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Do antiepileptic drugs accelerate forgetting?
Epilepsy & Behavior 6 (2005) 430–432 www.elsevier.com/locate/yebeh
Brief Communication
Do antiepileptic drugs accelerate forgetting? Hennric Jokeit
a,*
, Gu¨nter Kra¨mer a, Alois Ebner
b
a
b
Swiss Epilepsy Center, Bleulerstrasse 60, 8008 Zurich, Switzerland Bethel Epilepsy Center, Mara Hospital, Maraweg 21, 33617 Bielefeld, Germany
Received 7 October 2004; revised 21 December 2004; accepted 22 December 2004
Abstract The majority of patients with epilepsy become seizure-free with antiepileptic drug therapy. However, seizures in approximately one-third of patients with epilepsy are difficult to treat with antiepileptic drugs and require high doses or polytherapy. High dosages increase the risk of cognitive side effects. We retrospectively investigated 162 patients with refractory temporal lobe epilepsy to determine whether the antiepileptic drugs carbamazepine, phenobarbital, and phenytoin affect the acquisition and retention of verbal and visual information. We found that patients with high serum levels of these antiepileptic drugs were selectively impaired in the retention but not acquisition of new information. Intelligence, age, duration of epilepsy, and seizure frequency were controlled for and were not factors in the observed results. There were no differences in favor of a certain drug with respect to memory functioning. Our results suggest that patients with refractory epilepsy with high serum levels of the antiepileptic drugs studied are at higher risk of accelerated forgetting. Ó 2004 Elsevier Inc. All rights reserved. Keywords: Antiepileptic drugs; Memory; Cognition; Retention; Memory consolidation; Temporal lobe epilepsy
1. Introduction Slowing of mental or motor speed and attentional deficits are well known adverse effects of the frequently used antiepileptic drugs (AEDs) carbamazepine (CBZ), phenobarbital (PB), and phenytoin (PHT) [1]. It is generally assumed that these AEDs do not specifically impair memory and that patientsÕ memory complaints are secondary to the changes in their attentional level or mental processing speed induced by AEDs [2,3]. Recently, we demonstrated that CBZ may reduce the blood oxygen level-dependent (BOLD) response in memory activation fMRI studies but failed to report behavioral correlates [4]. The study of adverse effects of AEDs on cognition in patients with epilepsy is a complex issue because adverse and beneficial effects may compensate
*
Corresponding author. Fax: +41 1 387 63 46. E-mail address: [email protected] (H. Jokeit).
1525-5050/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2004.12.012
each other. That is, AEDs may well impair memory, but they also may bring about benefits to memory through their seizure suppression. Therefore, it is reasonable to assume that patients with medically refractory epilepsy may be at higher risk for AED-related memory deficits. In a retrospective study of patients with refractory temporal lobe epilepsy (TLE) we assessed the influence of the three most common AEDs used in treatment of focal epilepsies (CBZ, PHT, and PB) on the encoding, learning, and retention of new verbal and visual information.
2. Methods One hundred sixty-two adult patients were retrospectively selected from a database of more than 500 patients referred to the Bethel Epilepsy Center for presurgical evaluation between 1991 and 2001. The following criteria were applied: Selected patients underwent
Brief Communication / Epilepsy & Behavior 6 (2005) 430–432
presurgical evaluation including video/EEG monitoring, MRI, and neuropsychological testing; had unilateral TLE; and received monotherapy with CBZ, PB, or PHT. Clinical and demographic characteristics of the sample are given in Table 1. Serum levels of AEDs were determined on the day of or the day before presurgical neuropsychological testing. For each of the AEDs (CBZ, PB, or PHT) subjects were categorized into high and low serum level groups based on the median value of each AED subsample. Patients underwent a comprehensive neuropsychological evaluation including German versions of IQ tests (WAIS-R) and verbal (Logical Memory, WMS-R) and visual (Rey Visual Design Learning Test, RVDLT) memory tests [5,6]. The Logical Memory Test consists of two auditorily presented short stories that are to be repeated immediately after presentation (immediate recall) and 30 minutes later (delayed recall). Recall performance is measured as the number of correctly recalled details. The RVDLT consists of 15 geometric figures that are to be learned over five learning trials. Each figure is presented in a sequential order for 2 seconds during each learning trial. Learning performance is defined as the sum of correctly drawn figures over the five trials. Sixty minutes later the patients are asked to draw the figures they remember. The number of correctly drawn figures defines recall performance. Immediate recall and learning of figures are considered to reflect encoding processes of memory formation [5]. The difference between encoding performance and delayed recall is the measure of retention performance [5]. The influence of AEDs on encoding (immediate recall of story content, learning of geometric figures) and retention (delayed recall minus immediate recall of stories, delayed recall minus recall in the fifth learning trial of geometric figures) was analyzed separately with multiple analyses of variance. Four factors were submitted to analysis: (1) AEDs (CBZ, PB, PHT); (2) AED serum level (low, high); (3) laterality of TLE (left, right); (4) gender (female, male). Age, duration of epilepsy, seizure frequency, and Full Scale IQ served as control variables.
