Review Article

Management of a
Address correspondence to
Dr Gregory K. Bergey, Johns
Hopkins School of Medicine,
600 North Wolfe Street, Meyer
2-147, Department of Neurology,
Baltimore, MD 21287,
gbergey@jhmi.edu.
First Seizure
Relationship Disclosure: Gregory K. Bergey, MD, FAAN
Dr Bergey has received
personal compensation for
serving as an associate editor
of Neurotherapeutics and has ABSTRACT
received research support
from the National Institutes Purpose of Review: Assessment of the patient with a first seizure is a common and
of Health. important neurologic issue. Less than 50% of patients who have a first unprovoked
Unlabeled Use of seizure have a second seizure; thus, the evaluation should focus on determining the
Products/Investigational
Use Disclosure:
patients risk of seizure recurrence.
Dr Bergey reports no disclosure. Recent Findings: A number of population studies, including some classic reports,
* 2016 American Academy have identified the relative risk factors for subsequent seizure recurrence. The 2014
of Neurology. update of the International League Against Epilepsy definition of epilepsy incorporates
these findings, and in 2015, the American Academy of Neurology published a guide-
line that analyzed the available data.
Summary: Provoked or acute symptomatic seizures do not confer increased risk for
subsequent unprovoked seizure recurrence. Multiple seizures in a given 24-hour
period do not increase the risk of seizure recurrence. Remote symptomatic seizures, an
epileptiform EEG, a significant brain imaging abnormality, and nocturnal seizures are
risk factors for seizure recurrence. Antiepileptic drug therapy delays the time to second
seizure but may not influence long-term remission.

Continuum (Minneap Minn) 2016;22(1):3850.

INTRODUCTION of 2014, the International League

Patients presenting with a first seizure,
whether as a child or adult, are often
quite distressed. When one considers
that about 10% of the population will
have a seizure at some time in their
lives but less than half of these patients
will have multiple seizures, the impor-
tance of proper assessment is brought
into focus. The article Diagnosis of Epi-
lepsy and Related Episodic Disorders
by Erik K. St. Louis, MD, MS, FAAN, and
Gregory D. Cascino, MD, FAAN,1 in this
issue of Continuum discusses the
process of making the diagnosis and
proper evaluation, so for the purpose
of this article, it will be assumed that
the patient has had an epileptic seizure
(either convulsive or nonconvulsive),
and the evaluation will only be men-
tioned in the context of findings that
influence the risk of seizure recurrence.
It is worth repeating, however, that as
Against Epilepsy (ILAE) defines epi-
lepsy as at least two unprovoked sei-
zures occurring more than 24 hours
apart, one unprovoked seizure and a
probability of further seizures similar
to the general recurrence risk (approx-
imately 60% or more) over the subse-
quent 10 years after two unprovoked
seizures, or the diagnosis of an epilep-
tic syndrome.2 The components of this
definition are drawn from published
studies that are discussed in this article.
Accurately making an early assess-
ment avoids unnecessary treatment of
patients unlikely to have a second un-
provoked seizure. Indeed, because of
the importance of this early evaluation,
a number of epilepsy centers have es-
tablished first seizure clinics. In these
clinics, patients who have experienced
a first seizure are seen promptly by an
experienced epileptologist with the

