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Summary: Purpose: To review our experience of the efficacy and tolerability of levetiracetam (LEV) in .... A complete HIPAA waiver was obtained from the Emory ...

Epilepsia, 48(6):1123–1127, 2007 Blackwell Publishing, Inc.  C 2007 International League Against Epilepsy

Efficacy and Tolerability of Levetiracetam in Children Younger than 4 Years: A Retrospective Review ∗ M. Scott Perry and †Michael Benatar Departments of ∗ Pediatrics, Division of Pediatric Neurology, and †Neurology, Emory University, Atlanta, Georgia, U.S.A.

Summary: Purpose: To review our experience of the efficacy and tolerability of levetiracetam (LEV) in children younger than 4 years. Methods: We used retrospective chart review to identify 122 children with seizures who were younger than 4 years and followed for ≥6 months. Efficacy was evaluated on the basis of the occurrence and durability of seizure remission. Tolerability was based on parent- and patient-reported side effects. Results: Seventy (57%) subjects achieved seizure remission, and 52 (43%) did not. In univariate analysis, those achieving seizure remission were more likely to have partial epilepsy, require lower maintenance doses of LEV, and have fewer than two seizures per month at initiation of the medication. Only seizure frequency at initiation of LEV remained significant in

multivariate analysis. The median duration of seizure freedom (8.9 months) was not influenced by age, epilepsy type, gender, or pretreatment seizure frequency. The dose of LEV was the only significant predictor of the duration of seizure remission, with longer duration of seizure remission seen in those taking 30 mg/kg/d (median, 12.8 months vs. 3 months; p < 0.0001). Side effects of LEV occurred in 34% of subjects but required discontinuation in only 16%, most commonly because of behavioral disturbances. Conclusions: LEV is an effective medication in children younger than 4 years and at doses lower than previously reported. It is also well tolerated, suggesting that it represents an important option for the treatment of epilepsy in this age group. Key Words: Levetiracetam—Epilepsy—Children.

Within the first year of life, the incidence of epilepsy is the highest, and it declines throughout childhood and adolescence. Five of the newest antiepileptic drugs (AEDs)—gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OXC), topiramate (TPM), and levetiracetam (LEV)—have demonstrated efficacy as adjunctive therapy in children with treatment-resistant partial-onset seizures (Glauser et al., 2002). Only three of these medications have indications for children younger than 4 years (TPM, LTG, and GBP), and none is approved for children younger than 2 years. The discrepancy between the high incidence of epilepsy in children and the small number of approved AEDs for their treatment is striking. Because placebo-controlled medication trials in children are difficult, retrospective review of experience with these AEDs can be of great value. LEV is a novel AED recently approved for use as add-on therapy for partial seizures in children older than 4 years.

Retrospective studies have suggested broad-spectrum efficacy against both primary and secondary generalized epilepsies (Koukkari and Guarino, 2004; Vigevano, 2005). Compared with the extensive collection of data on the use of LEV in adults, limited literature documents the results in children. Vigevano (2005) recently reviewed the data on LEV use in children. Of the published studies, all were retrospective or open-label uncontrolled prospective studies (Wheless and Ng, 2002; Koukkari and Guarino, 2004; Grosso et al., 2005; Lagae et al., 2005; Vigevano, 2005). The data revealed 50% seizure-reduction rates ranging from 28 to 64% in the populations studied. Only one of these studies specifically reported data on patients younger than 4 years. Grosso et al. (2005) included 21 children younger than 4 years taking LEV. Patients with localization-related epilepsy more often achieved >50% seizure reduction versus those with generalized epilepsy (61% vs. 50%), although the small sample did not permit statistical analysis. More recently, Glauser et al. (2006) conducted a prospective double-blind placebo-controlled trial of LEV in children (4–16 years) with partial seizures, which demonstrated efficacy as adjunctive therapy. However, only one study has specifically targeted very young patients. Frost et al. (2002) treated 22 patients, all younger than 2 years, with a variety of epilepsy syndromes, and

Accepted November 29, 2006. Address correspondence and reprint requests to Dr. M.S. Perry at Department of Pediatrics, Division of Pediatric Neurology, Emory University, 2015 Uppergate Drive, NE, Atlanta, GA 30322, U.S.A. E-mail: Scott [email protected] doi: 10.1111/j.1528-1167.2007.01003.x

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reported a 50% reduction in seizure frequency in 50% of the patients. LEV has a favorable safety profile and lacks significant interaction with other AEDs, making it an attractive choice for add-on therapy. In children, side effects have been reported in 33–45% of patients treated with LEV, with somnolence and negative psychotropic effects the most frequently reported (Koukkari and Guarino, 2004; Lagae et al., 2005; Opp et al., 2005). We reviewed a large number of children younger than 4 years taking LEV to determine the tolerability, efficacy, and utility of the medication in this young age group. METHODS Subjects for this study were retrospectively identified from the Emory Children’s Center clinical database by a search for ICD-9 codes (345.x seizure, 780.x other convulsion). The study population comprised a consecutive series of children younger than 4 years who were treated with LEV between July 2000 and July 2005 and for whom ≥6 months of clinical follow-up was available. Subjects were excluded if the diagnosis of nonepileptic events was confirmed by video electroencephalography (EEG), or if the chart had been lost or destroyed. A complete HIPAA waiver was obtained from the Emory University Institutional Review Board for medical record review. All clinical diagnoses were made and clinical care provided by a pediatric neurologist. The general therapeutic strategy was to titrate the dose of LEV until patients were seizure free, adverse effects requiring discontinuation of therapy were reported, or the treating physician determined the drug to be ineffective. Estimates of seizure frequency and the occurrence of side effects were based on parental report. For the purposes of this study, data extracted from the chart included patient demographics, seizure type and frequency, epilepsy type, age at LEV initiation, dosage by weight at each visit, previous and concomitant AEDs, side effects, and duration of treatment. Epilepsy type was classified as partial or generalized based on the clinical history, seizure semiology, EEG, and magnetic resonance imaging (MRI) findings when possible. Epilepsy type was classified as “uncertain” when seizure semiology was unclear and EEG and MRI were normal. At each clinic visit, seizure-free status was classified dichotomously, based on the occurrence of any seizures since the time of the prior visit. If LEV was discontinued, the reason for drug discontinuation was categorized as lack of efficacy or side effects, based on the clinical record. For all subjects, the average daily dose of LEV was calculated as a weighted average based on the relative duration of therapy for each individual dose. Study subjects were initially dichotomized into two groups: those who achieved remission at any stage during follow-up Epilepsia, Vol. 48, No. 6, 2007

