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FULL-LENGTH ORIGINAL RESEARCH

Is the first seizure epilepsy—and when?

Nicholas Lawn, Josephine Chan, Judy Lee, and John Dunne

Epilepsia, 56(9):1425–1431, 2015

doi: 10.1111/epi.13093

SUMMARY
Objective: Epilepsy has recently been redefined to include a single unprovoked seizure
if the probability of recurrence is ≥60% over the following 10 years. This definition is
based on the estimated risk of a third seizure after two unprovoked seizures, using the
lower-limit 95% confidence interval (CI) at 4 years, and does not account for the
initially high recurrence rate after first-ever seizure that rapidly falls with increasing
duration of seizure freedom. We analyzed long-term outcomes after the first-ever sei-
zure, and the influence of duration of seizure freedom on the likelihood of seizure
recurrence, and their relevance to the new definition of epilepsy.
Methods: Prospective analysis of 798 adults with a first-ever unprovoked seizure seen
at a hospital-based first seizure clinic between 2000 and 2011. The likelihood of seizure
recurrence was analyzed according to the duration of seizure freedom, etiology, elec-
troencephalography (EEG), and neuroimaging findings.
Results: The likelihood of seizure recurrence at 10 years was ≥60% in patients with
epileptiform abnormalities on EEG or neuroimaging abnormalities, therefore, meet-
Dr. Nicholas Lawn is ing the new definition of epilepsy. However, the risk of recurrence was highly time
a neurologist at the dependent; after a brief period (≤12 weeks) of seizure freedom, no patient group con-
Western Australian tinued to fulfill the new definition of epilepsy. Of 407 patients who had a second seizure,
Comprehensive the likelihood of a third seizure at 4 years was 68% (95% CI 63–73%) and at 10 years
Epilepsy Centre, was 85% (95% CI 79–91%).
Perth, Australia. Significance: The duration of seizure freedom following first-ever seizure substantially
influences the risk of recurrence, with none of our patients fulfilling the new definition
of epilepsy after a short period of seizure freedom. When a threshold was applied
based on the 10-year risk of a third seizure from our data, no first-seizure patient group
ever had epilepsy. These data may be utilized in a definition of epilepsy after a first-
ever seizure.
KEY WORDS: First seizure, Prognosis, Definition of epilepsy.

In 2005 it was proposed that epilepsy (an enduring predis-
position to seizures) could be diagnosed in some patients
after a single seizure,1 and following some discussion,2,3 the
International League Against Epilepsy (ILAE) published a
new practical definition of epilepsy.4 The new definition
includes the following: “One unprovoked (or reflex) seizure
and a probability of further seizures similar to the general
recurrence risk (at least 60%) after two unprovoked
Accepted June 30, 2015; Early View publication July 27, 2015.
Department of Neurology, Royal Perth Hospital, Perth, Western
Australia, Australia
Address correspondence to Nicholas Lawn, Department of Neurology,
Royal Perth Hospital, GPO Box X2213, Perth, WA 6847, Australia. E-mail:
nicholas.lawn@health.wa.gov.au
Wiley Periodicals, Inc.
© 2015 International League Against Epilepsy
seizures, occurring over the next 10 years.” It was consid-
ered that the presence of factors such as prior central ner-
vous system (CNS) insult or epileptiform abnormalities on
electroencephalography (EEG) might allow epilepsy to be
diagnosed after a single seizure in some patients. The
threshold of at least a 60% risk of a second seizure within
10 years was determined by expert opinion rather than sub-
stantive data. This threshold is based on using the lower
95% confidence interval (CI) of the estimated 73% (95% CI
59–87) 4-year risk of having a further seizure after two
unprovoked seizures as a surrogate for the 10-year risk.5,6
This 60% figure, although intended to be only an approxi-
mate guide, is likely to be utilized in practice despite the
absence of supporting long-term follow-up data.6 Whether
this new definition has practical application to first seizure