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hope that this early expert assessment
will more appropriately guide treat-
ment. Decisions about treatment after a
single seizure include considerations of
the chance of having a second seizure,
the consequences of having a second
seizure, efficacy of medications in pre-
venting future seizures, and the poten-
tial toxicity of antiepileptic drugs (AEDs).
The chance of seizure recurrence is one
of the most important determinations
that will guide treatment decisions.
While one must still deal with proba-
bilities, fortunately, a number of pop-
ulation studies exist that can assist in
this determination. Of more than 180
practice parameters published by the
American Academy of Neurology (AAN),
six deal with initiation of AED therapy,
including evaluation of a first seizure in
children,3 treatment of the child with a
first unprovoked seizure,4 assessment of
a first seizure in adults,5 and the 2015
guideline for the management of an un-
provoked first seizure in adults.6 The
2015 guideline is the most relevant to
the discussion in this article. (Refer to
Appendix A for a summary of the AAN
evidence-based guideline for clinicians.)
In framing the discussion, it is worth-
while to review the classification of a
first seizure (Table 2-1). Provoked sei-
zures are due to identifiable causes,
such as medications, drugs of abuse,
or metabolic causes. Seizures resulting
from acute brain processes (eg, enceph-
alitis) are classified as acute symptomatic
KEY POINTS
seizures. Seizures due to a preexisting h The diagnosis of
brain abnormality or disorder (eg, trau- epilepsy is appropriately
matic brain injury [TBI]) are considered used even after a single
remote symptomatic seizures. While some unprovoked seizure
authors6 group provoked and acute if the risk of a
symptomatic seizures together, some second unprovoked
benefit exists in separating these two seizure is significant
categories, as will be discussed further. (approximately 60%
Sometimes a first seizure and the asso- or more).
ciated EEG findings allow a syndromic h A very important part
classification that indicates likely recur- of the history from
rence. Obviously, not all patients fit into patients with a first
these categories; in some, the cause of the seizure is determining
seizures is unknown even after evaluation. whether they have,
in fact, had other
In assessing the patient with a first
unrecognized seizures.
seizure, the neurologist must also de-
termine whether the patient has actually
had multiple seizures. It is common for
patients to seek medical care after the
first generalized tonic-clonic seizure,
but they may not have appreciated the
significance of myoclonic jerks after
awakening, nocturnal tongue biting,
or brief staring spells (absence or focal
seizures with dyscognitive features). A
careful history will often determine that
many patients with newly diagnosed
seizures have actually had multiple
events. This is particularly true in pa-
tients with complex partial seizures and
children with absence seizures.
If the patient has had multiple
seizures, it is important to determine
when these seizures occurred over
time. In a study by Kho and colleagues,7
72 patients with multiple seizures in
a 24-hour period as their first seizure

TABLE 2-1 Classification of a First Seizure

b Provoked seizure (eg, seizure caused by toxin, medication, or metabolic factors)

b Acute symptomatic seizure (seizure cause by acute illness such as stroke,
traumatic brain injury, encephalitis/meningitis)
b Remote symptomatic seizure (seizure caused by preexisting brain injury)
b Seizure associated with epileptic syndrome (eg, juvenile myoclonic epilepsy)
b Other unidentified

Continuum (Minneap Minn) 2016;22(1):3850 www.ContinuumJournal.com 39

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 Management of a First Seizure

KEY POINTS
h Multiple unprovoked
seizures within a 24-hour
period should be
considered a single
event, and this by itself
does not establish the
diagnosis of epilepsy.
h After two unprovoked
seizures separated by
more than 24 hours
occur, the risk of
additional seizures is
high (more than 60%),
the diagnosis of epilepsy
(seizure disorder) is
present, and antiepileptic
drug therapy is
often warranted.
presentation were compared with 425
patients presenting with a single sei-
zure. The recurrence rate overall was
38% (28% provoked, 38% idiopathic,
53% remote symptomatic); however,
those presenting with multiple seizures
in a 24-hour period were no more likely
to have seizure recurrence than those
presenting with a single seizure, irre-
spective of etiology or treatment
(Figure 2-1). The 2014 ILAE definition
incorporates these findings by stipulat-
ing at least two unprovoked seizures
occurring more than 24 hours apart.2
One might still elect to begin AED ther-
apy (eg, for remote symptomatic sei-
zures), but this decision to treat should
not be influenced by multiple seizures
in a 24-hour period.
After two unprovoked seizures (more
than 24 hours apart), the risk of sub-
sequent seizures increases dramatically.
In a study by Hauser and colleagues8
that prospectively followed 204 patients
after a first unprovoked seizure, the
overall risk for a second seizure was
only 33%. After a second seizure, how-
ever, the risk of a third unprovoked
seizure rose to 76%. This recurrence
risk is incorporated into the ILAE de-
finition. Most recurrences are within
1 year of the second or third seizure.
After a second symptomatic seizure,
the risk of a third seizure over 5 years
was 87%, compared to 64% recurrence
risk for idiopathic or cryptogenic sei-
zures. In another study in children, the
risk of a third seizure after a second
seizure was 72%.9
ANTIEPILEPTIC DRUG
PROPHYLAXIS
The only evidence supporting AED
prophylaxis is in patients with high-risk
head injury in the early posttraumatic
period10; this is addressed in an AAN
guideline.11 No evidence exists for AED
treatment of patients with brain tumors,12

FIGURE 2-1 Data showing no difference in cumulative chance of seizure recurrence whether
patients presented with a single seizure (n = 425) or multiple seizures (n = 72).
7
Reprinted with permission from Kho LK, et al, Neurology. www.neurology.org/content/67/6/1047.
B 2006 American Academy of Neurology.

