Efficacy of levetiracetam for reducing rolandic discharges in comparison with carbamazepine and valproate sodium in rolandic epilepsy

Accepted Manuscript Title: Efficacy of levetiracetam for reducing rolandic discharges in comparison with carbamazepine and valproate sodium in rolandic epilepsy Authors: Hideaki Kanemura, Fumikazu Sano, Tetsuo Ohyama, Masao Aihara PII: DOI: Reference:

S1059-1311(18)30246-2 https://doi.org/10.1016/j.seizure.2018.10.002 YSEIZ 3301

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Seizure

Received date: Revised date: Accepted date:

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Please cite this article as: Kanemura H, Sano F, Ohyama T, Aihara M, Efficacy of levetiracetam for reducing rolandic discharges in comparison with carbamazepine and valproate sodium in rolandic epilepsy, Seizure: European Journal of Epilepsy (2018), https://doi.org/10.1016/j.seizure.2018.10.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Efficacy of levetiracetam for reducing rolandic discharges in comparison with carbamazepine and valproate sodium in rolandic epilepsy

Hideaki Kanemuraa, *, Fumikazu Sanoa, Tetsuo Ohyamaa, Masao Aiharab

of Paediatrics, Faculty of Medicine, and bGraduate Faculty of

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aDepartment

Chuo, Yamanashi 409-3898, Japan

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Short running title: Levetiracetam for rolandic discharges

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Interdisciplinary Research, Graduate School, University of Yamanashi, 1110 shimokato,

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*Corresponding author. Hideaki Kanemura

Chuo, Yamanashi, 409-3898, Japan.

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Department of Pediatrics, Faculty of Medicine, University of Yamanashi, 1110 Shimokato,

We compared the efficacy of CBZ/VPA and LEV for reducing RD in children with RE.

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Highlights

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Tel: +81-55-273-9606; Fax: +81-55-273-6745; e-mail: [email protected]

12.5% of CBZ patients and 51.2% of VPA patients were considered responders.

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71.4% of 35 patients treated with LEV were considered responders.

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Durations before EEG response in CBZ/VPA/LEV groups were 36.3/23.1/14.7 months.

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EEG response was achieved more rapidly with LEV than with CBZ/VPA.

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ABSTRACT Purpose: The main purpose of this study was to compare the efficacy of levetiracetam (LEV) 1

with the older antiepileptic drugs (AEDs) for preventing atypical evolution in children with Rolandic epilepsy (RE). Accordingly, the present study compared the efficacy of older AEDs (carbamazepine (CBZ) and valproate sodium (VPA)) with LEV in reducing rolandic discharges (RDs) on interictal electroencephalogram (EEG) in children with RE. Methods: Patients in this heterogenous study were subdivided into CBZ, VPA and LEV

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groups in accordance with the initial monotherapy. The CBZ and VPA groups were studied retrospectively, but the LEV group was studied prospectively. Appearances of discharges

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were counted and these rates were computed. In comparison with the baseline RD frequency,

EEG response to AED treatment was classified such as complete disappearance and response

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(50% reduction in RD frequency). The time taken to attain complete disappearance or

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response in EEG responders was assessed for each AED treatment group.

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Results: Responders comprised 10 (11.2%) of the 89 patients treated with CBZ, 41 (56.2%)

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of the 73 patients with VPA, and 25 (71.4%) of the 35 patients with LEV. Mean interval to achievement of EEG response in the CBZ, VPA, and LEV groups were 36.3, 23.1, and 14.7

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months, respectively. EEG response was achieved significantly more rapidly with LEV than with CBZ (p<0.001) or VPA (p<0.005). Seizure control was not significantly different in all 3

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investigated drugs.

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Conclusions: LEV seems to be superior to CBZ and VPA in its ability to suppress RDs in

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children with RE.

