€pi/ejwiu. JI(Suppl. 4):SSO-S53, 1990 Raven Rss. Ltd.. New York Q International League Against Epilepsy
Discontinuation of Antiepileptic Drugs in Children Who Have Outgrown Epilepsy: Effects on Cognitive Function G. Blennow, J. Heijbel, P. Sandstedt, and B. Tonnby Department of Paediatrics, University Hospital, Lund, Sweden
Summary: Cognitive function is frequently impaired in children with epilepsy, compared with age-matched controls. It can be hard to evaluate the significance of various contributory factors. The effects of antiepileptic drugs may be studied in children who have outgrown their epilepsy but are still being treated. A multicenter study to assess various aspects of cognitive function in children with different forms of epilepsy, both during and after treatment with
antiepileptic drugs, is currently under way. Definitive results are not yet available; interim analysis of the findings suggests that short-term memory is decreased in all subgroups of children being treated for epilepsy, compared to controls. Key Words: Epilepsy-Seizures-ChildrenabCognitive disorders-Anticonvulsants-Drug-induced normalities-Prognosis.
When discussing epilepsy and education in childhood, many factors must be considered (for review, see American Academy of Pediatrics, 1985; Addy, 1987; Trimble, 1987; Vining, 1989). The cerebral disorder causing the epilepsy may lead to impairment of motor and/or intellectual ability, affecting cognition and learning behavior. The importance of the epilepsy per se, the seizure activity, and the deviating interictal electroencephalogram (EEG) activity have already been discussed (Binnie et al., 1990). The impact of epilepsy on personality development and thus on motivation and learning behavior (Aldenkamp, 1983; Wiberg et al., 1987) and the effects of antiepileptic drugs (AEDs) on brain development and cognitive function should also be considered. Among the numerous factors that can contribute to a reduction in cognitive function in children with epilepsy, the effects of AEDs are especially difficult to isolate and study as independent factors. Healthy volunteers may be used (Thompson et al., 1981; Thompson and Tnmble, 1981; Macphee et al., 1986), but only to study short-term effects; children who have outgrown their epilepsy are very suitable for such studies. The EEG is at best normalized, and the
condition causing the seizure propensity is no longer present. Children still receiving chronic medication can discontinue treatment, thereby serving as their own controls. There are only a few studies on cognitive function after treatment discontinuation. Gallassi et al. ( 1988) compared 25 adult and adolescent patients with epilepsy, who had been seizure free for at least 2 years with either carbamazepine (CBZ) or phenytoin (PHT), and 26 matched controls. PHT affected cognitive function more than carbamazepine, which affected only attention. The negative effects of both drugs disappeared following discontinuation, those of PHT persisting for much longer. The number of subjects studied was small, however, and the results need confirmation.
METHODS At present we are studying a group of children with various forms of epilepsy, during and after treatment with AEDs, in an open within-patient trial. Children matched for age, sex, and school level are used as controls. A computerized cognitive test battery, developed in close cooperation with the Epilepsy Center “Meer en Bosch” in The Netherlands, is used for testing (modified versions of the test battery by Moerland et al., 1986). Several cognitive domains are tested (Table 1 ).
Address correspondence and reprint requests to Dr. G . Blennow at Department of Paediatrics, University Hospital of Lund, Lund, Sweden.