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cerebral cavernous hemangiomas, cere-
brovascular events, or craniotomy13 be-
fore a first seizure occurs.
ANTIEPILEPTIC DRUG
TREATMENT INITIATION
After a first seizure occurs, the fol-
lowing factors should be considered
in deciding whether or not to start
AED treatment.
Provoked Versus Unprovoked
Seizures
The ILAE definition defines epilepsy as
unprovoked seizures. Table 2-2 is a
partial list of some of the more com-
mon causes of provoked seizures. While
on occasion hypoglycemia can produce
focal neurologic findings, in general,
provoked seizures are generalized
convulsive events, not focal seizures.
Alcohol-provoked seizures, either due
to intoxication or withdrawal, will not
be focal seizures, recognizing that in-
toxication may lower seizure thresh-
old in the patient with focal brain
injury. Therefore, a patient presenting
with symptoms suggesting either focal
seizures (eg, focal motor activity, tran-
sient confusion) or focal seizures with
secondary generalization should be
treated as having an unprovoked sei-
zure. Provoked seizures usually do not
warrant AED therapy. In some instances,
prescribed medication is essential yet
is a cause of provoked seizures in that
patient. AED therapy may be justified for
a period of time. Of course, provoked
TABLE 2-2 Examples of Provoked Seizures
b Alcohol withdrawal
b Barbiturate or benzodiazepine withdrawal
b Metabolic (eg, hyponatremia, hypocalcemia, hypoglycemia, hyperglycemia)
b Drugs of abuse (eg, cocaine, amphetamines, phencyclidine)
b Medications (eg, tramadol, imipenem, theophylline, bupropion)
Continuum (Minneap Minn) 2016;22(1):3850
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINTS
seizures may recur if the patient is ex- h Except for during the
posed again to the provocative agent. first week after severe
Obviously, if one could accurately head trauma, no
predict who would and who would not evidence exists to
have a second unprovoked seizure, then support administration
specific recommendations could be pro- of antiseizure medication
vided for all patients. In reality, only to prevent a first
predictions of probabilities of seizure unprovoked seizure.
recurrence can be made. For example, h Patients with provoked
the young child with a single convul- seizures do not have
sion and no risk factors (eg, normal epilepsy and do not
examination, EEG, and imaging) has a need seizure medication
relatively low risk of seizure recurrence. if the provoking cause
can be eliminated.
Type of Seizure
Simple partial (focal) seizures with only
sensory or focal motor symptoms with-
out alteration of consciousness are less
disabling than complex partial seizures
with alteration of awareness. The deci-
sion to treat these simple partial (focal)
minor seizures without alteration of
awareness should be individualized.
The 8-year-old with a focal motor sei-
zure of the mouth and an EEG showing
centrotemporal spikes consistent with
benign rolandic epilepsy can reason-
ably be left off medication unless gen-
eralized tonic-clonic seizures occur or
recurrent focal seizures produce psy-
chosocial distress. In contrast, the
23-year-old with a frontal cortically
based cavernous hemangioma with a
surrounding hemosiderin ring and a
focal motor seizure clinically similar
to that of the 8-year-old may warrant
therapy because of the risk of second-
ary generalization and the fact that
www.ContinuumJournal.com 41
 Management of a First Seizure
KEY POINTS
h Patients over the age
of 60 with a new
unprovoked seizure
should be considered
symptomatic (often
cerebrovascular disease)
even if the evaluation
is unrevealing.
h Patients with acute
symptomatic seizures
are much less likely
to have subsequent
seizures than are
patients with remote
symptomatic seizures.
h Patients with acute
symptomatic seizures
do not need long-term
antiepileptic drug
therapy after the
period of acute illness
unless a subsequent
seizure occurs.
42 www.ContinuumJournal.com
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
the consequences of a disabling sei-
zure (eg, focal with altered awareness,
secondarily generalized seizure) would
be much greater in this active adult and
because of the symptomatic nature of
the focal seizure. Febrile seizures are
another seizure type that typically does
not require therapy. Refer to the article
Febrile Seizures by Ajay Gupta, MD,14
in this issue of Continuum.
Patient Age
The question of whether the elderly
patient with a single unprovoked sei-
zure warrants different consideration
from a child is not fully resolved. The
incidence of new-onset epilepsy is
highest in children and the older adult.15
Elderly patients with unprovoked sei-
zures do not have idiopathic seizures.
Even if imaging is unrevealing or non-
specific, these seizures, while classi-
fied as due to unknown etiology, may
be due to an undefined cause rather
than being idiopathic. Cerebrovascu-
lar disease is the most common cause
of seizures in the elderly.16 Unprovoked
seizures in elderly patients should be
considered focal, with or without sec-
ondary generalization, even if the pre-
sentation is one of only a generalized
convulsive seizure. A study of all pa-
tients in Marshfield, Wisconsin, over
age 50 who experienced a first seizure
between 1996 and 1998 identified 48
patients (incidence 162 per 100,000
patient years).17 Of these, 12 had re-
current unprovoked seizures (ie, epi-
lepsy), 14 had a single seizure and
abnormal EEG or imaging, and 22 had
a single seizure with normal studies.
During a 12-month follow-up, 6 of the
22 patients (27%) with a single seizure
and a normal evaluation had a second
seizure. Interestingly, none of the 14
patients with abnormal tests had a sec-
ond seizure in the 12-month follow-up
period, but most of these patients (87.5%)
were treated; the influence of treatment
on this small group was undetermined
but certainly may have delayed the time
to second seizure. Of the 48 patients,
five were lost to follow-up before 1 year
and 16 died before 1 year, confound-
ing analyses. Many first unprovoked
seizures in older adults can be consid-
ered remote symptomatic seizures. Treat-
ment decisions in this age group should
also include the living and lifestyle
situation of the patient (eg, active and
driving versus long-term care resident).
Acute Versus Remote
Symptomatic Seizures
It is important to consider acute symp-
tomatic seizures separately from re-
mote symptomatic seizures. A study by
Hesdorffer and colleagues18 compared
262 patients with acute symptomatic
seizures with 148 patients with a first
unprovoked seizure due to a static brain
lesion (ie, remote symptomatic). They
defined acute symptomatic as within
7 days of stroke or TBI and during the
active infection for central nervous sys-
tem (CNS) infections. Patients with a
first acute symptomatic seizure were
8.9 times more likely to die within 30 days
compared to those with a first unpro-
voked seizure. After 30 days, the 10-year
risk of mortality did not differ between
the two groups. Over a 10-year period,
individuals with a first acute symptom-
atic seizure were 80% less likely to ex-
perience a second unprovoked seizure
compared to individuals with a first un-
provoked seizure due to a remote symp-
tomatic cause (Figure 2-2). The etiologies
of acute symptomatic seizures in this
study were stroke (34.7%), TBI (34.7%),
and CNS infection (30.6%). The etiol-
ogies of the first unprovoked remote
symptomatic seizure were stroke
(68.2%), TBI (25%), and CNS infection
(6.8%). Patients 65 years of age or older
accounted for 31.7% of the patients
with the first acute symptomatic seizure
but almost half (48.7%) of those with a
February 2016
 KEY POINT
h Patients with an
unprovoked remote
symptomatic seizure
have a high risk of
seizure recurrence and
often fulfill the
International League
Against Epilepsy criteria
for the diagnosis
of epilepsy.

