e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 1 ( 2 0 1 7 ) 4 6 5 e4 6 7

Official Journal of the European Paediatric Neurology Society

Original article

Early seizures predict the development of epilepsy

in children and adolescents with stroke

Ina Breitweg a,b,*, Celina von Stülpnagel a,c, Tom Pieper a, Karen Lidzba d,
Hans Holthausen a, Martin Staudt a,d,e, Gerhard Kluger a,c,e
a
Clinic for Neuropediatrics and Neurorehabilitation, Epilepsy Center for Children and Adolescents, Scho€n Klinik,
Krankenhausstr. 20, D-83569 Vogtareuth, Germany
b
Department of Epileptology, Children's Center Munich, Center for Social Pediatrics, Heiglhofstr. 63, D-81377
Munich, Germany
c
Paracelsus Medical University, Strubergasse 21, A-5020 Salzburg, Austria
d
Dept. Pediatric Neurology and Developmental Medicine, University Children's Hospital, Hoppe-Seyler-Str. 1,
D-72076 Tübingen, Germany

article info abstract

Article history: Purpose: To identify risk factors for the development of epilepsy after pediatric stroke.
Received 8 April 2016 Methods: Retrospective analysis of hospital charts of 93 children and adolescents with post-
Received in revised form neonatal non-traumatic stroke and a minimum follow-up of two years. Seizures during the
12 July 2016 first 48 h after onset of stroke symptoms were defined as “early seizures”; when two or
Accepted 12 December 2016 more seizures occurred after this period, the patient was classified as “epileptic”.
Results: Early seizures, young age at stroke and MRI evidence of cortical involvement were
Keywords: observed more frequently in the children who developed epilepsy. These factors were,
Childhood stroke however, significantly interrelated; a stepwise multiple regression analysis in 46/93 pa-
Risk factors tients with complete datasets identified only the occurrence of early seizures as a signifi-
Epilepsy cant risk factor: 15/19 (79%) children with early seizures developed epilepsy, as opposed to
Early seizures only 7/53 (13%) without early seizures.
Conclusion: Children with stroke who show seizures during the first 48 h after onset of
stroke symptoms have a high risk to develop post-stroke epilepsy, whereas in children
without early seizures, post-stroke epilepsy is rare.
© 2016 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.

implications for both the short-term and the long-term med-

1. Introduction ical management of these patients and their quality of life.1
The risk to develop epilepsy after adult stroke is low
The development of epilepsy is a significant threat in children (around 10%2,3). After pediatric stroke, it is apparently higher;
and adolescents who suffer stroke, and has major it has been determined as high as 16%,4 24%5 and 26%.6

Abbreviations: MRI, Magnetic resonance imaging.

* Corresponding author. kbo-Kinderzentrum München gGmbH, Abteilung für Epileptologie, Heiglhofstr. 63, D- 81377 München, Germany.
Fax: þ49 89 71009 148.
E-mail address: ina.breitweg@kbo.de (I. Breitweg).
e
These authors contributed equally.
http://dx.doi.org/10.1016/j.ejpn.2016.12.007
1090-3798/© 2016 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.