1425

1426
N. Lawn et al.
Key Points
• Epilepsy has been redefined to include a single unpro-
voked seizure if the probability of recurrence is ≥60%
over the following 10 years.
• The definition is based on the lower limit of the 95%
CI of the risk of a third seizure after two seizures, but
utilizes 4-year data.
• The overall 10-year risk of seizure recurrence in 798
patients with first-ever unprovoked seizure was 59%
(95% CI 55–64%).
• Of 407 patients who had a recurrence, the risk of a
third seizure at 10 years was 85% (95% CI 79–91%).
• Applying the new definition of epilepsy, but with
actual 10-year data, no patients with a first-ever unpro-
voked seizure would be regarded as having epilepsy.
patients is yet to be explored. Defining epilepsy after a
single seizure has difficulties other than employing a thresh-
old based on expert opinion rather than long-term follow-up
data. Most importantly, the risk of seizure recurrence is time
dependent, highest in the first few months and then falling
exponentially with increasing duration of seizure free-
dom.5,7 Therefore, the time at which a patient is seen after
the first-ever seizure will influence whether a patient has
epilepsy or not as defined by the new criteria.
Whether a neurologist can reliably diagnose epilepsy
prior to a patient’s second seizure is unknown. Even if this
is possible, most patients are initially or are only seen in the
emergency room or by their general practitioner. Well-
organized first seizure clinics often do not see patients until
some weeks after the first seizure, as suggested in guideli-
nes,8 and in prospective studies, many patients are initially
seen over a month after the first seizure, by which time their
risk of recurrence has significantly fallen if they remain sei-
zure-free.5,9
More data are required to inform a definition of epilepsy
after first seizure, including the influences of duration of
seizure freedom, the etiology, EEG, and neuroimaging find-
ings on the risk of recurrence. We investigated these issues
in a large prospective cohort of patients with first-ever
unprovoked seizure and with long-term follow-up.
Methods
The Western Australian first seizure database was estab-
lished in 2000 and is an ongoing prospective study of out-
comes in adults with first-ever seizure. The methodology
has been described previously.10,11 For this study, all
patients seen between 2000 and 2011 with first-ever unpro-
voked seizure were included. The majority (70%) of
patients were referred from local or regional emergency
Epilepsia, 56(9):1425–1431, 2015
doi: 10.1111/epi.13093
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departments, with the remainder being from general practi-
tioners (12%) and hospital inpatient or other subspecialty
referrals. Enrollment was at the time of the initial assess-
ment by the first seizure service, excluding those with a
recurrence while awaiting assessment. The median time to
be seen was 24 days, with 18% of patients seen within
1 day and 28% within 1 week of their first seizure.
Patients with first seizure provoked by any acute systemic
or CNS insult, and with prior seizures of any nature (except
febrile convulsions), were excluded. Unprovoked seizures
were defined as “remote symptomatic” if there was history
of or neuroimaging evidence of a prior CNS insult (includ-
ing brain tumors) and “idiopathic” if there was no obvious
cause (encompassing genetic epilepsy syndromes and the
category “cryptogenic”). Seizure type and electroclinical
syndrome (focal, generalized, or unclassified) were catego-
rized for the presenting seizure according to published
guidelines.12 EEG was performed in 98% of patients, and
the findings were classified as normal or abnormal (epilepti-
form or nonspecific). Neuroimaging (computed tomogra-
phy [CT], magnetic resonance imaging [MRI], or both,
undertaken in 98% of patients) abnormalities identified
were defined as epileptogenic if a lesion likely relevant to
the cause of the seizure was found.13
Follow-up
Patients were reviewed in clinic 3–9 months after the
index seizure, and if there had been no further seizures they
were contacted thereafter by phone every 1–2 years until
seizure recurrence occurred or death. For those not con-
tactable by phone at any stage (48 patients) the integrated
interhospital computer system was checked for attendance
at other major hospitals in Western Australia, after which
any related medical records were obtained. A seizure occur-
ring during follow-up at least 24 h after the first was consid-
ered a recurrence. Patients identified during follow-up (but
prior to any recurrence) to have developed a new process
after the first-ever seizure that may have contributed to risk
of further seizures (e.g., stroke, significant head injury) were
followed up until the time of the CNS insult, and were then
censored at that time. If a patient was treated with an
antiepileptic drug (AED) after a first seizure for at least
4 weeks but subsequently discontinued treatment during
follow-up, they were still considered treated.
Outcomes and statistical analysis
The primary outcome was occurrence of a second seizure.
Exclusion of patients with an early seizure recurrence while
awaiting assessment may underestimate seizure recurrence,
whereas their inclusion may overestimate seizure recur-
rence, with both of these approaches being influenced by
time of ascertainment bias.5 The actual recurrence rate
probably lies somewhere between these two estimates.
Therefore, we performed a primary analysis limited to only
those patients enrolled before any seizure recurrence and a
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1427
Is the First Seizure Epilepsy?

