Seizure 19 (2010) 185189

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Seizure
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Short communication

Levetiracetam in the treatment of neonatal seizures: A pilot study

Alexandra Furwentsches a,*, Cornelia Bussmann a, Georgia Ramantani a,b, Friedrich Ebinger a,
Heike Philippi a, Johannes Poschl c, Susanne Schubert a, Dietz Rating a, Thomas Bast a
a

Department of Pediatric Neurology, University Childrens Hospital, Heidelberg, Germany

Department of Pediatric Neurology, University Childrens Hospital, Dresden, Germany
c
Department of Neonatology, University Childrens Hospital, Heidelberg, Germany
b

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 1 March 2009
Received in revised form 5 January 2010
Accepted 7 January 2010

Purpose: At present, neonatal seizures are usually treated with Phenobarbital (PB) despite the limited
efcacy and the potential risk this treatment holds for the developing brain. We report here a prospective
pilot feasibility study on the use of Levetiracetam as monotherapy in the treatment of neonatal seizures.
Methods: Six newborns (body weight > 2000 g, gestational age > 30 weeks) presenting with neonatal
seizures were enrolled. Patients whose seizures were caused by electrolyte disturbances or
hypoglycemia, or whose seizures did respond to pyridoxine were excluded. Patients previously treated
with other antiepileptic drugs (AEDs), with the exception of single PB doses before and during titration,
were excluded. LEV was administered orally, increasing the dose by 10 mg/(kg day) over 3 days.
Endpoint was the need of any additional AEDs (or PB) after day 3, or 3 months of LEV treatment. A
decision regarding further treatment was made on an individual basis and follow-up was documented
up to 8 months of age.
Results: No severe adverse effects were observed. Mild sedation was reported in one infant. All six
patients treated with oral LEV became seizure free within 6 days. Five patients remained seizure free
after 3 months with ongoing LEV monotherapy. One infant developed pharmacoresistent epilepsy.
Seizures relapsed later in the clinical course of two more patients, one of whom was no longer under LEV
therapy.
Discussion: Results from our small patient group indicate that LEV may be an alternative therapeutic
option in neonatal seizures.
2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Keywords:
Levetiracetam
Neonatal seizures
Epilepsy

1. Introduction
Neonatal seizures occur with a frequency of approximately 2.6
per 1000 newborns.1 With the exceptions of benign familial and
non-familial neonatal seizures, they are usually caused by severe
cerebral pathology. Typical etiologies are post-hypoxic or postischemic encephalopathy, intracerebral hemorrhage, cerebral
infection, inborn errors of metabolism or malformations of cortical
development. Hypoglycemia, hypomagnesaemia, or hypocalcaemia can also cause symptomatic seizures in neonates. Pyridoxine
and pyridoxal phosphate dependency are rare, but treatable
etiologies. At present, phenobarbital (PB) is the treatment of choice
in neonatal seizures.2 However, PB has been found to increase
neuronal apoptosis in newborn rats.3 In addition, the known risk of

* Corresponding author at: Kinderheilkunde V, Padiatrische Neurologie, Zentrum

fur Kinder- und Jugendmedizin, Im Neuenheimer Feld 430, 69120 Heidelberg,
Germany. Tel.: +49 06221 56 38045; fax: +49 06221 56 5744.
E-mail address: a.fuerwentsches@med.uni-heidelberg.de (A. Furwentsches).

cognitive side effects of PB in infants and toddlers should be

considered.4
Levetiracetam (LEV) is an effective and well-tolerated antiepileptic drug for adjunctive treatment of partial onset seizures in
children aged 4 years.5 The mechanisms of action differ from
classical antiepileptic drugs.69 LEV is rapidly and almost
completely absorbed after oral administration,10 and its major
route of elimination is through renal loss. LEV does not appear to
interact with other drugs in a meaningful way.11 There is no report
of a signicant risk for severe, life threatening side effects. The
most frequently observed adverse effects were somnolence and
behavioral problems.5,12,13 In contrast to most other established
antiepileptic drugs3 LEV has not been found to increase apoptosis
in animal models.14 LEV prevents neurdegeneration after hypoxia/
ischemia in rodent models15 or epilepsy,16,17 and it does not
interfere with neuroprotective up-regulation of hypoxia inducible
transcription factor 1 (HIF-1a).18 Retrospective series in children
including patients younger than 4 years showed comparable
responder rates and side effect proles of add-on LEV treatment.19
21
Prospective studies with small patient groups in infants and very

