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Efficacy and safety of lacosamide in infants and

young children with refractory focal epilepsy.
ARTICLE in EUROPEAN JOURNAL OF PAEDIATRIC NEUROLOGY: EJPN: OFFICIAL JOURNAL OF THE EUROPEAN
PAEDIATRIC NEUROLOGY SOCIETY OCTOBER 2013
Impact Factor: 1.93 DOI: 10.1016/j.ejpn.2013.08.006 Source: PubMed

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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 x x x ( 2 0 1 3 ) 1 e5

Official Journal of the European Paediatric Neurology Society

Original article

Efficacy and safety of lacosamide in infants

and young children with refractory focal epilepsy
Salvatore Grosso a,e,*, Pasquale Parisi b, Alberto Spalice c, Alberto Verrotti d,
Paolo Balestri e
a

Child NeurologyeImmunology and Endocrinology Unit, University of Siena, Italy

Child Neurology, Chair of Pediatrics, NESMOS Department, Faculty of Medicine and Psychology,
Sapienza University, Rome, Italy
c
Department of Pediatrics, Child Neurology Division, Sapienza University of Rome, Italy
d
Clinical Pediatrics, University of Chieti, Italy
e
Department of Pediatrics, University of Siena, Italy
b

article info

abstract

Article history:

Background: Lacosamide is effective and well-tolerated antiepileptic drug (AED) in both

Received 10 July 2013

children and adults.

Received in revised form

Aim: This multicentric, prospective study investigates the efficacy and safety of lacosamide

10 August 2013

adjunctive therapy in children aged less than four years presenting with refractory focal

Accepted 22 August 2013

seizures.
Methods: Lacosamide was added to the baseline therapy at a starting dose of 1e2 mg/kg/day

Keywords:

and titrated to the final dose, ranging from 7 to 15.5 mg/kg/day. Efficacy was evaluated after

Antiepileptic drugs

a three-month period of therapy. When possible, we compared the initial efficacy and the

Partial seizures

retention after a minimum of 12 months of lacosamide, with regard to loss of efficacy

Epileptic encephalopathy

(defined as the return to the baseline seizure frequency).

Pediatrics

Results: Twenty-four children were enrolled in the study. Mean age was 2.7 years. After a

Drug resistant epilepsy

minimum three-month period of lacosamide add-on therapy, ten (42%) patients were responders (more than a 50% decrease in seizure frequency), of whom 4 (17%) became seizure
free. Retention rate, after a minimum of 12 months of lacosamide, was evaluated in a group
of 18 patients. In the latter group, eight patients (44%) were initial responders (three of
whom seizure free). After 12 months of follow-up, four of them (22%) maintained the
improvement, 2 (11%) of whom remained seizure free. A loss of efficacy was observed in 4
of the initial responders (50%). Adverse events were seen in 8 (33%) patients.
Conclusion: We conclude that lacosamide is an effective and a well-tolerated antiepileptic
drug in an etiologically wide range of focal seizures. Therefore, lacosamide might represent
a possible therapeutic option in infants and young children affected by uncontrolled focal
epilepsy.
2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights
reserved.

* Corresponding author. ImmunologyeNeurology and Endocrinology Unit, Department of Pediatrics, University of Siena, Via M. Bracci, Le
Scotte, 53100 Siena, Italy. Tel.: 39 057 7586 546.
E-mail address: grosso@unisi.it (S. Grosso).
1090-3798/$ e see front matter 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ejpn.2013.08.006

Please cite this article in press as: Grosso S, et al., Efficacy and safety of lacosamide in infants and young children with refractory
focal epilepsy, European Journal of Paediatric Neurology (2013), http://dx.doi.org/10.1016/j.ejpn.2013.08.006

1.

