihood of capturing a clinical
event is small, identification of
interictal discharges, such as
sharp waves and spikes, in-
9. Benbadis S. The differen-
creases the evidence supporting tial diagnosis of epilepsy:
the event as epileptic in nature. If a critical review. Epilepsy
Behav. 2009;15:15-21.
the patient's symptoms occur [PMID: 19236946]
In the Clinic ITC19 姝 2016 American College of Physicians

10. Gaitatzis A, Sisodiya SM,
Sander JW. The somatic
comorbidity of epilepsy:
a weighty but often un-
recognized burden.
Epilepsia. 2012;53:
1282-93. [PMID:
22691064]
姝 2016 American College of Physicians
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relatively frequently or can be
provoked by certain reproduc-
ible situations, ambulatory outpa-
tient or inpatient EEG monitoring
may be helpful. This involves
placing electrodes on the pa-
tient's scalp that capture data
that are then processed through
computer software with detec-
tion algorithms, such as auto-
mated spike detection and sei-
zure detection programs. The
subsequent recording, including
video if available, is reviewed
and interpreted by a trained elec-
troencephalographer. Extended
recording typically occurs for
days at a time and more readily
identifies electrical disturbances
that may be seen only in certain
sleep states. In addition to the
automated detection features,
the patient can activate a push-
button that saves a portion of the
recording preceding and follow-
ing the patient's clinical signal. For
patients who have identified situa-
tions or conditions that provoke
events, continuous EEG recording
may be a perfect mechanism for
diagnosis because the recording
can occur while the patient per-
forms the provocative maneuver.
Cardiac testing may also be of-
fered as part of a diagnostic eval-
uation. Routine electrocardiogra-
phy and ambulatory cardiac
monitoring can be used to look
for evidence of dysrhythmias
leading to altered awareness or
loss of consciousness. Echocardi-
ography can show evidence of
cardiac wall dysfunction as an
indicator of prior cardiac isch-
emia. Similarly, focal wall hypoki-
nesis or valvular disease could be
mechanisms to generate clots
that could be transferred via the
bloodstream to the brain, caus-
ing recurrent strokes.
Neuroimaging is mandatory for
patients with epilepsy, particu-
larly if it is newly diagnosed, to
look for focal lesions as a cause.
Focal or space-occupying le-
ITC20 In the Clinic
sions, such as malignant or meta-
static tumors, subdural or epidu-
ral hematomas, or empyemas,
may require acute surgical inter-
vention. Other focal findings,
such as migrational disorders or
vascular lesions, may serve as
evidence supporting focal onset
for a patient's presentation.
Do patients with epilepsy have
related comorbidities?
Once a definitive diagnosis of
epilepsy is made, consideration
of and ongoing monitoring for
comorbidities should occur. Epi-
lepsy is not protective against
common medical conditions,
such as hypertension, hypercho-
lesterolemia, or diabetes, so phy-
sicians must screen patients with
epilepsy as they would any other
patient. In addition, some anti-
convulsants have such adverse
effects as disturbances of calcium
homeostasis or appetite en-
hancement or suppression,
which can exacerbate concomi-
tant medical conditions. It is im-
portant for physicians, including
primary care providers, to be
aware of these potential effects
and to monitor for them.
Epidemiologic studies have identi-
fied other medical conditions,
such as pneumonia, asthma, and
upper gastrointestinal bleeding,
that seem to be more prevalent in
patients with epilepsy than in the
general population (10). The
mechanisms for this are not clear
but can include acute and chronic
adverse effects of anticonvulsants
as well as shared risk factors (10).
Other concomitant medical
problems may include hormonal
imbalances, which are known to
occur in both women and men
with epilepsy at rates higher than
those of the general public and
in patients with other neurologic
conditions. Reproductive endo-
crine disorders, such as polycys-
tic ovarian syndrome, occur more
than twice as often in women
Annals of Internal Medicine 2 February 2016
 with epilepsy than in those in the
general population (11). In sus-
ceptible women, the relative epi-
leptogenic potential of serum
estradiol can lead to perimen-
strual or periovulatory seizures or
seizures that occur during the
entire second half of the men-
strual cycle (12). The effect of
menopause on seizures and epi-
lepsy syndromes is not well-
understood, particularly because
factors that are commonly seen in
the perimenopausal period, such
as sleep disturbances, can also
affect seizures (13). Men with epi-
lepsy, even those who are not re-
ceiving anticonvulsant therapy,
can have low sexual function, and
those receiving enzyme-inducing
anticonvulsants, such as phenytoin
and carbamazepine, may have de-
creased testosterone bioactivity (14).
Cognitive impairment can occur
in patients with epilepsy (15).
This may be seen before the on-
set of seizures, as in patients with
cerebral lesions, which may also
be the cause of the epilepsy. Fre-
quent or prolonged seizures can
lead to disturbances of cortical
function during and after a sei-
zure, as can transient or more
consistent metabolic or hypoxic
derangements that may occur as
a consequence of the seizures.
Anticonvulsants themselves may
cause cognitive dysfunction,
which may be particularly notice-
able in patients using combina-
tion therapy (16).
Patients with temporal lobe epi-
lepsy may have associated cogni-
tive deficits related to the lateral-
ity of the seizure focus; for
example, language deficits may
be seen in patients with temporal
lobe epilepsy arising in the domi-
nant hemisphere for language.
These deficits may be seen even
if the epilepsy is well-controlled.
Finally, mood disorders, such as
depression and anxiety, occur
more frequently in patients with
2 February 2016 Annals of Internal Medicine
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epilepsy than in the general pop-
ulation (16). These can occur as
primary medical conditions but
also as consequences of anticon-
vulsant therapy and should be
watched for closely for the dura-
tion of the patient's medical
treatment. Suicide is more com-
mon in patients with epilepsy
than in the general population,
and because the disorder carries
a high burden of stigma, patients
may be reluctant to seek help for
a coexistent mood disorder. Like-
wise, fear of having a seizure in
public can lead to social isola-
tion, diminished opportunities to
develop friendships, and de-
creased social support (17). The
prohibition against driving for
people with active seizures can
also diminish quality of life, given
that many communities do not
have sufficient public transporta-
tion options to allow for commut-
ing to work or social events (18).
Endogenous depression seems
to be more common in patients
with temporal lobe epilepsy than
in those with focal epilepsy origi-
nating in other brain regions and
in patients with primary general-
ized epilepsy (19). Some anticon-
vulsants can cause mood distur-
bances, including suicidality,
whereas anticonvulsants with
mood-stabilizing properties, such
as lamotrigine and valproate, may
lead to depression if the dosage is
decreased or the medication is
withdrawn (16). The coincidence
of epilepsy and mood disorders
may also increase risk for recurrent
or breakthrough seizures (20).
A retrospective cohort study identified people
who submitted insurance claims for anticon-
vulsant medications and reviewed subsequent
claims to determine whether they visited an
emergency department, used an ambulance,
or were hospitalized for seizure treatment. A
total of 5.3% of patients receiving mono-
therapy required 1 of the 3 outcomes in the
first year of follow-up. Preexisting mental
health disorders, such as depression, anxiety,
substance abuse, or schizophrenia, further in-
creased risk (20).
In the Clinic
11. Herzog AG. Disorders of
reproduction in patients
with epilepsy: primary
neurological mecha-
nisms. Seizure. 2008;
17:101-10. [PMID:
18165118]
12. Herzog AG, Klein P,
Ransil BJ. Three patterns
of catamenial epilepsy.
Epilepsia. 1997;38:
1082-8. [PMID:
9579954]
13. Sveinsson O, Tomson T.
Epilepsy and meno-
pause: potential implica-
tions for pharmacother-
apy. Drugs Aging. 2014;
31:671-5. [PMID:
25079452]
14. Devinsky O. Neurologist-
induced sexual dysfunc-
tion: enzyme-inducing
antiepileptic drugs [Edi-
torial]. Neurology. 2005;
65:980-1. [PMID:
16217046]
15. Witt JA, Helmstaedter C.
Cognition in the early
stages of adult epilepsy.
Seizure. 2015;26:65-8.
[PMID: 25799904]
16. Schmidt D, Schachter SC.
Drug treatment of epi-
lepsy in adults. BMJ.
2014;348:g254. [PMID:
24583319]
17. McCagh J, Fisk JE, Baker
GA. Epilepsy, psychoso-
cial and cognitive func-
tioning. Epilepsy Res.
2009;86:1-14. [PMID:
19616921]
18. Naik PA, Fleming ME,
Bhatia P, Harden CL. Do
drivers with epilepsy
have higher rates of
motor vehicle accidents
than those without epi-
lepsy? Epilepsy Behav.
2015;47:111-4. [PMID:
25960422]
19. Garcia CS. Depression in
temporal lobe epilepsy:
a review of prevalence,
clinical features, and
management consider-
ations. Epilepsy Res
Treat. 2012;2012:1-12.
20. Shcherbakova N, Rascati
K, Brown C, Lawson K,
Novak S, Richards KM,
et al. Factors associated
with seizure recurrence
in epilepsy patients
treated with antiepileptic
monotherapy: a retro-
spective observational
cohort study using US
administrative insurance
claims. CNS Drugs.
2014;28:1047-58.
[PMID: 25086640]
ITC21 姝 2016 American College of Physicians
 Diagnosis... Epilepsy is best identified by a careful history and physical
examination. Proper neuroimaging with MRI may identify causal factors.
Ambulatory or continuous EEG monitoring may be especially helpful in
the differential diagnosis, even if seizures are not captured. Many co-
morbidities are associated with epilepsy, either from the etiologic cause
or from treatments for the condition. Proper identification and manage-
ment of these may lead to improved functioning and quality of life.