Abbreviations: AED, antiepileptic drug; LEV, levetiracetam; CBZ, carbamazepine; VPA, valproate sodium; RE, rolandic epilepsy; RD, rolandic discharge

Keywords: levetiracetam (LEV); rolandic epilepsy (RE); electroencephalogram (EEG);

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rolandic discharge (RD); anti-epileptic drug (AED)

1. Introduction

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Rolandic epilepsy (RE) usually presents with infrequent seizures and has excellent

prognosis presenting with characteristic abnormal discharges on electroencephalogram (EEG),

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mainly “rolandic discharges (RDs)” [1]. The most striking finding of RD is the significant

increase in frequency during drowsiness and through all sleep stages. Several studies have

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provided the clear evidence that children with RE display a profile of pervasive cognitive

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difficulties and behavioral disturbances, and thus RE is not always benign disorder [2, 3].

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With the course of time a number of investigations showed that a significant number of

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patients with RE did present atypical evolutions. These neuropsychological and behavioral disturbances are considered to have multifactorial origins. Among these factors, a significant

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number of children with RE present neuropsychological disturbances correlated to interictal epileptiform discharges [4-6]. Interictal epileptiform discharges on EEG are regarded as

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correlated with persistent pathological neuronal discharges [7]. Children presenting with RD might be at risk of minor behavioral disturbances or learning difficulties [8-12].

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Neuropsychological impairments, including learning and behavioral difficulties, are more prevalent in children with atypical seizure semiology and/or atypical EEG features [13-15].

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Our previous study showed significant correlations between atypical clinical features and prolonged frequent abnormal discharges on EEG (>24 months after onset) in RE [16]. These findings suggest that prolonged high frequency of RDs might lead to atypical evolutions of RE [16]. However, the benefit of drug treatment for suppression of RDs is under debate. Fernandez et al. reported that epileptiform discharges may cause neurologic dysfunction in

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the short term and that there is conflicting evidence on the impact of epileptiform discharges on long-term cognitive outcome [17]. They concluded that there is no evidence for or against treatment of asymptomatic epileptiform discharges [17]. In contrast, treatment for suppression of RDs has been reported in several studies. Tacke et al. showed that antiepileptic drug treatment of children with RE did not affect cognitive performance and that behavioral

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disturbances improved in a subset of patients [18]. Other studies also showed that some of RE children might experience improved intellectual functioning with antiepileptic treatment [5,

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19]. Accordingly, the benefit of drug treatment for suppression of RDs may be present to prevent atypical evolutions in at least some patients with RE. However, the efficacy of

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antiepileptic drugs (AEDs) for RD on EEG has not yet been fully evaluated in children with

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RE.

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The ultimate judgment of therapy must be made in the light of all the clinical data

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presented by the patient and by the treatment options locally available for the patient and their clinician. The main purpose of this study was to compare the efficacy of levetiracetam

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(LEV) with the older AEDs such as carbamazepine (CBZ) and valproate sodium (VPA) for preventing atypical evolutions presenting with both frequent RD and cognitive impairments

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in children with RE as early as possible. Accordingly, the present study compared the efficacy of LEV with CBZ and VPA for reducing interictal abnormal discharges on EEG such as RDs

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in children with RE.

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2. Materials and methods

Patients were recruited from among epilepsy outpatients of the authors’ hospital. Eligible patients were those diagnosed with RE. Patients with RE demonstrated the typical EEG abnormalities of this condition with normal neurological examination and fulfilled the

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following criteria for typical RE [1]: 1) nocturnal partial seizures associated with centrotemporal spikes on the EEG; 2) onset of seizures ranging from 3 to 14 years of age; 3) normal routine laboratory examination and normal results for the screening of metabolic diseases; 4) normal brain MRI; and 5) absence of other types of unprovoked seizures. Patients were subdivided into the following three groups in accordance with the initial

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monotherapy of CBZ, VPA or LEV. Patients in the CBZ and VPA groups, who were admitted to our hospital between January 01, 2000 and February 28, 2015, were reviewed