Table 1. Clinical, EEG, and neuroimaging findings in study patients, according to ascertainment method
All first-ever seizure patients, including those
Patients enrolled before seizure who had a recurrence after being referred but before
recurrence (primary analysis) being seen at the clinic (secondary analysis)
N = 798 N = 1,034
Age median (range) 39 (14–91) 38 (14–91)
Gender male, n (%) 525 (66) 657 (64)
Seizure type
GTCS, n (%) 759 (95) 965 (94)
Other, n (%) 39 (5) 69 (6)
Electroclinical syndrome
Partial, n (%) 375 (47) 512 (49)
Generalized, n (%) 66 (8) 93 (9)
Unclassified, n (%) 357 (45) 429 (42)
Etiology
Remote symptomatic, n (%) 253 (32) 338 (33)
Idiopathic, n (%) 545 (68) 696 (67)
EEG epileptiform, n (%) 133 (17) 178 (18)
Neuroimaging epileptogenic lesion, n (%) 221 (28) 296 (29)
Treated, n (%) 212 (27) 272 (26)
Mean duration of follow-up (days) 2,215 2,114
<1 year of follow-up (dead) n (%) 48 (22 died) 76 (31 died)
>10 years of follow-up n (%) 148 (19%) 164 (16%)
Seizure recurrence % (95% CI)
6 months 24 (21–27) 40 (37–43)
12 months 33 (30–36) 48 (45–51)
2 years 42 (38–45) 55 (52–58)
5 years 51 (47–55) 62 (59–65)
10 years 59 (55–64) 69 (65–72)
Patients who had a second seizure, n 407 643
Likelihood of a third seizure % (95% CI) at
4 years 68 (63–73) 72 (68–75)
10 years 85 (79–92) 85 (79–89)

secondary analysis of all patients, including those who had a
second seizure after being referred but before being seen at
the clinic.
Time to seizure recurrence was analyzed using Kaplan-
Meier curves and log-rank statistics, with censoring if sei-
zure recurrence had not occurred at time of last follow up or
death. The cumulative and conditional (given seizure free-
dom up to a specific time) survival rates were analyzed. The
conditional likelihoods of seizure freedom (survival) were
calculated for various intervals by dividing the cumulative
probability of seizure freedom at the end of the time interval
by that at the beginning of the time interval.14 For example,
if 50 of 100 patients were still seizure-free after 1 year
(cumulative survival of 50% at 1 year); and 25 of the
remaining 50 patients were still seizure-free at 11 years (cu-
mulative survival of 25% at 11 years), the conditional prob-
ability of seizure freedom for the 1–11 year period was 50%
(25%/50%); and conversely the conditional seizure recur-
rence rate for this period was 50% (recurrence occurring in
25 of those 50 patients who were still seizure-free at 1 year).
The risk factors for seizure recurrence consistently identi-
fied in prior studies (remote symptomatic etiology or the
presence of an epileptogenic abnormality on neuroimaging
and epileptiform abnormalities) were examined using Cox
proportional hazards models.5,7,11,15 Of patients who had a
second seizure, the overall likelihoods of a third seizure at
4 years and at 10 years were calculated. Results were con-
sidered statistically significant at the 5% level.
Results
Demographics and seizure recurrence
The clinical data of the patients studied, according to
method of analysis, are provided on Table 1. Other than sei-
zure recurrence, there were no significant differences
between the two groups analyzed. In the group of 798
patients with first-ever unprovoked seizures enrolled before
any seizure recurrence, 545 were idiopathic and 253 remote
symptomatic. The remote symptomatic etiologies were the
following: stroke (72), head trauma (56), CNS tumor (38),
and other (87) including malformations of cortical develop-
ment, infection, vascular lesions, and perinatal insult. Most
patients presented with a tonic–clonic seizure. The mean
duration of follow-up was 2,215 days (6.1 years). Four hun-
dred ninety-two patients (62%) had ≥4 years of follow-up,
and 148 patients (19%) had ≥10 years of follow-up. Forty-
eight patients (6%) had <1 year of follow-up of whom 22
patients died within the first year.