S.50
WITHDRAWAL OF ANTIEPILEPTIC DRUGS IN CHILDREN TABLE 1. Cognitivefunctions in test battery
S5 1
Carbamazepine
and test method Cognitive domain
Test method
Alertness and speed Attention and concentration
Speed and accuracy of information processing Memory: recognition and short-term memory span Motor fluency
Simple reaction time, auditory and visual Tapping task and binary choice reaction time Computerized visual searching task Recognition tasks and digit span Tapping task
To be included in the study, children have to meet the following criteria: age 7-18 years, diagnosis of epilepsy, treatment with monotherapy for at least the past year, and no seizures for 1 year. Thus, the subjects are children in whom medical treatment is no longer considered necessary. Exclusion criteria include mental retardation, treatment with any central nervous system (CNS)-depressing drug, and a history of mental disorder. The children are first tested while receiving AEDs and again 3-6 months after medication is stopped. Any children whose seizures recur after therapy is discontinued will be excluded from the study. EEG recordings are obtained within 1 month before each of the two testing sessions. Samples for measuring AED concentration are taken when the cognitive tests are performed. Eleven pediatric centers throughout Sweden are participating, enabling a sufficiently large sample to be collected within a reasonable period. Considerable care has been taken to reduce intercenter variability. Standardization includes testing at similar times of day, giving similar instructions to the children, allowing the same amount of time for pauses during testing, and testing in the same environment. So far, 69 epilepsy patients and 69 matched controls have been studied. The majority are receiving
Valproate 14 FIG. 1. Antiepileptic drugs received by the 69 trial subjects.
CBZ (68%) or valproate (VPA) (20%), as shown in Fig. 1. The mean age for both the epilepsy and the control groups is 12.2 & 2.3 years, with small variations for the different treatment groups. The range of dosages of the AEDs is shown in Fig. 2.
INTERIM EVALUATION Evaluation will focus on the differences between the results of the initial test and those of the repeated test after AED discontinuation. Performance of the children with epilepsy will also be compared with that of control children, to allow for practice effects. Because new patients may still be entered into the study, a definitive evaluation cannot yet be made without biasing interpretation of the final results. However, differences observed between the children with epilepsy and the controls during the initial tests (visit 1) can be described. The difference in memory function, shown in Fig. 3, was measured by a recognition task in which either six words or four
1,400 1.200
Ma
1 800
FIG. 2. Dosage ranges of the antiepileptic bugs studied.
Mean 600
Min 400 200
0 Carbamazepine Valproate
Phenytoin
Ethosuximide Epilepsia Vol. 31. Suppl. 4. 1990
G. BLENNO W ET AL.
S52
" I
;P
l5
10
5
5 0
-- -siultaneaus
serial
words
Simltaneoug
Simultaneous
serial
Fwms
mConed
FIG. 3. Recognition tasks, using words and figures, to study differences between epilepsy p a t i t s and controls.
figures are presented simultaneouslyor serially for 1 s each (learning phase). After 2 s, a further series of words or figures appears on the screen. All but one word/figure is different and the task is to identify the repeated word/figure (recognition phase). The words and figures are not presented in a fixed order, but randomly sampled from a database to eliminate practice effects as far as possible (Alpherts, 1987). Although the results have not yet been evaluated statistically, certain trends are apparent. Performance on all tasks is decreased in children with epilepsy compared to the controls; this difference is more pronounced for memory of simultaneously presented words, and does not seem to be related to any specific medication (Fig. 4). No differences between the groups as a whole have been found in the reaction time tests (simple auditory and visual tests, and binary choice test). However, the two patients treated with ethosuximide (ESM) had slower reactions to all tests. Figure 5 shows an inverse relationship between the number of errors and speed of response in the
Recognition task: performance IS decreased in children with epilepsy and more pronouncedfor memory of simultaneously presented words.
binary choice test. Children receiving CBZ and VPA perform faster, but at the expense of accuracy. The reverse is true for the PHT and ESM groups (Trimble, 1990). Slightly decreased motor fluency in the right hand related mainly to lowered performance in the PHT group and, to a lesser extent, in the VPA group was revealed among the epilepsy patients by means of the finger tapping test. Finally, information processing in the visual searching task (mean correct trial time to identify 1 geometrical figure among 24, with different patterns presented 24 times) was found to be slower only in the PHT and ESM groups.
CONCLUSIONS The main finding at this early stage of the study is that short-term memory is decreased in all subgroups of children being treated for epilepsy compared to controls. The definitive results may help us to differ-
500
10
400
8
300
6
200
4
100
2
-Reaction time --Errors
Epilepsia. Vol. 31. Suppl. 4. 1990
Carbamazepine
Valproate
Ethwuximide
Is1control
FIG. 4.