1059-1311/$ see front matter 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.seizure.2010.01.003

A. Furwentsches et al. / Seizure 19 (2010) 185189

186

young children revealed similar results.22,23 To date, three patients

with neonatal seizures who were successfully treated with LEV in
the neonatal period have been reported in detail.24,25 One patient
received LEV intravenously.24
In view of the favorable pharmacologic and clinical prole, we
initiated a prospective, open, single-center, proof-of-principle
study to examine feasibility and tolerability of oral LEV treatment
and to evaluate whether it could serve as a therapeutic alternative
to PB in newborn seizures.
2. Methods
The study was approved by the local ethic committee of the
University of Heidelberg, and parents were asked for informed
consent. In 2005, consecutive mature or premature newborns,
with a gestational age of at least 30 weeks and a birth weight of
more than 2000 g with neonatal seizures not responding to
pyridoxine, were enrolled. Patients were not included when
seizures had been caused by hypoglycemia, hypomagnesaemia, or
hypocalcaemia. Patients were not eligible for the study, if they had
already received more than two single doses of PB or medication
with any other antiepileptic drug.
Because Keppra1 oral solution was not available at the
beginning of the study, LEV medication was obtained from the
local pharmacy. We used Keppra1 250 mg tablets prepared in
small amounts of 530 mg for oral application by a registered
pharmacist. LEV was administered orally at a dose of 10 mg/
(kg day) initially. This dose was allowed to be increased by 10 mg/
(kg day) up to 50 mg/(kg day). Additional therapy with single
doses of PB was allowed only during the rst 3 days of LEV titration.
Patients were disclosed from the study if there was the need for
any additional antiepileptic drugs or PB after day 3. The study
ended regularly at 3 months of age. Treating neuropediatricians
were free to continue LEV medication and a last follow-up was
achieved at the age of 8 months.
The patients were followed regularly by a neuropediatrician
with daily visits in the rst 4 days followed by visits at days 7, 15,
30, and 90 after start of LEV treatment. Patients were clinically
examined, and seizure frequency, antiepileptic medication, and

adverse events were documented at every visit. After 3 months, a

decision regarding further treatment was considered on an
individual basis. A visit at day 180 was optional.
Neonatal seizures were diagnosed clinically. No continuous EEG
monitoring was performed at time of diagnosis and enrolment;
however, intermittent EEG had to show clear pathology with either
seizures (clinical/subclinical) or abnormal background activity.
EEG was obligatorily performed at days 1, 30, and 90. Laboratory
tests including complete blood count and renal function parameters were obligatory on days 1, 30, 90, and optional at day 180.
A formal statistical evaluation was not performed due to the
small number of patients.
3. Results
Six consecutive newborns fullling the study criteria were
included. Clinical data are summarized in Table 1. LEV was the rst
AED administered in patients 1 and 2. The other patients had already
received single doses of PB not leading to seizure freedom (Fig. 1). In
line with the protocol, 4 patients received single doses of 10 mg/kg
PB during days 13. Patient 5 had an additional dose of PB on day 4
shortly after the 72 h interval. When this protocol deviation was
realized, LEV treatment had already been continued and it was not
stopped. All 6 patients treated with oral LEV (1050 mg/(kg day))
(Table 2) became seizure free within 6 days (Fig. 2).
Four of the six patients remained seizure free during the study
period of 3 months. In patient 2, there was a single seizure after 4
weeks, after which the LEV dose was increased to 34 mg/(kg day).
After 3 months, ve out of six patients were seizure free under
monotherapy with LEV.
Patient 1 stopped seizing on day 6 and remained seizure free after
stopping LEV monotherapy at 5 months of age. Patient 2 had a single
seizure at the age of 4 weeks, resulting in a dose increase of LEV to
34 mg/(kg day). Treatment was stopped at age 3 months, and the
child has remained seizure free. Patient 3 had marked EEG
worsening without clinical seizures at 3 months of age. The treating
physician decided to add sulthiame (SLT) to the anticonvulsive
therapy, and the child has remained seizure free. Patient 4 stopped
receiving LEV at 6 months of age. He relapsed after 1 week, and, after

