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Seizure-inducing paradoxical reaction to antiepileptic drugs
Brain & Development 22 (2000) 243±245
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Case report
Seizure-inducing paradoxical reaction to antiepileptic drugs Peter Borusiak a,*, Ulrich Bettendorf b, Michael Karenfort b, Elisabeth Korn-Merker b, Hans E. Boenigk b a
Zentrum fuÈr Kinder-und Jugendmedizin Wuppertal, Heusnerstraûe 40, D-42283 Wuppertal, Germany b Kinderklinik Kidron, Epilepsiezentrum Bethel, Maraweg 25, D-33617 Bielefeld, Germany Received 8 July 1999; received in revised form 27 March 2000; accepted 27 March 2000
Abstract We report on an 18-month-old girl with a seizure frequency of ®ve/day, receiving an antiepileptic polytherapy consisting of primidone, clonazepam and phenytoin. Following discontinuation of clonazepam and primidone, the patient has been seizure-free under monotherapy for 2 years and shows marked developmental progress. Possible mechanisms of this paradoxical effect of antiepileptic drugs and the implications for antiepileptic therapy are discussed. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Phenobarbital; Benzodiazepines; Therapy
1. Introduction A paradoxical seizure-inducing effect is well known for all antiepileptic drugs under certain circumstances. Many children with symptomatic focal epilepsies have seizures which are dif®cult to control and this often leads to polypharmacotherapy. Although the advantage of using monotherapy vs. several drugs has been clari®ed in recent years, most children referred to our epilepsy center received polytherapy: in a recent study we found that 72% of all children admitted to our epilepsy center were treated with at least two and up to six different antiepileptic drugs (AEDs). Although the discussion of cognitive impairment due to AEDs remains controversial, possible side effects might occur. We present the case of a 18-month-old girl who has remained seizure-free for 2 years after treatment was changed from a combination of three AEDs to monotherapy and who now shows marked progress in both motor and mental development. We will discuss possible mechanisms of seizure provocation and implications for antiepileptic drug treatment. 2. Case report The parents noticed a slight hemiparesis on the right side of our patient when she was 2 months old. The girl developed a symptomatic focal epilepsy 1 month later. Magnetic * Corresponding author. Tel.: 149-202-8962420; fax: 149-202-8962519. E-mail address: [email protected] (P. Borusiak).
resonance imaging revealed a state of former infarction of the left middle cerebral artery (presumably of perinatal origin). A complete evaluation of possible defects regarding the coagulation or thrombocytes did not reveal any pathological values. The initial seizures consisted of myoclonic jerks and an anticonvulsive therapy with phenobarbital (PB) was administered. Since seizures persisted, treatment of the patient continued at a University Pediatric Hospital where various treatment regimens, mostly in combination therapy were used: vigabatrin (VGB), primidone (PRM), clonazepam (CLN), ACTH, phenytoin (PHT). The patient was admitted to our epilepsy center at the age of 18 months because of therapy resistant epilepsy. The medication consisted of PRM (blood serum level (BSL) 3.0±4.2 mg/l; BSL of PB 48.4±50.0 mg/l), CLN (0.08 mg/ kg per day) and PHT (BSL 14.7±26.8 mg/l). The neurological examination showed inconstant head control and ability to roll over onto her right side only. She was not able to actively sit up, but sat stable, when put into position. She uttered no meaningful words and had only rare vocalization. The electroencephalogram (EEG) (Fig. 1) showed a generalized slowing of background activity, a slowing in the left fronto±centro±temporal region and multiregional sharp waves. Under unchanged medication we saw about four to ®ve polymorphic myoclonic and single focal tonic seizures/ day over a period of 10 days, which was consistent with the observations the parents had also reported. We ®rst stopped CLN and the seizure frequency was slightly higher (approximately 6±7/day) in the following week. Three weeks after admission, PRM was stopped and again the
0387-7604/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S 0387-760 4(00)00122-4
244
P. Borusiak et al. / Brain & Development 22 (2000) 243±245
Fig. 1. EEG under therapy with PRM, CLN and PHT (300 mV/cm, l 1.0 Hz, h 70 Hz, n 50 Hz).