(i.e., were documented to be seizure free at the time of a follow-up clinic visit) and those who did not. Univariate statistics were used to compare these two groups. The Student’s t-test and Wilcoxon rank sum score test were used to compare continuous parametric and nonparametric data, respectively. The chi-square and Fisher’s exact tests were used for categorical variables. Unconditional multivariate logistic regression analysis was used to model the log odds of achieving seizure remission as a function of those variables that were significantly different between the two groups at the p < 0.05 level in univariate analysis. For those subjects who achieved seizure remission, the time to recurrence of seizures was calculated by using Kaplan–Meier survival analysis. Cox proportional hazards regression was used to evaluate the impact of potential predictors on the survival time (i.e., time from remission to recurrence of seizures). RESULTS The database search yielded 587 children with seizures who were younger than 4 years. One hundred twentytwo of these subjects met prespecified inclusion criteria. They ranged in age from 1 to 48 months. The median duration of follow-up was 20 months (interquartile range, 13.4–29.7). In 48 (39%) patients, LEV was initiated as monotherapy, and the remaining 74 (61%) patients received the medication as adjunctive therapy (mean number of concomitant AEDs, 1.9; range, 1–5). Phenobarbital (PB) was the most common concomitant AED (45%), followed by TPM (20%), carbamazepine (CBZ; 16%), phenytoin (PHT; 15%), clonazepam (CZP; 15%), valproic acid (VPA; 14%), OXC (14%), zonisamide (ZNS; 7%), LTG (7%), and GBP (1%). Seventy (57%) subjects achieved seizure remission at some time during the study, whereas 52 (43%) did not. These two groups differed with respect to several important demographic and clinical features (Table 1). Subjects that became seizure free tended to be older than those that never achieved seizure remission. Thirty-five percent of patients younger than 1 year (n = 20) achieved some period of seizure freedom, versus 53% of those aged from 1 to 2 years (n = 30), 67% of those from 2 to 3 years (n = 27), and 64% of patients from 3 to 4 years (n = 45). The rate of seizure freedom did not differ significantly as a function of age (p = 0.11). Partial seizures were more common among those who became seizure free, whereas generalized seizures were more common among those who did not. Among patients with generalized epilepsy, no statistically significant differences were found between those that became seizure free and those that did not, based on the type of seizure (data not shown). Overall, generalized seizure types were present in 33 (27%) patients. Of those with generalized seizures, myoclonic seizures

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TABLE 1. Study subject characteristics

Number of patients Median age (yr) (interquartile range) Gender Male Female Epilepsy type Partial (no.) Generalized (no.) Uncertain (no.) Mean seizure frequency per mo before LEV initiationa Average dose (mg/kg/d) Monotherapy initiation (n = 48) LEV discontinued Side effects (no.) Lack of efficacy (no.)

Never seizure-free

Seizure-free

p Value

52 1.97 (1–3.13)

70 2.68 (1.66–3.43)

0.08

27 (52%) 25 (48%)

42 (60%) 28 (40%)

37% (19) 48% (25) 15% (8) 66.7 (range, 0–300) n = 38 39.25 (range, 9–119) 18 (38%)

63% (44) 11% (8) 26% (18) 26.4 (range, 0–300) n = 48 31.92 (range, 10–139) 30 (62%)

600 seizures per mo) and were not included in the statistical analysis.

were most common (48%), followed by generalized tonic– clonic (45%), tonic (30%), atonic (12%), absence (12%), and clonic (6%). Several patients had multiple generalized seizure types. The use of LEV as monotherapy versus adjunctive therapy was not associated with the prognosis for seizure remission. Similarly, among those subjects in whom LEV was used as adjunctive therapy, no association occurred between the number of concomitant AEDs and the prognosis for achieving seizure remission. PreLEV treatment seizure frequency, as well as average LEV dose during the treatment period, however, were lower among those who subsequently achieved seizure remission. The pretreatment frequency of seizures was the only predictor of seizure remission that remained significant in multivariate analysis. Those with more than two seizures per month before initiation of LEV were significantly less likely to achieve seizure remission than were those with fewer than two seizures per month [odds ratio (OR), 0.29; 95% confidence interval (CI), 0.10–0.86). Subjects who never achieved seizure freedom were more likely to discontinue LEV for both adverse effects and lack of efficacy. Among those who achieved remission, the median duration of the seizure-free period was 8.9 months (95% CI, 6.2–12.2 months). No statistically significant differences in the time to seizure relapse were found, based on age, gender, epilepsy type, or pretreatment seizure frequency (data not shown). The median time to seizure recurrence (95% CIs) was, however, significantly shorter among those with an average dose >30 mg/kg/day (3 months, 1.6–11.3) compared with those with an average daily dose

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