12
Epilepsy overall
Serial
I3Phenytoh
600
0
Simultaneous
Figures
Carbamazepine Bvdpmate
KG3 EpibpQY
Control
Serial
words
Phenytoin
0
rn 3 3
Ethosuximide
FIG. 5. Inverse relationship between number of errors and speed of response.
WITHDRAWAL OF ANTIEPILEPTIC DRUGS IN CHILDREN
entiate the effects of antiepileptic drugs from those of epilepsy. Possible effects of cerebral maturation on the test results will be minimized by using agematched controls. So far, there have been few problems in carrying out this study. The children's parents have been keen to participate, despite the extra hospital visits necessary for testing and EEG recordings. Questions about the effects of AEDs on the growing child's mental functions reflect their own concerns. Nor have we had any problems finding control children, since the epileptic child's "best friend" has in most cases been very suitable and willing to participate. Thorough discussions among co-workers on various occasions, both before and during the initial phase of the study, have minimized center-to-center variability. The test situation is further standardized by computer techniques. Acknowledgment: The research group included the following: Heirno L. Nilsson, Eric W o w , A. P. Aldenkamp, W. C. J. Alpherts, Jan Arvidsson, Gunilla Steinwall, Staffan Edlund, Per-Ake Grahn, Hans Gylje, Christer L a m n , Lars Norkn, Jan Tenstam, Alf Wigertz, Ove Almqvkt, Dan Elmqvist, Matts Henning, and Lars Wihlander.
REFERENCES Addy DP. Cognitive function in children with epilepsy. Dev Med Child Neurol 1981:29:394-404.
s53
Aldenkamp AP. Epilepsy and learning behaviour. In: Parsonage M, Grant RHE, Craig AG, Ward AA, Jr, eds.Advances in epileptcr logy. The XIVrh Epilepsy International Symposium. New York Raven Press, 1983:221-8. Alpherts WCJ. Computers as a technique for neuropsychological assessment in epilepsy. In: Aldenkamp AP, Alpherts WCJ, Meinardi H, Stores G, eds. Education and epilepsy, 1987. Lisse/Benuyn: Swets & Zeitlinger, 1987:101-9. American Academy of Pediatrics. Committee on Drugs. Behavioral and cognitive effects of anticonvulsant therapy. Pedialrics 1985;76644-7. Gallassi R, Morreale A, Lorusso S, et al. Carbamazepine and phenytoin. Comparison of cognitive effects in epileptic patients during monotherapy and withdrawal. Arch Neurol 1988;45:892-4. MacPhee GJA, Goldie C, Roulsson, et al. Effects ofcarbarnaxpine on psychomotor performance in native subjects. Eur J Clin Pharmacol1986;3037-42. Moerland MC, Aldenkamp AP, Alpherts WCI. A neuropsychologi d test battery for the Apple 11-E. In1 J Man-Maehine Stud 1986;25:453-66. Thompson P, Huppert FA, Trimble MR. Phenytoin and cognitive function: effects on normal volunteers and implicationsfor epilepsy. BrJClin Psycho1 1981;20155-62. Thompson P, Trimble MR. Sodium valproate and cognitive function in nonnal volunteers. Br J Ciin Pharmacoi 1981;1281924. Trimble MR.Anticonvulsant drugs and cognitive function: a review of the literature. Epilepsia 1987;28(suppl3):S37-45. Trimble MR. Antiepilepticdrugs, cognitive function, and behavior in children: evidence from recent studies. Epilepsia 1990; 3l(suppl4):S30-4 (this issue). Vining EPG. Educational, social and life long effects of epilepsy. Pediatr Clin North Am 1989;36449-6 I. Wiberg M, Blennow G, Polski B. Epilepsy in the adolescence. Implications for the development of the personality. Epilepsia 198728~542-76.