FIGURE 2-2 Risk of subsequent seizure over 10 years after acute symptomatic seizure during
acute illness (eg, stroke, central nervous system infection, traumatic brain injury)
compared with risk of subsequent seizure in patients with remote symptomatic
unprovoked seizure (ie, previous stroke, central nervous system infection, traumatic brain injury).
18
Reprinted with permission from Hesdorffer DC, et al, Epilepsia. onlinelibrary. wiley.com/doi/10.1111/j.1528-1167.2008.
01945.x/full. B 2009 International League Against Epilepsy.

first unprovoked seizure, with many of
this second group being the patients
with cerebrovascular etiologies. In the
Hesdorffer study,18 the risk of a sub-
sequent seizure after a stroke was only
33% if the seizure was acute symptom-
atic, but 71.5% if unprovoked remote
symptomatic. In TBI patients, the risk
of seizure recurrence was 13.4% if acute
symptomatic and 46.6% if remote
symptomatic, and with CNS infections,
the risk was 16.6% if acute symptomatic
and 63.5% if remote symptomatic. The
authors of the study concluded that
the prognosis of a first acute symptom-
atic seizure differs from that of a first
unprovoked seizure when the etiology
is stroke, TBI, or CNS infection. Acute
symptomatic seizures have a higher
mortality in the first month and lower
risk for subsequent seizures than re-
mote symptomatic seizures, and the
authors appropriately concluded that
the evidence suggests that acute symp-
Continuum (Minneap Minn) 2016;22(1):3850
tomatic seizures are not epilepsy. This
is why these acute symptomatic seizures
are sometimes grouped with provoked
seizures as in the 2015 AAN guideline.6
While this is appropriate from the
standpoint of implications for treat-
ment, some rationale exists for separat-
ing acute symptomatic seizures from
other provoked seizures (eg, metabolic,
medications, drugs) since the former
can produce cerebral injury and chronic
changes (eg, gliosis, encephalomalacia)
that may be associated with later remote
symptomatic seizures, whereas other
provoked seizures do not. Case 2-1
provides an example of these consid-
erations in clinical practice.
STUDIES OF RISK OF
RECURRENCE
All of the above considerations per-
taining to the significance of a first sei-
zure essentially revolve around the idea
of risk of recurrence. Some of the best
www.ContinuumJournal.com 43