431
3. Results Encoding performance was related to age and IQ (P < 0.001). Learning of geometric figures was influenced by an interaction between side of TLE and gender (P = 0.011). Among patients with right-sided TLE, women performed better than men, and among those with left-sided TLE, men performed better than women. Neither specific AEDs nor serum levels were related to encoding performance. In contrast, retention performance for both verbal (P < 0.001) and nonverbal (P < 0.001) memory tasks was exclusively related to AED serum level (P < 0.0001, g2 = 0.144). No other factor or control variable was significantly related to retention performance. The figures illustrate the mean changes in retention of
Fig. 1. Loss of detail in two auditorily presented stories (Logical Memory, WMS-R) after a 30-minute retention interval as a function of antiepileptic drug (CBZ, PB, PHT) and serum level (low, high). The y axis represents the mean difference between 30-minute delayed and immediate recall of story details. Ninety-five percent confidence intervals of the mean values are given. Patients with high serum levels of AEDs (black circles) consistently recalled fewer story details as compared with patients with lower than median AED serum levels (white circles).
Table 1 N/women Temporal lobe left/right Median AED serum level (mg/L) Mean (low group/high group) SD (low group/high group) AED serum level N (low group/high group) Mean (SD)a age Mean (SD) duration of epilepsy (years)a Mean rank of seizure frequency, normalized to 100 WAIS-R Full Scale IQ (SD)a a
Difference in mean values, P < 0.10.
Carbamazepine
Phenobarbital
Phenytoin
Total
77/31 25/42 9 7.11/10.16 1.73/2.30
51/24 25/26 29 18.65/38.37 6.74/11.93
162/71 78/84
38/39 35.8 (9.2) 22.3 (9.3) 49.8 100.8 (15.1)
24/27 40.8 (10.3) 29 (12.8) 51.7 96.8 (17.7)
34/16 18/16 20 10.14/24.6 5.06/11.75 1 16/18 38.6 (8.5) 27 (9.3) 47.9 92.8 (17.8)
78/84 38 (9.6) 25.4 (10.9) 50 97.8 (16.8)
432
Brief Communication / Epilepsy & Behavior 6 (2005) 430–432
Fig. 2. Memory loss of geometric figures (RVDLT) during a 60minute retention interval as a function of antiepileptic drug (CBZ, PB, PHT) and AED serum level (low, high). The y axis represents the mean difference between 60-minute delayed recall and recall of geometric figures in the fifth learning trial. Ninety-five percent confidence intervals of the mean values are given. Patients with high AED serum levels (black circles) consistently recalled fewer figures as compared with patients with lower than median AED serum levels (white circles).
story content (Fig. 1) and retention of geometric figures (Fig. 2) separately for each AED and serum level group.
4. Discussion Our results demonstrate that patients with refractory TLE with high serum levels of CBZ, PB, or PHT perform less well in verbal and nonverbal memory retention tasks as compared with patients with lower AED serum levels. However, there was no differential effect of AEDs or AED serum levels on encoding or learning of new information. The influence of IQ, age, duration of epilepsy, and seizure frequency was controlled for by covariance analyses and failed to explain the observed results. Additionally, there was no effect of gender on retention. Although results of a parallel group design may be confounded by a hidden sample bias, the specificity of the effect, the observed effect size, and the control of important clinical and demographical variables, such as duration of epilepsy and seizure frequency, support the assumption of a specific effect of AEDs on memory retention. On the basis of these retrospective data, we cannot exclude that high dosages of certain AEDs may impair memory retention of newly acquired information. We assume that the AEDs studied may affect the complex neuronal and molecular cascade of memory consolidation processes [7–9]. Drug-related changes in mental speed or attention span cannot explain the loss of memory in this study as they would have affected encoding processes rather than retention processes, an effect that was not observed