Table 1
Clinical data of six neonates treated with levetiracetam.
Patient

Gender

Gestational
age (w + d)

Clinical conditions

Neurologic ndings

Seizure semiology major symptoms

Male

37 + 1

Male
Female

38 + 5
41 + 3

Muscular hypertonia,
hyperexcitability
Muscular hypotonia
Hemiparesis (right side)

Tonic and apnea

2
3
4

Male

31 + 3

Muscular hypotonia

Clonic and apnea

5
6

Female
Female

41 + 1
41 + 3

Hypogenesis of cerebellar vermis,

Cerebral atrophy
Asphyxia
Sinusoidal vein thrombosis,
post-hemorrhagic hydrocephalus
Polycystic kidneys, pulmonary
hypoplasia, arterial hypertonus
None
Agenesis of corpus callosum

Normal
Muscular hypotonia

Tonic and apnea

Oral automatisms, staring and apnea

Oral automatisms, staring and apnea

Tonic and apnea

Table 2
Efcacy of levetiracetam and treatment strategies.
Patient

LEV time

LEV dose

Age at seizure relapse

Action taken

Age at LEV treatment cessation

Psychomotor development

1
2
3
4
5
6

6d
2d
Immediately
6d
6d
5d

35
22
10
35
30
50

1m

LEV 34 mg/(kg day)

+SLT
Switch to SLT
+CBZ
+Various AEDs

5m
3m
Ongoing
6m
5m
7m

Severe developmental delay

Normal
Mild developmental delay
Severe developmental delay
Normal
Severe developmental delay

6m
4m
2m

LEV time = duration of LEV treatment when seizure free; LEV dose = LEV dose when seizure free in mg/(kg day); D = day(s); M = month(s).
a
Patient 3 had worsening of EEG without seizures at 3 months.

A. Furwentsches et al. / Seizure 19 (2010) 185189

Fig. 1. Neonatal period of six patients treated with Levetiracetam.

discussion with the parents, SLT monotherapy was initiated leading

to cessation of seizures. Patient 5 relapsed at 4 months of age.
Carbamazepine was added to the treatment regimen, and the
patient was tapered off of LEV. Patient 6 currently suffers from drugresistant epilepsy, which started at 2 months of age. Various AEDs
were tried without success, and LEV was stopped after 7 months.

187

= seizure, LEV = LEV treatment, PB = Phenobarbital.

In summary, seizures recurred after 3 months in two of ve

patients under maintenance LEV monotherapy (patients 2 and 5).
After a follow-up of 8 months, ve out of the six infants were
seizure free, two without any medication and one with LEV in
combination therapy. Other antiepileptic drugs lead to seizure
freedom in the two remaining patients.

Fig. 2. Treatment with LEV and follow-up of six infants treated with Levetiracetam. LEV = Levetiracetam, PB = Phenobarbital, SLT = Sulthiame, CBZ = Carbamazepine,
AEDs = antiepileptic drugs, = seizures.