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 x x x ( 2 0 1 3 ) 1 e5

Introduction

Lacosamide is one of the latest antiepileptic drug (AED)

available on the market.1 It is a functionalized amino acid that
selectively enhances slow inactivation of voltage-gated sodium channels, increasing the proportion of sodium channels
unavailable for depolarization. Unlike other anticonvulsants
lacosamide does not alter fast inactivation of voltage-gated
sodium channels.1 Lacosamide may also interact with collapsin response mediator protein 2 (CRMP-2); however, this
binding has recently been challenged.2 Studies of the pharmacokinetic profile of lacosamide in children are under way.1
However, in adults the drug appears to have a favorable profile
since it is completely absorbed after oral administration and
exhibits minimal protein binding (<15%; 3). Moreover, lacosamide has not been shown to induce or inhibit CYP enzymes
in preclinical studies or in clinical studies examining specific
CYP substrates.3
Double blind placebo-controlled clinical trials demonstrated the efficacy of lacosamide in adults.4e7 Indeed, the
drug is approved for the treatment of partial epilepsy in patients older than 16 years. By contrast, caution is still necessary when the drug is used in children since safety and
efficacy of lacosamide remain to be fully clarified in this
population.8e12
Here we report on a prospective, multicenter study which
has been conducted in order to acquire further information
about efficacy and tolerability of lacosamide in a pediatric
population under four years of age affected by drug resistant
focal seizures.

2.

Patients and methods

The present report is a multicenter, prospective, open-label

treatment study carried out between December 2011 and
June 2013 at 4 Italian pediatric neurology centers. The study
protocol, amendments and informed consent were reviewed
by ethics committees for each site. All patients legal representatives gave written informed consent before study
participation.
Patients were selected by the following criteria: (i) aged less
than four years; (ii) affected by focal seizures; (iii) exhibiting at
least four seizures a month during the three months before
lacosamide was administered. Patients with progressive
neurological disorders were excluded from the study. Family
and personal histories were taken and neurological examinations performed on all patients. Details of sex, age, antiepilepsy
drug (AED) usage before lacosamide therapy, concomitant
therapy, and duration of treatments and of epilepsy were
collected. Seizure frequency was recorded by parents and/or
nursing staff and reviewed at each follow-up visit. All patients
underwent brain magnetic resonance imaging (MRI). Biochemical analyses, chromosomal investigations, and screening for
metabolic disorders were carried out in all patients.
Lacosamide was administered in two equal daily doses of
1e2 mg/kg. The dose was increased every week up to a
maximum of 15.5 mg/kg/day. In the event of an adverse reaction, the titration phase was prolonged based on the clinical
condition. During treatment complete peripheral blood

counts, urinary analysis, determinations of blood creatinine

level and alanine and aspartate aminotransferase levels were
taken every threeefour months.

2.1.

Response

In comparison with baseline seizure frequency and severity,

the response to lacosamide treatment was classified as follows: complete cessation (100% seizure control); very good
(decrease in seizure frequency by 50e99%); minimal (21e50%
seizure reduction with minimal change in seizure severity);
unmodified (less than 20% seizure reduction) or worsening
(increase seizure frequency to >50%). We defined responders
those patients who at the last follow-up visit had more than
50% reduction in seizure frequency during a minimum period
of 3 months. Physicians openly reported adverse events
related to the drug administration.

2.2.

Lacosamide retention at 12 months

In a group of 18 patients, the initial lacosamide efficacy,

defined as the number of responsive patients at a minimum
period of three months follow-up (range 3e4 months), was
compared with the retention at 12 months of lacosamide, to
examine the loss of efficacy. Retention at 12 months of lacosamide, a composite measure of efficacy and adverse events
in clinical practice, was defined as the percentage of patients
still taking lacosamide after a 12-month period of follow-up.
Loss of efficacy was defined as the return to the baseline
seizure frequency.

2.3.

Statistics

Wilcoxon rank sum score test was used to compare

nonparametric data (SPSS 11 software version 11.0; SPSS Inc.,
Chicago, IL, USA).

3.