[2,3]. Several studies in patients and animals aimed at studying memory effects of AEDs have produced contradictory results [2,3,9,10]. It is likely that smaller dosages, especially in healthy controls, beneficial effects of seizure suppression in patients, and comparisons between different AEDs may have obscured the specific effect of CBZ, PB, and PHT on retention. Very high dosages of AEDs are avoided, especially in randomized doubleblinded placebo-controlled studies, because of ethical considerations. The majority of patients become seizure-free with serum levels lower than those measured in our high-dosage subgroups. Seizures in about one-third of epilepsy patients, however, are difficult to treat. In these patients, monotherapy with high dosages is often necessary and recommended. Our results show that these patients may be at risk for AED-induced impairment of memory retention. However, prospective studies using repeatedmeasures designs have yet to provide definitive evidence as to whether AEDs accelerate forgetting. Moreover, future studies are necessary to examine whether new-generation AEDs can bypass this possible side effect. Acknowledgments We thank B. Rambeck, T.W. May, R. Luerding, and S. Oertmann for their valuable help in data collection, and T. Grunwald, N. Degonda, S. Bosshardt, and V. Reed for their helpful comments. References [1] Kwan P, Brodie MJ. Neuropsychological effects of epilepsy and antiepileptic drugs. Lancet 2001;357:216–22. [2] Thompson PJ. Antiepileptic drugs and memory. Epilepsia 1992;33(Suppl. 6):S37–S40. [3] Aldenkamp AP. Cognitive side-effects of newer antiepileptic drugs relative to the established AEDs. In: Stefan H, Kra¨mer G, Mamoli B, editors. Challenge epilepsy—new antiepileptic drugs. Berlin: Blackwell Science; 1998. [4] Jokeit H, Okujava M, Woermann FG. Carbamazepine reduces memory induced activation of mesial temporal lobe structures: A pharmacological fMRI-study. BMC Neurol 2001;1:6. [5] Lezak M. Neuropsychological assessment. Oxford Univ. Press, New York; 1995. [6] Wechsler, D., 1987. Wechsler Memory Scale—revised: manual. Psychological Corp. San Antonio. [7] McGaugh JL. Memory: A century of consolidation. Science 2000;287:248–51. [8] Wittenberg GM, Sullivan MR, Tsien JZ. Synaptic reentry reinforcement based network model for long-term memory consolidation. Hippocampus 2002;12:637–47. [9] Wu Y, Wang L. The effects of antiepileptic drugs on spatial learning and hippocampal protein kinase C gamma in immature rats. Brain Dev 2002;24:82–7. [10] Sudha S, Lakshmana MK, Pradhan N. Changes in learning and memory, acetylcholinesterase activity and monoamines in brain after chronic carbamazepine administration in rats. Epilepsia 1995;36:416–22.
Brief Communication
Do antiepileptic drugs accelerate forgetting? Hennric Jokeit
a,*
, Gu¨nter Kra¨mer a, Alois Ebner
b
a
b
Swiss Epilepsy Center, Bleulerstrasse 60, 8008 Zurich, Switzerland Bethel Epilepsy Center, Mara Hospital, Maraweg 21, 33617 Bielefeld, Germany
Received 7 October 2004; revised 21 December 2004; accepted 22 December 2004
Abstract The majority of patients with epilepsy become seizure-free with antiepileptic drug therapy. However, seizures in approximately one-third of patients with epilepsy are difficult to treat with antiepileptic drugs and require high doses or polytherapy. High dosages increase the risk of cognitive side effects. We retrospectively investigated 162 patients with refractory temporal lobe epilepsy to determine whether the antiepileptic drugs carbamazepine, phenobarbital, and phenytoin affect the acquisition and retention of verbal and visual information. We found that patients with high serum levels of these antiepileptic drugs were selectively impaired in the retention but not acquisition of new information. Intelligence, age, duration of epilepsy, and seizure frequency were controlled for and were not factors in the observed results. There were no differences in favor of a certain drug with respect to memory functioning. Our results suggest that patients with refractory epilepsy with high serum levels of the antiepileptic drugs studied are at higher risk of accelerated forgetting. Ó 2004 Elsevier Inc. All rights reserved. Keywords: Antiepileptic drugs; Memory; Cognition; Retention; Memory consolidation; Temporal lobe epilepsy
1. Introduction Slowing of mental or motor speed and attentional deficits are well known adverse effects of the frequently used antiepileptic drugs (AEDs) carbamazepine (CBZ), phenobarbital (PB), and phenytoin (PHT) [1]. It is generally assumed that these AEDs do not specifically impair memory and that patientsÕ memory complaints are secondary to the changes in their attentional level or mental processing speed induced by AEDs [2,3]. Recently, we demonstrated that CBZ may reduce the blood oxygen level-dependent (BOLD) response in memory activation fMRI studies but failed to report behavioral correlates [4]. The study of adverse effects of AEDs on cognition in patients with epilepsy is a complex issue because adverse and beneficial effects may compensate
*
Corresponding author. Fax: +41 1 387 63 46. E-mail address: [email protected] (H. Jokeit).