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466 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 1 ( 2 0 1 7 ) 4 6 5 e4 6 7
Previous studies have identified three major risk factors for
the development of post-stroke epilepsy in children: 1. The
occurrence of early seizures, i.e. seizures at presentation or
during the first days after the stroke,4,5,7 2. Young age at onset
of the stroke7 and 3. Radiological evidence of cortical
involvement.8 On the other hand, these factors are also clearly
inter-related: Young age at onset of stroke and cortical
involvement are not only associated with post-stroke epi-
lepsy, but also with the occurrence of early seizures.8e10 It is
therefore unclear whether these two factors hold additional
information regarding the risk for the development of post-
stroke epilepsy e beyond their influence on the occurrence
of early seizures. The purpose of the current study was
therefore to investigate these risk factors for the development
of post-stroke epilepsy with special respect to their inter-
relations.
2. Methods
This retrospective analysis included 93 children and adoles-
cents (up to 18 years of age) with post-neonatal non-traumatic
stroke and a minimum follow-up of two years who were
admitted in the years 1986e2003 to the Clinic for Neuro-
pediatrics and Neurorehabilitation, Epilepsy Center for Chil-
dren and Adolescents in Vogtareuth, Germany. The patients
were identified by searching the databank of the hospital for
the term “Schlaganfall”, “Hirnblutung” and “Infarkt”. The ad-
missions to this specialized institution were never at pre-
sentation; rather, the patients were transferred either for in-
patient neurorehabilitation after the stroke, or for conserva-
tive or surgical treatment of post-stroke epilepsy. This
recruitment strategy implies a clear bias towards patients with
epilepsy.
Patients were classified as epileptic when at least two
unprovoked seizures had occurred between 48 h and two
years after the stroke; when no seizures had occurred during
these first two years, the patient was classified as non-
epileptic. Seizures during the first 48 h after onset of stroke
symptoms were defined as “early seizures” in accordance with
Kilpatrick et al., who showed that 98% of early seizures
occurred within the first 48 h in their prospective evaluation of
1000 stroke patients.11
The following additional data were collected from hospital
charts as: Sex, type of stroke (ischemic/hemorrhagic), age at
stroke (available in 83/93 patients), occurrence of “early sei-
zures” (¼ seizures within the first 48 h after the stroke; suffi-
cient information about the acute phase available in 72/93
patients), and structural involvement of cortical/subcortical/
infratentorial brain structures (MRI available for re-evaluation
in 46/93 patients). Note that “hemorrhagic” also included ce-
rebral venous thrombosis and subarachnoidal hemorrhage.
3. Results
Post-stroke epilepsy developed in 25/93 patients (27%) of our
cohort. Early seizures had occurred much more frequently in
the epileptic sample (15/22; 68%) than in the non-epileptic
sample (4/50; 8%). The age at stroke was lower in the
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patients with epilepsy (median 40.5 months) than in the non-
epileptic patients (median 108 months), and was also lower in
the patients who developed early seizures (median, 33
months) than in those who did not (median, 106 months).
Finally, cortical involvement (with or without additional
involvement of the basal ganglia) was found more frequently
in the epileptic group (8/10; 80%) than in the non-epileptic
group (16/36; 44%), and also more frequently in the patients
with early seizures (5/6 ¼ 83%) than in those without early
seizures (12/30 ¼ 40%). No differences were found for sex or
type of stroke (15 boys/10 girls in the epileptic sample; 36 boys/
32 girls in the non-epileptic sample; p ¼ 0.544; 12 ischemic/13
hemorrhagic strokes in the epileptic sample; 36 ischemic/32
hemorrhagic strokes in the non-epileptic sample; p ¼ 0.672).
To investigate the differential effects of the variables early
seizures, age at stroke and cortical involvement on the develop-
ment of epilepsy, we conducted a stepwise linear multiple
regression analysis (pairwise exclusion of missing variables) in
all n ¼ 46 patients who had an MRI available for re-evaluation.
This analysis demonstrated that all three variables are
significantly correlated with the outcome variable develop-
ment of epilepsy (Table 1). They are, however, also signifi-
cantly interrelated, and only the factor presence/absence of early
seizures was retained in the model as a statistically significant
predictor (R2 ¼ 0.396, beta ¼ 0.629, t ¼ 4.718, p < 0.0001),
explaining 39% of the variance in the development of epilepsy.
4. Discussion
The major finding of this study was the identification of early
seizures as the most important predictor for the development
of epilepsy after childhood stroke: Of the 19 children with early
seizures in our cohort, 15 children (79%) developed epilepsy; in
contrast, only 7 of the 53 children (13%) without early seizures
developed epilepsy. This marked difference nicely confirms
the findings recently published by Hsu et al., who detected
