Pharmacodynamics of low-dose clonazepam in children with epilepsy or spasticity : neurophysiological and clinical studies

In children with epilepsy the evaluation of the efficacy of an antiepileptic drug (AED) is usually made by recording the seizure frequency. Some seizures are subtle and difficult to detect and epileptiform activity even without clinical seizures may cause cognitive dysfunctions. Therefore, the addition of objective quantitative methods to measure the amount of epileptiform discharges is important in the evaluation of AED effects. In clinical practice, we noticed an effect on seizure frequency and spasticity even at very low doses of the AED clonazepam (CZP). At the higher recommended doses, side effects are often prominent. The aim of these studies was to improve quantitative objective methods for measuring the pharmacodynamic effects in children with epilepsy and spasticity and, using these methods, evaluate the short-term effects of low-dose CZP, 0.02 mg/kg BW, as a single injection. In a double-blind, randomized, cross-over study of 12 children with cerebral palsy, the spastic restraint in response to low-dose CZP was quantified by means of a dynamic dynamometer and the averaged EMG activity in stretched muscles. A significant reduction of spastic restraint was demonstrated (p<0.001) at mean plasma levels of 21 nmol/L (range 11-33) during examinations. Epileptiform discharges fluctuate over time and knowing whether systematic spontaneous fluctuations occur is important for the evaluation of therapy. The number of epileptiform discharges in 24-h EEG recordings on two consecutive days and on days with an interval of a month were compared in children with epilepsy. Intraindividual changes on different days counterbalanced one another and no systematic differences were found. The variability was larger though when the interval was one month than it was on consecutive days (SD 86% and 33%). The mean magnitude of change was 55% between days separated by a month compared to 24% on consecutive days. In a double-blind, randomized, cross-over study in children with epilepsy the amount of epileptiform activity was compared on 24-h digital EEG recordings in response to low-dose CZP. A significant reduction (p=0.001 5) was found with median plasma levels ranging from 18 down to