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Anticonvulsant drugs affect particular steps of verbal memory processing—An evaluation of 13 patients with intractable complex partial seizures of left temporal lobe origin
Nuuropswhloyiu. Vol. 30. No. 7. pp. 623-631. 1992. Punted I” Great Bnram.
CO?&3932 92 S5.00+0.00 ,N 1992 Pergamon Pres, Lid
ANTICONVULSANT DRUGS AFFECT PARTICULAR STEPS OF VERBAL MEMORY PROCESSING-AN EVALUATION OF 13 PATIENTS WITH INTRACTABLE COMPLEX PARTIAL SEIZURES OF LEFT TEMPORAL LOBE ORIGIN H. F. DURWEN,*~ A. HUFNAGEL$ and C. E. ELGER: tDepartment
of Neurology, Ruhr-University, Bochum, F.R.G.; and IDepartment (Received
Knappschafts-Krankenhaus (Director: Prof. Dr W. Gehlen), of Epileptology, Bonn University, Bonn, F.R.G.
19 November
1990: accepted 3 December
1991)
Abstract-Thirteen patients with intractable complex partial seizures of left temporal lobe origin were tested for verbal memory performance under the conditions of full and reduced anticonvulsant medication. As suggested by previous investigations memory performance improved significantly with the reduction of anticonvulsants. However, our observations refute assumptions that the effects of antiepileptic drugs act primarily by non-specific mechanisms affecting attention and/or memory diffusely. Our data rather suggest that very specific and circumscribed steps of verbal memory processing, particularly retrieval abilities after interference, are affected by anticonvulsants. The possible implications of these findings in relation to morphological and electrophysiological aspects in patients with temporal lobe epilepsy are discussed.
INTRODUCTION PREVIOUSNEUROPSYCHOLOGICAL evaluations of right-handed patients with left temporal lobe infarct [2,7] or unilateral left temporal lobe resection for control of intractable seizures [ 19, 20, 371 have clearly revealed a significant relationship between the left temporal lobe and functions of verbal memory and learning. However, the literature on memory deficits associated with temporal lobe epilepsy (TLE) in non-surgical cases or prior to surgery has been less clear. Several studies did not find there to be significant differences in memory performance between patients with TLE, other seizure disorders or normal control subjects [17, 18, 221. Other investigations revealed memory deficits in temporal lobe epilepsy, however they failed to relate them to the lateralization of the seizure focus [9, 13, 311. Particularly in recent years and with the development of subtle psychometric test instruments, some studies have shown lateralized functional disturbances with verbal memory deficits in cases with left temporal seizure focus and non-verbal memory deficits associated with right temporal lobe focus 18, 11, 141. In a previous study [lo] we were able to confirm these findings of circumscribed cognitive deficits in relation to the lateralization of the seizure focus, in particular for verbal memory performance. While patients with right TLE had no deficits of verbal memory, patients with left TLE showed significant impairment. Our results, however, suggested that to a major extent these defined deficits were due to the anticonvulsant drug effect. With moderate * Address Krankenhaus
for correspondance: In der Schornau,
Dr H. F. Durwen, Neurologische 4630 Bochum-Langendreer. F.R.G. 623
Klinik der Ruhr-Universitat,
Knappschafts-
624
H. F.
DLKWEN,
A. HUFNAGLL and C. E. ELGEK
reduction of the anticonvulsants the patients with left TLE improved significantly in their verbal memory abilities, while performance of patients with right TLE remained unchanged. The aim of the present study was to clarify, whether the improvement of verbal memory in patients with left TLE under reduced medication was an overall effect, affecting memory performance in general, or whether it was possible to identify certain steps of learning and memory processing which were particularly susceptible to the anticonvulsant drug effects. In an attempt to answer this question a word list learning paradigm with the theoretical framework of a storage hypothesis of memory was used.
MATERIAL
AND METHODS
Subject.\ All subjects of this investigation were patients who suffered from intractable complex partial seizures of left temporal lobe origin and had been referred to our in-patient monitoring unit. The primary reason for admission was to assess the patients’ suitability for focal resection of the epileptogenic lesion. In order to conclusively localize the area of major electrophysiological pathology, all patients underwent continuous closed circuit TV/EEG monitoring with scalp and sphenoidal electrodes. In addition, five patients had electrocorticography with strip electrodes. The study sample consisted of 13 patients with intractable complex partial seizures of clearly left temporal lobe origin (LTLE) established by the presurgical work-up. The exact localization of the seizure focus as being temporolateral or temporomesial was defined by the locus of seizure onset using strip or surface and sphenoidal electrodes. With surface and sphenoidal electrodes it was required in addition, that interictal epileptogenic activity was restricted to one of both areas. According to the OLUFIELU handedness questionnaire 1251 all patients had a clear left hemispherical motor dominance, that corrlates in 96”/, with a left hemisphere dominance for language and verbal memory processing [Zl]. This was further approved by tachistoscopic hemifield stimuation with verbal material 1391 and the WADAtest procedure [35] carried out in eight cases who were operated on electively and/or had a temporolateral seizure focus. The subject pool of this study consisted of four males and nine females. The mean age was 25.7 years (SD 8.9; range 1650 years). The handedness score according to the OLDFIELD questionnaire [25] was + 82.2 (SD 3 1.2; range +2 to + 100). Two patients had familial left-handedness. Seizure parameters and neurological variables are shown in Table I.