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retrospectively. In contrast, data for patients in the LEV group, who were admitted to our

hospital between March 01, 2015 and June 30, 2016, were collected prospectively. Children

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with benign focal epilepsies who were initially treated with CBZ, VPA or LEV monotherapy

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were included if data were available for a follow-up period of 18 months. Exclusion criteria

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were: 1) poor compliance by parents/caregivers in completing the diary of seizure frequency

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and adverse events and making the necessary visits; 2) problematic setting of the baseline period and need to take other approaches in addition to treatment with an AED because of

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progressive neurological and/or severe medical disorders; 3) evidence of persistent nonadherence to medication therapy; 4) use of more than one AED; or 5) concurrent

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neurological or other chronic disorders. New-onset epilepsy was defined as two or more unprovoked seizures without any prior seizure history, apart from febrile seizures. Personal

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and family histories were recorded, and neurological examinations were performed on all patients.

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We reviewed demographic data, diagnostic evaluation of epilepsy, seizure types and

seizure frequency prior to and following initiation of each AED monotherapy. In the LEV group, all patients had follow-up visits at regular intervals every week for the first month to evaluate the presence or absence of drug efficacy and adverse events. Subsequently, all patients undertook follow-up visits at regular intervals every 2 weeks or 1 month. In LEV

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groups, patients were administered LEV twice daily at an initial dose of 5 mg/kg/day to reduce the likelihood of adverse events and to facilitate assessment of efficacy at relatively low doses. The LEV dose was increased to 10 mg/kg/day after 1 week if seizures appeared during this 1 week. Similarly, the dose of LEV could be increased by 5 mg/kg/day each week if seizures appeared. During this period, LEV doses could be increased up to 60 mg/kg/day

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(or 3000 mg/day), in accordance with the clinician’s judgment. Seizure-freedom was defined as complete seizure cessation for more than 6 months. The present study included

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retrospective and prospective data, therefore if there were no seizures, the doses of older AEDs (CBZ/VPA) and newer AED (LEV) were left unchanged to avoid this bias.

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EEGs were performed on a 12- or 16-channel machine every 3 months. The duration of

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tracings was at least 20 min. For inclusion, at least one EEG needed to be obtained without

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drug induction, showing a clear sequence of awake-drowsy-sleep-arousal-awake states. For

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this reason, parents were instructed to keep the child awake the night before the visit. Intermittent photic activation was performed routinely, and hyperventilation was used when

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the ability of the child to cooperate permitted.

Assessment of interictal EEG abnormalities is summarized as follows. All EEGs in this

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study were recorded during both awake and sleep states. EEG readers were blinded to the clinical details and groupings. Two child neurologists analyzed EEG recordings with the

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words “rolandic,” “central,” or “centrotemporal.” EEG reports chosen for analysis were solely those for which both child neurologists agreed that the EEG findings showed REs.

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Occurrence of spikes in both awake and sleep states was scored as follows: 1) number of spikes with bipolar montage; 2) localization of spikes; and 3) duration of spike activity. The highest number of spikes from each state was used. The number of spikes was longer in sleep stages 1 and 2 than in the awake state. Accordingly, all appearances of abnormal discharges during sleep 1 and 2 were counted by visual inspection, and appearance rates of discharges

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were computed and expressed as the number of discharges per minute. And then, percent changes from baseline period were evaluated. These evaluations were made by visual inspection. EEG recordings and clinical evaluations were performed every 3 months, focusing on RD. Spikes were quantified by the same EEG readers. In comparison with the baseline RD frequency, EEG response to AED treatment was

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classified as follows: complete disappearance; response (50% reduction in RD frequency); no response (<50% reduction to <50% increase in RD frequency); and exacerbation (50%

EEG responders was assessed in each AED treatment group.

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increase in RD frequency). The time required to attain complete disappearance or response in

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Statistical analysis was performed using SPSS version 19 (IBM, New York, NY).

