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Efficacy and Safety of Adjunctive Levetiracetam Therapy in Pediatric Intractable Epilepsy
Original Articles
Efficacy and Safety of Adjunctive Levetiracetam Therapy in Pediatric Intractable Epilepsy Yun Jin Lee, MD, Hoon-Chul Kang, MD, PhD, Heung Dong Kim, MD, PhD, and Joon Soo Lee, MD, PhD To investigate the efficacy and safety of levetiracetam adjunctive therapy in childhood intractable epilepsy, data were reviewed for 130 children who had $4 seizures per month, whose seizures were intractable to an initial $2 antiepileptic drugs, and who could be monitored for at least 6 months after levetiracetam add-on. Reduction in seizure frequency and related variables were investigated. Sixty-two of the 130 patients (48%) showed a seizure reduction of $50%, and 28 patients (22%) became seizure-free. A reduction in seizures by $50% was observed in 33/64 in children with partial seizures (52%) and in 29/66 children with generalized seizures (44%). Efficacy did not differ significantly among seizure types. Overall efficacy was unaffected by abnormalities evident from magnetic resonance imaging, by mental retardation, or by maintenance dose of levetiracetam. The mean maintenance dose of levetiracetam was 47.0mg/kg per day (S.D. = ± 29.7), and mean follow-up duration was 13.4 months (S.D. =± 8.7). No demographic features differed significantly between patients with seizure freedom and without seizure remission. Levetiracetam was discontinued in 24 children at last visit (retention rate, 82%). The most common complaint was irritability (5%), and none of the adverse events were life threatening. In conclusion, levetiracetam adjunctive therapy is effective and safe for childhood intractable epilepsy. Ó 2010 by Elsevier Inc. All rights reserved. Lee YJ, Kang H-C, Kim HD, Lee JS. Efficacy and safety of adjunctive levetiracetam therapy in pediatric intractable epilepsy. Pediatr Neurol 2010;42:86-92.
From the Department of Pediatrics, Pediatric Epilepsy Clinics, Severance Children’s Hospital, Brain Research Institute, Yonsei University College of Medicine, Seoul, Korea.
86 PEDIATRIC NEUROLOGY Vol. 42 No. 2
Introduction The antiepileptic drug levetiracetam has been approved in Europe and the United States as adjunctive therapy in the treatment of partial onset seizures in adults since 2000 and in children age 4 years and older since 2005 [1]. Levetiracetam acts by binding to and modulating the synaptic vesicle protein SV2A [2], a mechanism different from that of other antiepileptic drugs; however, the exact mechanism of action remains unknown. Levetiracetam has a favorable pharmacological profile, with almost complete absorption after oral administration, linear pharmacokinetics, and a low extent of metabolism. Levetiracetam is unlikely to interact with other drugs (such as lamotrigine, valproic acid, and carbamazepine), because it has a low protein binding (<10%) and is not cytochrome P450-dependent [3,4]. An additional advantage is the ability to quickly reach the target dosage. Numerous reports have indicated seizure reduction in children treated with levetiracetam; however, most of the previous studies were conducted over the short term, with marked variability in follow-up durations within studies, or only involved a small number of patients [1,5-11]. Few studies to date have examined the long-term efficacy of levetiracetam adjunctive therapy in children with intractable epilepsy. The aim of the present study was to determine the long-term efficacy and tolerability of levetiracetam adjunctive therapy in 130 children with epilepsy intractable to treatment with existing antiepileptic drugs, with a mean follow-up period of 13 months and maximal follow-up period of 21 months.
Communications should be addressed to: Dr. Joon Soo Lee; Department of Pediatrics, Severance Children’s Hospital; Yonsei University College of Medicine; 134, Shinchon-dong, Seodaemun-ku; Seoul 120-752, Republic of Korea. E-mail: [email protected] Received April 6, 2009; accepted August 5, 2009.
Ó 2010 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2009.08.002 0887-8994/10/$—see front matter
Materials and Methods
Table 1. Clinicodemographic profiles of patients with pediatric intractable epilepsy
Patients The present study was performed retrospectively between March 2007 and September 2008 at the pediatric epilepsy clinics of Severance Children’s Hospital in South Korea. The inclusion criteria of study subjects were as follows: (a) patients had experienced more than four seizures per month before start of levetiracetam, (b) their seizures were not controlled by two or more conventional antiepileptic drugs before start of levetiracetam, (c) patient age was between 10 months and 18 years, and (d) patients were monitored for at least 6 months after start of levetiracetam. Excluded were patients with progressive cerebral lesion or neurodegenerative metabolic disorder. In all, 130 children fulfilled the above criteria. The study was approved by the medical ethical committees (Yonsei University Institutional Review Board for medical record review).
Methods Levetiracetam was initially administered in a twice daily administration with a starting dose of 10-30 mg/kg per day. Further doses were titrated in 10 mg/kg per day increments every 1-2 weeks with a target dose of 20-60 mg/kg per day until patients were seizure-free or the response had reached a plateau, adverse events requiring discontinuation of therapy were reported, or the physician determined the drug to be ineffective. Patients were regularly evaluated for seizure response and adverse events at clinical visits in the first 2 to 4 weeks after the start of levetiracetam and every 1 to 2 months subsequently. All patients were monitored for at least 6 months after the start of levetiracetam and until add-on therapy with other antiepileptic drugs or a change to therapeutic modalities such as a ketogenic diet or epilepsy surgery occurred. Seizure response was assessed in patients with ongoing levetiracetam treatment at the last visit just prior to the new therapy being added. Seizure frequencies were recorded using seizures diaries (compliance 103/130, or 79%) or, if diaries were not filled, by documentation of testimony given by primary caregivers (27/130, or 21%). Baseline seizure frequency was retrospectively evaluated for 4 weeks before levetiracetam adjunctive therapy was begun. In patients with more than two types of seizures, major seizures were counted to evaluate efficacy. Efficacy was based on a change of seizure frequency, with data obtained from seizure diaries kept by parents or caregivers or the children’s own reports. Seizure reduction after levetiracetam adjunctive therapy was classified relative to baseline seizure frequency, as follows: seizure-free (100% seizure control), response ($50% but <100% reduction), no significant response (<50% reduction of seizure frequency or no effect), or worsening (increase in seizure frequency). Favorable responders were defined as patients who achieved a $50% decrease in seizure frequency after the start of levetiracetam, compared with baseline seizure frequency. Tolerability and adverse events were assessed by documenting adverse events spontaneously reported by the parents or caregivers or the children. Treatment was discontinued if there were persisting serious adverse events despite levetiracetam dose reduction, or an aggravation of seizure frequency relative to baseline. If levetiracetam was discontinued, the reason for drug discontinuation was categorized as inefficacy, adverse events, or both, based on clinical reports. The data for the present study were obtained from individual patient medical charts. Variables included patient demographic data, seizure type and frequency, specific epilepsy syndrome, abnormality on magnetic resonance imaging, known etiology, mental retardation, age at seizure onset, age at start of levetiracetam adjunctive therapy, duration of epilepsy before start of levetiracetam, concomitant antiepileptic drugs, starting dose and maintenance dose of levetiracetam, follow-up duration of levetiracetam therapy, efficacy, adverse events, and reasons for drug discontinuation. Seizure types and epilepsy syndromes were classified using the International League Against Epilepsy 1981 classification system [12]. Independent Student’s t test and Pearson’s c2 were used to compare continued and discontinued parametric data, respectively. The chi-square test
Characteristic
Value
Sample size Sex distribution Male/female, no. Male/female, % Age at seizure onset, no. (%) <1 yr 1 yr to <5 yr 5 yr to <10 yr 10 yr to <15 yr Age at start of levetiracetam, no. (%) <1 yr 1 yr to <5 yr 5 yr to <10 yr 10 yr to <15 yr 15 yr to <20 yr Seizure types, no. (%) Generalized Generalized tonic/tonic-clonic Spasms Atonic Myoclonic Atypical absence Partial Complex Simple Mental retardation, no. (%) Abnormality on magnetic resonance on imaging, no. (%) Age at seizure onset, yr* Age at start of levetiracetam, yr* Follow-up duration of levetiracetam on therapy, mo* Starting dose of levetiracetam, mg/kg on per day* Maintenance dose of levetiracetam, on mg/kg per day* Concomitant antiepileptic drugs, no.*
n = 130 79/51 61/39 60 (46) 34 (26) 23 (18) 13 (10) 7 (5) 42 (32) 39 (30) 34 (26) 8 (6) 66 (51) 43 (33) 12 (9) 9 (7) 1 (<1) 1 (<1) 64 (49) 52 (40) 12 (9) 90 (69) 81 (62) 3.2 3.0 (0.1-13.6) 7.7 6.1 (0.7-17.4) 13.4 8.7 (6.0-21.0) 21.2 10.2 (8.8-31.8) 47.0 29.7 (17.6-88.8) 2.7 1.1 (2.0-4.0)
* Values are reported as mean 1 S.D. (range).