Epilepsia. Vd 31. SWP!. 4. 1990
Discontinuation of Antiepileptic Drugs in Children Who Have Outgrown Epilepsy: Effects on Cognitive Function G. Blennow, J. Heijbel, P. Sandstedt, and B. Tonnby Department of Paediatrics, University Hospital, Lund, Sweden
Summary: Cognitive function is frequently impaired in children with epilepsy, compared with age-matched controls. It can be hard to evaluate the significance of various contributory factors. The effects of antiepileptic drugs may be studied in children who have outgrown their epilepsy but are still being treated. A multicenter study to assess various aspects of cognitive function in children with different forms of epilepsy, both during and after treatment with
antiepileptic drugs, is currently under way. Definitive results are not yet available; interim analysis of the findings suggests that short-term memory is decreased in all subgroups of children being treated for epilepsy, compared to controls. Key Words: Epilepsy-Seizures-ChildrenabCognitive disorders-Anticonvulsants-Drug-induced normalities-Prognosis.
When discussing epilepsy and education in childhood, many factors must be considered (for review, see American Academy of Pediatrics, 1985; Addy, 1987; Trimble, 1987; Vining, 1989). The cerebral disorder causing the epilepsy may lead to impairment of motor and/or intellectual ability, affecting cognition and learning behavior. The importance of the epilepsy per se, the seizure activity, and the deviating interictal electroencephalogram (EEG) activity have already been discussed (Binnie et al., 1990). The impact of epilepsy on personality development and thus on motivation and learning behavior (Aldenkamp, 1983; Wiberg et al., 1987) and the effects of antiepileptic drugs (AEDs) on brain development and cognitive function should also be considered. Among the numerous factors that can contribute to a reduction in cognitive function in children with epilepsy, the effects of AEDs are especially difficult to isolate and study as independent factors. Healthy volunteers may be used (Thompson et al., 1981; Thompson and Tnmble, 1981; Macphee et al., 1986), but only to study short-term effects; children who have outgrown their epilepsy are very suitable for such studies. The EEG is at best normalized, and the
condition causing the seizure propensity is no longer present. Children still receiving chronic medication can discontinue treatment, thereby serving as their own controls. There are only a few studies on cognitive function after treatment discontinuation. Gallassi et al. ( 1988) compared 25 adult and adolescent patients with epilepsy, who had been seizure free for at least 2 years with either carbamazepine (CBZ) or phenytoin (PHT), and 26 matched controls. PHT affected cognitive function more than carbamazepine, which affected only attention. The negative effects of both drugs disappeared following discontinuation, those of PHT persisting for much longer. The number of subjects studied was small, however, and the results need confirmation.
METHODS At present we are studying a group of children with various forms of epilepsy, during and after treatment with AEDs, in an open within-patient trial. Children matched for age, sex, and school level are used as controls. A computerized cognitive test battery, developed in close cooperation with the Epilepsy Center “Meer en Bosch” in The Netherlands, is used for testing (modified versions of the test battery by Moerland et al., 1986). Several cognitive domains are tested (Table 1 ).
Address correspondence and reprint requests to Dr. G . Blennow at Department of Paediatrics, University Hospital of Lund, Lund, Sweden.