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Continuous variables were presented as mean ± standard deviation. Chi-square test or

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Fisher’s exact test was used, as appropriate, for analysis of between-group differences in

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discrete variables, and analysis of variance (ANOVA) with a Bonferroni correction was used for continuous variables. Logrank test was used for analysis of Kaplan-Meier curve. Values

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of p<0.05 were defined as statistically significant. This study was carried out in accordance with the Declaration of Helsinki. Approval

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from our local ethics committee was obtained for this research. All parents and those

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participants 12 years old were provided with full details about the protocol and informed consent was obtained.

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3. Results

In the CBZ and VPA groups, a total of 186 children diagnosed with RE were identified. Of these, patients for whom data were missing for fixed scheduled EEG recordings (n=19) and patients who were lost to follow-up (n=5) were excluded from the study. Data from the 7

remaining162 children with RE who received CBZ (n=89) and VPA (n=73) monotherapy were analyzed. The LEV group comprised 37 children with new-onset RE. Of these, 1 patient for whom data were missing for a fixed scheduled EEG recording and 1 patient who was lost to follow-up were excluded from the study. Data from the remaining 35 children with newly diagnosed RE who received LEV monotherapy for at least an 18-month period were analyzed.

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Demographic characteristics of subjects in each treatment group are presented in Table 1. All patients treated with CBZ and VPA had drug concentrations at the reference range (mean

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trough concentrations, 5.9 μg/mL and 62.1 μg/mL, respectively).

Mean age at epilepsy onset was 6.7 years (range, 3.4-10.4 years) in the CBZ group, 6.9

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years (range, 3.1-11.2 years) in the VPA group, and 6.8 years (range, 3.2-10.3 years) in the

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LEV group. There was no significant difference in mean age between the groups. Gender

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distribution was 46 males (52.5%) and 43 females (47.5%) in the CBZ group, 39 (53.4%) and

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34 (46.6%) in the VPA group, and 19 (54.3%) and 16 (45.7%) in the LEV group, again showing no significant difference between treatment groups.

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Overall, 61 patients (68.5%) in the CBZ group and 54 patients (74.0%) in the VPA group were seizure-free with the first prescribed AED as of the end of 12 months of therapy. In

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addition, 4 patients (2.2%) treated with CBZ and 3 patients (3.3%) treated with VPA showed a >50% reduction in seizure frequency. In contrast, 30 patients (85.7%) in the LEV group

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were seizure-free with the first prescribed AED as of the end of 12 months of therapy. One patient (2.9%) had a >50% reduction in seizure frequency. There was a trend to higher

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efficacy in the LEV group compared with the CBZ group but this was not statistically significant (p=0.09) (Table 2). The efficacy of AEDs for PAs is summarized in Table 3. All patients had stage 2 sleep on EEG. Responders (i.e., 50% in RD frequency on EEG) comprised 10 (11.2%) of the 89 patients treated with CBZ, 41 (56.2%) of the 73 patients treated with VPA, and 25 (71.4%) of

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the 35 patients treated with LEV. RDs completely disappeared in 18 patients (24.7%) in the VPA group and 15 patients (42.9%) in the LEV group. In addition, in 11 (26.8%) of the 41 responders in the VPA group, EEG response was achieved within 6 months after starting VPA administration. In nine (36.0%) of the 25 responders in the LEV group, EEG response was achieved within 6 months after starting LEV administration. In contrast, none of the 10

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responders in the CBZ group showed EEG response within 6 months after CBZ

administration. Patients treated with VPA and LEV showed no exacerbations in EEG findings.

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In contrast, eight patients treated with CBZ showed exacerbations in EEG findings. In EEG responders, mean interval to achievement of EEG response in the CBZ, VPA, and LEV

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groups were 36.3, 23.1, and 14.7 months, respectively. Efficacy for EEG was achieved more

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rapidly in the LEV group than in the CBZ (p<0.001) and VPA (p<0.005) groups (Fig. 1).

