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

University dissertation from Stockholm : Karolinska Institutet, Department of Women's and Children's Health

Abstract: 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 <14m- nol/L. Magnetoencephalography (MEG) was used in a pilot study of children with partial epilepsy. In 4 out of 5 children, a decrease in the magnitude of the current source generating epileptiform discharges was paralleled by a decrease in the number of discharges as well as their repetitiveness within episodes in response to low-dose CZP. In one child the opposite findings were noted. In an open study of 19 children with a high seizure frequency, a reduction of seizures was found in response to low-dose CZP (p=0.003 1) and was obtained at median maximal plasma levels of 23 nmol/L (range 11-41). In conclusion, using three objective quantitative methods, short-term effects of CZP in epilepsy and spasticity were demonstrated at doses and plasma levels well below those recommended. These dose levels could be used in the clinic for short-term treatment. The duration of effects during longterm treatment has to be determined in further studies. In studies of AEDs, it should be possible to use as a baseline day either a day immediately before or a month apart from the day of the AED examination. When evaluating AED effects in an individual child with prolonged EEGs, the large spontaneous variability must be taken into account. Our results also indicate that prolonged EEG recordings can be employed in children and that they give information concerning the extent to which an AED may influence epileptiform discharges. MEG may provide additional information. To make an optimal treatment choice taking into account both seizures and epileptiform activity, a knowledge of how different AEDs affect epileptiform discharges is needed. To measure these effects, quantitative methods of evaluation are necessary. The methodology for quantification used in these studies can be applied to other AEDs.

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