Results

A total of 24 children (10 girls and 14 boys) aged less than four
years were recruited (Table 1). Neuromotor retardation, evaluated before starting lacosamide by BruneteLezine13 or TermaneMerrill14 tests, was observed in 19 (79%) patients. It was
considered to be severe in 8, moderate in 7, and mild in 2.
Median seizure frequency was 38 per month (range 5e56). The
mean age to the first seizure was 10.5 months (range 1e25),
and mean duration of the epileptic history was 17 months
(range 3e35 months). Epilepsy was symptomatic in 14 (58%)
patients and cryptogenic in 10 (42%). In 5 (21%) patients, partial seizures evolved to secondary generalization. The mean
number of antiepileptic drugs (AEDs) tried before starting
lacosamide treatment was three (range 1e7). The median
number of AEDs administered when lacosamide treatment
was started was two (range 1e4) (Table 1).
The mean age of patients at the time of initial lacosamide
treatment was 22 months (range 14e42 months). The mean
duration of treatment was 10.3 months (range 3e26 months).
Mean lacosamide daily dose was 12.5 mg/kg (range 7e15.5 mg/
kg/day).

Please cite this article in press as: Grosso S, et al., Efficacy and safety of lacosamide in infants and young children with refractory
focal epilepsy, European Journal of Paediatric Neurology (2013), http://dx.doi.org/10.1016/j.ejpn.2013.08.006

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 x x x ( 2 0 1 3 ) 1 e5

Table 1 e Clinical findings of patients.

Characteristics
Age (year)
Mean  SD
Range
Sex
M
F
Age at seizure onset (months)
Mean
Range
Age lacosamide initiated (months)
Mean
Range
Seizure types, n (%)
Dyscognitive
Focal versive
Focal motor
Focal somatosensory
Secondary generalization
Etiology classification, n (%)
Symptomatic
Cryptogenic
N of AEDs when LCM initiated, n (%)
1
2
3
4
Concomitant AEDs, n (%)
VPA
TPM
LEV
BDZ
CBZ
OXC
RUF
PHT
Efficacy after 3-month follow-up
Symptomatic
Responders n (%)
Nonresponders n (%)
Cryptogenic
Responders n (%)
Nonresponders n (%)

Value
2.7  1.1
1.9e3.9
14
10
10.5  3.2
1e25
22  5.5
14e42
16 (58%)
5 (21%)
3 (12.5%)
3 (12.5%)
5 (21%)
14 (58%)
10 (42%)
2 (12.5%)
12 (50%)
7 (25%
4 (17%)
10 (42%)
7 (30%)
6 (21%)
5 (21%)
4 (17%)
4 (17%)
3 (12.5%)
1 (4%)

3 (21%)
11 (79%)
6 (60%)
4 (40%)

Legend. M: male; F: female; AED: antiepileptic drug; VPA: valproic acid; TPM: topiramate; LEV: levetiracetam; BDZ: benzodiazepines; CBZ: carbamazepine; OXC: oxcarbazepine; RUF:
rufinamide; PHT: phenytoin.

3.1.

Efficacy

After three month-period of lacosamide add-on therapy, ten

(42%) patients were considered to be responders because they
showed a reduction in their seizure frequency by more than
50%. Specifically, 4 (17%) children became seizure free and 6
(25%) showed a seizure reduction of more than 50%. Seizure
frequency remained unchanged in 9 (37.5%) patients, and
slightly increased in another one (4%) in comparison with the
baseline. Adverse events prompted lacosamide discontinuation in 4 (17%) patients (Table 1). Lacosamide appeared to be
effective in an etiologically wide range of epileptic disorders.
However, patients with a cryptogenic etiology tended to be
more responder than those with symptomatic epilepsy (21%
and 60%, respectively).

In one patient affected by perinatal anoxic-ischemic encephalopathy, lacosamide monotherapy was successful after
the previous AED was tailored-off. In a further two (8%) children, one or more concomitant drugs was reduced without
affecting seizure frequency.

3.2.

Lacosamide retention at 12 months

The group of 18 patients was not different from the remaining

patients in terms of age, sex, epilepsy history, seizure frequency, and number of antiepileptic drugs administered
(Wilcoxon sum rank test). Efficacy retention at 12 months was
observed in 4 out of 18 patients (22%), of whom 2 (8%)
remained seizure free. A loss of efficacy was seen in four (50%)
of the eight initial responders of whom 2 (11%) still seizure
free. With respect to etiology, efficacy loss was less obvious in
patients with cryptogenic focal epilepsy (Fig. 1B).