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Adverse events occurred in two patients in the LEV group. The treatment-related adverse

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effect was drowsiness. This symptom was mild and LEV discontinuation was not necessary. Hematological biochemical tests were normal in all patients. None presented with behavioral

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or psychiatric problems. Allergic reaction was not seen in any patients. Moreover, none of the events causing hospitalization were considered by the investigators to be related to the

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medications in the present study.

Median treatment dose and blood level of LEV was 14.8 mg/kg/day (range, 5.4-30.6

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mg/kg/day) and 8.4 µg/mL (range, 3.1-24.6 µg/mL), respectively. No correlation was

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identified between LEV blood level and seizure reduction rate / EEG improvements.

4. Discussion

LEV was recently introduced into clinical practice as a drug with potentially favorable efficacy and tolerability profiles. This agent is used in both focal and generalized epilepsies,

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usually as add-on therapy, but also as monotherapy in children with epilepsy [20, 21]. In our previous study, LEV was effective and well tolerated as monotherapy in pediatric patients with RE and may be suitable for those who have adverse effects from, or who are at risk of, undesirable adverse effects with other first-line AEDs [22]. In the present study, the efficacy tended to be higher in the LEV group than in the CBZ and VPA groups, supporting previous

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studies, but this result was not statistically significant. These findings suggest that LEV monotherapy appeared effective and well tolerated in RE.

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Data regarding the efficiency of various drugs regarding their ability to suppress

epileptiform discharges have been sparse. Epileptic seizures are considered to result from an excessive, synchronous discharge of cerebral neurons. Engel reported that transient oromotor

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deficits such as drooling may be caused by increased interictal spike activity as part of an

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inhibitory mechanism affecting the functions of the lower motor strip [23]. Previous studies

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have shown that a reduction in synchronization due to drugs was associated with a reduction in seizures [24, 25]. Bast et al. reported the influence of sulthiame (SLT) on the EEG in RE

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[26]. Continuous treatment in RE should be considered only in patients with frequent seizures. However, these studies suggest that treatment of abnormal discharges on EEG might be

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justified even when no seizures are obvious, if neuropsychiatric impairment is present. Accordingly, an approach for reducing abnormal discharges on EEG may be needed in at

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least some patients.

For localization-related epilepsies, the relationships between seizures and interictal

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epileptiform discharges are controversial, but some interictal epileptiform activities have subtle clinical manifestations. Our previous study showed significant correlations between atypical clinical features and longer periods of frequent abnormal discharges on EEG (>24 months after onset) in RE [16]. Freedom from epileptiform EEG abnormalities was taken as the primary indicator of efficacy for optimal outcome. Accordingly, it may be important to

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identify and use the treatment options to treat both seizures and EEG abnormalities to achieve the optimal prognosis for at least of some patients with RE children with atypical evolutions. However, the efficacy of LEV for RD on EEG has not yet been fully evaluated in children with RE. Thus, it is meaningful that the efficacy of LEV for RD has been compared with those of CBZ and VPA.

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The present results indicate that LEV may be more effective than CBZ (p<0.001) and

VPA (p<0.005) in reducing interictal EEG abnormalities such as RDs in patients with RE. In

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addition, LEV treatment may be effective in reducing seizure frequency in RE. This study

suggests that LEV monotherapy can be effective in treating newly diagnosed RE patients. In

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addition, the present study also aimed to compare the efficacy of these 3 drugs with different

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modes of action for RE. The present study has also indicated that LEV treatment seems to be

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more effective in reducing RD compared with older AEDs such as CBZ and VPA. Moreover,

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the present study confirms that a drug acting on the sodium pump such as CBZ might not always be the best choice for the treatment of children with RE, in agreement with previous

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reports [27, 28]. Particularly, RD frequency at 12 months dropped to 60 percent of baseline for the LEV group compared to 0 for the CBZ group and 75% for the VPA group. As the

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possibility of spontaneous disappearance of RDs over time in RE must be considered, regarding the ability of suppression of RDs in RE CBZ might not have a beneficial effect at

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all.