was used for categorical variables. Significance was set at the P < 0.05 level in analysis.
Results Demographic Data In all, 130 patients (79 boys and 51 girls) were included in the present study (Table 1). The mean age at start of levetiracetam adjunctive therapy was 7.7 years (range, 0.717.4 years). The mean baseline seizure frequency was 16 seizures per month, but the range varied from 4 to 110 seizures per month. Mean starting and maintenance doses of levetiracetam were 21.2 mg/kg per day (range, 8.8-31.8 mg/kg per day) and 47.0 mg/kg per day (range, 17.6-88.8 mg/kg per day), respectively. Mean follow-up duration after start of levetiracetam was 13.4 months (range, 6.0-21.0 months). Approximately two thirds of the patients were
Lee et al: Levetiracetam in Pediatric Epilepsy 87
Table 2. Seizure reduction according to seizure type
Seizure type
Seizure-free, no. (%)
$50 to <100% reduction, no. (%)
No significant response, no. (%)
Worse, no. (%)
Total (n = 130) Generalized (n = 66) GT/GTC (n = 43) Spasm (n = 12) Atonic (n = 9) Partial (n = 64) Complex (n = 52) Simple (n = 12)
28 (22) 17 (26) 8 (19) 5 (42) 3 (33) 11 (17) 9 (17) 2 (17)
34 (26) 12 (18) 9 (21) 2 (17) 1 (11) 22 (34) 18 (35) 4 (33)
64 (49) 36 (55) 26 (60) 4 (33) 5 (57) 28 (44) 23 (44) 5 (42)
4 (3) 1 (2) 0 (0) 1 (8) 0 (0) 3 (5) 2 (4) 1 (8)
Abbreviations: GT = Generalized tonic GTC = Generalized tonic clonic
mentally retarded (90/130, or 69%), and abnormalities were observed on magnetic resonance imaging in 81/130 children (62%). In terms of seizure type, 52/130 children (40%) had complex partial seizures and 43/130 children (33%) had generalized tonic or generalized tonic-clonic seizures. The pediatric epilepsy syndromes observed were Lennox-Gastaut syndrome (28/130, or 22%), infantile spasms (12/130, or 9%), severe myoclonic epilepsy in infancy or Dravet syndrome (11/130, or 8%), and LandauKleffner syndrome (2/130, or 2%). Efficacy After 3 months of levetiracetam adjunctive therapy, 114 of the 130 patients were still being administered levetiracetam (retention rate, 88%). Nine children discontinued therapy because levetiracetam was ineffective, three because seizure frequency increased or because seizures became more severe (or for both reasons), three because they developed adverse events (aggressive behavior in two patients and irritability in one), and one because of inefficacy and adverse events. The results of levetiracetam adjunctive therapy ranged from seizure-free to inefficacy or worsening. Of the 130 patients, 62 (48%) were favorable responders and experienced a reduction in seizure frequency of $50% and 28 of these 62 patients (22% of the total) became seizure-free; 64 patients (49%) had no significant reduction in seizures, and 4 patients (3%) got worse (Table 2). Among children with partial seizures, 33/64 (52%) responded to treatment. Levetiracetam was also efficacious in children with generalized seizures, and achieved a favorable response in 29/66 (44%). A status of seizure-free was achieved in 5/12 patients with spasms (42%), 3/9 patients with atonic seizures (33%), 8/43 patients with generalized tonic or generalized tonic-clonic seizures (19%), and 9/52 patients with complex partial seizures (17%). Favorable responders included 7/12 of patients with spasms (58%), 27/52 of patients with complex partial seizures (52%), and 6/12 patients with simple partial
88 PEDIATRIC NEUROLOGY Vol. 42 No. 2
seizures (50%). Efficacy did not differ significantly among the many seizure types. Efficacy of levetiracetam adjunctive therapy according to MRI abnormalities and mental retardation was investigated. Favorable response rate was similar between children with MRI abnormalities (36/81, or 44%) and those without MRI abnormalities (26/49, or 53%), and did not differ significantly between mentally retarded children (47/90, or 52%) and those with normal mentality (15/40, or 38%). Also, overall efficacy was unaffected by age or levetiracetam maintenance dose (data not shown). Twenty-eight patients (22% of the total) became seizurefree during the period from the start of treatment to 5 months after levetiracetam therapy. Of these 28 children, 15 (12% of the total) became seizure-free immediately within 1 month from the start of levetiracetam and 11 others (8% of the total) achieved a seizure-free state between 1 and 3 months. In the remaining two children (2% of the total), the seizure-free period varied from 3 to 5 months after start of levetiracetam therapy (Fig 1). Duration of levetiracetam therapy for obtaining seizure-free was unaffected by seizure types, MRI abnormalities, and mental retardation. There was no significant difference in efficacy among the specific syndromes (Table 3). Favorable response was observed in 7/12 patients with infantile spasms (58%), in 6/11 patients with Dravet syndrome (also known as severe myoclonic epilepsy in infancy) (54%), and in 13/28 patients with Lennox-Gastaut syndrome (46%). Levetiracetam was discontinued in a greater proportion of patients with infantile spasms (5/12, or 42%), compared with the other two syndromes (2/28 and 0/11) (P < 0.05). During the study, 28/130 patients (22%) achieved seizure freedom during the present study, whereas 102/130 patients (78%) did not. These two groups did not differ significantly with respect to several demographic and clinical features, such as seizure type, abnormality on MRI scan, mental retardation, age at seizure onset, age at start of levetiracetam adjunctive therapy, duration of epilepsy before start of levetiracetam therapy, numbers of concomitant antiepileptic
Of the 130 patients, 9 (7%) reported mild to moderate adverse events while being treated with levetiracetam, but only 5 of the 9 patients (4% of the total) dropped out; the reason for discontinuation was excessive irritability in 3 patients and increased aggressiveness in the other 2. The adverse events in the remaining 4 patients subsided within 4 to 6 weeks during maintenance. The most common complaints were irritability in 6/130 patients (5%), additional aggressive behavior in 2 patients (2%) and somnolence in 1 patient (<1%). None of the adverse events were life threatening. Figure 1. Cumulative curves illustrating the percentage of seizure-free patients after the start of levetiracetam therapy.
drugs, and starting dose and maintenance dose of levetiracetam.