seizure frequency increased to eight/day in the following week. Seventeen days after discontinuation of PRM the girl was seizure-free. In the meantime we had to reduce PHT at a BSL of 27.5 mg/l because of mild ataxia. The PHT levels then remained constant between 10 and 12 mg/l. The girl is now 3.5 years of age and has been seizure-free for 2 years under a monotherapy with PHT (BSL 6±8 mg/l). The parents report marked progression in her development. She is able to walk on her own. She can brush her teeth and comb her hair without assistance. She can count to three, talk in single word sentences and is able to distinguish between `I' and `you'. She plays role games. The EEG has never shown any sharp waves again. 3. Discussion Sometimes it is dif®cult to distinguish between the effect
of an AED and the natural course of the disease. Especially epilepsies in children tend to show a marked ¯uctuation of seizure frequency and semiology over the course of time. However, a seizure-inducing effect of AED under certain circumstances can be observed in some patients [1]. Several explanations for this condition are discussed in the literature: paradoxical reaction of the drug, AED-induced encephalopathy, AED-intoxication, inappropriate choice of AED regarding epilepsy syndrome or seizure type (as reviewed by Bauer [1]). The exact mechanism in our patient remains unclear. One could speculate about the relatively high levels of PHT as a cause for seizure exacerbation as was described by Troupin and Ojemann [2], but the PHT levels before and at admission were considerably lower (between 10 and 14 mg/l), and the seizure frequency was unchanged during polytherapy, regardless of the concentration of PHT. We do not think that PHT was involved in the paradoxical reaction. We can not clearly determine whether
P. Borusiak et al. / Brain & Development 22 (2000) 243±245
PRM or CLN was responsible for the reaction because the period of time between tapering off of the ®rst and the second drug was too short. However, both drugs may cause sedation and some authors suggest that this might be the reason for an increase in seizure activity [1]. We want to emphasize the fact that an exacerbation in seizure frequency shortly after discontinuation of an AED does not necessarily mean that this drug was still an effective one for this patient. We see transitory exacerbation after discontinuation of CLN in 40±50% [3]. It is important to remember the mostly transitory nature of these effects. Withdrawal seizures might occur for weeks in the case of an AED with a long half-life. There is normally no indication to readminister the withdrawn drug and, as a matter of fact, this often results in polytherapy. Withdrawal seizures should not be misinterpreted as persisting ef®cacy of the discontinued drug. Theodore and Porter [4] published their data concerning the withdrawal of barbiturates and benzodiazepines in 78 patients with intractable epilepsy and showed that 82% bene®ted from the removal of sedativehypnotic AED. The discussion about cognitive side effects of AEDs is still going on and has been well addressed in several recent reviews [5±7]. For most children, one or two AEDs are as effective or even more ef®cient than polytherapy with three
245
or more AEDs. The marked progress in development in our patient and her substantial gain in independence underlines the importance of a repeated critical analysis of the antiepileptic therapy and the examination of the necessity for each applied drug.
References [1] Bauer J. Seizure-inducing effects of antiepileptic drugs: a review. Acta Neurol Scand 1996;94:367±377. [2] Troupin AS, Ojemann LM. Paradoxical intoxication ± a complication of anticonvulsant administration. Epilepsia 1975;16:753±758. [3] Specht U, Boenigk HE, Wolf P. Discontinuation of clonazepam after long-term treatment. Epilepsia 1989;30:458±463. [4] Theodore WH, Porter RJ. Removal of sedative-hypnotic antiepileptic drugs from the regimens of patients with intractable epilepsy. Ann Neurol 1983;13:320±324. [5] Aldenkamp AP, Alpherts WCJ, Sandstedt P, Blennow G, Elmquist D, Heijbel J, et al. Antiepileptic drug-related cognitive complaints in seizure-free children with epilepsy before and after drug discontinuation. Epilepsia 1998;39:1070±1074. [6] Bourgeois BFD. Antiepileptic drugs, learning, and behavior in childhood epilepsy. Epilepsia 1998;39:913±921. [7] Vermeulen J, Aldenkamp AP. Cognitive side-effects of chronic antiepileptic drug treatment: a review of 25 years of research. Epilepsy Res 1995;22:65±95.