CLINICAL BOTTOM LINE

Prevention
21. Pandey S, Rathore C,
Michael BD. Antiepileptic
drugs for the primary
and secondary preven-
tion of seizures in viral
encephalitis. Cochrane
Database Syst Rev. 2014;
10:CD010247. [PMID:
25300175]
22. Thompson K, Pohlmann-
Eden B, Campbell LA,
Abel H. Pharmacological
treatments for prevent-
ing epilepsy following
traumatic head injury.
Cochrane Database Syst
Rev. 2015;8:CD009900.
[PMID: 26259048]
How can epilepsy be
prevented?
There are no consistent mecha-
nisms to prevent the develop-
ment of epilepsy. Avoidance of
risk factors may not be possible
given that most do not require
recurrent exposure; mild head
injury, such as a concussion, may
be the exception because emerg-
ing data suggest that recurrent
mild head injuries can lead to epi-
lepsy. Few if any randomized, con-
trolled trials have been done to
determine whether early introduc-
tion of anticonvulsant therapy in,
for example, patients with viral en-
cephalitides alters subsequent
development of seizures (21). After
a significant head injury, the use of
anticonvulsant therapy versus pla-
cebo does not seem to reduce the
risk for early or late posttraumatic
seizures (22).
Although there may be no effec-
tive mechanisms to prevent the
development of epilepsy, there
may be ways to prevent seizures
in patients who are prone to the
disorder. For example, for pa-
tients with clear reflex epilepsy,
identification of situations or
events that can trigger seizures
may be clear, whereas triggers
for those with nonreflex forms of
epilepsy may become apparent
only after several seizures have
occurred. Encouraging patients
to keep a record of events occur-
ring over the 24 hours after each
seizure may allow patterns to be-
come more evident. For many
patients, insufficient sleep or al-
cohol use can trigger seizures.
Initial and recurrent counseling
on ways to improve sleep dura-
tion and quality may help to pre-
vent further occurrences, particu-
larly for adolescents, elderly
patients, and those with newborn
children. Likewise, assisting pa-
tients in identifying alternative
strategies to avoid or limit alco-
hol use in social situations may
help to allow them to maintain
normal or age-appropriate social
interactions, thereby reducing the
stigma of epilepsy. Providing
thoughtful alternatives, such as
limiting alcohol intake to 1 or 2
drinks on a weekend night rather
than prohibiting all alcohol intake,
not only allows patients to feel
comfortable asking for help and
support from their physicians but
also provides reasonable modifi-
cations that patients are likely to
adopt.
Finally, some patients are at risk
for recurrent seizures. These can
occur in situations where normal
absorption of seizure medica-
tions can be impaired, such as
with comorbid gastrointestinal
illness or during colonoscopy
preparation. Other patients show
a clustering pattern of seizures as
a feature of their particular epi-
lepsy syndrome. For these pa-
tients and for those who may be
at risk for recurrent seizures, in-
termittent use of short-term ben-

姝 2016 American College of Physicians ITC22 In the Clinic Annals of Internal Medicine 2 February 2016