Retention Rate and Tolerability At the final visit, levetiracetam was discontinued in 24/ 130 children (18%), with a mean follow-up duration of 13.4 months. The retention rate (82%) was in general inversely correlated to the duration of follow-up (Fig 2). Reasons for discontinuation included inefficacy in 19/ 130 patients (14%), adverse events in 4/130 patients (3%), and a combination of inefficacy and adverse events in 1 patient (<1%). Patients who discontinued levetiracetam because of adverse events were more often younger (2.6 vs 6.9 years) (P < 0.05), had shorter duration of epilepsy before levetiracetam medication (1.4 vs 3.3 years), were taking lower maintenance doses (39.0 vs 44.6 mg/ kg per day), and discontinued the drug much sooner (1.7 vs 3.6 months) than those who discontinued levetiracetam because of inefficacy.
Discussion The present study reports on seizure reduction and adverse events in 130 children with intractable epilepsy treated with levetiracetam adjunctive therapy. In this large group, levetiracetam was effective and well tolerated, and there were no reports of serious adverse events. At the end of the study, across all seizure types, 62/130 patients (48%) had seizure reductions of $50%, including 28 patients (22%) who became seizure-free. Adverse events were observed in only 9/130 patients (7%). Thus, levetiracetam was helpful as an adjunctive therapy for childhood intractable epilepsy across a broad range of seizure types. A literature review identified previous studies that examined the efficacy and tolerability of levetiracetam as an adjunctive therapy in children with epilepsy (Table 4) [1,5-11]. The follow-up duration for the present study (13.4 months, S.D. = 8.7 months) was much longer than in other studies (14 weeks to 12 months). The retention rate for the present study (82%) was higher than for other studies (33-93%). The proportion of children with $50% seizure reduction ranged from 25% to 61% in other studies, compared with 48% in the present study. A relatively large portion of the present study population (22%) became seizure-free, compared with 5-27% in other studies. In contrast to other studies, the children in the present study had
Table 3. Patient characteristics in three epilepsy syndromes Characteristic
Lennox-Gastaut syndrome
Infantile spasms
Dravet syndrome
Sample size Male/female, no. Seizure reduction, no. (%) Seizure-free $ 50% but <100% No significant response Worse Discontinuing, no. (%) Age at start of levetiracetam, yr† Duration of epilepsy before start levetiracetam, yr† Starting dose of levetiracetam, mg/kg per day† Maintenance dose, mg/kg per day†
n = 28 21/7
n = 12 7/5
n = 11 6/5
4 (14) 9 (32) 15 (54) 0 (0) 2 (7) 7.27 4.43 25.41 52.03
5 (42) 2 (17) 4 (33) 1 (8) 5 (42)* 3.02 2.38 22.70 46.03
3 (27) 3 (27) 5 (46) 0 (0) 0 (0) 7.95 5.97 23.10 39.13
* P value < 0.05. † Mean values.
Lee et al: Levetiracetam in Pediatric Epilepsy 89
Figure 2. Survival curves illustrating the retention rate of patients still being treated with levetiracetam.
intractable epilepsy; they were treated with several antiepileptic drugs before levetiracetam was added on (mean; 2.7 antiepileptic drugs), had a long duration of epilepsy (mean, 4.5 years) relative to the age at start of levetiracetam (mean, 7.7 years), and were frequently mentally retarded (69%). Unlike reports from several studies [1,5,7,9], but in accord with a few others [6,8], the present findings demonstrate that levetiracetam was equally effective in seizure reduction of partial and generalized seizures. Also, levetiracetam was effective in various seizure types, including spasm, atonic, generalized tonic, and generalized tonicclonic seizures, all of which are known to be more intractable to treatment than are other seizure types. A reasonable conclusion is therefore to advocate the use of levetiracetam adjunctive therapy in intractable partial or generalized epilepsy. Supplementary advantages of levetiracetam include lesser interaction with other drugs and fast titration up to target dose [3,4]. Of the 130 patients, children with specific epilepsy syndromes revealed generally favorable efficacy, with favor-
able response observed in 7/12 patients with infantile spasms (58%), in 6/11 patients with Dravet syndrome (54%), and in 13/28 patients with Lennox-Gastaut syndrome (46%). All had intractable epilepsy and were treated with several antiepileptic drugs before levetiracetam was added (mean, 3.3 antiepileptic drugs). Notably, the discontinuation rate of levetiracetam was significantly higher in patients with infantile spasms (42%) (P < 0.05) than in the other two syndromes. This finding indicates that patients with infantile spasms more frequently experience unfavorable effects of levetiracetam and are more prone to adverse events. Dravet syndrome also usually follows a progressive clinical course, but it is not related to any specific symptomatic cerebral lesions or known inborn errors of metabolism. In the 11 patients with Dravet syndrome, even such a clinically predicted degenerative course was improved during the use of levetiracetam adjunctive therapy, although the duration of treatment was only 6-13 months. The data for nonsymptomatic, nonmetabolic progressive intractable childhood epilepsies (including Dravet syndrome) were included in the cohort. In addition to the responder rate, retention rate is an important measure of overall drug compliance, as a reliable compound measure of efficacy and adverse events over time [13]. In a long-term study of levetiracetam in childhood epilepsy, the retention rate for responders after 3 years was 22% [14]. In adults, the long-term retention rates of levetiracetam have been reported as 74% [15] and 60% [13] after 1 year, and 32% after 5 years [13]. At the last follow-up visit of the present study, 106/130 patients (82%) had been on medication with levetiracetam for the entire 13.4-month mean follow-up duration. Thus, in addition to the 62 favorable responders, 44 other children continued levetiracetam. Possible explanations include seizure reduction of <50%
Table 4. Reported efficacy and tolerability of levetiracetam in children with epilepsy
Follow-up duration (range)
Age, yr
n
Seizure type
Retention rate, %
Seizure-free, %
$50% but <100% reduction, %
References
Avg* 8 mo (1-30 mo) Avg* 33 wk (12-86 wk) 20 wk Avg* 7 mo (2-20 mo) 14 wk Avg* 9 mo (3-42 mo) 12 mo 26 wk Avg* 13 mo (3-21 mo)
1.2-10 0-18 0.5-16 0.5-16 4-16 <4 0.3-19 4-16 0.3-17.4
26 209 67 110 101 81 200 33 130
I, G, P I, G, P G, P I, G, P I, P I, G, P I, G, P I, G, P I, G, P
81 33 73 41 93 46 49 70 82
8 6 4 9 7 12 5 27 22
61 25 49 39 45 30 32 52 48
Tan and Appleton, 2004 [7] Opp et al., 2005 [5] Lagae et al., 2005 [8] Grosso et al., 2005 [9]† Glauser et al., 2006 [11]† Grosso et al., 2007 [6] Peake et al., 2007 [10] Callenbach et al., 2008 [1]† Present study†
* Average indicates either mean or median in the cited report. † The children with intractable epilepsy were treated with levetiracetam adjunctive therapy. Abbreviations: G = Generalized I = Intractable P = Partial