1525-5050/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2004.12.012
each other. That is, AEDs may well impair memory, but they also may bring about benefits to memory through their seizure suppression. Therefore, it is reasonable to assume that patients with medically refractory epilepsy may be at higher risk for AED-related memory deficits. In a retrospective study of patients with refractory temporal lobe epilepsy (TLE) we assessed the influence of the three most common AEDs used in treatment of focal epilepsies (CBZ, PHT, and PB) on the encoding, learning, and retention of new verbal and visual information.
2. Methods One hundred sixty-two adult patients were retrospectively selected from a database of more than 500 patients referred to the Bethel Epilepsy Center for presurgical evaluation between 1991 and 2001. The following criteria were applied: Selected patients underwent
Brief Communication / Epilepsy & Behavior 6 (2005) 430–432
presurgical evaluation including video/EEG monitoring, MRI, and neuropsychological testing; had unilateral TLE; and received monotherapy with CBZ, PB, or PHT. Clinical and demographic characteristics of the sample are given in Table 1. Serum levels of AEDs were determined on the day of or the day before presurgical neuropsychological testing. For each of the AEDs (CBZ, PB, or PHT) subjects were categorized into high and low serum level groups based on the median value of each AED subsample. Patients underwent a comprehensive neuropsychological evaluation including German versions of IQ tests (WAIS-R) and verbal (Logical Memory, WMS-R) and visual (Rey Visual Design Learning Test, RVDLT) memory tests [5,6]. The Logical Memory Test consists of two auditorily presented short stories that are to be repeated immediately after presentation (immediate recall) and 30 minutes later (delayed recall). Recall performance is measured as the number of correctly recalled details. The RVDLT consists of 15 geometric figures that are to be learned over five learning trials. Each figure is presented in a sequential order for 2 seconds during each learning trial. Learning performance is defined as the sum of correctly drawn figures over the five trials. Sixty minutes later the patients are asked to draw the figures they remember. The number of correctly drawn figures defines recall performance. Immediate recall and learning of figures are considered to reflect encoding processes of memory formation [5]. The difference between encoding performance and delayed recall is the measure of retention performance [5]. The influence of AEDs on encoding (immediate recall of story content, learning of geometric figures) and retention (delayed recall minus immediate recall of stories, delayed recall minus recall in the fifth learning trial of geometric figures) was analyzed separately with multiple analyses of variance. Four factors were submitted to analysis: (1) AEDs (CBZ, PB, PHT); (2) AED serum level (low, high); (3) laterality of TLE (left, right); (4) gender (female, male). Age, duration of epilepsy, seizure frequency, and Full Scale IQ served as control variables.
431
3. Results Encoding performance was related to age and IQ (P < 0.001). Learning of geometric figures was influenced by an interaction between side of TLE and gender (P = 0.011). Among patients with right-sided TLE, women performed better than men, and among those with left-sided TLE, men performed better than women. Neither specific AEDs nor serum levels were related to encoding performance. In contrast, retention performance for both verbal (P < 0.001) and nonverbal (P < 0.001) memory tasks was exclusively related to AED serum level (P < 0.0001, g2 = 0.144). No other factor or control variable was significantly related to retention performance. The figures illustrate the mean changes in retention of
Fig. 1. Loss of detail in two auditorily presented stories (Logical Memory, WMS-R) after a 30-minute retention interval as a function of antiepileptic drug (CBZ, PB, PHT) and serum level (low, high). The y axis represents the mean difference between 30-minute delayed and immediate recall of story details. Ninety-five percent confidence intervals of the mean values are given. Patients with high serum levels of AEDs (black circles) consistently recalled fewer story details as compared with patients with lower than median AED serum levels (white circles).
Table 1 N/women Temporal lobe left/right Median AED serum level (mg/L) Mean (low group/high group) SD (low group/high group) AED serum level N (low group/high group) Mean (SD)a age Mean (SD) duration of epilepsy (years)a Mean rank of seizure frequency, normalized to 100 WAIS-R Full Scale IQ (SD)a a
Difference in mean values, P < 0.10.