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 zodiazepine therapy may prevent
progression into status epilepti-
cus (23). Patients must be care-
fully counseled to ensure that the
rescue medication is used only in
emergency situations, with due
consideration given to the ad-
verse effects of benzodiazepine.
Patients should also be advised
that if seizures persist despite 1–2
doses of benzodiazepine treat-
ment, they may require emer-
gency transport to a hospital for
further treatment (24).
Prevention... There are no proven strategies to prevent epilepsy. How-
ever, taking a careful history may identify avoidable seizure triggers,
such as sleep deprivation, alcohol use, and planned or inadvertent non-
adherence to medication. Providing patients with a small quantity of
low-dose oral benzodiazepines may decrease risk for recurrent seizures
in the setting of intercurrent illness.
How should epilepsy be treated
initially?
The risk for seizure recurrence in
adults with an unprovoked first
seizure is 21%– 45% in the first 2
years; initiation of treatment after
the first event reduces risk over
the next 2 years but does not
seem to improve the chances of
long-term remission (25). Thus,
introduction of therapy after a
single seizure requires careful
discussion between the patient
and the health care provider.
A second seizure typically results
in the initiation of treatment. Al-
though there are several meth-
ods to treat epilepsy, including
medications and devices ap-
proved by the U.S. Food and
Drug Administration (FDA), surgi-
cal options, and hormonal inter-
ventions, pharmacotherapy is
typically offered as the initial
treatment. More than 2 dozen
anticonvulsants have been ap-
proved by the FDA for treatment
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An emergency-use study in San Francisco, Cal-
ifornia, allowed paramedics to administer 1 of
3 randomly assigned intravenous medications
to adult patients with prolonged or repetitive
convulsive seizures (status epilepticus): 5 mg
of diazepam, 2 mg of lorazepam, or placebo,
with a second injection given if seizures did
not resolve. Status epilepticus resolved in
59.1% of patients who received lorazepam and
42.6% of those who received diazepam com-
pared with 21.1% of those who received pla-
cebo. Of note, the rate of respiratory or circula-
tory problems in patients who received
benzodiazepines was approximately 10% ver-
sus 22.5% in the placebo group (24).
CLINICAL BOTTOM LINE 23. Lowenstein DH. Treat-
ment options for status
epilepticus. Curr Opin
Pharmacol. 2005;5:
334-9. [PMID:
15907922]
Treatment 24. Alldredge BK, Gelb AM,
Isaacs SM, Corry MD,
of adults with epilepsy. Head-to- Allen F, Ulrich S, et al. A
comparison of loraz-
head comparisons of these medi- epam, diazepam, and
placebo for the treatment
cations have not been done; of out-of-hospital status
however, trials that have com- epilepticus. N Engl J
Med. 2001;345:631-7.
pared specific drug regimens [PMID: 11547716]
25. Krumholz A, Wiebe S,
have not found clear evidence Gronseth GS, Gloss DS,
supporting the use of a specific Sanchez AM, Kabir AA,
et al. Evidence-based
medication over another in cir- guideline: management
cumstances where both medica- of an unprovoked first
seizure in adults: report
tions have proven efficacy in a of the Guideline Devel-
opment Subcommittee
particular epilepsy syndrome or of the American Acad-
seizure type (26). emy of Neurology and
the American Epilepsy
Society. Neurology.
Thus, after an initial filtering pro- 2015;84:1705-13.
[PMID: 25901057]
cess to identify the set of anticon- 26. French JA, Kanner AM,
vulsants with efficacy in the pa- Bautista J, Abou-Khalil B,
Browne T, Harden CL,
tient's type of epilepsy, further et al; Therapeutics and
Technology Assessment
consideration must be given to Subcommittee of the
potential adverse effects; interac- American Academy of
Neurology. Efficacy and
tions with other medical condi- tolerability of the new
antiepileptic drugs I:
tions or medications; time to treatment of new onset
reach optimal dosing; plans for epilepsy: report of the
Therapeutics and Tech-
childbearing; and other lifestyle nology Assessment Sub-
committee and Quality
factors, including the patient's Standards Subcommittee
preferences with respect to the of the American Acad-
emy of Neurology and
dosing schedule. Although some the American Epilepsy
patients may have to consider Society. Neurology.
2004;62:1252-60.
cost or affordability of the anti- [PMID: 15111659]
In the Clinic ITC23 姝 2016 American College of Physicians

27. Mohanraj R, Brodie MJ.
Early predictors of out-
come in newly diag-
nosed epilepsy. Seizure.
2013;22:333-44. [PMID:
23583115]
28. Jacoby A, Sudell M,
Tudur Smith C, Crossley
J, Marson AG, Baker GA;
SANAD Study Group.
Quality-of-life outcomes
of initiating treatment
with standard and newer
antiepileptic drugs in
adults with new-onset
epilepsy: findings from
the SANAD trial. Epilep-
sia. 2015;56:460-72.
[PMID: 25630353]
29. French JA, Kanner AM,
Bautista J, Abou-Khalil B,
Browne T, Harden CL,
et al; Therapeutics and
Technology Assessment
Subcommittee of the
American Academy of
Neurology. Efficacy and
tolerability of the new
antiepileptic drugs II:
treatment of refractory
epilepsy: report of the
Therapeutics and Tech-
nology Assessment Sub-
committee and Quality
Standards Subcommittee
of the American Acad-
emy of Neurology and
the American Epilepsy
Society. Neurology.
2004;62:1261-73.
[PMID: 15111660]
姝 2016 American College of Physicians
Downloaded From: http://annals.org/ by a University of York User on 11/21/2016
convulsant, this may be mitigated
by patient-assistance programs
provided by most of the pharma-
ceutical companies that manufac-
ture anticonvulsant medications
in the United States. Drugs used
to treat epilepsy in the United
States are listed in the Appendix
Table (available at www.annals
.org).
Before any medication is intro-
duced, a period of counseling is
warranted to educate patients on
the need for consistency with re-
spect to anticonvulsant therapy.
Seizure medications are not ef-
fective unless they are taken reg-
ularly and in accordance with
guidelines that render a consis-
tent serum concentration that is
individualized for the patient.
Some patients may achieve sei-
zure freedom with serum concen-
trations that are above or below
the listed therapeutic blood lev-
els; for those patients, increasing
or decreasing dosing to achieve
a level within the therapeutic
range is not indicated because
this may cause toxicity if the dose
is too high or lack of efficacy if
the dose is too low. Once an effi-
cacious dose is established, it
may be helpful to document a
serum concentration so that if
problems occur, such as clinical
signs of overmedication or
breakthrough seizures, one can
ascertain whether they are re-
lated to a change in serum con-
centration or whether other fac-
tors, such as lack of adherence or
duplicate dosing, may have
caused the problem. Many newly
diagnosed patients with epilepsy
are young and may not be habit-
ually taking other daily medi-
cines. Thus, suggestions and
guidance on strategies to re-
member to take medications
at a specific time may improve
adherence.
Patients are more likely to adhere
to once-daily treatment regi-
mens, and many anticonvulsant
ITC24 In the Clinic
medications have chemical prop-
erties or specific formulations
that enable them to be taken
once daily. For patients who use
smartphones or computer apps
for scheduling, programming
daily reminders can improve
adherence.
Medications differ in how they
can be introduced and in-
creased. Thus, it is important to
determine the likelihood of an-
other event before the medica-
tion reaches an effective serum
concentration. If the likelihood is
high, introducing a medication
that can be increased quickly
would be better than initiating
treatment with a medication that
might take weeks or months to
reach a reasonable effective se-
rum concentration.
One of the strongest predictors
of favorable long-term outcomes
for patients with epilepsy is a
positive response to the first anti-
convulsant (27). Furthermore, the
likelihood of seizure freedom
decreases “proportionately with
the number of other antiepileptic
drugs unsuccessfully tried” (4).
Although there are no significant
differences in patients' self-
reported quality of life with differ-
ent initial anticonvulsant agents,
adverse effects and break-
through seizures affect quality of
life (28). Thus, for patients who
do not respond to the first agent
or who have unacceptable ad-
verse effects, use of a second
agent is indicated, either as an
adjunct to the first or with plans
for a cross-taper to allow for re-
sultant monotherapy. All of the
newer anticonvulsant agents are
appropriate for adjunctive treat-
ment of refractory partial sei-
zures, the most common type in
adults (29).
Seizure medications work by sta-
bilizing cellular mechanisms that
prevent spontaneous neuronal
depolarization. The exact mecha-
Annals of Internal Medicine 2 February 2016
 nisms by which various medica-
tions influence this function in-
clude interaction through
sodium, calcium, or potassium
channels and/or effects on
such neurotransmitters as
␥-aminobutyric acid or gluta-
mate. Some anticonvulsants in-
volve several mechanisms of ac-
tion, but the exact mechanism
has not been identified for oth-
ers. Recognition of the mecha-
nism may be particularly impor-
tant for patients in whom initial
anticonvulsant therapy fails be-
cause use of a second agent with
a different mechanism of action is
more likely to be effective (30).
Because the first or second pre-
scribed medication fails in up to
one third of patients with epi-
lepsy, it is important to consider
additional strategies to choose
subsequent medications or com-
binations of medications that
may improve outcomes (31).
If a patient continues to have sei-
zures while receiving 2 anticon-
vulsants at adequate dosages,
referral to a neurologist or a spe-
cialty center is indicated, both to
ensure accuracy of the diagnosis
and to offer additional treatment
options, including implantable
devices and surgery.
What are the adverse effects of
epilepsy treatment?
Many of the common adverse
effects of anticonvulsant therapy
are linked more to escalation
rates and absolute quantities of
medications given than to spe-
cific mechanisms of action. For
example, all seizure medications
can cause fatigue, dizziness,
blurred vision, incoordination,
and gait imbalance. These tend
to be dose-dependent rather
than idiosyncratic and can some-
times be alleviated by using a
slower dose-escalation plan or
administering the medication on
a full stomach rather than ran-
domly during the day. However,
each anticonvulsant also has
2 February 2016 Annals of Internal Medicine
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idiosyncratic or non– dose-
dependent adverse effects that
may not be amenable to modifi-
cation and can lead to intoler-
ance by patients.
One controversial effect that the
FDA found to be common to all
anticonvulsant medications is an
increased tendency to suicidality,
which can be seen as early as 1
week after initiation of treatment
(32). Although other studies have
not found an increased risk for
suicidality in patients using anti-
convulsants, the FDA warning
requires that physicians warn pa-
tients of the risk for suicidality
and screen for depression or sui-
cidality at regular intervals during
dose escalation (33).
Are there devices to treat
epilepsy?
Two FDA-approved devices are
used to treat epilepsy. The vagus
nerve stimulator is approved for
adjunctive use in adult patients
with partial-onset seizures that
are refractory to anticonvulsant
treatment. Of note, this device
has been approved by the FDA
for adjunctive treatment of
chronic or recurrent depression,
and data support mood improve-
ment in patients with epilepsy
(34). The device consists of a
generator implanted subcutane-
ously in the anterior chest wall or
axilla and a lead threaded subcu-
taneously from the generator to
the left vagus nerve. It can be
programmed to provide regular
electrical impulses every few min-
utes and can also be triggered to
deliver a train of impulses
through use of an external hand-
held magnet. The second feature
can be used to treat seizures
when a patient is aware that an
event is occurring or may be
used by health care providers in
an attempt to decrease the
length of an event after it has
started. In addition to the surgical
risks of pain and infection,
hoarseness can occur through
In the Clinic ITC25
30. 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;71:985-93. [PMID:
24911669]
31. Divino V, Petrilla AA,
Bollu V, Velez F, Ettinger
A, Makin C. Clinical and
economic burden of
breakthrough seizures.
Epilepsy Behav. 2015;
51:40-7. [PMID:
26255884]
32. U.S. Food and Drug
Administration. Suicidal
Behavior and Ideation
and Antiepileptic Drugs.
Silver Spring, MD: U.S.
Food and Drug Adminis-
tration; 2014. Accessed
at www.fda.gov/Drugs
/DrugSafety/Postmarket-
DrugSafetyInformation-
forPatientsandProviders
/ucm100190.htm on 10
December 2015.
33. Rissanen I, Jääskeläinen
E, Isohanni M, Koponen
H, Ansakorpi H, Miet-
tunen J. Use of antiepi-
leptic or benzodiazepine
medication and suicidal
ideation—The Northern
Finland Birth Cohort
1966. Epilepsy Behav.
2015;46:198-204.
[PMID: 25935512]
34. Morris GL 3rd, Gloss D,
Buchhalter J, Mack KJ,
Nickels K, Harden C.
Evidence-based guide-
line update: vagus nerve
stimulation for the treat-
ment of epilepsy: report
of the Guideline Devel-
opment Subcommittee
of the American Acad-
emy of Neurology. Neu-
rology. 2013;81:1453-9.
[PMID: 23986299]
姝 2016 American College of Physicians

