Onset of action of levetiracetam:: A RCT trial using therapeutic intensive seizure analysis (TISA)

Objectives: To correlate the onset of clinical effects of add-on levetiracetam (LEV) therapy with daily serum LEV concentration, in pharmacoresistant focal epilepsies, using the TISA method. Methods: 25 adult patients (aged > 16 years) with pharmacoresistant focal epilepsies undergoing presurgical evaluation at the Epilepsy Center Erlangen were enrolled in the study. Eligible patients on a maximum of one other antiepileptic drug (AED) were recruited into the 48-hour baseline phase. Those who had at least two seizures during this phase were randomized into the seven-day treatment phase, when they received either LEV or placebo, under continuous day-and-night video-EEG monitoring. The starting daily dose of LEV was 500 mg bid, titrated from the second treatment day to 1000 mg bid. The peak serum concentration of LEV was monitored daily at 8:00 am (one hour after drug administration) for every patient. The number and duration of seizures per 24h (N/24h and D/24h respectively) were investigated. Results: 23 patients completed the study (LEV group n = 11 and placebo group n = 12). Seven patients in the LEV group and two patients in the placebo group achieved seizure-freedom during the treatment phase. The intergroup comparison of the decrease in N/24h and D/24h from the baseline phase to the treatment phase was in favor of the LEV group (p < 0.05). A significant effect of LEV on D/24h was seen as early as the second treatment day (p = 0.013), becoming more apparent on the third treatment day (p = 0.009). Conclusion: The present study objectively quantified the correlation between the anticonvulsant effects of LEV in focal epilepsies and the peak serum concentration of the drug. For the first time, direct measurement was used to demonstrate the onset of action of LEV to be two days after drug initiation.