S.50
WITHDRAWAL OF ANTIEPILEPTIC DRUGS IN CHILDREN TABLE 1. Cognitivefunctions in test battery
S5 1
Carbamazepine
and test method Cognitive domain
Test method
Alertness and speed Attention and concentration
Speed and accuracy of information processing Memory: recognition and short-term memory span Motor fluency
Simple reaction time, auditory and visual Tapping task and binary choice reaction time Computerized visual searching task Recognition tasks and digit span Tapping task
To be included in the study, children have to meet the following criteria: age 7-18 years, diagnosis of epilepsy, treatment with monotherapy for at least the past year, and no seizures for 1 year. Thus, the subjects are children in whom medical treatment is no longer considered necessary. Exclusion criteria include mental retardation, treatment with any central nervous system (CNS)-depressing drug, and a history of mental disorder. The children are first tested while receiving AEDs and again 3-6 months after medication is stopped. Any children whose seizures recur after therapy is discontinued will be excluded from the study. EEG recordings are obtained within 1 month before each of the two testing sessions. Samples for measuring AED concentration are taken when the cognitive tests are performed. Eleven pediatric centers throughout Sweden are participating, enabling a sufficiently large sample to be collected within a reasonable period. Considerable care has been taken to reduce intercenter variability. Standardization includes testing at similar times of day, giving similar instructions to the children, allowing the same amount of time for pauses during testing, and testing in the same environment. So far, 69 epilepsy patients and 69 matched controls have been studied. The majority are receiving
Valproate 14 FIG. 1. Antiepileptic drugs received by the 69 trial subjects.
CBZ (68%) or valproate (VPA) (20%), as shown in Fig. 1. The mean age for both the epilepsy and the control groups is 12.2 & 2.3 years, with small variations for the different treatment groups. The range of dosages of the AEDs is shown in Fig. 2.
INTERIM EVALUATION Evaluation will focus on the differences between the results of the initial test and those of the repeated test after AED discontinuation. Performance of the children with epilepsy will also be compared with that of control children, to allow for practice effects. Because new patients may still be entered into the study, a definitive evaluation cannot yet be made without biasing interpretation of the final results. However, differences observed between the children with epilepsy and the controls during the initial tests (visit 1) can be described. The difference in memory function, shown in Fig. 3, was measured by a recognition task in which either six words or four
1,400 1.200
Ma
1 800
FIG. 2. Dosage ranges of the antiepileptic bugs studied.
Mean 600
Min 400 200
0 Carbamazepine Valproate
Phenytoin
Ethosuximide Epilepsia Vol. 31. Suppl. 4. 1990
G. BLENNO W ET AL.
S52
" I
;P
l5
10
5
5 0
-- -siultaneaus
serial
words
Simltaneoug
Simultaneous
serial
Fwms
mConed
FIG. 3. Recognition tasks, using words and figures, to study differences between epilepsy p a t i t s and controls.
figures are presented simultaneouslyor serially for 1 s each (learning phase). After 2 s, a further series of words or figures appears on the screen. All but one word/figure is different and the task is to identify the repeated word/figure (recognition phase). The words and figures are not presented in a fixed order, but randomly sampled from a database to eliminate practice effects as far as possible (Alpherts, 1987). Although the results have not yet been evaluated statistically, certain trends are apparent. Performance on all tasks is decreased in children with epilepsy compared to the controls; this difference is more pronounced for memory of simultaneously presented words, and does not seem to be related to any specific medication (Fig. 4). No differences between the groups as a whole have been found in the reaction time tests (simple auditory and visual tests, and binary choice test). However, the two patients treated with ethosuximide (ESM) had slower reactions to all tests. Figure 5 shows an inverse relationship between the number of errors and speed of response in the
Recognition task: performance IS decreased in children with epilepsy and more pronouncedfor memory of simultaneously presented words.
binary choice test. Children receiving CBZ and VPA perform faster, but at the expense of accuracy. The reverse is true for the PHT and ESM groups (Trimble, 1990). Slightly decreased motor fluency in the right hand related mainly to lowered performance in the PHT group and, to a lesser extent, in the VPA group was revealed among the epilepsy patients by means of the finger tapping test. Finally, information processing in the visual searching task (mean correct trial time to identify 1 geometrical figure among 24, with different patterns presented 24 times) was found to be slower only in the PHT and ESM groups.
CONCLUSIONS The main finding at this early stage of the study is that short-term memory is decreased in all subgroups of children being treated for epilepsy compared to controls. The definitive results may help us to differ-
500
10
400
8
300
6
200
4
100
2
-Reaction time --Errors
Epilepsia. Vol. 31. Suppl. 4. 1990
Carbamazepine
Valproate
Ethwuximide
Is1control
FIG. 4.