35. Morrell MJ; RNS System
in Epilepsy Study Group.
Responsive cortical stim-
ulation for the treatment
of medically intractable
partial epilepsy. Neurol-
ogy. 2011;77:1295-304.
[PMID: 21917777]
36. Tebo CC, Evins AI, Chris-
tos PJ, Kwon J, Schwartz
TH. Evolution of cranial
epilepsy surgery compli-
cation rates: a 32-year
systematic review and
meta-analysis. J Neuro-
surg. 2014;120:1415-
27. [PMID: 24559222]
37. Engel J Jr, Wiebe S,
French J, Sperling M,
Williamson P, Spencer D,
et al; Quality Standards
Subcommittee of the
American Academy of
Neurology. Practice pa-
rameter: temporal lobe
and localized neocortical
resections for epilepsy:
report of the Quality
Standards Subcommittee
of the American Acad-
emy of Neurology, in
association with the
American Epilepsy Soci-
ety and the American
Association of Neurologi-
cal Surgeons. Neurology.
2003;60:538-47. [PMID:
12601090]
38. Quigg M, Harden C.
Minimally invasive tech-
niques for epilepsy sur-
gery: stereotactic radio-
surgery and other
technologies. J Neuro-
surg. 2014;121 Suppl:
232-40. [PMID:
25434958]
姝 2016 American College of Physicians
Downloaded From: http://annals.org/ by a University of York User on 11/21/2016
disruption of the recurrent laryn-
geal nerve in the neck. This may
be transient or permanent and
can recur during stimulation
periods.
The second FDA-approved de-
vice is the responsive neuro-
stimulation system for epilepsy,
which consists of a stimulator sur-
gically implanted in the skull,
with leads extending from the
generator to the surface of the
brain or into the brain paren-
chyma and placed where sei-
zures are believed to originate.
After a period of recording and
identifying seizure patterns, the
device can be programmed to
respond to seizures directly,
sending electrical impulses into
the seizure focus or foci to abort
seizure propagation (35).
What is the role of surgery?
For patients in whom adequate
quantities of 2 or more anticon-
vulsants have failed or who have
intolerable adverse effects,
surgery—the only existing cure for
epilepsy—should be offered. If
the focal area of the brain from
which a patient's seizures origi-
nate can be identified, removal
of this area would, in theory, pre-
vent the onset of seizures. How-
ever, the evaluation process is
complex and requires not only
electrographic identification of
the seizure source but also ascer-
tainment of the potential deficits
that could occur if the focal re-
gion of the brain were resected.
At this point, referral to an epi-
lepsy center is indicated because
the evaluation process for surgi-
cal consideration is best per-
formed in the center where sur-
gery may be done.
Several risks are associated with
intracranial surgery for the treat-
ment of epilepsy. These can in-
clude wound infections and
meningitis, hemorrhagic compli-
cations, and persistent neuro-
logic deficits. These complica-
ITC26 In the Clinic
tions have decreased over the
past 30 years, possibly because
of improvements in operative
techniques or in perioperative
care (36). Nevertheless, patients
must understand the magnitude
and significance of these residual
risks when considering elective
surgery.
To evaluate surgical complication rates over
time, Tebo and colleagues performed a litera-
ture search of articles that included at least 2
patients and discussed complications of intra-
cranial epilepsy surgery. They found 61 arti-
cles, which included a total of 5623 patients,
and divided them into those published be-
tween 1980 and 1995 and those published
between 1996 and 2012. In a comparison of
patients who had temporal lobectomies dur-
ing these time frames, the occurrence of neu-
rologic deficits decreased from 41.8% to 5.2%,
persistent neurologic deficits decreased from
9.7% to 0.8%, and wound infections and/or
meningitis decreased from 2.5% to 1.1%. Sim-
ilar findings were seen in patients who under-
went extratemporal or multilobar resections
(36).
Many patients have a transient
period of psychiatric disturbance
in the postsurgical period; this
risk is higher for patients with a
preexisting mood disorder.
Proper screening and postopera-
tive monitoring can help to mini-
mize the consequences.
Current recommendations state
that anticonvulsants may be re-
duced or withdrawn in patients
who become seizure-free after
surgery, but the risk for subse-
quent relapse is higher in those
for whom all anticonvulsant ther-
apy is stopped. Approximately
two thirds of patients with spe-
cific types of resections, such as
anterior temporal lobectomies,
may become free of all but sim-
ple partial seizures (37).
Several minimally invasive surgi-
cal techniques are being investi-
gated, including stereotactic ra-
diosurgery, laser-induced
thermal ablation and thermoco-
agulation, and ultrasound abla-
tion (38). Preliminary results
Annals of Internal Medicine 2 February 2016
 seem promising in terms of pre-
venting some complications of
open-brain surgery, but the
larger volume of epileptogenic
tissue capable of propagating
seizures may make the more fo-
cused approach less effective
overall.
Is there a role for hormonal
treatment of epilepsy?
Another treatment method for
women who have hormonally
sensitive seizures is exogenously
administered hormonal treat-
ment to mitigate the hormonal
oscillations that can trigger
events. In women with a 3-fold or
greater increase in seizures
around the time of menses, allo-
pregnanolone (a reduced-
progesterone metabolite) was
shown to reduce seizure fre-
quency (39). This approach to
treatment requires extensive re-
cordkeeping to identify a cata-
menial pattern of events along
with serial blood work to identify
hormonal changes, but it can
provide improvement in seizure
control in a subset of women with
epilepsy without additional anti-
convulsant therapy.