LEV may reduce the incidence of seizures and interictal epileptiform discharges in

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patients with epilepsy. Stodieck et al. reported that a single acute dose of LEV induced a reduction of interictal epileptiform discharges [29]. In addition, LEV is effective in treating children with specific epilepsy syndromes, such as RE with atypical evolution including epilepsy with continuous spike-waves during slow sleep (CSWS), resulting in seizure reduction, improvement of alertness, and cessation of electrical status epilepticus during the

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sleep pattern on EEG [30, 31]. A recent study by Tacke et al. showed the efficacy of LEV and SLT on EEG in RE [32]. These findings suggest that LEV may be effective in decreasing abnormal discharges on EEG in RE, in agreement with present results. No statistically significant correlation was found between the LEV plasma level and the seizure reduction rate / EEG improvements. This is in agreement with the results of a

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previous study by Stodieck et al. [29]. They found no correlation between the percentage difference in area under the curve for interictal epileptic discharge frequency and LEV

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plasma levels [29]. In our previous study, dosages for effective cases were bimodal [31]. In another current study, Sheinberg et al. found no correlations of LEV serum levels with

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clinical efficacy, tolerability or the administered dosage or between serum concentrations and

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adverse events [33]. Moreover, the occurrence of adverse events was independent of the

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mean daily dose and continuation time in the cohort [33]. In contrast, Iwasaki et al. [34]

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showed that blood levels were higher in effective cases than in ineffective cases. Those authors also demonstrated that blood concentration and seizure reduction rate correlated

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positively at 2 weeks after reaching maintenance dosage and 1 year later. These findings suggest that appropriate dosage or serum levels of LEV may differ in individual patients, and

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that LEV may decrease seizure frequency in a dose- or serum level-dependent manner in some patients, in agreement with our previous reports.

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A limitation of this study was the comparatively small sample size of the LEV group.

LEV has only recently begun to be used in the initial treatment of childhood epilepsy in Japan.

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This significant difference in the number of patients between drug groups may well have obscured our ability to identify differences between groups. The present study had mixed retrospective/prospective data, which might increase bias. In addition, the present study also had no neuropsychological data. Further research will clarify these aspects. The present results strongly suggest the utility of LEV in reducing abnormal discharges

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on EEG in RE. LEV seems to be superior to CBZ and VPA in its ability to suppress RDs in children with RE, and may prevent atypical evolutions in children with RE. However, as this was not a controlled study and cognitive and behavioral data were absent, firm conclusions cannot be drawn. Further research with prospective controlled studies and larger cohorts will

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be needed to discuss these aspects.

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Declaration of interest

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We confirm that we have read the Journal’s position on issues involved in ethical

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publication and affirm that this report is consistent with those guidelines.

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Dr. Hideaki Kanemura has received speaker’s fees from Otsuka Pharmaceutical Co., Ltd.

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None of the other authors has any conflict of interest to disclose.

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Funding

This research did not receive any specific grant from funding agencies in the public,

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commercial, or not-for-profit sectors.

Conflict of interest

We confirm that we have read the Journal’s position on issues involved in ethical

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publication and affirm that this report is consistent with those guidelines. Dr. Hideaki Kanemura has received speaker’s fees from Otsuka Pharmaceutical Co., Ltd.

None of the other authors has any conflict of interest to disclose.

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patients with epilepsy and interictal epileptiform discharges. Seizure 2001;10 583-7. [30] Wang SB, Weng WC, Fan PC, Lee WT. Levetiracetam in continuous spike waves during slow-wave sleep syndrome. Pediatr Neurol 2008; 39: 85-90. [31] Kanemura H, Sano F, Tando T, Sugita K, Aihara M. Efficacy and safety of add-on levetiracetam in refractory childhood epilepsy. Brain Dev 2013; 35: 386-91.