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being regarded as nonetheless a benefit to the child, perhaps because seizure durations also shortened or a positive cognitive function effect appeared. A retrospective review found that in 122 children younger than 4 years treated with levetiracetam, univariate analysis suggested that children achieving seizure freedom were more likely to have had partial seizures and lower seizure frequency before starting drug treatment, and to have been exposed to a lower maintenance dose of levetiracetam [16]. In the present study, 22% of children became seizurefree, but 78% of did not. These two groups did not differ significantly in terms of seizure types, abnormalities on magnetic resonance imaging, mental retardation, age at start of levetiracetam therapy, or doses and duration of levetiracetam. The clinical trials of levetiracetam in children older than 4 years used a starting dose of 20 mg/kg per day, with titration to a goal of 60 mg/kg per day, which is the current recommended dosing schedule (levetiracetam package insert; UCB, Brussels, Belgium). Opp et al. [5] and Grosso et al. [9] reported lower mean doses of levetiracetam in children who became seizure-free than in those who did not become seizure-free. Studies in adults have yielded discordant results, with one report indicating a inverse relation between mean dose of levetiracetam and efficacy [17], but others disclosing that high doses are associated with a more favorable response [18]. The present analysis suggested that overall efficacy of levetiracetam adjunctive therapy in childhood intractable epilepsy was unaffected by age or dose. A recently published a study assessed long-term outcome of levetiracetam in 129 children with severe intractable epilepsy for up to 3 years [14]. The authors reported that younger patients are more susceptible to adverse events, and that behavioral problems such as aggressiveness, mood changes, or irritability occur more frequently in pediatric patients, compared with findings of studies in adults [5,19-21]. In a study conducted in Germany [5], sleep disturbances and behavioral disorders were most frequent in patients with physical handicaps or mental retardation. In the present study, mild to moderate adverse events, such as irritability and aggressive behavior, were observed in 9/130 patients (7%). These adverse events occurred within 2 weeks after start of levetiracetam in 5 of the 9 patients, and occurred within 1 month in the remaining 4 patients. The incidence of adverse events was exceedingly low in the present study. A possible explanation for this phenomenon could be the failure to use a standardized questionnaire regarding the incidence of adverse events. Presence of adverse reactions were inquired for in general term only, and it seems likely that far fewer children or caregivers report such incidences spontaneously than if they were asked about them in a more specific manner. It is also possible that improvement in seizure frequencies have resulted in far better tolerability of adverse events than would have otherwise been endured. Adverse events did lead to the discontinuation of drug treatment in 5 of 9
patients, and the patients who discontinued levetiracetam because of adverse events were younger and discontinued the drug much sooner than did those in whom levetiracetam was regarded ineffective. In 4/130 patients (3%), seizures were more frequent after the start of levetiracetam therapy. Other authors have noted this occurrence of adverse events in mentally retarded patients or patients with behavioral problems [22]; in the present study, however, roughly two thirds of the patients (90/ 130) were mentally retarded, but seizures increased in only 4 patients. Increase of seizure frequency during levetiracetam treatment had also been observed in 9-18% by other authors [1,6,10]. This phenomenon may, however, indicate the natural course of the epilepsy rather than a true activation due to levetiracetam add-on therapy. Further prospective comparative studies are needed to assess the efficacy and tolerability and to elucidate potential variables for the use of levetiracetam in treatment of children with intractable epilepsy. Nonetheless, levetiracetam can be considered an effective and well-tolerated treatment as adjunctive therapy in children with intractable partial or generalized epilepsy without incurring significant adverse events. References [1] Callenbach PM, Arts WF, ten Houten R, et al. Add-on levetiracetam in children and adolescents with refractory epilepsy: results of an openlabel multi-centre study. Eur J Paediatr Neurol 2008;12:321-7. [2] Lynch BA, Lambeng N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci U S A 2004;101:9861-6. [3] Patsalos PN. Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol Ther 2000;85:77-85. [4] Pellock JM, Glauser TA, Bebin EM, et al. Pharmacokinetic study of levetiracetam in children. Epilepsia 2001;42:1574-9. [5] Opp J, Tuxhorn I, May T, et al. Levetiracetam in children with refractory epilepsy: a multicenter open label study in Germany. Seizure 2005;14:476-84. [6] Grosso S, Cordelli DM, Franzoni E, et al. Efficacy and safety of levetiracetam in infants and young children with refractory epilepsy. Seizure 2007;16:345-50. [7] Tan MJ, Appleton RE. Efficacy and tolerability of levetiracetam in children aged 10 years and younger: a clinical experience. Seizure 2004; 13:142-5. [8] Lagae L, Buyse G, Ceulemans B. Clinical experience with levetiracetam in childhood epilepsy: an add-on and mono-therapy trial. Seizure 2005;14:66-71. [9] Grosso S, Franzoni E, Coppola G, et al. Efficacy and safety of levetiracetam: an add-on trial in children with refractory epilepsy. Seizure 2005;14:248-53. [10] Peake D, Mordekar S, Gosalakkal J, et al. Retention rate of levetiracetam in children with intractable epilepsy at 1 year. Seizure 2007;16: 185-9. [11] Glauser TA, Ayala R, Elterman RD, et al. N159 Study Group. Double-blind placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology 2006;66:1654-60. [12] International League Against Epilepsy, Commission on Classification and Terminology. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22: 489-501. [13] Krakow K, Walker M, Otoul C, Sander JW. Long-term continuation of levetiracetam in patients with refractory epilepsy. Neurology 2001; 56:1772-4.
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[14] von Stuelpnagel C, Holthausen H, Kluger G. Long-term use of levetiracetam in patients with severe childhood-onset epilepsy. Eur J Paediatr Neurol 2007;11:341-5. [15] Nicolson A, Lewis SA, Smith DF. A prospective analysis of the outcome of levetiracetam in clinical practice. Neurology 2004;63:568-70. [16] Perry MS, Benatar M. Efficacy and tolerability of levetiracetam in children younger than 4 years: a retrospective review. Epilepsia 2007;48: 1123-7. [17] Betts T, Waegemans T, Crawford P. A multicentre, double-blind, randomized, parallel group study to evaluate the tolerability and efficacy of two oral doses of levetiracetam, 2000 mg daily and 4000 mg daily, without titration in patients with refractory epilepsy. Seizure 2000;9:80-7. [18] Privitera M. Efficacy of levetiracetam: a review of three pivotal clinical trials. Epilepsia 2001;42(Suppl. 4):31-5.
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[19] Shorvon SD, Lo¨wenthal A, Janz D, Bielen E, Loiseau P; European Levetiracetam Study Group. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. Epilepsia 2000;41: 1179-86. [20] Cereghino JJ, Biton V, Abou-Khalil B, Dreifuss F, Gauer LJ, Leppik I. Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology 2000;55:236-42. [21] Mula M, Trimble MR, Sander JW. Psychiatric adverse events in patients with epilepsy and learning disabilities taking levetiracetam. Seizure 2004;13:55-7. [22] Nakken KO, Eriksson AS, Lossius R, Johannessen SI. A paradoxical effect of levetiracetam may be seen in both children and adults with refractory epilepsy. Seizure 2003;12:42-6.
