The effects of different anticonvulsants on the system of cir-cadian and ultradian rhythms in the EEG of children was investigated

in ten 24*-h recordings of children with different forms

of epilepsy. Circadian dysrhythmias could be found in children

with Clonazepam treatment

Arbogast, B.

Arbogast, Helmut

Hallek, M.

Hellbrügge, T.

Schmid, R.

English

Open Access LMU

C I R C A D I A N D Y S R H Y T H M I A S I N T H E E E G O F C H I L D R E N W I T H C L O N A Z E P A M T R E A T M E N T B. Arbogast, Μ. Hallek, Η. Arbogast, Τ. Hellbrügge and R. Schmid Institute of Social Pediatrics. University of Munich, Lindwurmstrasse 131, 8000 Munich 2, F.R.G. ABSTRACT The e f f e c t s of d i f f e r e n t anticonvulsants on the system o f c i r -cadian and u l t r a d i a n rhythms i n t h e EEG o f c h i l d r e n was i n v e s t i -gated i n t e n 24*-h recordings of c h i l d r e n w i t h d i f f e r e n t forms of epilepsy. Circadian dysrhythmias could be found i n c h i l d r e n w i t h Clonazepam treatment, KEYWORDS Circadian dysrhythmia, EEG, Ant i c o n v u l s a n t s , Chronobiologic Fre-quency p r o f i l e , Clonazepam INTRODUCTION I t i s a g e n e r a l l y accepted f a c t t h a t medication w i t h a n t i c o n -vulsants i s connected w i t h numerous p h y s i o l o g i c and psychologic side e f f e c t s which depend on. the choice o f medicaments ( K u t t and Louis, 1972), and changes of b e h a v i o r a l schedules (sleep, a c t i -v i t y , etc.) can o f t e n be observed. The purpose o f t h i s study i s the d e t e c t i o n o f eventual changes i n the EEG rhvthm soectrum due to d i f f e r e n t a n t i c o n v u l s a n t s . METHOD Ten 24-h-EEGs were recorded f o r c h i l d r e n s u f f e r i n g from d i f f e -r ent forms o f epilepsy. There were f o u r medication crroups which are shown i n t a b l e 1. Table 1: D i f f e r e n t medication groups ( c l a s s i f i c a t i o n o f subjects) 0 No medication (2 subj.,average age 15.5 months) Ρ Phenobarbital (2 subj.,average aae 11.5 months) CP Clonazepam and Phenobarbital (4 s.,av.aqe 1 3.8ni c I Clonazepam (2 SUbi . . averanP acre* g.5 m o n t h s 17 18 Β. Arbogast et al. The EEG was recorded using small-surface c h l o r i n a t e d s i l v e r electrodes which were pasted t o the c h i l d ' s head according t o a reduced Ten-Twenty-system (Figure 1). On-line computations of 5-minutely "frequency histograms" (see M e i e r - K o l l , 1978, Arbo­gast et a l . , i n press) t o obtain EEG c h a r a c t e r i s t i c s t o be used for f o r f u r t h e r analyses. Spectral analyses of variance were computed,using the data of the temporal and p a r i e t o - o c c i p i t a l channels of the l e f t hemisphere, w i t h i n e i g h t chronobiologic period ranges from 24 hours t o 45 minutes (see Arbogast, 1984). Multiple c l a s s i f i c a t i o n C: C e n t r a l Dt P a r i e t a l Figure 1 analysis based on spec- ' -t r a l analysis of variance was applied t o quantify the e f f e c t s due t o medi­cation . Chronobiologic frequency p r o f i l e s (see Arbogast, Ϊ984, Arbogast et a l . , i n press) were used t o summarize r e s u l t s . RESULTS The impact of medication on the spectrum of chronobiologic rhythms i n the EEG was found t o be h i g h l y dependent on the choice of anticonvulsants. I n terms of percentual c o n t r i b u t i o n s of d i f f e r e n t chronobiologic p e r i o d i c i t i e s t o the t o t a l v a r i a ­b i l i t y in.the EEG, the fo l l o w i n a s t a t i s t i c a l l y s i g n i f i c a n t e f ­fects could be detected (p<.05): Circadian v a r i a t i o n i s s l i g h t l y increased i n case of Phenobar^-b i t a l treatment, while Clonazepam seems t o cause a strong r e ­duction. The semidian component i s reduced i n case of Pheno­b a r b i t a l or Clonazepam treatment (groups Ρ and C, see t a b l e 1 ) . A prominent 8-hour component can be found i n EEG v a r i a t i o n o f children treated w i t h Clonazepam (group C i n Table 1 ) . Circaduohoran rhythms are more prominent f o r a l l kinds o f medi­cation, especially f o r Clonazepam alone (group C i n t a b l e 1) . Figure 2 displays a l l s i g n i f i c a n t medication "effects a r a o h i c a l l y i VARIATION 2*h 12h 8h CHRGNOBIOLOÜtC PERIOD RANGE 'i.7h Figure 2: Bar Diagram of rhythm percentaaes of different chronobioloaic pe^ -riods i n the EEG within different medication groups (total of 10 children with ages rangincr from 8 to 20 months. Results of spectral analyses of variance including multiple classification analysis. Q : No medication m : Phenobarbital 0 0 : Phenobarbital and Clonazepam Μ : Clonazepam •fS? i? overview of the average structure of chronobiolocric rhvthmicity L ^ n ? ^ ^ S ? i s g i v e n ^ the chronobioiocric freouencv 22« i f r^Lli^ ?" ^ s t r f ^ Effects of Clonazepam treatment can be " seen by comparing c), d) to a), b). C i r c a d i a n dysrhythmias w i t h clonazepam 19 Figure 3 Chronobiologic frequency profiles for children with different forms of therapy: Percentual contribution (z-axis) of different chronobjoloqic periodicities (x-axis) within different EEG freauency ranaes (y axis) . a) 2 individuals, 11 resp. 2θ months; b) 2 individuals, 11 resp. 12 months c) 4 ind., 11,12,12, resp. 23 months; d) 2 ind., 8 resp. 11 months of aae. 20 Β. Arbogast et al. DISCUSSION Up to now, only time-unspecified side effects of anticonvulsants were con­sidered and described : sleepiness, general tiredness, reduced mental a b i l i ­ty and specific physiologic changes (compare Kutt and Louis, 1972). In this study, i t could be shown that medication with anticonvulsants can also cause circadian dysrhythmias in the EEG. Especially i f the medicament of choice i s Clonazepam, the circadian component I s strongly reduced while ultradians become predominant, corresponding to behavioral observations which can often be made i n c l i n i c a l routine. Dyschronisms of t h i s kind can eventually be avoided i f therapy i s oriented towards cihronqphannacological aspects, which i s postulated by Halberg (1978) because of evident circadian receptor rhythms in the CNS. Arbogast, Β., Arbogast,- Η., Kleiser, Β., Hawel, W., Hellbrügge, Τ., Schiel, W., Schmid, R. (in press) Circadian and ultradian rhythms i n the EEG of young children. Proc. XVI. Conf. of the ISC, Dublin 1983 (Pergamon Press) Arbogast, Β. (1984). Methoden für die chronobiologische Analyse von Lang-zeit-Eiektroenzeriialograimien und einige Anwendungen i n der Päd-iatr i e . Dissertation, Univ. of Munich" Halberg, F. (1978). The chronobiology of convulsive disorders with notes on drugs affecting the CNS. Totus Homo, 10, 8 Kutt, Η., Louis, S. (1972). Untoward effects of anticonvulsants. New Engl. J . Med., 286, p. 1316 — Meier-Kbll, A. (1978). Analysis automatico del electroencephalcctrama en pediatria. I Metcdologia, I I Aplicaciones c l i n i c a s . Arch.IWh^t. Uruguay 

Ciradian dysrhythmias in the EEG of children with clonazepam treatment

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Ciradian dysrhythmias in the EEG of children with clonazepam treatment

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