3.3.

Safety

At least one adverse event was seen in 8 (33%) patients. The

most common adverse events were drowsiness (21%),
nervousness (12.5%), vomiting (8%), instability and difficulty
walking (4%). Five patients showed more than one side effect.
No life threatening side effects were observed during the
study. All side effects were either tolerable or resolved in time
through dosage reduction (drowsiness in two patients and
vomiting in another one) or discontinuation of the drug (in a
child with walking instability). There were no significant laboratory anomalies in liver function, renal function, or
hematology.

4.

Discussion

In randomized controlled trials conducted in adults, lacosamide has shown to be an effective and safe AED in treating
refractory seizures, with 30%e40% of patients achieving a
50% reduction in seizure frequency at doses of 400e600 mg/
day.1,4e7 Since 2010, five studies have been published that
report similar efficacy and tolerability of lacosamide in children and young adults with refractory epilepsy.8e12 Thirty-six
percent of 18 children placed under lacosamide, at a mean
dose of 6.3 mg/kg/day (rage 1.7e10), were found to be
responder (50% in seizure reduction) for a mean period of 8
months.8 In a retrospective study, Guilhoto et al.9 evaluated
the efficacy and safety of lacosamide in a series of adolescent
patients (mean age 14.9 years) and reported that six of them
(37.5%) were classified as responder to therapy. Similar results
(35% of responders) were observed by Heyman et al.10 in
seventeen younger children (mean age 8 years) placed under
lacosamide for a mean follow-up period of 9.1 months. In a
recent, prospective, study including 21 pediatric patients
affected by refractory epilepsy with various seizure types,
lacosamide demonstrated to be an effective AED.11 In particular, 62.5% of patients with localization-related epilepsy and
25% of those having generalized epilepsy were defined as responders at the last visit. Of interest, two patients with
Lennox-Gastaut syndrome showed greater than 90% seizure
reduction. However, none of these very refractory patients

Please cite this article in press as: Grosso S, et al., Efficacy and safety of lacosamide in infants and young children with refractory
focal epilepsy, European Journal of Paediatric Neurology (2013), http://dx.doi.org/10.1016/j.ejpn.2013.08.006

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 x x x ( 2 0 1 3 ) 1 e5

Fig. 1 e Study design (A). Retention rate after 12 months of follow-up (B).
remained seizure free.11 In a prospective, open-label, multicenter study including 130 patients aged less than 16 years
with a variety of etiologies including refractory partial epilepsies and symptomatic, generalized epilepsy syndromes.
The drug was dosed at a mean of 6.8 mg/kg/day. After 3
months of lacosamide add-on therapy, 62.3% of patients
achieved a 50% reduction in seizure frequency.12 Lacosamide efficacy and safety were also evaluated in two series
including both children and adults.15,16 In particular, a comparison study of lacosamide efficacy and safety in pediatric
and adult patients with uncontrolled focal and generalized
epilepsy, showed similar response rates (47% of patients with
>50% of seizure reduction) after three months of therapy.15
Novy et al.,16 recently reported that forty-five percent of the
376 people included were still taking LCM at last follow-up.
Eighteen percent reported a period of improvement in terms
of significant seizure reduction or seizure freedom of at least
six months duration whilst on LCM, of whom four people were
seizure free for at least one year. The authors concluded that
long-term efficacy appeared similar to zonisamide and pregabalin when compared to historical controls.
Lacosamide has been approved by the licensing authorities
in the European Union and in the United States as an add-on
treatment of partial seizures in patients 16 years of age or
older. Although, a number of infants and young children were
treated with lacosamide and reported in other studies,8e12,15,16
systematic data are not yet available. In this context, we
believe this study is the first evaluation of the efficacy and
safety of lacosamide in patients aged less than four years
affected by focal seizures. The design of the present study