188

A. Furwentsches et al. / Seizure 19 (2010) 185189

No clear adverse events were observed during the study. Mild

sedation was reported in one neonate during the titration of LEV;
however, the patient was concomitantly treated with Phenobarbital at this time.
4. Discussion
Levetiracetam therapy was effective in controlling neonatal
seizures in six patients. During a 3-month study period, only one
child needed additional antiepileptic therapy. LEV was tolerated
excellently in our small study group, with only one report of
somnolence during titration.
Because of limited experience with LEV in newborns we chose a
conservative endpoint for the study, allowing single doses of PB
only during the rst 3 days of LEV treatment. By mistake, one of the
patients received an additional PB dose on day 4. The treating
physician was not aware, that the time point of application was out
of the 72-h interval. When this protocol deviation was realized,
LEV administration had already been continued. We decided to
continue the study in this infant after discussion and in agreement
with the parents.
The fact, that the patients stopped seizing under LEV cannot
easily be attributed to the LEV treatment. In the absence of a
control group, spontaneous recovery as well as the effect of
phenobarbital cannot be ruled out. It is important to point out, that
LEV was initiated only when further seizures occurred despite
treatment with PB, except in patient 1, who received LEV as the
rst drug. A delay in efcacy of initial PB administration, as well as
synergistic effects may still be possible causes of seizure control.
However, when this feasibility study was planned, we expected a
drop-out rate of more than 50% because of seizure relapses.
Surprisingly, all 6 newborns receiving LEV became seizure free
within a few days at LEV doses of 1050 mg/(kg day).
Epilepsy remained controlled by LEV monotherapy for at least 3
months in ve infants. Only one child relapsed after 2 months and
did not respond to an increase of LEV. This child suffers from
pharmacoresistent epilepsy not responding to various other
antiepileptic drugs.
After the study period of 3 months, a variety of treatment
strategies were chosen by different pediatricians. LEV was
successfully stopped in two seizure free infants. In another infant,
sulthiame was added because of marked EEG worsening and
continued in combination with LEV for 8 months. All three children
were doing well at the last follow-up point after 8 months. Seizures
relapsed after LEV termination in another child. Instead of
reestablishing LEV therapy, a decision involving the parents and
the treating neuropediatrician (not an investigator) was made to
switch to sulthiame monotherapy. This treatment has been
successful.
Patient 5 experienced seizure relapse at 5 months of age and
treatment was changed to carbamazepine.
The normal dosage of LEV in children and adults is 3060 mg/
(kg day); however, there is lack of data on pharmacokinetics and
pharmacodynamics in the neonatal age group. Furthermore,
resorption of orally administered LEV can be postulated to be
limited in sick newborn infants. In view of the lack of this data, we
decided on relatively low LEV doses, which were not further
increased. Clearance of LEV is signicantly higher in infants.10
Doses up to more than 100 mg/(kg day) without side effects have
been reported in very young children.24,22 It remains unclear,
whether our patients may have had additional benet from further
increase in LEV dose or not.
In contrast to recent reports on LEV therapy in neonatal
seizures,24,25 our patients received LEV in monotherapy after
titration period. Initial treatment with PB may have contributed to
a favorable outcome.

The most important shortcoming of our study is the lack of

continuous EEG monitoring before and during the rst week of
treatment. It is well recognised that clinical diagnosis of neonatal
seizures is unreliable2628 and limited as a method useful for
clinical trials.29 However, even amplitude integrated EEG (aEEG) is
not reliable enough to denitely diagnose seizures in the setting of
a clinical trial. Furthermore, electro-clinical dissociation of seizures
increases after AED treatment30 emphasizing the need for ongoing
EEG monitoring during seizure treatment in babies. These
limitations especially apply to the diagnosis of subtle seizures
with apnoea, which is a more or less unspecic clinical feature with
other possible causes in newborns. However, study patients
presenting with apnea had other, discrete symptoms of epileptic
seizures such as mild myoclonia, chewing, and arrest in behavior;
additionally intermittent EEGs were pathological in the sense of
abnomal background activity or ictal epileptiform activity. With
the limited setting of this study we were not able to document
seizures by ictal EEG recordings. In addition, evaluation of seizure
response was based only on clinical observations. Subclinical,
electroencephalographic seizures cannot be ruled out. Freedom
from clinical seizures was accompanied by improving general
condition in all infants. Treating neonatologists and neuropediatricians were condent about presence of neonatal seizures and
efcacy of treatment.
5. Conclusions
Our observations show that the oral administration of
levetiracetam in newborns is feasible. We observed no evident
harmful effects. Although all six patients became seizure free and
tolerated LEV well, the small number of treated newborns, the
heterogeneity of the group and the lack of EEG monitoring do not
allow a general judgment on efcacy and potential adverse effects
of this medication. However, these results could be the basis for a
controlled randomized study with concomitant continuous EEG
monitoring to further assess LEV as an optional treatment for
neonatal seizures.
Conicts of interest
The study was supported by UCB Pharma GmbH Monheim,
Germany. None of the authors has any conict of interest to
disclose.
Acknowledgements
We conrm that we have read the Journals position on issues
involved in ethical publication and afrm that this report is
consistent with those guidelines.
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