Abstracts

Rationale: Levetiracetam s favorable safety profile, low potential for drug interactions, high bioavailability and linear pharmacokinetics make it an attractive agent for epilepsy in children (Patsalos, P.N., Clinical pharmacokinetics of levetiracetam. Clin.Pharmacokinet. 2004:43,707-724). While typically titrated up to a maximum of 40-60 mg/kg/day, intravenous levetiracetam doses as high as 228 mg/kg/day were effective in controlling acute seizure exacerbations, and were not associated with serious adverse effects in a recent report (Depositario-Cabacar, D.T. et al., High-dose intravenous levetiracetam for acute seizure exacerbation in children with intractable epilepsy. Epilepsia. 2010 Feb 12). We sought to determine whether oral LEV is tolerable and helpful in seizure control at doses higher than 60 mg/kg/day in the pediatric outpatient population. Methods: A retrospective chart review over a 1.5-year period was performed at the Columbia Comprehensive Epilepsy Center to identify children who were treated with levetiracetam doses titrated above 40-60 mg/kg/day. Data was collected on seizure semiology, epilepsy type, seizure frequency, other antiepileptic drugs used concomitantly with levetiracetam, and adverse effects. Results: Thirty-two children, ranging in age from 1 year to 19 years, required high dose levetiracetam. Seizure types included epileptic spasms, atypical absence, head drops, myoclonic, astatic, generalized tonic-clonic, and absence seizures. Sixteen children (50%) had complex partial seizures. Five children had generalized and focal seizures. All but one patient were concomitantly treated with other antiepileptic drugs: 13 children (41%) were taking one other antiepileptic drug, 12 (37%) were taking two, 5 (16%) were taking 3, and one child was taking 4. The most common concomitant antiepileptic drugs were valproate and clonazepam. The mean dosage of levetiracetam was 148mg/kg/day (range, 70-275 mg/kg/day), and the mean maximum serum trough level was 47 mcg/ml (range, 20-121 mcg/ml). Levetiracetam serum levels increased linearly with the daily weight-based dosage. A more than 50% reduction in seizure frequency was observed in 14 children (44%), with 5 achieving seizure freedom. No response to high dose levetiracetam was found in 14 children, and worsening of seizure frequency occurred in 4. The proportion of responders was the same in children with generalized and those with partial seizures. A favorable response was recorded in all the main etiologic subgroups. Adverse effects occurred in 4 children (12.5%), and included irritability in 3 children at doses of 73.5, 142, and 150 mg/kg/day, and hyperactivity in a child at a dose of 96 mg/kg/day. Conclusions: Not only do some children tolerate high doses and serum levels of levetiracetam, but they may also benefit from them, suggesting that doses higher than 60 mg/kg/day may be considered in children who partially respond to the lower doses.