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 Management of a First Seizure

KEY POINT
h An idiopathic seizure
with an EEG pattern of
spike-wave discharges is
likely to recur and
may represent an
epileptic syndrome.
Case 2-1
A 27-year-old man presented to the emergency department after an
episode of right leg jerking that progressed to secondary generalization
with tongue biting. His past medical history was significant for a history of
a depressed skull fracture 2 years previously. He was treated with prophylactic
antiepileptic drugs (AEDs) at the time of the trauma but he had no seizures,
and his levetiracetam had been discontinued shortly thereafter.
His neurologic examination was normal. Brain MRI showed an area of
increased cortical and subcortical signal in the anterior left frontal lobe
consistent with his previous injury. EEG revealed no epileptiform activity,
but some mild focal slowing was seen in the left frontocentral region.
He acknowledged he had been drinking (four beers) while watching a
sporting event on television with his friends 36 hours prior to the seizure.
Comment. This patient has experienced a first seizure. The remote
alcohol intake was probably not enough to produce an alcohol-withdrawal
seizure, and, in any case, his seizure had focal features and provoked
seizures are not focal. His initial treatment at the time of his high-risk
(depressed skull fracture) head injury was appropriate since prophylactic
AEDs can reduce the risk of early (but not late) posttraumatic seizures.
His treating physicians at that time were correct in not continuing his
levetiracetam after the acute period since no evidence exists that AEDs
prevent late posttraumatic epilepsy. Now, however, he has had a remote
symptomatic seizure due to the previous head injury. His MRI documents
this previous injury. That his EEG is nonspecific (ie, not epileptiform) does
not alter the fact that his risk now of seizure recurrence is significant, and the
patient should now be placed on long-term AED therapy. This patient
embodies the considerations of risk factors addressed in the text of a remote
symptomatic seizure resulting from a previous high-risk head injury.

epidemiologic studies regarding the risk
of seizure recurrence are now over
25 years old and predate MRI tech-
nology. Nevertheless, the findings from
these studies remain relevant today,
and, indeed, these studies were very
important in drafting the 2015 AAN
guideline. The lack of imaging with
MRI in these earlier studies served to
underrepresent the group with remote
symptomatic seizures, so the conclu-
sions in this highest-risk group remain
valid, and the risk of patients with a
negative evaluation (including MRI)
today might be even lower than re-
ported. In the landmark study by
Hauser and colleagues,19 244 patients
of all ages who presented with a first
unprovoked seizure were followed
for a median of 22 months to ascer-
tain the risk of a subsequent seizure,
and the cumulative risks of recurrence
for the entire cohort were 16%, 21%,
and 27% at 12, 24, and 36 months,
respectively. If the seizures were
deemed idiopathic, only 17% had a
recurrence at 20 months, rising to 26%
by 36 months. If the seizures were
idiopathic with spike-wave discharges
on EEG, however, the risk of seizure
recurrence was 50% at 18 months. If
the seizure was idiopathic and the pa-
tient had a sibling with seizures, the
risk of seizure recurrence was 29% at
4 months. Age at first seizure, seizure
type, and onset with status were not
risk factors in this study. It is interesting
that, in this study and others, whether
an individual had partial (focal) or gen-
eralized seizures did not influence the