post-stroke epilepsy in 13/20 (65%) children with early sei-
zures, but only in 5/58 (9%) children without early seizures.7
Similarly, Fox4 et al. found a more than fourfold increase for
the risk of post-stroke epilepsy in children in whom seizures
had occurred during the first 24 h after the stroke.
We could also confirm previous studies7e9 reporting that
younger children have a higher risk to suffer from early
Table 1 e Pearson correlations between predictor
variables and development of epilepsy (n ¼ 46 patients
with complete dataset).
Age at Early Cortical
Stroke Seizures Involvement
(months) (yes/no) (yes/no)
Epilepsy (yes/ 0.268** 0.629*** 0.294*
no)
Age at Stroke 0.236* 0.057
(months)
Early Seizures 0.323*
(yes/no)
*p < 0.05; **p < 0.01; ***p < 0.0001.
 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 1 ( 2 0 1 7 ) 4 6 5 e4 6 7
seizures. And since early seizures predict the development of
post-stroke epilepsy, it is not surprising to find that young age
at stroke is also associated with a higher risk for post-stroke
epilepsy. The interesting question in this context is whether
a child who has not shown early seizures is still at a higher
risk to develop epilepsy when the stroke had occurred at a
young age. Looking only at the subgroup of 53 children
without early seizures in our study, the 7 children who
developed epilepsy were still younger (median, 40 months)
than the 46 children who did not develop epilepsy (median,
108 months). Our statistical analysis, however, failed to
confirm young age as an independent risk factor, so that this
question remains unanswered.
Cortical involvement could also be confirmed as a risk
factor for the development of early seizures7 and for post-
stroke epilepsy.8 But in contrast to age at stroke, here our
data do not even suggest an independent risk factor: In the
subgroup of children without early seizures, epilepsy devel-
oped in 2/12 children (17%) with cortical involvement and in 2/
18 children without cortical involvement (11%).
A multivariate analysis similar to ours was also performed
by Fox et al. (including early seizures and age) and by Mallick
et al. (including early seizures, age and cortical involvement),
and both found “early seizures” as the major predictor for
post-stroke epilepsy.4,12 These findings are nicely reproduced
by our analysis.
The main finding of our study, that early seizures predict
the development of post-stroke epilepsy, should, however,
not be misinterpreted as indicating that “cortical involve-
ment” or “young age at stroke” are not related at all to post-
stroke epilepsy. Rather, our findings suggest that those chil-
dren with cortical involvement (or young age) who develop
epilepsy will most likely also have suffered from early
seizures.
This has important clinical implications: It means that,
when trying to identify children with a high risk for the devel-
opment of post-stroke epilepsy, the most important feature we
have to check is the presence of early seizures. This knowledge
will influence our prognosis (and its communication with the
family), and might even influence our decisions towards
continuation or discontinuation on antiepileptic drugs.
Biologically, it is attractive to speculate that early seizures
and post-stroke epilepsy share common pre-disposing fac-
tors, one of which might be a (genetically determined?) low
seizure threshold in this subgroup of patients.
The following limitations need to be addressed. First, this is
a retrospective study, and a large proportion of cases had
incomplete data. Most importantly, MRI was available only in
approximately half of the cases. We found no reason, how-
ever, to suspect a systematic bias in the missing data: When
comparing the group of patients with MRI with the group of
patients in whom no MRI was available, we found no differ-
ence in age (median, 94.5 vs 91.0 months) nor in the preva-
lence of early seizures or epilepsy (early seizures: 6/46 vs. 13/
47; epilepsy: 10/46 vs. 15/47). Second, since our hospital is also
an epilepsy center, our recruitment strategy implies a clear
bias towards patients with epilepsy.
In conclusion, the current study confirms that early sei-
zures are the most important risk factor for the development
of post-stroke epilepsy: When seizures occur during the first
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467
48 h after onset of stroke symptoms, the development of post-
stroke epilepsy is very likely (79% in our study); in contrast,
children without early seizures only rarely develop epilepsy
later on (13%). This information aids in counseling parents
and caregivers of pediatric stroke patients, and also in de-
cisions concerning antiepileptic treatment.
Young age at stroke and MRI evidence of cortical involve-
ment were also confirmed as risk factors both for the develop-
ment of early seizures and for the development of post-stroke
epilepsy, but we were unable to demonstrate that these factors
influence the likelihood to develop epilepsy independent from
the occurrence of early seizures as the major risk factor.
Disclosure
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.
Conflict of interest
None of the authors has any conflict of interest to disclose.
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