Epilepsia, 56(9):1425–1431, 2015

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1428
N. Lawn et al.
The overall cumulative likelihoods of seizure recurrence
at various time points are provided on Table 1. The risk of
seizure recurrence according to etiology and EEG findings
is shown on Figure 1.
Independent predictors of seizure recurrence were remote
symptomatic etiology (hazards ratio [HR] 1.42, 95% CI
1.16–1.75; p = 0.001), simple partial seizures (HR 2.26,
95% CI 1.20–4.25; p = 0.01), epileptiform abnormality on
EEG (HR 1.49, 95% CI 1.17–1.89; p = 0.001), and first sei-
zure from sleep (HR 1.37, 95% CI 1.10–1.71; p = 0.005).
An epileptogenic lesion on neuroimaging was highly corre-
lated with remote symptomatic etiology, and was only an
independent predictor of recurrence when remote symp-
tomatic etiology was removed from the multivariate model.
Epilepsia, 56(9):1425–1431, 2015
doi: 10.1111/epi.13093
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Figure 1.
Cumulative probability of seizure
recurrence according to etiology and
presence or absence of epileptiform
abnormalities on EEG.
Epilepsia ILAE
Overall, 40% of patients had an initial 10-year risk of
seizure recurrence of ≥60%, but after a brief period of
seizure freedom, no patient group fulfilled the new defi-
nition of epilepsy, irrespective of the etiology or findings
on investigation (Fig. 2). For idiopathic first seizures
with normal EEG, the 10-year risk of seizure recurrence
was initially 53% (95% CI 47–58). For idiopathic first
seizures with epileptiform abnormalities, the 10-year risk
of seizure recurrence was initially 76% (95% CI 64–87),
falling below 60% within 12 months of seizure freedom,
with the 95% CI falling below 60% within 9 weeks. For
remote symptomatic first seizures, the 10-year risk of
seizure recurrence was initially 67% (95% CI 60–74),
falling below 60% within 3 months of seizure freedom.
Figure 2.
Conditional 10-year risk of seizure
recurrence after various durations of
seizure freedom (months = M),
according to etiology and presence
or absence of epileptiform
abnormalities on EEG. The shaded
area represents the 95% CI of the 10-
year risk of a third seizure after a
second seizure from our data. The
red line at 60% indicates the
threshold for seizure recurrence
utilized in the new definition of
epilepsy (see text).
Epilepsia ILAE
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1429
Is the First Seizure Epilepsy?

Figure 3.
Cumulative risk of a third seizure in
patients seen before recurrence
(primary analysis) and those who had
a recurrence while awaiting
assessment by the first seizure
service (secondary analysis, see text).
Epilepsia ILAE

In patients with a remote symptomatic first seizure, the
presence or absence of epileptiform abnormalities had no
effect on risk of seizure recurrence (logrank p = 0.60).
Patients with tumors (n = 54) had the highest risk of
recurrence, occurring mainly within the first 6 months,
like other remote symptomatic causes. The 10-year recur-
rence rate was <60% within 5 months, but this is based
on only 19 patients remaining at risk.
The conditional 10-year risks of seizure recurrence after
various durations of seizure freedom following a first unpro-
voked seizure are shown in Figure 2.
Secondary analysis that included patients with early
seizure recurrence while waiting for their appointment,
showed comparable findings both with respect to indepen-
dent predictors of seizure recurrence, and the fleeting fulfill-
ment of the new definition of epilepsy. The overall
cumulative likelihood of seizure recurrence at 10 years was
≥60% for all patients and in all patient subgroups, but after a
short period of seizure freedom, no patient subgroups ful-
filled the new definition of epilepsy. Further limiting analy-
sis to those patients enrolled within 1 week of their first
seizure (n = 249) also shows comparable findings, with
recurrence rates being intermediate between those seen with
the primary and secondary analyses: the overall cumulative
likelihood of seizure recurrence at 10 years was 67% (95%
CI 60–73%), and was ≥60% in all patient subgroups, and
after a brief period of seizure freedom, no patient subgroups
fulfilled the new definition of epilepsy.

Figure 4.
Conditional 4-year risks of seizure
recurrence after various durations of
seizure freedom (months = M),
according to etiology and presence
or absence of epileptiform
abnormalities on EEG. The light
shaded area represents the 4-year
risk with 95% CI of a third seizure as
determined by Hauser et al.5 and the
dark shaded area indicates the 4-year
risk with 95% CI identified in our
study.
Epilepsia ILAE