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chance of later recurrence. One might
hypothesize that since focal seizures
are often remote symptomatic, they
would be more likely to recur, but
this has not been demonstrated, per-
haps because many primary general-
ized seizures have high recurrence
rates and some patients with general-
ized seizures may have unrecognized
partial onset.
In the 1982 Hauser study,19 patients
with remote symptomatic seizures had
a risk of seizure recurrence of 34% over
36 months, but all of these seizures oc-
curred in the first 20 months. In patients
with head trauma, who comprised 37%
of the remote symptomatic group, the
recurrence risk was 40% at 12 months
and 46% at 20 months. Most of these
patients (69%) were treated after the
first seizure; no difference in recurrence
was noted between those treated and
the small number of untreated patients.
Overall, a prior neurologic insult was
the most powerful predictor found. A
spike-wave pattern on EEG was also a
risk factor; a spike-wave pattern could
suggest the possibility of an epileptic
syndrome (eg, juvenile myoclonic epi-
lepsy) with a known high risk of seizure
recurrence. Interestingly, a focal EEG
abnormality was not a predictor in this
study by Hauser and colleagues.19 A
positive family history was also an inde-
pendent risk factor in these patients.
These initial 1982 studies were ex-
tended to longer follow-up that was
subsequently published in 1990.20 These
208 patients were followed for a mean
duration of 4 years after their first un-
provoked seizure. Overall recurrence
risks were 14%, 29%, and 34% at 1, 3,
and 5 years, respectively, following the
first episode. In the 149 patients with
idiopathic seizures, the recurrence risks
were 10%, 24%, and 29%, compared to
recurrence risks of 26%, 41%, and 48%
at 1, 3, and 5 years, respectively, for
patients with remote symptomatic sei-
Continuum (Minneap Minn) 2016;22(1):3850
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
zures. Again, treatment was administered
in 80% of patients, but no evidence
showed that treatment favorably af-
fected seizure recurrence. A history of
a previous neurologic insult (ie, remote
symptomatic) was associated with a
2.5-fold increased risk of recurrence.
In this report, risk factors for seizure
recurrence in patients with idiopathic
seizures were: (1) a sibling with epilepsy,
(2) generalized spike-wave discharges
on EEG, and (3) a history of acute symp-
tomatic seizures. The latter two risk factors
increased the risk of seizure recurrence
to 60% or more.
Status epilepticus, prior acute symp-
tomatic seizures, or a Todd paralysis
increased the risk of seizure recurrence
in those patients with remote symp-
tomatic seizures. These analyses pro-
vide additional support for separating
provoked seizures due to drugs or
substances that have no influence on
recurrence risk of later unprovoked sei-
zures from acute symptomatic seizures.
As discussed, acute symptomatic sei-
zures have a low risk of seizure recur-
rence (less than 25%), and chronic
AED treatment is often not warranted.
But once the patient has a subsequent
unprovoked seizure, a history of a pre-
vious acute symptomatic seizure in-
creases the risk of seizure recurrence to
60% or more.
SEIZURE RECURRENCE IN
CHILDREN
Interestingly, no population studies have
demonstrated age as an independent
risk factor for seizure recurrence. Sei-
zures that begin in childhood are much
more likely to be idiopathic than in adults,
and children are more likely to be diag-
nosed with epileptic syndromes. Both
of these factors can influence the chance
of seizure remission, a topic that will not
be addressed here. As mentioned, the
AAN has a separate guideline for treat-
ment of the child with a first unprovoked
www.ContinuumJournal.com 45
 Management of a First Seizure
KEY POINT
h Risk factors for seizure
recurrence in children
are similar to those in
adults, with epileptiform
EEG and remote
symptomatology being
important factors.
46 www.ContinuumJournal.com
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
seizure.4 This is reasonable since the
causes of unprovoked seizures in chil-
dren are different than those in adults.
While children may bike, swim, and
climb trees, they are not going to be
driving, and the risks of injury due to
a second seizure may be less than for
an adult. Sudden unexpected death in
epilepsy (SUDEP) is a concern for pa-
tients of all ages; no evidence exists that
treatment after a first unprovoked sei-
zure reduces this risk. Although many
of the second- and third-generation
AEDs have better cognitive profiles
than the first-generation agents, medi-
cations can still have effects on learn-
ing, and the taking of daily medication
may be stigmatizing to the otherwise
healthy young child in school.
Shinnar and colleagues9,21 have con-
ducted very thorough studies of sei-
zure recurrence in children. In one study
of 407 children followed a mean of
6.3 years after an unprovoked seizure,
42% had subsequent seizures, with the
cumulative risk of 29% at 1 year rising
to 37% at 2 years and 42% at 3 years.9
Risk factors for seizure recurrence in
this group included remote symptom-
atology, abnormal EEG, seizures occur-
ring during sleep, history of prior febrile
seizures, and a Todd paralysis. An
epileptiform EEG was more predictive
of seizure recurrence than an EEG that
was abnormal but nonspecific. The risk
of seizure recurrence with a normal
EEG was less than 30% over 5 years.
This risk rose to 45% with a nonep-
ileptiform abnormal EEG and to over
60% with an epileptiform EEG. Focal
slowing was also associated with a high
risk of seizure recurrence in these
studies, in contrast to the studies by
Hauser and colleagues.19 In the studies
of Shinnar and colleagues,9,21 the EEG
was the most important predictor in
patients with idiopathic first seizures.
Symptomatic first seizures were more
commonly associated with an abnor-
mal EEG. Interestingly, in children with
symptomatic unprovoked seizures (eg,
structural lesions), an abnormal EEG
was not associated with increased risk;
that is, the increased risk was conferred
by the structural lesion. Risk factors are
similar for early or late seizure recur-
rence.21 In another study by the same
group,22 the 5-year recurrence risk for
children having a first unprovoked
seizure was only 21% if the seizures
were idiopathic/cryptogenic and the
EEG was normal. Only 3% of children
had a second seizure after 5 years from
the first.
EFFECT OF TREATMENT ON
RISK OF RELAPSE
In assessing the risk of a second seizure,
treating physicians are trying to deter-
mine when to start AED therapy. It is
hoped that AED therapy will provide
seizure control or at least reduce the
risk of a second seizure. As mentioned,
no evidence has shown that prophylac-
tic AED therapy prevents the develop-
ment of epilepsy. Does AED therapy
reduce the risk of a second seizure in
patients who have already had their first
unprovoked seizure?
Two randomized trials have attempted
to answer that question. The First Seizure
Trial (FIR.S.T) Group studied 397 pa-
tients, 2 to 70 years of age, 193 of whom
were randomly assigned to delayed
treatment.23 The risk of recurrence in the
untreated cohort was 18% at 3 months,
28% at 6 months, and 51% at 24 months.
Among the treated cohort, the risk of
relapse was 25% in the first 24 months,
suggesting that treatment does lead to
significant reduction of risk.
The European Multicenter Epilepsy
and Single Seizure Study (MESS) was
an unmasked multicenter randomized
study of immediate versus deferred
AED treatment in 1847 patients with
single seizures or early infrequent un-
provoked seizures.24 Of the 408 patients
February 2016

