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 4 ) 1 e7

Official Journal of the European Paediatric Neurology Society

Original article

Effect of levetiracetam on behavioral problems in pervasive developmental disorder children with epilepsy Hideaki Kanemura a,*, Fumikazu Sano a, Tetsuo Ohyama a, Kanji Sugita a, Masao Aihara b a b

Department of Paediatrics, Faculty of Medicine, University of Yamanashi, Japan Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Japan

article info

abstract

Article history:

Aims: We investigated the relationship between behavioral problems, location of electro-

Received 5 October 2013

encephalogram (EEG) paroxysmal abnormalities (PA), and treatment with levetiracetam in

Received in revised form

children with pervasive developmental disorder (PDD) and epilepsy.

4 March 2014

Methods: Twelve PDD children with epilepsy were included in the study. All patients had

Accepted 15 March 2014

EEG PA (frontal spikes, 8; rolandic, 3; generalized, 1). After a 3-month baseline period, patients were given levetiracetam with an initial dose of 10 mg/kg/day for the first week,

Keywords:

followed by increments of 5 mg/kg/day every week. Levetiracetam dosage was then

Levetiracetam

adjusted up to a maximum of 60 mg/kg/day. EEG recordings were performed every 3

Pervasive developmental disorder

months, focusing on PA frequency. We counted the frequency of seizures and EEG PA, and

(PDD)

scored instances of panic/aggressive behaviors.

Refractory epilepsy

Results: Eight (66.7%) of the 12 patients were considered to be responders to clinical seizures

EEG paroxysmal abnormalities

and EEG findings (50% reduction in both seizures and PA frequency). Six (75%) of these

Behavior

eight patients were considered to be responders for behavioral problems (50% reduction

Frontal

in panic/aggressive behavior). These six patients had frontal EEG paroxysms, whereas the remaining two patients without behavioral responses had rolandic EEG paroxysms. Patients with frontal PA showed a significantly higher correlation between EEG/clinical seizures and behavioral improvements (p < 0.05). Conclusion: The present data indicated the usefulness of LEV in reducing behavioral problems related to the reduction of seizures and frontal spikes in PDD for some but not all of the patients. Thus, levetiracetam represents an important addition to treatment for PDD children with epilepsy presenting with frontal EEG paroxysms. ª 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

* Corresponding author. Department of Paediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan. Tel.: þ81 55 273 9606; fax: þ81 55 273 6745. E-mail address: [email protected] (H. Kanemura). http://dx.doi.org/10.1016/j.ejpn.2014.03.007 1090-3798/ª 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Kanemura H, et al., Effect of levetiracetam on behavioral problems in pervasive developmental disorder children with epilepsy, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/ j.ejpn.2014.03.007

2

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 4 ) 1 e7

Introduction

Levetiracetam (LEV), one of several new antiepileptic drugs (AEDs), has become widely used in the treatment of various types of epilepsy in adults and children.1 LEV is an effective adjunctive treatment for medication-resistant partial seizures with or without secondary generalization.2 Studies published on the use of LEV in epileptic children have shown excellent pharmacokinetic and tolerability profiles, with few deleterious effects on cognitive function and no known pharmacokinetic interactions.3 Furthermore, a recent study showed a good response in refractory childhood epilepsy with a broad spectrum as well as good safety profiles.2 Pervasive developmental disorder (PDD) is one of the most common neuropsychiatric disorders in children with epilepsy.4 The high occurrence of epilepsy in children with PDD is a clear indication that PDD may have a neurobiological basis. Epilepsy is more common in people with PDD than in the general population,5 and PDD is more common in people with epilepsy than in those without.6 Thus, there appears to be a strong association between PDD and seizure disorders, which warrants further investigation.7 For partial epilepsies, the relationship between interictal epileptiform discharges on electroencephalogram (EEG) and behavioral abnormalities is controversial, but some interictal epileptiform activities have subtle clinical manifestations. The relationship between epilepsy and cognitive/behavioral disturbances is influenced by several factors, including etiology, age at onset, type of epilepsy, and treatment.8 On the other hand, in patients with PDD, EEG paroxysmal abnormalities (PA) are frequently recorded. A recent study has reported that the majority of PA at the time of epilepsy onset appeared in the frontal areas of the brain.9 Frontal lobe dysfunction is associated with seizure onset in 58% of cases based on EEG findings.10 Accordingly, the presence of frontal paroxysms may indicate a higher risk of epilepsy and cognitive/behavioral impairments in PDD.11 Recently, reports have indicated that LEV may cause neuropsychiatric manifestations such as aggressiveness. Therefore, it has been recommended that special consideration should be given when using LEV in PDD patients. Nevertheless, LEV reduces the incidence of seizures1 and interictal epileptiform discharges12 in adult patients with localization-related epilepsy. A recent study showed that treatment with LEV reduced interictal epileptiform discharges in children with attention deficit hyperactivity disorder (ADHD).13 Another recent study showed decreased hyperactivity and impulsivity after LEV administration in children with epilepsy presenting with secondary bilateral synchrony on EEG.14 However, little is known about the safety and efficacy of LEV for PDD children with epilepsy. The present study aimed to determine the relationship between behavioral problems, location of PA, and treatment with LEV in PDD children with epilepsy.