Efficacy and Safety of Adjunctive Levetiracetam Therapy in Pediatric Intractable Epilepsy Yun Jin Lee, MD, Hoon-Chul Kang, MD, PhD, Heung Dong Kim, MD, PhD, and Joon Soo Lee, MD, PhD To investigate the efficacy and safety of levetiracetam adjunctive therapy in childhood intractable epilepsy, data were reviewed for 130 children who had $4 seizures per month, whose seizures were intractable to an initial $2 antiepileptic drugs, and who could be monitored for at least 6 months after levetiracetam add-on. Reduction in seizure frequency and related variables were investigated. Sixty-two of the 130 patients (48%) showed a seizure reduction of $50%, and 28 patients (22%) became seizure-free. A reduction in seizures by $50% was observed in 33/64 in children with partial seizures (52%) and in 29/66 children with generalized seizures (44%). Efficacy did not differ significantly among seizure types. Overall efficacy was unaffected by abnormalities evident from magnetic resonance imaging, by mental retardation, or by maintenance dose of levetiracetam. The mean maintenance dose of levetiracetam was 47.0mg/kg per day (S.D. = ± 29.7), and mean follow-up duration was 13.4 months (S.D. =± 8.7). No demographic features differed significantly between patients with seizure freedom and without seizure remission. Levetiracetam was discontinued in 24 children at last visit (retention rate, 82%). The most common complaint was irritability (5%), and none of the adverse events were life threatening. In conclusion, levetiracetam adjunctive therapy is effective and safe for childhood intractable epilepsy. Ó 2010 by Elsevier Inc. All rights reserved. Lee YJ, Kang H-C, Kim HD, Lee JS. Efficacy and safety of adjunctive levetiracetam therapy in pediatric intractable epilepsy. Pediatr Neurol 2010;42:86-92.
From the Department of Pediatrics, Pediatric Epilepsy Clinics, Severance Children’s Hospital, Brain Research Institute, Yonsei University College of Medicine, Seoul, Korea.
86 PEDIATRIC NEUROLOGY Vol. 42 No. 2
Introduction The antiepileptic drug levetiracetam has been approved in Europe and the United States as adjunctive therapy in the treatment of partial onset seizures in adults since 2000 and in children age 4 years and older since 2005 [1]. Levetiracetam acts by binding to and modulating the synaptic vesicle protein SV2A [2], a mechanism different from that of other antiepileptic drugs; however, the exact mechanism of action remains unknown. Levetiracetam has a favorable pharmacological profile, with almost complete absorption after oral administration, linear pharmacokinetics, and a low extent of metabolism. Levetiracetam is unlikely to interact with other drugs (such as lamotrigine, valproic acid, and carbamazepine), because it has a low protein binding (<10%) and is not cytochrome P450-dependent [3,4]. An additional advantage is the ability to quickly reach the target dosage. Numerous reports have indicated seizure reduction in children treated with levetiracetam; however, most of the previous studies were conducted over the short term, with marked variability in follow-up durations within studies, or only involved a small number of patients [1,5-11]. Few studies to date have examined the long-term efficacy of levetiracetam adjunctive therapy in children with intractable epilepsy. The aim of the present study was to determine the long-term efficacy and tolerability of levetiracetam adjunctive therapy in 130 children with epilepsy intractable to treatment with existing antiepileptic drugs, with a mean follow-up period of 13 months and maximal follow-up period of 21 months.
Communications should be addressed to: Dr. Joon Soo Lee; Department of Pediatrics, Severance Children’s Hospital; Yonsei University College of Medicine; 134, Shinchon-dong, Seodaemun-ku; Seoul 120-752, Republic of Korea. E-mail: [email protected] Received April 6, 2009; accepted August 5, 2009.
Ó 2010 by Elsevier Inc. All rights reserved. doi:10.1016/j.pediatrneurol.2009.08.002 0887-8994/10/$—see front matter
Materials and Methods
Table 1. Clinicodemographic profiles of patients with pediatric intractable epilepsy
Patients The present study was performed retrospectively between March 2007 and September 2008 at the pediatric epilepsy clinics of Severance Children’s Hospital in South Korea. The inclusion criteria of study subjects were as follows: (a) patients had experienced more than four seizures per month before start of levetiracetam, (b) their seizures were not controlled by two or more conventional antiepileptic drugs before start of levetiracetam, (c) patient age was between 10 months and 18 years, and (d) patients were monitored for at least 6 months after start of levetiracetam. Excluded were patients with progressive cerebral lesion or neurodegenerative metabolic disorder. In all, 130 children fulfilled the above criteria. The study was approved by the medical ethical committees (Yonsei University Institutional Review Board for medical record review).
Methods Levetiracetam was initially administered in a twice daily administration with a starting dose of 10-30 mg/kg per day. Further doses were titrated in 10 mg/kg per day increments every 1-2 weeks with a target dose of 20-60 mg/kg per day until patients were seizure-free or the response had reached a plateau, adverse events requiring discontinuation of therapy were reported, or the physician determined the drug to be ineffective. Patients were regularly evaluated for seizure response and adverse events at clinical visits in the first 2 to 4 weeks after the start of levetiracetam and every 1 to 2 months subsequently. All patients were monitored for at least 6 months after the start of levetiracetam and until add-on therapy with other antiepileptic drugs or a change to therapeutic modalities such as a ketogenic diet or epilepsy surgery occurred. Seizure response was assessed in patients with ongoing levetiracetam treatment at the last visit just prior to the new therapy being added. Seizure frequencies were recorded using seizures diaries (compliance 103/130, or 79%) or, if diaries were not filled, by documentation of testimony given by primary caregivers (27/130, or 21%). Baseline seizure frequency was retrospectively evaluated for 4 weeks before levetiracetam adjunctive therapy was begun. In patients with more than two types of seizures, major seizures were counted to evaluate efficacy. Efficacy was based on a change of seizure frequency, with data obtained from seizure diaries kept by parents or caregivers or the children’s own reports. Seizure reduction after levetiracetam adjunctive therapy was classified relative to baseline seizure frequency, as follows: seizure-free (100% seizure control), response ($50% but <100% reduction), no significant response (<50% reduction of seizure frequency or no effect), or worsening (increase in seizure frequency). Favorable responders were defined as patients who achieved a $50% decrease in seizure frequency after the start of levetiracetam, compared with baseline seizure frequency. Tolerability and adverse events were assessed by documenting adverse events spontaneously reported by the parents or caregivers or the children. Treatment was discontinued if there were persisting serious adverse events despite levetiracetam dose reduction, or an aggravation of seizure frequency relative to baseline. If levetiracetam was discontinued, the reason for drug discontinuation was categorized as inefficacy, adverse events, or both, based on clinical reports. The data for the present study were obtained from individual patient medical charts. Variables included patient demographic data, seizure type and frequency, specific epilepsy syndrome, abnormality on magnetic resonance imaging, known etiology, mental retardation, age at seizure onset, age at start of levetiracetam adjunctive therapy, duration of epilepsy before start of levetiracetam, concomitant antiepileptic drugs, starting dose and maintenance dose of levetiracetam, follow-up duration of levetiracetam therapy, efficacy, adverse events, and reasons for drug discontinuation. Seizure types and epilepsy syndromes were classified using the International League Against Epilepsy 1981 classification system [12]. Independent Student’s t test and Pearson’s c2 were used to compare continued and discontinued parametric data, respectively. The chi-square test
Characteristic
Value
Sample size Sex distribution Male/female, no. Male/female, % Age at seizure onset, no. (%) <1 yr 1 yr to <5 yr 5 yr to <10 yr 10 yr to <15 yr Age at start of levetiracetam, no. (%) <1 yr 1 yr to <5 yr 5 yr to <10 yr 10 yr to <15 yr 15 yr to <20 yr Seizure types, no. (%) Generalized Generalized tonic/tonic-clonic Spasms Atonic Myoclonic Atypical absence Partial Complex Simple Mental retardation, no. (%) Abnormality on magnetic resonance on imaging, no. (%) Age at seizure onset, yr* Age at start of levetiracetam, yr* Follow-up duration of levetiracetam on therapy, mo* Starting dose of levetiracetam, mg/kg on per day* Maintenance dose of levetiracetam, on mg/kg per day* Concomitant antiepileptic drugs, no.*
n = 130 79/51 61/39 60 (46) 34 (26) 23 (18) 13 (10) 7 (5) 42 (32) 39 (30) 34 (26) 8 (6) 66 (51) 43 (33) 12 (9) 9 (7) 1 (<1) 1 (<1) 64 (49) 52 (40) 12 (9) 90 (69) 81 (62) 3.2 3.0 (0.1-13.6) 7.7 6.1 (0.7-17.4) 13.4 8.7 (6.0-21.0) 21.2 10.2 (8.8-31.8) 47.0 29.7 (17.6-88.8) 2.7 1.1 (2.0-4.0)
* Values are reported as mean 1 S.D. (range).