www.elsevier.com/locate/braindev
Case report
Seizure-inducing paradoxical reaction to antiepileptic drugs Peter Borusiak a,*, Ulrich Bettendorf b, Michael Karenfort b, Elisabeth Korn-Merker b, Hans E. Boenigk b a
Zentrum fuÈr Kinder-und Jugendmedizin Wuppertal, Heusnerstraûe 40, D-42283 Wuppertal, Germany b Kinderklinik Kidron, Epilepsiezentrum Bethel, Maraweg 25, D-33617 Bielefeld, Germany Received 8 July 1999; received in revised form 27 March 2000; accepted 27 March 2000
Abstract We report on an 18-month-old girl with a seizure frequency of ®ve/day, receiving an antiepileptic polytherapy consisting of primidone, clonazepam and phenytoin. Following discontinuation of clonazepam and primidone, the patient has been seizure-free under monotherapy for 2 years and shows marked developmental progress. Possible mechanisms of this paradoxical effect of antiepileptic drugs and the implications for antiepileptic therapy are discussed. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Phenobarbital; Benzodiazepines; Therapy
1. Introduction A paradoxical seizure-inducing effect is well known for all antiepileptic drugs under certain circumstances. Many children with symptomatic focal epilepsies have seizures which are dif®cult to control and this often leads to polypharmacotherapy. Although the advantage of using monotherapy vs. several drugs has been clari®ed in recent years, most children referred to our epilepsy center received polytherapy: in a recent study we found that 72% of all children admitted to our epilepsy center were treated with at least two and up to six different antiepileptic drugs (AEDs). Although the discussion of cognitive impairment due to AEDs remains controversial, possible side effects might occur. We present the case of a 18-month-old girl who has remained seizure-free for 2 years after treatment was changed from a combination of three AEDs to monotherapy and who now shows marked progress in both motor and mental development. We will discuss possible mechanisms of seizure provocation and implications for antiepileptic drug treatment. 2. Case report The parents noticed a slight hemiparesis on the right side of our patient when she was 2 months old. The girl developed a symptomatic focal epilepsy 1 month later. Magnetic * Corresponding author. Tel.: 149-202-8962420; fax: 149-202-8962519. E-mail address: [email protected] (P. Borusiak).
resonance imaging revealed a state of former infarction of the left middle cerebral artery (presumably of perinatal origin). A complete evaluation of possible defects regarding the coagulation or thrombocytes did not reveal any pathological values. The initial seizures consisted of myoclonic jerks and an anticonvulsive therapy with phenobarbital (PB) was administered. Since seizures persisted, treatment of the patient continued at a University Pediatric Hospital where various treatment regimens, mostly in combination therapy were used: vigabatrin (VGB), primidone (PRM), clonazepam (CLN), ACTH, phenytoin (PHT). The patient was admitted to our epilepsy center at the age of 18 months because of therapy resistant epilepsy. The medication consisted of PRM (blood serum level (BSL) 3.0±4.2 mg/l; BSL of PB 48.4±50.0 mg/l), CLN (0.08 mg/ kg per day) and PHT (BSL 14.7±26.8 mg/l). The neurological examination showed inconstant head control and ability to roll over onto her right side only. She was not able to actively sit up, but sat stable, when put into position. She uttered no meaningful words and had only rare vocalization. The electroencephalogram (EEG) (Fig. 1) showed a generalized slowing of background activity, a slowing in the left fronto±centro±temporal region and multiregional sharp waves. Under unchanged medication we saw about four to ®ve polymorphic myoclonic and single focal tonic seizures/ day over a period of 10 days, which was consistent with the observations the parents had also reported. We ®rst stopped CLN and the seizure frequency was slightly higher (approximately 6±7/day) in the following week. Three weeks after admission, PRM was stopped and again the
0387-7604/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S 0387-760 4(00)00122-4
244
P. Borusiak et al. / Brain & Development 22 (2000) 243±245
Fig. 1. EEG under therapy with PRM, CLN and PHT (300 mV/cm, l 1.0 Hz, h 70 Hz, n 50 Hz).