between May 1, 2011 and April 30, 2012, and selected according to the criteria as below. Twelve (7 males, 5 females) PDD patients with refractory epilepsy, aged between 8.6 years and 14.2 years (with a mean age of 10.3 years) at enrollment, were included in the present study. The diagnosis of PDD was made according to DSM IV criteria (299.00 Autistic Disorder), such as qualitative impairment in social interaction, qualitative impairment in communication, and restrictive, repetitive, and stereotypic pattern of behavior, interests, and activities.15 The following criteria had to be fulfilled: 1) seizures refractory to at least two first-line AEDs (appropriate AED for each seizure type or epileptic syndrome, with therapeutic concentrations of AEDs); 2) at least four seizures a month during the 3 months before LEV administration; 3) neuropsychological impairments such as impulsivity and aggressiveness, as referred to in the DSM-IV15; and 4) at least 12 months of follow-up. Age at onset of epilepsy ranged from 5.9 years to 11.8 years (mean, 7.2 years). The mean duration of epilepsy history was 3.1 years (range, 1.9e4.3 years). All patients were affected by localizationrelated epilepsy. In 11 patients, partial seizures evolved to secondary generalization. Participants in the present study were taking a stable regimen of two or three concomitant AEDs, such as carbamazepine, valproate sodium, zonisamide, phenytoin, or clobazam. The mean number of AEDs taken before introducing LEV treatment was 4.3 (range, 2-6 AEDs). The study was carried out in accordance with the Declaration of Helsinki. Informed consent was obtained from the parents of each patient following a full explanation of the procedures to be undertaken.

2.2.

Strategy for LEV administration

2.

Methods

After a 3-month baseline period, patients with epilepsy were given LEV at an initial dose of 10 mg/kg/day twice daily, followed by increments of 5 mg/kg/day every week. The dosage was increased to 15 mg/kg/day after 1 week, and then subsequently increased to 20 mg/kg/day after another week. During this period, LEV dosage could be increased up to 60 mg/kg/day (or 3000 mg/day), according to the clinician’s judgment. The goal of treatment in this protocol was to obtain a seizure response (50% seizure reduction) without adverse effects. The LEV dose was not increased in cases of complete seizure control and could be decreased in cases of adverse effects. The final dose regimen that was reached was maintained unchanged during the first 3 months of the evaluation period and could be adjusted for the following 3 months in cases of inadequate seizure control or adverse effects. The comedication remained unchanged from baseline to the end of the 12-month evaluation period. Before entering the trial, children were tested for intellectual achievement, using a variety of well-established methods such as the Wechsler Intelligence Scale for Children, third edition (WISC-III). Complete blood count, platelet count, liver enzyme levels, and blood concentrations of AEDs prior to LEV administration were recorded at baseline for all children.

2.1.

Participants

2.3.

The patients were recruited from among epilepsy with PDD outpatients of authors’ hospital and five related hospitals

EEG analyses

EEGs were performed using a 12- or 16-channel machine every 3 months. The duration of tracings was at least 20 min. For

Please cite this article in press as: Kanemura H, et al., Effect of levetiracetam on behavioral problems in pervasive developmental disorder children with epilepsy, European Journal of Paediatric Neurology (2014), http://dx.doi.org/10.1016/ j.ejpn.2014.03.007

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 4 ) 1 e7

3

inclusion, it was necessary that at least one collection of EEG be obtained without drug induction, showing a clear sequence of awakeedrowsyesleepearousaleawake states. For this reason, parents were instructed to keep their children awake the night before the visit. Intermittent photic activation was done routinely, and hyperventilation was used when age permitted. EEG studies were coded by number and read independently by two pediatric epileptologists or neurologists blinded to the identity of the patients. Agreement regarding the presence of PA was required for inclusion of the patient in the study. Recordings included sleep in all of patients. Analyses of PA frequency are outlined briefly as follows. EEG recordings and clinical evaluations were performed every 3 months, focusing on PA. PA, including focal spikes (frontal spikes, mid-temporal spikes, rolandic or parietal spikes, and occipital spikes), multifocal spikes, and generalized spike- and wave complexes were separately coded. The occurrence of PA on EEG with bipolar montage was scored, and the relationship between the score and the response to LEV treatment was evaluated. The 3-month period before starting treatment was used as the baseline period for PA frequency. PA frequency on EEG was defined as the mean PA frequency per minute. PA frequency was compared within the same sleep stage for each patient. Twelve months later, the response to the dose increment for maintenance was assessed. In comparison with the baseline PA frequency, the EEG response to LEV treatment was classified as follows: complete disappearance; response (50% reduction in PA frequency); no response (75% reduction) in PA frequency. The PA locations of these three patients were frontal spikes in one and rolandic spikes in two. Six of these eight (75.0%) patients with EEG responders were considered as responders for behavioral problems (50% reduction in panic/aggressive behavior and increase in GAF >2 levels). These six patients had frontal EEG paroxysms, whereas remaining two patients

Clinical seizures/behavioral analyses

Analyses of seizure frequency and behavior data are outlined briefly as follows. Spike frequency and behavioral problems from scoring with the frequency of panic/aggressive behavior episodes obtained from parents were estimated 3 months before starting treatment with LEV as a baseline. The number of seizures was recorded by parents and caregivers both at home and at the child’s day nursery, kindergarten, or school. Seizure frequency, type, and duration, as well as adverse effects, were recorded in an epilepsy diary completed by parents and/or caregivers. Seizure frequency was defined as the mean frequency of seizures per month. Twelve months after the dose increment for maintenance therapy, the response was assessed. In comparison to the baseline seizure frequency, response to LEV treatment was classified as follows: complete cessation (100% seizure control); response (50% reduction in seizures); minimal response (

Effect of levetiracetam on behavioral problems in pervasive developmental disorder children with epilepsy.

We investigated the relationship between behavioral problems, location of electroencephalogram (EEG) paroxysmal abnormalities (PA), and treatment with...
557KB Sizes 1 Downloads 3 Views