Treatment... Many anticonvulsants are available for initial treatment of

seizures. Should 2 or more fail in a patient, referral to a neurologist or
epilepsy center is warranted to consider further treatment options, such
as implantable devices; resective or minimally invasive surgery; or, for
women with catamenial epilepsy, hormonal manipulation.

CLINICAL BOTTOM LINE

What additional measures
should be taken to prevent
morbidity and mortality from
seizures?
In addition to the obvious need
for treatment to prevent further
seizures, several ancillary difficul-
ties affect people with epilepsy
and require comprehensive and
coordinated care between all
members of a patient's treatment
team. The first such matter in-
volves patient safety (see the
Box: Safety and General Health
Counseling for Patients With Epi-
lepsy). People with epilepsy have
a standardized mortality rate that
is up to 10 times higher than that
of age-matched controls, with
40% of the deaths related to such
factors as accidents during sei-
zures (for example, drowning,
trauma, choking, or burns), sui-
cide, status epilepticus, and sud-
den unexpected death in epi-
lepsy (SUDEP) (40).
Further Considerations
Injuries can be caused directly by
seizures or indirectly through
confused behavior in the postic-
tal state. Patients should be coun-
seled to avoid situations that can
result in injury both at the time of
initial diagnosis and at annual
visits for reinforcement. For ex-
ample, suggesting that patients
use elevators instead of escala-
tors or use crosswalks when pos-
sible instead of jaywalking can
diminish the risk for injury should
a patient have a seizure in these
situations. Use of harnesses and
rigging while rock climbing or
39. Herzog AG, Frye CA;
hiking in mountainous terrain Progesterone Trial Study
should be recommended if Group. Allopregnanolone
levels and seizure fre-
avoidance of these activities is quency in progesterone-
not possible. treated women with
epilepsy. Neurology.
2014;83:345-8. [PMID:
Urging patients to confine swim- 24944264]
40. Téllez-Zenteno JF, Ron-
ming to locations where a life- quillo LH, Wiebe S. Sud-
guard is on duty at poolside or den unexpected death in
epilepsy: evidence-based
beachside can improve the analysis of incidence and
chances of rescue should a pa- risk factors. Epilepsy Res.
2005;65:101-15. [PMID:
tient have a seizure in the water. 16005188]

2 February 2016 Annals of Internal Medicine In the Clinic ITC27 姝 2016 American College of Physicians

Downloaded From: http://annals.org/ by a University of York User on 11/21/2016


Safety and General Health
Counseling for Patients With
Epilepsy
Identify/avoid seizure triggers:
Sleep deprivation, missed
medications, alcohol,
menstrual period
Injury prevention: Use of safety/
protective equipment for
sports (life vests for water
sports, helmets for biking,
skating, skiing)
General health: Calcium/vitamin
D supplementation,
encourage daily walking for
weight-bearing exercise, folic
acid supplementation for
women, contraception,
family planning
Home safety: Turn down water
temperature, purchase/
install overflow valves, pad
hard surfaces; avoid
stairs/escalators, use
crosswalks and cross with
lights, keep identification at
all times
Consider prescription for rescue
medication (lorazepam,
diazepam) for use during
illness or other high-risk
period
41. Prasad V, Kendrick D,
Sayal K, Thomas SL, West
J. Injury among children
and young adults with
epilepsy. Pediatrics.
2014;133:827-35.
[PMID: 24733872]
姝 2016 American College of Physicians
Downloaded From: http://annals.org/ by a University of York User on 11/21/2016
For open-water swimming or raft-
ing, use of a life jacket can keep a
patient's head above water if he
or she loses awareness. Patients
should be counseled to avoid
swimming or engaging in water
sports alone.
Water safety in the home should
also be discussed. Patients who
have seizures and lose con-
sciousness in the shower or bath-
tub can drown in as little as 2
inches of water. Use of a water
intake cutoff device, available at
hardware stores, can help pre-
vent accumulation of water if a
patient has a seizure in a bathtub,
and adjusting the water tempera-
ture on the hot water reservoir
could prevent burns.
Additional safety measures to be
discussed include use of helmets
while biking or skiing. If patients
have young children in the home,
counseling on parenting safety
(such as proper securing of guns
and doors) should be offered.
Proper storage and monitored
administration of seizure medica-
tion should also be discussed,
especially for young children and
adolescents because they may
inadvertently or purposely take
incorrect quantities of anticonvul-
sant therapy (41).
Researchers in the United Kingdom reviewed a
database of primary care records to identify co-
horts of persons aged 1 to 24 years with and
without epilepsy. Subsequent medical records
were reviewed for a median of 2.6 years. Peo-
ple with epilepsy had an 18% increased risk
for fracture, a 49% increased risk for burns,
and 2.5 times the risk for poisoning from med-
ications (41).
Medicolegal considerations for
patients with epilepsy include
proper counseling and docu-
mentation around driving restric-
tions, which vary among states.
Most states do not require physi-
cians to report patients who vio-
late the state-specific driving reg-
ulations; the exception is under
circumstances in which children
ITC28 In the Clinic Annals of Internal Medicine
or elderly adults may be at risk.
Even so, for patients who are no
longer legally able to drive due
to recent seizures, physicians
should properly document
whether they counseled the pa-
tient on the driving restriction
and how long it will be in place.
For patients who lose their li-
censes, state-specific require-
ments for license reinstatement
are in place. For the practitioner,
it is important to stay abreast of
the ever-changing driving restric-
tions, particularly as they pertain
to reporting to government
agencies. If available, referral to
social service agencies that may
be able to assist with transporta-
tion can increase the likelihood
that patients with recent seizures
will adhere to the driving
restrictions.
Stress has been identified as a
risk factor for seizures in many
patients with epilepsy. Use of
stress modification techniques,
such as yoga, meditation, or reg-
ular exercise, can be helpful, and
referral for counseling should
also be considered.
Many general medical consider-
ations should be discussed with
patients with newly diagnosed
epilepsy. Because some anticon-
vulsants have been shown to in-
terfere with proper bone metab-
olism, recommendations for
appropriate calcium and vitamin
D supplementation should be
given, along with appropriate
counseling for weight-bearing
exercise. Regular bone densi-
tometry should be arranged to
monitor for osteopenia or osteo-
porosis for these patients, with
treatment as indicated. For fe-
male patients with childbearing
potential, folic acid should be
prescribed and patients should
be educated about the need for
regular use of this vitamin sup-
plement throughout the child-
bearing years, regardless of
2 February 2016
 whether the patient has an active azepine and oxcarbazepine have
42. Harden CL, Pennell PB,
desire to conceive (42). been associated with hyponatre- Koppel BS, Hovinga CA,
Gidal B, Meador KJ,
mia, and topiramate and zoni- et al; American Academy
For women with epilepsy during samide have been associated of Neurology. Practice
the childbearing years, offering with renal stones (45). These
parameter update: man-
agement issues for
advice and information about the acute and chronic adverse effects women with epilepsy—
risks and benefits of using anti- focus on pregnancy (an
are rare, but if they occur, practi- evidence-based review):
convulsant therapy during preg- vitamin K, folic acid,
tioners must recognize that they blood levels, and breast-
nancy, including the possible
are related to the specific anti- feeding: report of the
need for upward adjustment of Quality Standards Sub-
convulsant so that appropriate committee and Thera-
dosing, is important and should peutics and Technology
treatment adjustments can be Assessment Subcommit-
be done before conception
made. tee of the American
to prevent inadvertent self- Academy of Neurology
and American Epilepsy
discontinuation of medication Are patients with epilepsy Society. Neurology.
(43). Avoidance of valproate and stigmatized? 2009;73:142-9. [PMID:
19398680]
polypharmacy can reduce the Patients with epilepsy frequently 43. Harden CL, Hopp J, Ting
TY, Pennell PB, French
risk for major congenital malfor- encounter social and workplace JA, Hauser WA, et al;
mations in women with epilepsy discrimination. Patients are more American Academy of
Neurology. Practice pa-
(44). likely to self-report stigma if they rameter update: man-
agement issues for
are single or have poor quality of women with epilepsy—
Patients with epilepsy could ben-
life or decreased health literacy, focus on pregnancy (an
efit from regular screening for evidence-based review):
mood disorders, not only at the whereas married patients have obstetrical complications
and change in seizure
onset of therapy but annually as a better self-reported quality of life frequency: report of the

