Journal Club Neuropsychological effects of levetiracetam and carbamazepine in children with focal epilepsy. Rebecca Luke 2/9/2016

Article Jung DE, Yu R, Yoon JR, et al. Neuropsychological effects of levetiracetam and carbamazepine in children with focal epilepsy. Neurology 2015;84:

Importance Choice of anti-epileptic drugs in the pediatric population is generally based on seizure type, efficacy, and side effect profile Pediatric epilepsy patients are still developing their nervous system and cognitive impairment is always a concern with the use of anti-epileptic drugs Studies have demonstrated that Keppra has a limited cognitive effect but rarely studied as monotherapy with a focus on the cognitive effects FDA approved for focal seizures in children ages 1 month and older Limited data as monotherapy

KEPPRA INDICATION KEPPRA (levetiracetam) is a prescription medicine taken by mouth that is used with other medicines to treat primary generalized tonic-clonic seizures in people 6 years of age and older with certain types of generalized epilepsy, myoclonic seizures in people 12 years of age and older with juvenile myoclonic epilepsy, and partial onset seizures in people 1 month of age and older with epilepsy.

Methods Multicenter – 7 centers in South Korea Randomized, open label, non-inferiority Children ages 4-16 Newly diagnosed with focal epilepsy Randomized into two treatment groups Blinded

4 week titration period Dosing 20mg/kg/day LVT titrated up to minimum 40mg/kg/day 10mg/kg/day CBZ titrated up to minimum 20mg/kg/day 24 weeks of stabilization If any seizures, increased up to max dose 60mg/kg/day (max 3000mg/day) LVT 30mg/kg/day (max 1200mg/day) CBZ 24 weeks of maintenance

Inclusion Criteria Ages 4-16 years of age Newly diagnosed focal epilepsy International League Against Epilepsy classification At least 2 unprovoked seizures >24 hours apart 1 unprovoked seizure and probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years Diagnosis of epilepsy syndrome No previous AEDs Above-borderline intelligence Informed consent

Exclusion criteria Any coexisting progressive neurologic or systemic disease Use of AEDs (Benzos okay as rescue therapy) > 2fold elevation of serum glutamic oxaloacetic transaminase/serum glutamic pyruvic transaminase or > 3 fold elevation of BUN/Cr Hypersensitivity reactions Concurrent serious psychiatric diagnosis

Neuropsych Testing Up to 14 days before initiation At the end of 52 weeks of treatment To assess intellectual ability Two different tests – one ages 4-6 and one 6-16 Korean Wechsler Intelligence Scales To assess behavioral problems Korean Child Behavior Checklist Filled out by guardian/parents To assess depression/anxiety – self reporting? Children’s Depression Inventory Revised Children’s Manifest Anxiety Scale

Efficacy Daily seizure reports Filled out by parents/guardians Ictal events based on ILAE criteria 2010 Baseline seizure frequency – previous 24 weeks before first visit Mean percentage reduction >50% reduction from baseline Seizure freedom rate

Analysis Minimum 42 subjects per group needed for 80% power Enrolled 120 – 60 randomized to each group 41 and 40 completed the trial

Results No significant demographic or clinical differences between the two groups Both groups with comparable neuropsychological scores at baseline

LVT treated patients with improvement in internalizing behavioral problems (p=0.004) CBZ treated patients showed more improvement in their depression scores (p=0.027) Neither group had worsening of test scores at the end of the treatment

Efficacy Final doses CBZ mean dosing mg/kg/day LV mean mg/kg/day Reduction of seizure frequency Went from 3.50 to 0.15 for the CBZ group Went from 3.15 to 0.09 fro the LVT group

Side effects Slightly higher number of adverse events in CBZ group but not significant Somnolence, rash, pruritus, headache One LVT patient with anxiety and another with inattentiveness

Conclusions LVT did not negatively affect cognitive function over the study period of a year LVT showed improvement in internalizing behavioral problems CBZ demonstrated improvement in depression CBZ has mood stabilizing properties in psychiatric patients LVT and CBZ are equally effective in controlling newly diagnosed focal epilepsy as monotherapy LVT and CBZ are relatively well tolerated

Limitations Only parents/guardians were able to report on behavioral changes No teachers or caregivers – parents concerned about stigma of epilepsy Did not have 42 subjects per study group which was desired Did not included patients with lower intelligence Does not include patients with significant psychiatric conditions Paper notes that LVT behavioral side effects have been reported to occur more frequently in patients with a learning disability or prior psychiatric history Does not included effects of polypharmacy Does not report on long-term effects greater than a year

Would I be okay with Keppra for my children?