12
Epilepsy overall
Serial
I3Phenytoh
600
0
Simultaneous
Figures
Carbamazepine Bvdpmate
KG3 EpibpQY
Control
Serial
words
Phenytoin
0
rn 3 3
Ethosuximide
FIG. 5. Inverse relationship between number of errors and speed of response.
WITHDRAWAL OF ANTIEPILEPTIC DRUGS IN CHILDREN
entiate the effects of antiepileptic drugs from those of epilepsy. Possible effects of cerebral maturation on the test results will be minimized by using agematched controls. So far, there have been few problems in carrying out this study. The children's parents have been keen to participate, despite the extra hospital visits necessary for testing and EEG recordings. Questions about the effects of AEDs on the growing child's mental functions reflect their own concerns. Nor have we had any problems finding control children, since the epileptic child's "best friend" has in most cases been very suitable and willing to participate. Thorough discussions among co-workers on various occasions, both before and during the initial phase of the study, have minimized center-to-center variability. The test situation is further standardized by computer techniques. Acknowledgment: The research group included the following: Heirno L. Nilsson, Eric W o w , A. P. Aldenkamp, W. C. J. Alpherts, Jan Arvidsson, Gunilla Steinwall, Staffan Edlund, Per-Ake Grahn, Hans Gylje, Christer L a m n , Lars Norkn, Jan Tenstam, Alf Wigertz, Ove Almqvkt, Dan Elmqvist, Matts Henning, and Lars Wihlander.
REFERENCES Addy DP. Cognitive function in children with epilepsy. Dev Med Child Neurol 1981:29:394-404.
s53
Aldenkamp AP. Epilepsy and learning behaviour. In: Parsonage M, Grant RHE, Craig AG, Ward AA, Jr, eds.Advances in epileptcr logy. The XIVrh Epilepsy International Symposium. New York Raven Press, 1983:221-8. Alpherts WCJ. Computers as a technique for neuropsychological assessment in epilepsy. In: Aldenkamp AP, Alpherts WCJ, Meinardi H, Stores G, eds. Education and epilepsy, 1987. Lisse/Benuyn: Swets & Zeitlinger, 1987:101-9. American Academy of Pediatrics. Committee on Drugs. Behavioral and cognitive effects of anticonvulsant therapy. Pedialrics 1985;76644-7. Gallassi R, Morreale A, Lorusso S, et al. Carbamazepine and phenytoin. Comparison of cognitive effects in epileptic patients during monotherapy and withdrawal. Arch Neurol 1988;45:892-4. MacPhee GJA, Goldie C, Roulsson, et al. Effects ofcarbarnaxpine on psychomotor performance in native subjects. Eur J Clin Pharmacol1986;3037-42. Moerland MC, Aldenkamp AP, Alpherts WCI. A neuropsychologi d test battery for the Apple 11-E. In1 J Man-Maehine Stud 1986;25:453-66. Thompson P, Huppert FA, Trimble MR. Phenytoin and cognitive function: effects on normal volunteers and implicationsfor epilepsy. BrJClin Psycho1 1981;20155-62. Thompson P, Trimble MR. Sodium valproate and cognitive function in nonnal volunteers. Br J Ciin Pharmacoi 1981;1281924. Trimble MR.Anticonvulsant drugs and cognitive function: a review of the literature. Epilepsia 1987;28(suppl3):S37-45. Trimble MR. Antiepilepticdrugs, cognitive function, and behavior in children: evidence from recent studies. Epilepsia 1990; 3l(suppl4):S30-4 (this issue). Vining EPG. Educational, social and life long effects of epilepsy. Pediatr Clin North Am 1989;36449-6 I. Wiberg M, Blennow G, Polski B. Epilepsy in the adolescence. Implications for the development of the personality. Epilepsia 198728~542-76.
Epilepsia. Vd 31. SWP!. 4. 1990