feature of ongoing care. Depres- (46, 47). This has been seen in Quality Standards Sub-
committee and Thera-
sion and anxiety symptoms may many cultures and ethnicities and peutics and Technology
Assessment Subcommit-
be ictal phenomena, can be reac- may be influenced by beliefs tee of the American
tive to the disorder (particularly about the causes of epilepsy, Academy of Neurology
and American Epilepsy
at times of breakthrough sei- which is believed to be due to Society. Neurology.
witchcraft or other supernatural 2009;73:126-32. [PMID:
zures), and can be secondary to 19398682]
anticonvulsant use. Treatment causes in some communities 44. Harden CL, Meador KJ,
Pennell PB, Hauser WA,
may involve counseling or may (48, 49). Gronseth GS, French JA,
et al; American Academy
require intervention with phar- Patients also report stigma re- of Neurology. Practice
macotherapy. Because some an- parameter update: man-
lated to employment status (50). agement issues for
ticonvulsants also affect mood, it Unemployment and underem-
women with epilepsy—
focus on pregnancy (an
may be helpful to review ongo-
ployment are common among evidence-based review):
ing anticonvulsant choices to see teratogenesis and peri-
patients, and early referrals natal outcomes: report of
whether they may be causing a the Quality Standards
should be offered for access to Subcommittee and Ther-
mood disturbance. Similarly, if
resources, including job training. apeutics and Technology
treatment of a mood disorder Assessment Subcommit-
Patients with epilepsy who are tee of the American
seems warranted, use of an anti- Academy of Neurology
referred for vocational rehabilita-
convulsant with mood-stabilizing and American Epilepsy
tion services are more likely to Society. Neurology.
properties may preclude the 2009;73:133-41. [PMID:
find employment than those who 19398681]
need for independent medica- 45. Gaitatzis A, Sander JW.
are not (51). For patients who
tion for the mood disorder itself. The long-term safety of
may have a seizure at work, phy- antiepileptic drugs. CNS
Drugs. 2013;27:435-55.
Many idiosyncratic acute and sicians are commonly asked to [PMID: 23673774]
chronic toxicities occur with complete paperwork attesting to 46. Bautista RE, Shapovalov
D, Shoraka AR. Factors
greater-than-expected frequency the patient's ability to return to associated with increased
felt stigma among indi-
when particular anticonvulsants work safely. Practitioners need to viduals with epilepsy.
are used. For example, valproate be careful in their responses be- Seizure. 2015;30:106-
12. [PMID: 26216694]
has been associated with poly- cause employers may misinter- 47. Zou X, Hong Z, Chen J,
Zhou D. Is antiepileptic
cystic ovarian syndrome, pancre- pret them, causing patients to be drug withdrawal status
atitis, and nonalcoholic fatty liver, wrongly fired. If patients recog- related to quality of life
in seizure-free adult
among other systemic effects. nize that discrimination is occur- patients with epilepsy?
Phenytoin has been associated ring, referral to nonprofit agen- Epilepsy Behav. 2014;
31:129-35. [PMID:
with pseudolymphoma, carbam- cies designed to help and 24407247]