was used for categorical variables. Significance was set at the P < 0.05 level in analysis.
Results Demographic Data In all, 130 patients (79 boys and 51 girls) were included in the present study (Table 1). The mean age at start of levetiracetam adjunctive therapy was 7.7 years (range, 0.717.4 years). The mean baseline seizure frequency was 16 seizures per month, but the range varied from 4 to 110 seizures per month. Mean starting and maintenance doses of levetiracetam were 21.2 mg/kg per day (range, 8.8-31.8 mg/kg per day) and 47.0 mg/kg per day (range, 17.6-88.8 mg/kg per day), respectively. Mean follow-up duration after start of levetiracetam was 13.4 months (range, 6.0-21.0 months). Approximately two thirds of the patients were
Lee et al: Levetiracetam in Pediatric Epilepsy 87
Table 2. Seizure reduction according to seizure type
Seizure type
Seizure-free, no. (%)
$50 to <100% reduction, no. (%)
No significant response, no. (%)
Worse, no. (%)
Total (n = 130) Generalized (n = 66) GT/GTC (n = 43) Spasm (n = 12) Atonic (n = 9) Partial (n = 64) Complex (n = 52) Simple (n = 12)
28 (22) 17 (26) 8 (19) 5 (42) 3 (33) 11 (17) 9 (17) 2 (17)
34 (26) 12 (18) 9 (21) 2 (17) 1 (11) 22 (34) 18 (35) 4 (33)
64 (49) 36 (55) 26 (60) 4 (33) 5 (57) 28 (44) 23 (44) 5 (42)
4 (3) 1 (2) 0 (0) 1 (8) 0 (0) 3 (5) 2 (4) 1 (8)
Abbreviations: GT = Generalized tonic GTC = Generalized tonic clonic
mentally retarded (90/130, or 69%), and abnormalities were observed on magnetic resonance imaging in 81/130 children (62%). In terms of seizure type, 52/130 children (40%) had complex partial seizures and 43/130 children (33%) had generalized tonic or generalized tonic-clonic seizures. The pediatric epilepsy syndromes observed were Lennox-Gastaut syndrome (28/130, or 22%), infantile spasms (12/130, or 9%), severe myoclonic epilepsy in infancy or Dravet syndrome (11/130, or 8%), and LandauKleffner syndrome (2/130, or 2%). Efficacy After 3 months of levetiracetam adjunctive therapy, 114 of the 130 patients were still being administered levetiracetam (retention rate, 88%). Nine children discontinued therapy because levetiracetam was ineffective, three because seizure frequency increased or because seizures became more severe (or for both reasons), three because they developed adverse events (aggressive behavior in two patients and irritability in one), and one because of inefficacy and adverse events. The results of levetiracetam adjunctive therapy ranged from seizure-free to inefficacy or worsening. Of the 130 patients, 62 (48%) were favorable responders and experienced a reduction in seizure frequency of $50% and 28 of these 62 patients (22% of the total) became seizure-free; 64 patients (49%) had no significant reduction in seizures, and 4 patients (3%) got worse (Table 2). Among children with partial seizures, 33/64 (52%) responded to treatment. Levetiracetam was also efficacious in children with generalized seizures, and achieved a favorable response in 29/66 (44%). A status of seizure-free was achieved in 5/12 patients with spasms (42%), 3/9 patients with atonic seizures (33%), 8/43 patients with generalized tonic or generalized tonic-clonic seizures (19%), and 9/52 patients with complex partial seizures (17%). Favorable responders included 7/12 of patients with spasms (58%), 27/52 of patients with complex partial seizures (52%), and 6/12 patients with simple partial
88 PEDIATRIC NEUROLOGY Vol. 42 No. 2
seizures (50%). Efficacy did not differ significantly among the many seizure types. Efficacy of levetiracetam adjunctive therapy according to MRI abnormalities and mental retardation was investigated. Favorable response rate was similar between children with MRI abnormalities (36/81, or 44%) and those without MRI abnormalities (26/49, or 53%), and did not differ significantly between mentally retarded children (47/90, or 52%) and those with normal mentality (15/40, or 38%). Also, overall efficacy was unaffected by age or levetiracetam maintenance dose (data not shown). Twenty-eight patients (22% of the total) became seizurefree during the period from the start of treatment to 5 months after levetiracetam therapy. Of these 28 children, 15 (12% of the total) became seizure-free immediately within 1 month from the start of levetiracetam and 11 others (8% of the total) achieved a seizure-free state between 1 and 3 months. In the remaining two children (2% of the total), the seizure-free period varied from 3 to 5 months after start of levetiracetam therapy (Fig 1). Duration of levetiracetam therapy for obtaining seizure-free was unaffected by seizure types, MRI abnormalities, and mental retardation. There was no significant difference in efficacy among the specific syndromes (Table 3). Favorable response was observed in 7/12 patients with infantile spasms (58%), in 6/11 patients with Dravet syndrome (also known as severe myoclonic epilepsy in infancy) (54%), and in 13/28 patients with Lennox-Gastaut syndrome (46%). Levetiracetam was discontinued in a greater proportion of patients with infantile spasms (5/12, or 42%), compared with the other two syndromes (2/28 and 0/11) (P < 0.05). During the study, 28/130 patients (22%) achieved seizure freedom during the present study, whereas 102/130 patients (78%) did not. These two groups did not differ significantly with respect to several demographic and clinical features, such as seizure type, abnormality on MRI scan, mental retardation, age at seizure onset, age at start of levetiracetam adjunctive therapy, duration of epilepsy before start of levetiracetam therapy, numbers of concomitant antiepileptic
Of the 130 patients, 9 (7%) reported mild to moderate adverse events while being treated with levetiracetam, but only 5 of the 9 patients (4% of the total) dropped out; the reason for discontinuation was excessive irritability in 3 patients and increased aggressiveness in the other 2. The adverse events in the remaining 4 patients subsided within 4 to 6 weeks during maintenance. The most common complaints were irritability in 6/130 patients (5%), additional aggressive behavior in 2 patients (2%) and somnolence in 1 patient (<1%). None of the adverse events were life threatening. Figure 1. Cumulative curves illustrating the percentage of seizure-free patients after the start of levetiracetam therapy.
drugs, and starting dose and maintenance dose of levetiracetam.