in MESS who were randomly assigned
to deferred treatment, 26% had recur-
rence at 6 months and 39% at 2 years,
similar to the FIR.S.T results. At 5 years,
51% of the untreated MESS cohort had
a recurrence of seizures; those patients
followed for 8 years had a 52% recur-
rence rate. In this later study by Marson
and colleagues,24 immediate AED ther-
apy increased the time to first seizure,
second seizure, and first tonic-clonic
seizure, as well as significantly reduced
the time to achieve a 2-year remission
of seizures, but at 5-year follow-up, 76%
of the patients in the immediate treat-
ment group and 77% of those in the
deferred treatment group were seizure
free, indicating that immediate AED
treatment did not reduce the long-term
remission rate in individuals who had
infrequent or single seizures.
Kim and colleagues25 further ana-
lyzed the MESS patient cohort. Using
the 1443-patient cohort, they developed
a prognostic model. The hazard ratio for
seizure recurrence in the untreated arm
was 1.35 for remote symptomatic seizures
and 1.54 for an abnormal EEG. In de-
veloping their model, they assigned two
points for three or four seizures prior to
presentation and one point each for an
abnormal EEG, a neurologic disorder,
or two or three seizures prior to pre-
sentation. The low-risk group included
those patients with only a single seizure.
The high-risk group was more than
three seizures or two or more risk
factors. The remaining patients were
classified as medium risk. There was
little benefit to immediate treatment in
the low-risk group, but potential benefit
in the medium- and high-risk groups.
Other studies have looked at pat-
terns of treatment response in newly
diagnosed epilepsy in which all patients
were treated with AEDs. While these
studies do not fulfill the requirements
of evidence-based assessment, they do
provide information regarding the nat-
Continuum (Minneap Minn) 2016;22(1):3850
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINTS
ural history of patients receiving treat- h Antiepileptic drug
ment. In one large series of over 1000 therapy after a first
patients, 37% achieved early (within unprovoked seizure
6 months of initiation of therapy) sus- increases the time to
tained seizure freedom, and 22% second seizure.
achieved delayed (after 6 months of h Seizure recurrence in
initiation of therapy) seizure freedom adults presenting with a
on AED monotherapy.26 The chance first unprovoked seizure
of achieving seizure freedom declines is greatest in the first
dramatically from the first to third drug 2 years (21% to 45%
regimen, particularly in patients with for all patients).
focal epilepsy for whom therapy has
failed because of lack of efficacy, not
side effects.26,27
AMERICAN ACADEMY OF
NEUROLOGY PRACTICE
GUIDELINES AND PRACTICE
PARAMETERS
In 2015, the AAN published an evidence-
based guideline on the management of
an unprovoked first seizure in adults.6
(Refer to Appendix A for a summary of
the AAN evidence-based guideline for
clinicians.) As is required with these
evidence-based guidelines, the authors
did an exhaustive review. They identi-
fied 2613 articles and selected 281 for
full review. A number of the studies they
used in their analyses have been dis-
cussed above, but the reader is referred
to the guideline for the complete anal-
ysis. Drawing from the best available
published information (Class I and
Class II studies), they found that risk
of recurrence was greatest in the first
2 years and was 21% to 45% for the un-
selected patients (Figure 2-3). Patients
with a prior brain lesion or insult (re-
mote symptomatic), an EEG with epi-
leptiform abnormalities, a significant
brain imaging abnormality, or nocturnal
seizures were at increased risk of seizure
recurrence (Table 2-3). Two Class II
studies supported the increased risk of
nocturnal seizures; certain seizures (eg,
frontal lobe focal seizures) have a pre-
disposition to occur at night. The au-
thors found evidence that immediate
www.ContinuumJournal.com 47
 Management of a First Seizure