seizure frequency increased to eight/day in the following week. Seventeen days after discontinuation of PRM the girl was seizure-free. In the meantime we had to reduce PHT at a BSL of 27.5 mg/l because of mild ataxia. The PHT levels then remained constant between 10 and 12 mg/l. The girl is now 3.5 years of age and has been seizure-free for 2 years under a monotherapy with PHT (BSL 6±8 mg/l). The parents report marked progression in her development. She is able to walk on her own. She can brush her teeth and comb her hair without assistance. She can count to three, talk in single word sentences and is able to distinguish between `I' and `you'. She plays role games. The EEG has never shown any sharp waves again. 3. Discussion Sometimes it is dif®cult to distinguish between the effect
of an AED and the natural course of the disease. Especially epilepsies in children tend to show a marked ¯uctuation of seizure frequency and semiology over the course of time. However, a seizure-inducing effect of AED under certain circumstances can be observed in some patients [1]. Several explanations for this condition are discussed in the literature: paradoxical reaction of the drug, AED-induced encephalopathy, AED-intoxication, inappropriate choice of AED regarding epilepsy syndrome or seizure type (as reviewed by Bauer [1]). The exact mechanism in our patient remains unclear. One could speculate about the relatively high levels of PHT as a cause for seizure exacerbation as was described by Troupin and Ojemann [2], but the PHT levels before and at admission were considerably lower (between 10 and 14 mg/l), and the seizure frequency was unchanged during polytherapy, regardless of the concentration of PHT. We do not think that PHT was involved in the paradoxical reaction. We can not clearly determine whether
P. Borusiak et al. / Brain & Development 22 (2000) 243±245
PRM or CLN was responsible for the reaction because the period of time between tapering off of the ®rst and the second drug was too short. However, both drugs may cause sedation and some authors suggest that this might be the reason for an increase in seizure activity [1]. We want to emphasize the fact that an exacerbation in seizure frequency shortly after discontinuation of an AED does not necessarily mean that this drug was still an effective one for this patient. We see transitory exacerbation after discontinuation of CLN in 40±50% [3]. It is important to remember the mostly transitory nature of these effects. Withdrawal seizures might occur for weeks in the case of an AED with a long half-life. There is normally no indication to readminister the withdrawn drug and, as a matter of fact, this often results in polytherapy. Withdrawal seizures should not be misinterpreted as persisting ef®cacy of the discontinued drug. Theodore and Porter [4] published their data concerning the withdrawal of barbiturates and benzodiazepines in 78 patients with intractable epilepsy and showed that 82% bene®ted from the removal of sedativehypnotic AED. The discussion about cognitive side effects of AEDs is still going on and has been well addressed in several recent reviews [5±7]. For most children, one or two AEDs are as effective or even more ef®cient than polytherapy with three
245
or more AEDs. The marked progress in development in our patient and her substantial gain in independence underlines the importance of a repeated critical analysis of the antiepileptic therapy and the examination of the necessity for each applied drug.
References [1] Bauer J. Seizure-inducing effects of antiepileptic drugs: a review. Acta Neurol Scand 1996;94:367±377. [2] Troupin AS, Ojemann LM. Paradoxical intoxication ± a complication of anticonvulsant administration. Epilepsia 1975;16:753±758. [3] Specht U, Boenigk HE, Wolf P. Discontinuation of clonazepam after long-term treatment. Epilepsia 1989;30:458±463. [4] Theodore WH, Porter RJ. Removal of sedative-hypnotic antiepileptic drugs from the regimens of patients with intractable epilepsy. Ann Neurol 1983;13:320±324. [5] Aldenkamp AP, Alpherts WCJ, Sandstedt P, Blennow G, Elmquist D, Heijbel J, et al. Antiepileptic drug-related cognitive complaints in seizure-free children with epilepsy before and after drug discontinuation. Epilepsia 1998;39:1070±1074. [6] Bourgeois BFD. Antiepileptic drugs, learning, and behavior in childhood epilepsy. Epilepsia 1998;39:913±921. [7] Vermeulen J, Aldenkamp AP. Cognitive side-effects of chronic antiepileptic drug treatment: a review of 25 years of research. Epilepsy Res 1995;22:65±95.