Table 1. Seizure parameters and neurological variables in I3 patients with left temporal lobe epilepsy Seizure type (CP = complex partial seizures): CP 7 patients CP + secondary 6 patients generalization Seizure frequency Mean SD Range
per month (on admission): 14.8 13.7 3 -50
Etiology: Cryptogenic Posttraumatic Vascular Tumorous Age at seizure onset: Mean (years) SD Range (years)
4 patients 2 patients 1 patient 6 patients 13.7 6.1 I 22
ANTICONVULSANTDRUGSAFFECTVERBAL
Morphological
and electrophysiological
MEMORY
625
PROCESSING
characteristics
All 13 patients clearly showed a left temporal EEG focus. In five cases the focus had a temporomesial and in eight cases a temporolateral localization. Of the five patients with temporomesial EEG focus two patients also had a temporomesial lesion in the CT scan, one patient had a temporolateral lesion and two subjects had a normal CT. Of the eight patients with a temporolateral EEG focus two patients also had a temporolateral lesion in the CT scan, four patients had a temporomesial lesion and two subjects had a normal CT. Considering the localization of electrophysiological and morphological pathology combined, nine patients had either one aspect or both in the temporolateral as well as in the temporomesial region. The morphological and electrophysiological data are presented in more detail in Table 2.
Table 2. Localization of EEG focus and CT lesion in 13 patients with intractable complex partial seizures of left temporal lobe origin EEG focus Temporomesial Temporolateral
CT scan Normal Temporomesial Temporolateral Total
lesion lesion
2 2
1 5
2 4 2 8
Total 4 6 3 13
Test instruments A short version of our basic psychometric test battery was administered to all subjects in that particular investigation and included attentional parameters, psychomotor speed as well as measures for verbal memory. The battery consisted of the Corsi Block Test (forward and backward), Digit Span (forward and backward), d2--Aufmerksamkeits-Belastungstest by BRICKENKAMP [4], tapping test and finally of the REY Auditory Verbal Learning Test (AVLT) for verbal memory 1261. The AVLT was used in a German version and consisted of five presentations with free recall of a 15-word list (list a), measuring immediate memory span in trial 1and providing a learning curve by trials 2 5 and giving information about the patient’s learning capacity. Thereafter, a second 15-word list (list b) for interference effects was presented and immediately recalled, followed by a sixth free recall, a delayed free recall after 30 min and a cued recall of the initial word list, thus providing information on retrieval and retention abilities. Subtraction of the performance score in trial 6 from the score in trial 5 reflected an information loss by interference and provided information on the patient’s capacity for retention and retrieval. The cued recall trial as a recognition trial helped to clarify the nature of the patient’s recall problem; adequate performance in the cued recall trial rather suggested a retrieval than a retention problem of memory. The scores for each trial as well as the calculated score (556) were registered for further statistical analysis. The d22AufmerksamkeitssBelastungstest by Brickenkamp is based on a target selection paradigm, comparable to a letter cancellation task, and measures the capacity for sustained attention as well as psychomotor speed. While measuring the span of immediate recall Corsi Block Test as well as Digit Span were used as attentional parameters within this context. They were presented twice and a mean score was calculated. Furthermore the Tapping Test was performed twice for each hand and a mean score calculated for each side. Procedurr A neuropsychologist administered individually the complete psychometric test battery twice. One presentation took place under the condition of full medication. On the same day a blood sample was drawn to determine the serum levels ofthe anticonvulsants. As pointed out in Table 3, levels ofanticonvulsants were not within toxic ranges under condition of full medication. In order to enhance the chances of registering an ictal event, which is required during presurgical work-up of epilepsy patients, there was also a condition of reduced anticonvulsant medication, according to the individual needs of each patient. With reduced medication each patient had a second neuropsychological evaluation and again, on the same day, a blood sample drawn to determine the serum levels of the anticonvulsants (Table 3). On average, there was a 5-day interval between the two test sessions. The test procedures were carried out always at the same time during the morning. Furthermore, in order to avoid practice effects, we used alternative and counterbalanced forms of the AVLT in the two psychometric sessions. As pointed out in an earlier paper [IO] practice effects were most unlikely, because verbal memory performance benefited from drug reduction only in patients with a left temporal seizure focus, whereas performance in RTLE patients remained unaffected under both conditions. None of the patients of this series had clinical seizures either during the testing itself or at least 12 h before.
H. F. DURWEN, A. HUFNACEL and C. E. ELGER
626
Table 3. Serum levels of anticonvulsants under full and reduced in 13 patients with left temporal lobe epilepsy
No.
