Seizure: European Journal of Epilepsy
Volume 19, Issue 3 , Pages 185-189, April 2010

Levetiracetam in the treatment of neonatal seizures: A pilot study

  • Alexandra Fürwentsches

      Affiliations

    • Department of Pediatric Neurology, University Children's Hospital, Heidelberg, Germany
    • Corresponding Author InformationCorresponding author at: Kinderheilkunde V, Pädiatrische Neurologie, Zentrum für Kinder- und Jugendmedizin, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany. Tel.: +49 06221 56 38045; fax: +49 06221 56 5744.
    • ,
  • Cornelia Bussmann

      Affiliations

    • Department of Pediatric Neurology, University Children's Hospital, Heidelberg, Germany
    • ,
  • Georgia Ramantani

      Affiliations

    • Department of Pediatric Neurology, University Children's Hospital, Heidelberg, Germany
    • Department of Pediatric Neurology, University Children's Hospital, Dresden, Germany
    • ,
  • Friedrich Ebinger

      Affiliations

    • Department of Pediatric Neurology, University Children's Hospital, Heidelberg, Germany
    • ,
  • Heike Philippi

      Affiliations

    • Department of Pediatric Neurology, University Children's Hospital, Heidelberg, Germany
    • ,
  • Johannes Pöschl

      Affiliations

    • Department of Neonatology, University Children's Hospital, Heidelberg, Germany
    • ,
  • Susanne Schubert

      Affiliations

    • Department of Pediatric Neurology, University Children's Hospital, Heidelberg, Germany
    • ,
  • Dietz Rating

      Affiliations

    • Department of Pediatric Neurology, University Children's Hospital, Heidelberg, Germany
    • ,
  • Thomas Bast

      Affiliations

    • Department of Pediatric Neurology, University Children's Hospital, Heidelberg, Germany

Received 1 March 2009; received in revised form 5 January 2010; accepted 7 January 2010. published online 05 February 2010.

Article Outline

Abstract 

Purpose

At present, neonatal seizures are usually treated with Phenobarbital (PB) despite the limited efficacy 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>2000g, 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 10mg/(kgday) 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.

Keywords: Levetiracetam, Neonatal seizures, Epilepsy

 

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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 post-ischemic 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 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.6, 7, 8, 9 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 significant 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-1α).18 Retrospective series in children including patients younger than 4 years showed comparable responder rates and side effect profiles of add-on LEV treatment.19, 20, 21 Prospective studies with small patient groups in infants and very 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 profile, 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.

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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 2000g 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 Keppra® oral solution was not available at the beginning of the study, LEV medication was obtained from the local pharmacy. We used Keppra® 250mg tablets prepared in small amounts of 5–30mg for oral application by a registered pharmacist. LEV was administered orally at a dose of 10mg/(kgday) initially. This dose was allowed to be increased by 10mg/(kgday) up to 50mg/(kgday). Additional therapy with single doses of PB was allowed only during the first 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 first 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.

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3. Results 

Six consecutive newborns fulfilling the study criteria were included. Clinical data are summarized in Table 1. LEV was the first 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 10mg/kg PB during days 1–3. Patient 5 had an additional dose of PB on day 4 shortly after the 72h 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 (10–50mg/(kgday)) (Table 2) became seizure free within 6 days (Fig. 2).

Table 1. Clinical data of six neonates treated with levetiracetam.
PatientGenderGestational age (w+d)Clinical conditionsNeurologic findingsSeizure semiology major symptoms
1Male37+1Hypogenesis of cerebellar vermis, Cerebral atrophyMuscular hypertonia, hyperexcitabilityTonic and apnea
2Male38+5AsphyxiaMuscular hypotoniaOral automatisms, staring and apnea
3Female41+3Sinusoidal vein thrombosis, post-hemorrhagic hydrocephalusHemiparesis (right side)Tonic and apnea
4Male31+3Polycystic kidneys, pulmonary hypoplasia, arterial hypertonusMuscular hypotoniaClonic and apnea
5Female41+1NoneNormalTonic and apnea
6Female41+3Agenesis of corpus callosumMuscular hypotoniaOral automatisms, staring and apnea
Table 2. Efficacy of levetiracetam and treatment strategies.
PatientLEV timeLEV doseAge at seizure relapseAction takenAge at LEV treatment cessationPsychomotor development
16 d35––5 mSevere developmental delay
22 d221 mLEV 34 mg/(kgday)3 mNormal
3Immediately10a+SLTOngoingMild developmental delay
46 d356 mSwitch to SLT6 mSevere developmental delay
56 d304 m+CBZ5 mNormal
65 d502 m+Various AEDs7 mSevere developmental delay

LEV time=duration of LEV treatment when seizure free; LEV dose=LEV dose when seizure free in mg/(kgday); D=day(s); M=month(s).

aPatient 3 had worsening of EEG without seizures at 3 months.

  • View full-size image.
  • 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.

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 34mg/(kgday). After 3 months, five 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 34mg/(kgday). 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 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 drug-resistant epilepsy, which started at 2 months of age. Various AEDs were tried without success, and LEV was stopped after 7 months.

In summary, seizures recurred after 3 months in two of five patients under maintenance LEV monotherapy (patients 2 and 5). After a follow-up of 8 months, five 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.

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.

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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 first 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 first drug. A delay in efficacy 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 10–50mg/(kgday).

Epilepsy remained controlled by LEV monotherapy for at least 3 months in five 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 30–60mg/(kgday); 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 significantly higher in infants.10 Doses up to more than 100mg/(kgday) without side effects have been reported in very young children.24, 22 It remains unclear, whether our patients may have had additional benefit 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 first week of treatment. It is well recognised that clinical diagnosis of neonatal seizures is unreliable26, 27, 28 and limited as a method useful for clinical trials.29 However, even amplitude integrated EEG (aEEG) is not reliable enough to definitely 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 unspecific 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 confident about presence of neonatal seizures and efficacy of treatment.

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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 efficacy 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.

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Conflicts of interest 

The study was supported by UCB Pharma GmbH Monheim, Germany. None of the authors has any conflict of interest to disclose.

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Acknowledgements 

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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PII: S1059-1311(10)00004-X

doi:10.1016/j.seizure.2010.01.003

Seizure: European Journal of Epilepsy
Volume 19, Issue 3 , Pages 185-189, April 2010

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