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N. Lawn et al.
AED treatment was commenced after the first seizure in
212 patients (27%), more frequently in remote symp-
tomatic than idiopathic seizures (51% vs. 15%), but in sim-
ilar proportions of the analysis subgroups. Treatment did
not alter the likelihood of seizure recurrence, including in
subgroup analysis of remote symptomatic or idiopathic
unprovoked first seizure patients, although 27% of patients
started on an AED were not taking this at the time of sei-
zure recurrence. However, exclusion of all treated patients
did not alter our findings.
Of 407 patients who had a second seizure, the overall
likelihood of a third seizure at 4 years was 68% (95% CI
63–73%), and at 10 years was 85% (95% CI 79–92%). Sec-
ondary analysis that included patients with early seizure
recurrence while waiting for their appointment showed
essentially identical findings (Table 1 and Fig. 3). Using
these data and either the likelihood of a third seizure at
4 years (the basis of the new definition of epilepsy) or the
threshold for the new definition of epilepsy proposed by the
ILAE (lower limit of the 95% CI for the risk of a third sei-
zure at 10 years), no first seizure patient group ever satisfied
the diagnosis of epilepsy from the outset (Fig. 4).
Discussion
Our long-term follow-up data of patients with first
unprovoked seizure reveal three main findings. First, the
overall cumulative likelihood of first seizure recurrence at
10 years was initially at least 60% in a substantial propor-
tion of patients (40%), therefore meeting the new definition
of epilepsy. Secondary analysis to include those patients
with early recurrence while waiting for their appointment
showed the cumulative likelihood of first seizure recur-
rence at 10 years was initially at least 60% in all patients
and subgroups, irrespective of etiology or investigation
findings. Our recurrence rates are comparable to those of
other published series.7 The variation in published findings
probably reflects a number of factors, including the study
population, differing inclusion criteria, and variations in
the time of ascertainment, as illustrated by our primary and
secondary analyses.5
Second, the overall likelihood of a third seizure at 4 years
was 68% (95% CI 63–73%) and 10 years was 85% (95% CI
80–90%), with essentially the same findings when patients
who had a second seizure while waiting to be seen in the
clinic are included. Our data confirm that the threshold used
in the new definition of epilepsy underestimates the long-
term risk of a third seizure after a second seizure, as pre-
dicted by Hauser.6 Using either the actual likelihood of a
third seizure at 4 years or the new definition of epilepsy
informed by our data (the lower threshold for the risk of a
third seizure at 10 years becomes 79% rather than 60%),
none of the patients seen at the time of the first seizure
would be regarded as having epilepsy.
Epilepsia, 56(9):1425–1431, 2015
doi: 10.1111/epi.13093
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Third, we confirm that the risk of seizure recurrence fol-
lowing a first-ever seizure is highly time dependent, rapidly
falling with increasing duration of seizure freedom. No
patient group with first-ever seizure, irrespective of the eti-
ology or presence of other risk factors for recurrence,
reached the threshold for the new ILAE definition of epi-
lepsy after being seizure-free for a short time. This has prac-
tical relevance given that by the time many first seizure
patients are seen by a neurologist (if at all), they will no
longer meet the new definition.5,8,9
Epilepsy requires an enduring predisposition to sei-
zures. All ILAE Taskforce members agreed that an indi-
vidual with two unprovoked seizures had epilepsy,4
referring to data indicating the best estimate of the risk
of a third seizure was about 73% (95% CIs of 59–87%)
at 4 years.16 The wide CIs reflect the relatively small
numbers (63 patients) and greater uncertainty.16 Our find-
ings, based on follow-up of a greater number of patients
after a second seizure, are remarkably similar to those of
Hauser et al.,16 but with narrower CIs. The ILAE task
force, in an initial draft document,17 proposed “approxi-
mately 75% or more” as the threshold for epilepsy, using
Hauser’s estimated risk of recurrence within 4 years.
However, for the final publication, the task force arbitrar-
ily chose at least 60%, the lower extreme of wide confi-
dence intervals for the 4-year risk of a third seizure, to
represent the enduring risk at 10 years.4 This unusual
decision considerably increases the likelihood of epilepsy
misdiagnosis.
Individual patient circumstances at times clearly justify
treatment after a single unprovoked seizure, but this requires
a personalized approach to patient care with adequate dis-
cussion regarding the benefits and risks of AED treatment,
rather than making a premature and enduring diagnosis of
epilepsy.18 The diagnosis of epilepsy has major ramifica-
tions, and is difficult if not impossible to reverse, requiring
10 years of seizure freedom after being off AEDs for at least
5 years.4 Further study in similar cohorts may identify some
patient groups as having epilepsy after their first seizure. In
the interim, our data supports waiting for seizure recurrence
prior to making a diagnosis of epilepsy.
Acknowledgments
Funding for the establishment and maintenance of the first-seizure data-
base in the form of a grant to cover the costs of a research assistant was
received from the Medical Research Foundation of Royal Perth Hospital
and UCB-Pharma.
Disclosure
None of the authors has any conflict of interest to disclose. We
confirm that we have read the Journal’s position on issues involved in
ethical publication and affirm that this report is consistent with those
guidelines.

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