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 support people with disabilities with a family history of sudden
can be helpful. death unrelated to epilepsy, re-
ferral to a cardiologist for screen-
What is SUDEP, and how can it ing for such disorders as long QT
be prevented? syndrome or to a sleep specialist
48. Lim YJ, Chan SY, Ko Y. An important topic patients for evaluation of obstructive
Stigma and health-
related quality of life in
should be counseled on is sleep apnea may address comor-
Asian adults with epi- SUDEP. This refers to death in a bidities that could increase risk
lepsy. Epilepsy Res.
2009;87:107-19. [PMID: patient with known epilepsy that for SUDEP (55, 56). However,
19782536]
49. Winkler AS, Mayer M,
is “not due to trauma, drowning, most of the risk factors believed
Schnaitmann S, Ombay status epilepticus, or other to be associated with SUDEP are
M, Mathias B, Schmut-
zhard E, et al. Belief
known causes, but for which not modifiable because they
systems of epilepsy and there is often evidence of an as- probably represent the presence
attitudes toward people
living with epilepsy in a sociated seizure” (52). of a more severe form of epi-
rural community of
northern Tanzania. Epi- lepsy. However, to the extent that
lepsy Behav. 2010;19: The incidence of sudden death is poorly controlled epilepsy relates
596-601. [PMID: estimated to be 20 times higher to poor adherence to anticonvul-
20965788]
50. Smith G, Ferguson PL, in patients with epilepsy than in sant use, discussion of this as a
Saunders LL, Wagner JL,
Wannamaker BB,
the general population. In the risk factor may provide patients
Selassie AW. Psychoso- United States, approximately with additional impetus to look
cial factors associated
with stigma in adults 5000 people die of SUDEP each for ways to be more involved in
with epilepsy. Epilepsy year (53). Although the precise their self-management (57). With
Behav. 2009;16:484-90.
[PMID: 19782005] mechanisms are not well- the ready availability of online
51. Sung C, Muller V, Jones
JE, Chan F. Vocational
understood, there is evidence to resources for health-related infor-
rehabilitation service support seizure-related auto- mation, many patients and fami-
patterns and employ-
ment outcomes of peo- nomic dysfunction, cardiac dys- lies are aware of this condition
ple with epilepsy. Epi- rhythmias, and respiratory dys- and should be given an opportu-
lepsy Res. 2014;108:
1469-79. [PMID: function (54). Several risk factors nity for discussion and support,
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52. Devinsky O. Sudden,
have been identified, including despite the general reluctance of
unexpected death in poorly controlled convulsive sei- health care providers to address
epilepsy. N Engl J Med.
2011;365:1801-11. zures, long-term exposure to an- this topic. Referrals for psycho-
[PMID: 22070477] ticonvulsant therapy, and need therapy and counseling should
53. Jehi L, Schuele S. Sud-
den death in epilepsy: for polypharmacy. For patients also be offered.
where is the “heart” of
the problem? [Editorial].
Neurology. 2015;85:
208-9. [PMID:
26092913] Further Considerations... Patients with epilepsy are at risk for social
54. Shorvon S, Tomson T.
Sudden unexpected isolation, workplace discrimination, and increased morbidity and mor-
death in epilepsy. Lancet. tality. Early intervention to identify causal factors and to identify support
2011;378:2028-38.
[PMID: 21737136] and resources may diminish the effect of stigma on patients with epi-
55. Massey CA, Sowers LP, lepsy. Proper counseling and identification and treatment of modifiable
Dlouhy BJ, Richerson GB. risk factors may help to decrease the occurrence of injury and/or death
Mechanisms of sudden
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82. [PMID: 24752120]
56. Lamberts RJ, Blom MT,
CLINICAL BOTTOM LINE
Wassenaar M, Bardai A,
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26092917]
57. Shankar R, Cox D, Jalihal
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 IntheClinic
In the Clinic Patient Information
www.ninds.nih.gov/disorders/epilepsy/epilepsy.htm

Tool Kit Brochures and fact sheets that can be printed and given to
patients and links to other related resources, including
some in Spanish.
www.cdc.gov/epilepsy/family-and-friends.htm
Information for family and friends of people with
epilepsy.
Epilepsy www.cdc.gov/epilepsy/basics/index.htm
http://patient.info/health/epilepsy-a-general
-introduction
www.aan.com/Guidelines/home/GetGuidelineContent
/689
Patient summaries of epilepsy guidelines from the
American Academy of Neurology.

Clinical Guidelines
www.aesnet.org/clinical_resources/guidelines
American Epilepsy Society.
www.aan.com/Guidelines/home/ByTopic?topicId=23
American Academy of Neurology.
www.nice.org.uk/guidance/cg137
National Institute for Health and Care Excellence.