reflects daily clinical practice. Although this introduces some

methodological weaknesses, it provides a more natural and
realistic view of the use of lacosamide in infants and young
children. All patients we studied were refractory to first line
drugs. The main aim of add-on treatment in these patients
was to improve their quality of life by decreasing seizure frequency as much as possible and by limiting adverse events,
rather than to make them seizure free.17
Forty-two percent of patients had a more than a 50% reduction in seizure frequency after a three-month period of therapy.
The percentage of responders was slightly higher than that reported in older children with focal epilepsy in previous studies8e10 and lower than that observed in studies including patients
with both focal and generalized uncontrolled seizures.12,15
We compared the efficacy in 18 patients observed after a
mean of three months of follow-up with retention after 12
months of lacosamide, with regard to loss of efficacy. According to Krakow et al.18 the retention rate is an important
measure of the efficacy and adverse events of the drug
because it is a reliable indicator over time. Twenty-two
percent of our patients were still responsive to lacosamide
after a minimum of 12 months of follow-up. Loss of efficacy
was observed in 50% of the initial responders. Although our
series is small, it seems to suggest a sustained lacosamide
efficacy over time in patients with focal epilepsy. Since
comedication was not (or only slightly) altered before seizure
relapse, we suggest that the loss of efficacy with lacosamide
was likely related to the development of tolerance to the drug.
However, the percentage of responders after 12 month-period
of lacosamide therapy, was lower than that observed in older

Please cite this article in press as: Grosso S, et al., Efficacy and safety of lacosamide in infants and young children with refractory
focal epilepsy, European Journal of Paediatric Neurology (2013), http://dx.doi.org/10.1016/j.ejpn.2013.08.006

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 x x x ( 2 0 1 3 ) 1 e5

children and adults in previous studies.15 In particular, Novy

et al.,16 found that lacosamide retention was 62% at one year,
45% at two years and 35% at three years. The lower retention
rate we observed may be because of insufficient experience
with lacosamide in young children, resulting in a very strong
selection bias for infants with very difficult-to-treat epilepsies
This bias is further enhanced in our data which are constituted by pooled data of the first experiences with lacosamide
coming from 4 pediatric neurology departments. Although the
patients we investigated did not have long histories of epilepsy, up to 7 AEDs had been used before lacosamide therapy
was started. Moreover, the majority of children were mentally
retarded, with epilepsy being mainly related to brain injuries
or brain malformations.
Lacosamide has been reported to be a well-tolerated,
relatively safe drug.19 Adverse reactions, such as dizziness,
headache, diplopia, nausea and somnolence have an incidence varying from 29% to 61%.15,16 Similar adverse effect data
have been observed in pediatric case reports and case series,
with dizziness and nausea being the most commonly reported.9,10,12,19 In contrast, drowsiness was the most common
adverse event we observed in our study (21% of patients),
being our data congruent with those reported by Cavatha
et al.,.8 Most adverse effects seen with lacosamide in adults
are dose-related and are reversible upon discontinuation or
dose reduction.19 In children, lacosamide doses up to 20 mg/
kg/day may be well-tolerated.19,20 The mean dose of lacosamide in our study was 12.5 mg/kg/day, with an incidence of
adverse events (33%), which is similar to that reported in
previous studies.8,9,11 Lacosamide was discontinued in only
one patient (4%) because of severe instability. Dosage reduction was necessary in another three cases with gradual
disappearance of side effects.
In conclusion, although caution may still be necessary when
lacosamide is used in infants and children younger than 4 years,
our observations suggest that lacosamide is effective and safe
and represents a possible option in treating uncontrolled focal
epilepsy in this population. Of course, further clinical trials are
needed to validate our data. In fact, the size of our population
was not so large to enable us to draw definite conclusions.

4.

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6.

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Please cite this article in press as: Grosso S, et al., Efficacy and safety of lacosamide in infants and young children with refractory
focal epilepsy, European Journal of Paediatric Neurology (2013), http://dx.doi.org/10.1016/j.ejpn.2013.08.006