Carbamazepine
Phenobarbital
Phenytoin
Total
77/31 25/42 9 7.11/10.16 1.73/2.30
51/24 25/26 29 18.65/38.37 6.74/11.93
162/71 78/84
38/39 35.8 (9.2) 22.3 (9.3) 49.8 100.8 (15.1)
24/27 40.8 (10.3) 29 (12.8) 51.7 96.8 (17.7)
34/16 18/16 20 10.14/24.6 5.06/11.75 1 16/18 38.6 (8.5) 27 (9.3) 47.9 92.8 (17.8)
78/84 38 (9.6) 25.4 (10.9) 50 97.8 (16.8)
432
Brief Communication / Epilepsy & Behavior 6 (2005) 430–432
Fig. 2. Memory loss of geometric figures (RVDLT) during a 60minute retention interval as a function of antiepileptic drug (CBZ, PB, PHT) and AED serum level (low, high). The y axis represents the mean difference between 60-minute delayed recall and recall of geometric figures in the fifth learning trial. Ninety-five percent confidence intervals of the mean values are given. Patients with high AED serum levels (black circles) consistently recalled fewer figures as compared with patients with lower than median AED serum levels (white circles).
story content (Fig. 1) and retention of geometric figures (Fig. 2) separately for each AED and serum level group.
4. Discussion Our results demonstrate that patients with refractory TLE with high serum levels of CBZ, PB, or PHT perform less well in verbal and nonverbal memory retention tasks as compared with patients with lower AED serum levels. However, there was no differential effect of AEDs or AED serum levels on encoding or learning of new information. The influence of IQ, age, duration of epilepsy, and seizure frequency was controlled for by covariance analyses and failed to explain the observed results. Additionally, there was no effect of gender on retention. Although results of a parallel group design may be confounded by a hidden sample bias, the specificity of the effect, the observed effect size, and the control of important clinical and demographical variables, such as duration of epilepsy and seizure frequency, support the assumption of a specific effect of AEDs on memory retention. On the basis of these retrospective data, we cannot exclude that high dosages of certain AEDs may impair memory retention of newly acquired information. We assume that the AEDs studied may affect the complex neuronal and molecular cascade of memory consolidation processes [7–9]. Drug-related changes in mental speed or attention span cannot explain the loss of memory in this study as they would have affected encoding processes rather than retention processes, an effect that was not observed
[2,3]. Several studies in patients and animals aimed at studying memory effects of AEDs have produced contradictory results [2,3,9,10]. It is likely that smaller dosages, especially in healthy controls, beneficial effects of seizure suppression in patients, and comparisons between different AEDs may have obscured the specific effect of CBZ, PB, and PHT on retention. Very high dosages of AEDs are avoided, especially in randomized doubleblinded placebo-controlled studies, because of ethical considerations. The majority of patients become seizure-free with serum levels lower than those measured in our high-dosage subgroups. Seizures in about one-third of epilepsy patients, however, are difficult to treat. In these patients, monotherapy with high dosages is often necessary and recommended. Our results show that these patients may be at risk for AED-induced impairment of memory retention. However, prospective studies using repeatedmeasures designs have yet to provide definitive evidence as to whether AEDs accelerate forgetting. Moreover, future studies are necessary to examine whether new-generation AEDs can bypass this possible side effect. Acknowledgments We thank B. Rambeck, T.W. May, R. Luerding, and S. Oertmann for their valuable help in data collection, and T. Grunwald, N. Degonda, S. Bosshardt, and V. Reed for their helpful comments. References [1] Kwan P, Brodie MJ. Neuropsychological effects of epilepsy and antiepileptic drugs. Lancet 2001;357:216–22. [2] Thompson PJ. Antiepileptic drugs and memory. Epilepsia 1992;33(Suppl. 6):S37–S40. [3] Aldenkamp AP. Cognitive side-effects of newer antiepileptic drugs relative to the established AEDs. In: Stefan H, Kra¨mer G, Mamoli B, editors. Challenge epilepsy—new antiepileptic drugs. Berlin: Blackwell Science; 1998. [4] Jokeit H, Okujava M, Woermann FG. Carbamazepine reduces memory induced activation of mesial temporal lobe structures: A pharmacological fMRI-study. BMC Neurol 2001;1:6. [5] Lezak M. Neuropsychological assessment. Oxford Univ. Press, New York; 1995. [6] Wechsler, D., 1987. Wechsler Memory Scale—revised: manual. Psychological Corp. San Antonio. [7] McGaugh JL. Memory: A century of consolidation. Science 2000;287:248–51. [8] Wittenberg GM, Sullivan MR, Tsien JZ. Synaptic reentry reinforcement based network model for long-term memory consolidation. Hippocampus 2002;12:637–47. [9] Wu Y, Wang L. The effects of antiepileptic drugs on spatial learning and hippocampal protein kinase C gamma in immature rats. Brain Dev 2002;24:82–7. [10] Sudha S, Lakshmana MK, Pradhan N. Changes in learning and memory, acetylcholinesterase activity and monoamines in brain after chronic carbamazepine administration in rats. Epilepsia 1995;36:416–22.