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 WHAT YOU SHOULD
KNOW ABOUT EPILEPSY
What Is Epilepsy?
Epilepsy is a brain disorder that causes seizures.
Seizures occur when there is abnormal electrical
activity in your brain cells. People with epilepsy
have had 2 or more seizures in their lifetime. The
cause of epilepsy is not always known. Your risk
increases if you:
• Have a family history of epilepsy
• Were born prematurely
• Had unexplained fevers as a child
• Have had infections, such as meningitis
• Have had a head injury
What Are the Warning Signs?
Seizures are the main symptoms. Signs can differ
depending on the type of seizure. They can in-
clude changes in mental status, such as:
• Unexplained fear, sadness, or laughing
• Feeling unusual or different from normal
• Losing awareness or passing out
• Trouble responding to questions
• Feeling confused and disoriented
• Stiffening, jerking, or twitching
• Numbness, tingling, or pain
• Tongue biting
• Loss of bladder control
How Is It Diagnosed?
Your doctor will first need to rule out all other pos-
sible causes of your seizures. You will be asked
about your medical history, your symptoms, and
what happens when you have a seizure. Your
doctor will then complete a physical examina-
tion. Testing may be needed, including:
• A test that measures brain waves, called an EEG
• Imaging tests, such as an MRI
How Is It Treated?
Medicines called anticonvulsants are usually used
to reduce or stop seizures. It is important to take
these medicines as directed. It is also important
to avoid seizure “triggers,” such as lack of sleep
and drug or alcohol use. If these treatments do
not help with your symptoms, your doctor may
refer you to a specialist to explore other options.
These may include:
• An electrical device implanted in your chest to
help reduce seizures
MedlinePlus
www.nlm.nih.gov/medlineplus/epilepsy.html
National Institute of Neurological Disorders and Stroke
www.ninds.nih.gov/disorders/epilepsy/epilepsy.htm
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In the Clinic
Annals of Internal Medicine
• Surgery to remove the damaged part of your
brain that is causing the seizures
• Hormone medicines in women if seizures are
related to hormone changes
Questions for My Doctor
• What is causing my seizures?
• How can I tell if I will have another seizure?
• What are the side effects of the medicines?
• Is it safe for me to drive?
• Can I still do the things I enjoy?
• Could my seizures cause long-term damage?
• Should I wear a medic alert bracelet?
• Are there other lifestyle changes I need to
make because of my epilepsy?
Patient Information
Bottom Line
• Epilepsy is a disorder in which too much
electrical activity in the brain causes seizures.
The cause of epilepsy is not always known.
• The symptoms of a seizure vary and can differ
for everyone. Signs can include unexplained
fear or sadness, loss of awareness, trouble
responding to questions, and confusion.
Physical signs can include jerking and
twitching, numbness and tingling, tongue
biting, passing out, or loss of bladder control.
• To diagnose epilepsy, your doctor will ask you
questions about your medical history and
what happens when you have a seizure. Your
doctor will give you a physical examination
and may run other tests.
• Medicines called anticonvulsants are used to
help limit seizures. If these medicines do not
help, you may be referred to a specialist to
discuss other treatment options.
For More Information
 Appendix Table. Drug Treatment for Seizures
Anticonvulsant†
*Carbamazepine
(Carbatrol, Tegretol,
Tegretol-XR, Epitol)
Oxcarbazepine (Trileptal)
(first-line agent)
Topiramate (Topamax)
*Lamotrigine (first-line
agent) (Lamictal,
Lamictal XR, Lamictal
ODT)
*Valproic acid (first-line
agent) (Stavzor,
Depakene)
*Divalproex sodium
(Depakote, Depakote
ER)
Gabapentin (Neurontin)
Levetiracetam (Keppra,
Keppra XR)
Pregabalin (Lyrica)
Tiagabine (Gabitril)
Zonisamide (Zonegran)
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Dosing
Initial dose: 200 mg bid.
Usual dose: 800–1200
mg total daily dose,
dosed tid–qid for
regular-release or bid
for extended-release.
Monitor serum
concentrations
Initially, 300 mg bid.
Usual dose 1200 mg
bid
Initially, 25 mg bid. Usual
dose 200 mg bid
Immediate-release: Start
at 50 mg qd. Usual
dose 250 mg bid.
Extended-release: Start
at 50 mg qd. Usual
dose 250–500 mg qd.
Dose varies with
concomitant
anticonvulsants
Initially, 10–15 mg/kg
total daily dose, dosed
bid–tid (bid for
delayed-release, qd for
Depakote ER). Usual
dose is below 60
mg/kg daily
Immediate-release:
Initially, 300 mg tid.
Usual dose 300–800
mg tid
IV or PO Immediate-
release: Initially, 500
mg bid. Usual dose
1500 mg bid.
Extended-release:
1000 mg qd, up to
3000 mg qd
Initially, 150 mg total
daily dose, dosed
bid–tid. Maximum 600
mg total daily dose,
dosed bid–tid
Initially, 4 mg qd. Usual
32–56 mg total daily
dose, dosed bid–qid
Initially, 100 mg qd.
Usual dose 100–400
mg qd
Side Effects
Hepatic, CV adverse events,
ocular adverse events,
hyponatremia
Hyponatremia, visual impairment
Weight loss, metabolic acidosis,
oligohidrosis
Weight loss, abdominal pain,
diarrhea, blurred vision,
dysmenorrhea, hyponatremia,
aseptic meningitis
Alopecia, elevated blood
ammonia, thrombocytopenia,
menstrual disturbances
Peripheral edema, weight gain,
diplopia, blurred vision,
myoclonus
Infection, anorexia behavioral
symptoms
Peripheral neuropathy, amnesia,
xerostomia, myoclonus,
peripheral edema, weight
gain, angioedema, diplopia,
thrombocytopenia,
dependence, creatine kinase
elevation
Diarrhea, pharyngitis, serious
rash
Severe rash, metabolic acidosis,
azotemia, diplopia, dysgeusia,
psychosis, weight loss
Annals of Internal Medicine
Precautions
Serious hematologic and
dermatologic reactions.
Caution with Asian patients.
Consider dose reduction with
hepatic disease. Caution with:
cardiac disease, glaucoma,
sunlight. Complex drug
interactions
Caution with severe hepatic
disease. If CrCl<30, decrease
dose by half. Inhibitor of
CYP2C19, inducer of CYP3A4
Caution with: hepatic disease,
ocular disease. If CrCl<70,
decrease dose by half.
CYP3A4 inducer and CYP2C19
inhibitor. Caution with CYP3A4
inducer
Serious dermatologic reactions.
Decrease dose by 25%–50%
with moderate-severe hepatic
disease and by >50% with
concomitant valproic acid.
Consider decreased dose with
CKD. Caution with cardiac
disease. Clearance is lower in
nonwhites
Hepatotoxicity, teratogenicity,
pancreatitis. Avoid with:
hepatic disease, pregnancy.
Caution with CKD. Monitor
platelet counts and
coagulation. Metabolized via
CYPs 2C19 and 2C9. Inhibits
CYP2C9
Decrease dose if CrCl<60. Does
not interact with other
anticonvulsants
Decrease dose if CrCl<80. Few
drug interactions, possibly
carbamazepine
Decrease dose if CrCl<60. Few
drug interactions. Caution with
HF
Caution with hepatic disease.
Substrate of CYP3A4
Avoid with sulfonamide
hypersensitivity. Caution with:
hepatic disease, CKD.
Metabolized by CYP3A4
Continued on following page
2 February 2016
 Appendix Table—Continued
Anticonvulsant†
Lacosamide (Vimpat)
Ethosuximide (first-line
agent) (Zarontin)
*Felbamate (Felbatol)
Rufinamide (Banzel)
*Phenytoin (Dilantin,
Phenytek)
Phenobarbital
Dosing Side Effects Precautions
PO or IV: Initially, 50 mg Diplopia, blurred vision, AV Avoid with severe hepatic
bid. Usual dose block, PR prolongation, DRESS, disease. Maximum dose 150
100–200 mg bid dependence mg bid with: mild–moderate
hepatic disease, CKD.
Substrate and inhibitor of
CYP2C19
Initially, 250 mg bid. Weight loss, elevated hepatic Caution with: hepatic disease,
Usual dose 20–40 enzymes, Stevens-Johnson CKD. Monitor: LFTs, CBC.
mg/kg total daily dose, syndrome, hematologic Substrate for CYP3A4
dosed bid. Maximum reactions, nephrotic syndrome
total daily dose 1.5 g
Initially, 1200 mg total Dermatologic reactions Serious hematologic reactions,
daily dose, dosed hepatotoxicity. Avoid with
tid–qid. Usual total hepatic disease. Decrease
daily dose 2400 mg. dose by half with CKD.
Maximum total daily Inhibitor of CYP2C19, inducer
dose 3600 mg of CYP3A4
200–400 mg bid. Usual Shortened QT interval, status Avoid with severe hepatic
dose 1600 mg bid epilepticus, diplopia, blurred disease. Consider decreased
vision, anemia, leukopenia dose with mild–moderate
hepatic disease. Weak inducer
of CYP3A4, weak inhibitor of
CYP2E1
IV or PO immediate- Gingival hyperplasia, peripheral CV risk with rapid infusion. Avoid
release: 4–7 mg/kg neuropathy, hirsutism, with pregnancy. Caution with:
total daily dose, given hematologic reactions, serious hepatic disease, CrCl<10,
in divided doses. dermatologic reactions, severe diabetes, thyroid disease,
Administer hypersensitivity reactions, arrhythmias. Inducer of CYPs
sustained-release qd. lymphadenopathy, CV adverse 3A4, 2C9, 2C19. Substrate of
Monitor serum levels events, blurred vision, CYPs 2C9, 2C19. Highly
decreased bone mineral protein bound
density with long-term use
IV or PO: 1–3 mg/kg total Long-term use: megaloblastic Avoid with: pregnancy, severe
daily dose, dosed anemia, osteopenia, hepatic disease, acute pain.
qd–bid. For status osteomalacia, miosis, Caution with: elderly, CKD. If
epilepticus: loading dependence IV: respiratory CrCl<10, avoid chronic use.
dose 10 mg/kg IV, depression, bronchospasm, Inducer of CYPs 2C, 3A, 1A2
followed by 5 mg/kg IV hypotension
in 30–60 min.
Maximum loading
dose 25–30 mg/kg

AV = atrioventricular; bid = twice daily; CBC = complete blood count; CKD = chronic kidney disease; CNS = central nervous
system; CrCl = creatinine clearance; CV = cardiovascular; CYP = cytochrome P450 isoenzyme; DRESS = Drug Reaction with
Eosinophilia and Systemic Symptoms; GI = gastrointestinal; HF = heart failure; IM = intramuscular; IV = intravenous; LFT = liver
function test; PO = oral; q12hr = every 12 hours; qd = once daily; qid = 4 times daily; SC = subcutaneous; SCr = serum creatinine;
tid = three times daily.
* = Black box warning.
† All anticonvulsants have CNS side effects (drowsiness, dizziness, headache, insomnia, anxiety, asthenia, tremor, others), hyper-
sensitivity reactions, nausea, vomiting, depression. Avoid abrupt discontinuation. Caution with: elderly, pregnancy. Monitor for
depression. Complex drug interactions between anticonvulsants.

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