Retention Rate and Tolerability At the final visit, levetiracetam was discontinued in 24/ 130 children (18%), with a mean follow-up duration of 13.4 months. The retention rate (82%) was in general inversely correlated to the duration of follow-up (Fig 2). Reasons for discontinuation included inefficacy in 19/ 130 patients (14%), adverse events in 4/130 patients (3%), and a combination of inefficacy and adverse events in 1 patient (<1%). Patients who discontinued levetiracetam because of adverse events were more often younger (2.6 vs 6.9 years) (P < 0.05), had shorter duration of epilepsy before levetiracetam medication (1.4 vs 3.3 years), were taking lower maintenance doses (39.0 vs 44.6 mg/ kg per day), and discontinued the drug much sooner (1.7 vs 3.6 months) than those who discontinued levetiracetam because of inefficacy.
Discussion The present study reports on seizure reduction and adverse events in 130 children with intractable epilepsy treated with levetiracetam adjunctive therapy. In this large group, levetiracetam was effective and well tolerated, and there were no reports of serious adverse events. At the end of the study, across all seizure types, 62/130 patients (48%) had seizure reductions of $50%, including 28 patients (22%) who became seizure-free. Adverse events were observed in only 9/130 patients (7%). Thus, levetiracetam was helpful as an adjunctive therapy for childhood intractable epilepsy across a broad range of seizure types. A literature review identified previous studies that examined the efficacy and tolerability of levetiracetam as an adjunctive therapy in children with epilepsy (Table 4) [1,5-11]. The follow-up duration for the present study (13.4 months, S.D. = 8.7 months) was much longer than in other studies (14 weeks to 12 months). The retention rate for the present study (82%) was higher than for other studies (33-93%). The proportion of children with $50% seizure reduction ranged from 25% to 61% in other studies, compared with 48% in the present study. A relatively large portion of the present study population (22%) became seizure-free, compared with 5-27% in other studies. In contrast to other studies, the children in the present study had
Table 3. Patient characteristics in three epilepsy syndromes Characteristic
Lennox-Gastaut syndrome
Infantile spasms
Dravet syndrome
Sample size Male/female, no. Seizure reduction, no. (%) Seizure-free $ 50% but <100% No significant response Worse Discontinuing, no. (%) Age at start of levetiracetam, yr† Duration of epilepsy before start levetiracetam, yr† Starting dose of levetiracetam, mg/kg per day† Maintenance dose, mg/kg per day†
n = 28 21/7
n = 12 7/5
n = 11 6/5
4 (14) 9 (32) 15 (54) 0 (0) 2 (7) 7.27 4.43 25.41 52.03
5 (42) 2 (17) 4 (33) 1 (8) 5 (42)* 3.02 2.38 22.70 46.03
3 (27) 3 (27) 5 (46) 0 (0) 0 (0) 7.95 5.97 23.10 39.13
* P value < 0.05. † Mean values.
Lee et al: Levetiracetam in Pediatric Epilepsy 89
Figure 2. Survival curves illustrating the retention rate of patients still being treated with levetiracetam.
intractable epilepsy; they were treated with several antiepileptic drugs before levetiracetam was added on (mean; 2.7 antiepileptic drugs), had a long duration of epilepsy (mean, 4.5 years) relative to the age at start of levetiracetam (mean, 7.7 years), and were frequently mentally retarded (69%). Unlike reports from several studies [1,5,7,9], but in accord with a few others [6,8], the present findings demonstrate that levetiracetam was equally effective in seizure reduction of partial and generalized seizures. Also, levetiracetam was effective in various seizure types, including spasm, atonic, generalized tonic, and generalized tonicclonic seizures, all of which are known to be more intractable to treatment than are other seizure types. A reasonable conclusion is therefore to advocate the use of levetiracetam adjunctive therapy in intractable partial or generalized epilepsy. Supplementary advantages of levetiracetam include lesser interaction with other drugs and fast titration up to target dose [3,4]. Of the 130 patients, children with specific epilepsy syndromes revealed generally favorable efficacy, with favor-
able response observed in 7/12 patients with infantile spasms (58%), in 6/11 patients with Dravet syndrome (54%), and in 13/28 patients with Lennox-Gastaut syndrome (46%). All had intractable epilepsy and were treated with several antiepileptic drugs before levetiracetam was added (mean, 3.3 antiepileptic drugs). Notably, the discontinuation rate of levetiracetam was significantly higher in patients with infantile spasms (42%) (P < 0.05) than in the other two syndromes. This finding indicates that patients with infantile spasms more frequently experience unfavorable effects of levetiracetam and are more prone to adverse events. Dravet syndrome also usually follows a progressive clinical course, but it is not related to any specific symptomatic cerebral lesions or known inborn errors of metabolism. In the 11 patients with Dravet syndrome, even such a clinically predicted degenerative course was improved during the use of levetiracetam adjunctive therapy, although the duration of treatment was only 6-13 months. The data for nonsymptomatic, nonmetabolic progressive intractable childhood epilepsies (including Dravet syndrome) were included in the cohort. In addition to the responder rate, retention rate is an important measure of overall drug compliance, as a reliable compound measure of efficacy and adverse events over time [13]. In a long-term study of levetiracetam in childhood epilepsy, the retention rate for responders after 3 years was 22% [14]. In adults, the long-term retention rates of levetiracetam have been reported as 74% [15] and 60% [13] after 1 year, and 32% after 5 years [13]. At the last follow-up visit of the present study, 106/130 patients (82%) had been on medication with levetiracetam for the entire 13.4-month mean follow-up duration. Thus, in addition to the 62 favorable responders, 44 other children continued levetiracetam. Possible explanations include seizure reduction of <50%
Table 4. Reported efficacy and tolerability of levetiracetam in children with epilepsy
Follow-up duration (range)
Age, yr
n
Seizure type
Retention rate, %
Seizure-free, %
$50% but <100% reduction, %
References
Avg* 8 mo (1-30 mo) Avg* 33 wk (12-86 wk) 20 wk Avg* 7 mo (2-20 mo) 14 wk Avg* 9 mo (3-42 mo) 12 mo 26 wk Avg* 13 mo (3-21 mo)
1.2-10 0-18 0.5-16 0.5-16 4-16 <4 0.3-19 4-16 0.3-17.4
26 209 67 110 101 81 200 33 130
I, G, P I, G, P G, P I, G, P I, P I, G, P I, G, P I, G, P I, G, P
81 33 73 41 93 46 49 70 82
8 6 4 9 7 12 5 27 22
61 25 49 39 45 30 32 52 48
Tan and Appleton, 2004 [7] Opp et al., 2005 [5] Lagae et al., 2005 [8] Grosso et al., 2005 [9]† Glauser et al., 2006 [11]† Grosso et al., 2007 [6] Peake et al., 2007 [10] Callenbach et al., 2008 [1]† Present study†
* Average indicates either mean or median in the cited report. † The children with intractable epilepsy were treated with levetiracetam adjunctive therapy. Abbreviations: G = Generalized I = Intractable P = Partial
90 PEDIATRIC NEUROLOGY Vol. 42 No. 2