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[32] Tacke M, Borggraefe I, Gerstl L, Heinen F, Vill K, Bonfert M, et al. Effects of

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SC R

levetiracetam and sulthiame on EEG in benign epilepsy with centrotemporal spikes: a

[33] Sheinberg R, Heyman E, Dagan Z, Youngster I, Kohn E, Gandelman-Marton R, et al.

N

refractory epilepsy. Pediatr Neurol 2015; 52: 624-8.

U

Correlation between efficacy of levetiracetam and serum levels among children with

A

[34] Iwasaki T, Toki T, Nonoda Y, Ishii M. 2015. The efficacy of levetiracetam for focal

ED

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seizures and its blood levels in children. Brain Dev 2015; 37: 773-9.

Figure legends

PT

Figure 1. Kaplan-Meier curves for probability of RD reduction after administration of AEDs. Efficacy for EEG was achieved more rapidly in the LEV group than in the CBZ (p<0.001)

CC E

and VPA (p<0.005) groups. Sequential plots for CBZ (triangle marks-dotted lines); VPA (circle marks-dotted lines); and LEV (square marks-solid lines).

A

EEG, electroencephalogram; RD, rolandic discharge; AEDs, anti-epileptic drugs; LEV, levetiracetam; CBZ, carbamazepine; VPA, valproate sodium.

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IP T SC R U N A M ED PT CC E A Table 1. Clinical characteristics of participants in the present study

Patients enrolled, n

CBZ

VPA

LEV

89

73

35

18

Sex 46

39

19

Female

43

34

16

Age (mean, years)

8.1

7.8

8

Age at onset (mean, years)

6.7 (3.4-10.4)

6.9 (3.1-11.2)

6.8 (3.2-10.3)

Previous history of FS (n)

10 (11.2%)

8 (11.0%)

4 (11.4%)

6 (8.2%)

3 (8.6%)

Mean trough concentration 5.9 (3.8-9.2)

62.1 (46.2-90.3)

7.9 (3.1-24.6)

U

(µg/mL)

SC R

Family history of epilepsy (n) 8 (9.0%)

IP T

Male

Table 2. Seizure response with AEDs

CC E

Seizure-free

VPA

LEV

(n=89)

(n=73)

(n=35)

54 (74.0%)

30 (85.7%)

ED

CBZ

PT

Seizure response

M

A

N

FS, febrile seizure; CBZ, carbamazepine; VPA, valproate sodium; LEV, levetiracetam.

61 (68.5%)

p-value

LEV vs CBZ; 0.07 LEV vs VPA; 0.22

50% reduction of

LEV vs CBZ; 0.99 4 (2.2%)

3 (3.3%)

1 (2.9%)

A

seizures

Total responder

LEV vs VPA; 0.99 LEV vs CBZ; 0.09 65 (73.0%)

57 (78.1%)

31 (88.6%) LEV vs CBZ; 0.29

AEDs, antiepileptic drugs; CBZ, carbamazepine; VPA, valproate sodium; LEV,

19

levetiracetam.

Table 3. EEG response with AEDs CBZ

VPA

LEV

(n=89)

(n=73)

(n=35)

0 (0.0%)

18 (24.7%)

15 (42.9%)

IP T

p-value

LEV vs CBZ: <0.01 Complete disappearance

SC R

LEV vs VPA:0.07

LEV vs CBZ: 0.03

Responder

10 (11.2%)

23 (31.5%)

10 (28.6%)

Exacerbation

Duration of response in

ED

8 (9.0%)

36.3

LEV vs CBZ: <0.01

N

25 (71.4%)

0 (0.0%)

0 (0.0%)

23.1

14.7

LEV vs VPA:0.14

LEV vs CBZ: <0.001 LEV vs VPA: <0.005

PT

EEG responder (months)

41 (56.2%)

A

10 (11.2%)

M

Total responder

U

LEV vs VPA:0.83

CC E

EEG, electroencephalogram; AEDs, antiepileptic drugs; CBZ, carbamazepine; VPA, valproate

A

sodium; LEV, levetiracetam.

20