KEY POINT
h Delay in antiepileptic
drug initiation until
after the second
unprovoked seizure
does not influence
the chance of
long-term remission.

FIGURE 2-3 Percentage of patients with first seizure

experiencing a recurrent seizure over time.
6
Reprinted with permission from Krumholz A, et al, Neurology.
www.neurology.org/content/84/16/1705.full. B 2015 American Academy
of Neurology.

AED therapy was likely to reduce the
risk of a second unprovoked seizure
by about 35% over the next 2 years but
that delay in initiating therapy until
after a second unprovoked seizure did
not influence the chance of long-term
remission. The MESS reports discussed
above addresses these issues.24,25 The
guidelines state that the risk for ad-
verse events from AEDs was 7% to
31%, but the authors acknowledged
that a number of the studies employed
first-generation AEDs and that selected
second- or third-generation AEDs could
be better tolerated.
In 2003, the AAN published a
practice parameter on the treatment
of the child with a first unprovoked
seizure.4 Their analyses used only
studies that included children, but
the authors acknowledged that few
good studies limited to children
existed. Having said this, it should be
mentioned that age has not been
shown to be an independent variable
in multiple studies. Their conclusion
was that treatment with an AED is not
indicated for the prevention of epi-
lepsy. Although treatment after a first
unprovoked seizure appears to decrease

TABLE 2-3 Patients at Increased Risk for Seizure Recurrence After

First Seizure: American Academy of Neurology
Guideline Analysisa

b Patients with prior brain lesion or insult (remote symptomatic)

b Epileptiform EEG abnormality
b Significant brain-imaging abnormality
b Nocturnal seizure
EEG = electroencephalogram.
a
Data from Krumholz A, et al, Neurology.6 www.neurology.org/content/84/16/1705.full.

48 www.ContinuumJournal.com February 2016

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

the risk of a second seizure, no evi-
dence existed that treatment affected
the chance of long-term remission. They
found that remote symptomatic seizures
associated with a known brain insult,
significant brain imaging abnormality,
or an abnormal EEG (particularly epi-
leptiform) were more likely to be as-
sociated with seizure recurrence. The
duration of the first seizure (ie, whether
prolonged or associated with status
epilepticus) did not influence the risk
of recurrence apart from the known
risk factors. As one would expect when
considering treatment in children,
concern was increased regarding the
potential side effects of AEDs, and the
authors stressed that treatment deci-
sions should be based on a risk-benefit
assessment and individualized to take
into account specific medical, social,
and family issues.
CONCLUSION
After it has been determined that a
patient has indeed had an epileptic
seizure, the evaluation of the patient
with a first seizure should focus on as-
sessing the risk for subsequent seizures,
recognizing that many patients will
not have a second seizure. A careful
history should focus on identifying
possible provoking or acute causes or
unrecognized previous seizures, con-
vulsive or nonconvulsive. This should
be supplemented by good imaging
(MRI preferred) and EEG to help iden-
tify those patients with remote symp-
tomatic causes or epileptic syndromes.
This information can then be used to
identify those patients at high risk
for seizure recurrence. The 2015 AAN
guideline provides an excellent criti-
cal review of these risk factors that
can be extremely useful in guiding
therapy, recognizing that the decision
to start AED therapy depends also
upon the patient and his or her spe-
cific life situation.
Continuum (Minneap Minn) 2016;22(1):3850
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
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