being regarded as nonetheless a benefit to the child, perhaps because seizure durations also shortened or a positive cognitive function effect appeared. A retrospective review found that in 122 children younger than 4 years treated with levetiracetam, univariate analysis suggested that children achieving seizure freedom were more likely to have had partial seizures and lower seizure frequency before starting drug treatment, and to have been exposed to a lower maintenance dose of levetiracetam [16]. In the present study, 22% of children became seizurefree, but 78% of did not. These two groups did not differ significantly in terms of seizure types, abnormalities on magnetic resonance imaging, mental retardation, age at start of levetiracetam therapy, or doses and duration of levetiracetam. The clinical trials of levetiracetam in children older than 4 years used a starting dose of 20 mg/kg per day, with titration to a goal of 60 mg/kg per day, which is the current recommended dosing schedule (levetiracetam package insert; UCB, Brussels, Belgium). Opp et al. [5] and Grosso et al. [9] reported lower mean doses of levetiracetam in children who became seizure-free than in those who did not become seizure-free. Studies in adults have yielded discordant results, with one report indicating a inverse relation between mean dose of levetiracetam and efficacy [17], but others disclosing that high doses are associated with a more favorable response [18]. The present analysis suggested that overall efficacy of levetiracetam adjunctive therapy in childhood intractable epilepsy was unaffected by age or dose. A recently published a study assessed long-term outcome of levetiracetam in 129 children with severe intractable epilepsy for up to 3 years [14]. The authors reported that younger patients are more susceptible to adverse events, and that behavioral problems such as aggressiveness, mood changes, or irritability occur more frequently in pediatric patients, compared with findings of studies in adults [5,19-21]. In a study conducted in Germany [5], sleep disturbances and behavioral disorders were most frequent in patients with physical handicaps or mental retardation. In the present study, mild to moderate adverse events, such as irritability and aggressive behavior, were observed in 9/130 patients (7%). These adverse events occurred within 2 weeks after start of levetiracetam in 5 of the 9 patients, and occurred within 1 month in the remaining 4 patients. The incidence of adverse events was exceedingly low in the present study. A possible explanation for this phenomenon could be the failure to use a standardized questionnaire regarding the incidence of adverse events. Presence of adverse reactions were inquired for in general term only, and it seems likely that far fewer children or caregivers report such incidences spontaneously than if they were asked about them in a more specific manner. It is also possible that improvement in seizure frequencies have resulted in far better tolerability of adverse events than would have otherwise been endured. Adverse events did lead to the discontinuation of drug treatment in 5 of 9
patients, and the patients who discontinued levetiracetam because of adverse events were younger and discontinued the drug much sooner than did those in whom levetiracetam was regarded ineffective. In 4/130 patients (3%), seizures were more frequent after the start of levetiracetam therapy. Other authors have noted this occurrence of adverse events in mentally retarded patients or patients with behavioral problems [22]; in the present study, however, roughly two thirds of the patients (90/ 130) were mentally retarded, but seizures increased in only 4 patients. Increase of seizure frequency during levetiracetam treatment had also been observed in 9-18% by other authors [1,6,10]. This phenomenon may, however, indicate the natural course of the epilepsy rather than a true activation due to levetiracetam add-on therapy. Further prospective comparative studies are needed to assess the efficacy and tolerability and to elucidate potential variables for the use of levetiracetam in treatment of children with intractable epilepsy. Nonetheless, levetiracetam can be considered an effective and well-tolerated treatment as adjunctive therapy in children with intractable partial or generalized epilepsy without incurring significant adverse events. References [1] Callenbach PM, Arts WF, ten Houten R, et al. Add-on levetiracetam in children and adolescents with refractory epilepsy: results of an openlabel multi-centre study. Eur J Paediatr Neurol 2008;12:321-7. [2] Lynch BA, Lambeng N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci U S A 2004;101:9861-6. [3] Patsalos PN. Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol Ther 2000;85:77-85. [4] Pellock JM, Glauser TA, Bebin EM, et al. Pharmacokinetic study of levetiracetam in children. Epilepsia 2001;42:1574-9. [5] Opp J, Tuxhorn I, May T, et al. Levetiracetam in children with refractory epilepsy: a multicenter open label study in Germany. Seizure 2005;14:476-84. [6] Grosso S, Cordelli DM, Franzoni E, et al. Efficacy and safety of levetiracetam in infants and young children with refractory epilepsy. Seizure 2007;16:345-50. [7] Tan MJ, Appleton RE. Efficacy and tolerability of levetiracetam in children aged 10 years and younger: a clinical experience. Seizure 2004; 13:142-5. [8] Lagae L, Buyse G, Ceulemans B. Clinical experience with levetiracetam in childhood epilepsy: an add-on and mono-therapy trial. Seizure 2005;14:66-71. [9] Grosso S, Franzoni E, Coppola G, et al. Efficacy and safety of levetiracetam: an add-on trial in children with refractory epilepsy. Seizure 2005;14:248-53. [10] Peake D, Mordekar S, Gosalakkal J, et al. Retention rate of levetiracetam in children with intractable epilepsy at 1 year. Seizure 2007;16: 185-9. [11] Glauser TA, Ayala R, Elterman RD, et al. N159 Study Group. Double-blind placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology 2006;66:1654-60. [12] International League Against Epilepsy, Commission on Classification and Terminology. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22: 489-501. [13] Krakow K, Walker M, Otoul C, Sander JW. Long-term continuation of levetiracetam in patients with refractory epilepsy. Neurology 2001; 56:1772-4.
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[14] von Stuelpnagel C, Holthausen H, Kluger G. Long-term use of levetiracetam in patients with severe childhood-onset epilepsy. Eur J Paediatr Neurol 2007;11:341-5. [15] Nicolson A, Lewis SA, Smith DF. A prospective analysis of the outcome of levetiracetam in clinical practice. Neurology 2004;63:568-70. [16] Perry MS, Benatar M. Efficacy and tolerability of levetiracetam in children younger than 4 years: a retrospective review. Epilepsia 2007;48: 1123-7. [17] Betts T, Waegemans T, Crawford P. A multicentre, double-blind, randomized, parallel group study to evaluate the tolerability and efficacy of two oral doses of levetiracetam, 2000 mg daily and 4000 mg daily, without titration in patients with refractory epilepsy. Seizure 2000;9:80-7. [18] Privitera M. Efficacy of levetiracetam: a review of three pivotal clinical trials. Epilepsia 2001;42(Suppl. 4):31-5.
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[19] Shorvon SD, Lo¨wenthal A, Janz D, Bielen E, Loiseau P; European Levetiracetam Study Group. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. Epilepsia 2000;41: 1179-86. [20] Cereghino JJ, Biton V, Abou-Khalil B, Dreifuss F, Gauer LJ, Leppik I. Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology 2000;55:236-42. [21] Mula M, Trimble MR, Sander JW. Psychiatric adverse events in patients with epilepsy and learning disabilities taking levetiracetam. Seizure 2004;13:55-7. [22] Nakken KO, Eriksson AS, Lossius R, Johannessen SI. A paradoxical effect of levetiracetam may be seen in both children and adults with refractory epilepsy. Seizure 2003;12:42-6.