Initials
Drugs
Full med. @g/ml)
medication
Red. med. (pgiml)
(1)
Sch.M.
Phenytoin Phenobarbital
15.5 20.3
4.7 6.7
(2)
L.B.
Carbamazepin Phenytoin
8.4 2.1
4.1 0.0
(3)
M.J.
Carbamazepin
8.5
6.9
(4)
G.M.
Phenytoin
25.0
4.1
(5)
D.J.
Carbamazepin Valproic Acid
10.4 24.2
10.7 0.0
(6)
Sch.G.
Carbamazepin Phenobarbital
4.4 16.2
8.4 0.0
(7)
G.S.
Carbamazepin Phenytoin
4.5 13.7
3.8 0.0
(8)
D.I.
Phenobarbital
20.3
14.6
(9)
Z.R.
Phenytoin Phenobarbital
12.0 21.1
5.1 0.0
(10)
B.A.
Carbamazepin
10.9
6.8
(11)
K.D.
Carbamazepin Phenytoin Valproic Acid
7.2 3.7 49.2
6.2 0.0 0.0
(12)
Sch.U.
Carbamazepin Phenytoin Phenobarbital
6.2 7.1 12.2
5.8 3.2 0.0
(13)
1.K
Carbamazepin Vatproic Acid
5.0 38.1
6.5 0.0
Most of the patients in this first evaluation only had moderate reduction of the anticonvulsants depending on the increase of seizure frequency and the risk of developing generalized seizures. For ethical reasons, therefore. the reduction of medication at this time occurred on the basis of clinical needs and did not focus on particular serum levels of different groups of anticonvulsants. Sfafislical
anulysis
A group comparison of LTLE patients between the conditions of full and reduced medication each variable under consideration, using Student’s f-test (two-tailed) for paired variables.
was performed
for
RESULTS Attentional
measures
Previous investigations [32-341 have shown that anticonvulsants can affect attention as well as psychomotor speed and thus cognitive performance in general. Therefore, in order to look out for significant effects of anticonvulsants on vigilance and thus indirectly on higher cognitive functions like memory performance even under the condition of moderate drug reduction, we used a comprehensive attentional test battery to monitor attention, sustained attention and psychomotor speed, including Digit Span (forward and backward), Corsi Block Test (forward and backward) d2-Aufmerksamkeits-Belastungstest by Brickenkamp (psychomotor speed and capacity for sustained attention) as well as the finger tapping test.
ANTICONVULSANT
DRUGS
AFFECT
VERBAL
MEMORY
PROCESSING
627
The results for each single test are presented in detail in Table 4(a). Separate comparisons for each variable of attention and psychomotor speed in LTLE patients with full and reduced medication levels were performed. Using Students r-test (two-tailed) for paired variables there was no statistically significant difference between the two conditions of different medication levels for each variable of attention or psychomotor speed. Table 4. Cognitive test data (attentional parameters and AVLT) of 13 patients with left temporal lobe epilepsy-psychometric testing under full and reduced medication (group mean scores) Full medication Mean SD
Reduced Mean
medication SD
(a) d2 Aufmerksamkeits-Belastungstest Psychomotor speed (Arbeitstempo) Capacity for sustained attention (Aufmerksamkeitsbelastbarkeit)
(raw scores): 389 382
91 87
404 396
109 I06
Digit Span (raw scores): Forward Backward
5.3 4.6
0.8
1.1
5.4 4.9
0.9 I .4
Corsi Block Test (raw scores): Forward Backward
6.0 5.4
I .2 I .3
5.7 5.5
0.9 I .2
61.6 54.9
8.5 9.6
59.6 57.3
6.5 11.1
(raw scores): I (list a) 2 (list a) 3 (list a) 4 (list a) 5 (list a)
7.0 8.8 10.2 Il.1 12.1
I .8 I .8 I .9 2.1 I .5
6.0 9.2 I I .2 12.5 13.2
I .8 2.0 2.0 2.5 2.0
List (b) recall Trial 6 (list a) Trial 7 (list a) (delayed
5.5 8.5t 9.0
I .6 2.9 3.5
6.7 12.0t 10.9
2.6 2.5 2.9
12.9
2.4
13.6
I .8
Tapping Test (raw scores) Right hand Left hand
(b) AVLT Trial Trial Trial Trial Trial
free recall)
Cued recall (list a)
Trial 5-6 (list a) Student’s
Verbal
t-test: *P
3.7*
2.1
I .5*
I .2
tP
memory
As suggested earlier by MUNGAS [24] to test the memory performance in temporal lobe epileptics, we used a word list learning paradigm, in order to evaluate the possible effects of drug reduction on different aspects of verbal memory performance. Alternative and counterbalanced versions of the Auditory Verbal Learning Test by Rey (AVLT) were presented to the patients under the conditions of full and moderately reduced medication. The results for all variables of verbal learning and memory are presented in detail in Table 4(b). Comparing the performances with full and reduced medication levels, there were significant group effects on LTLE patients for particular steps of verbal memory processing
H. F. DUKWEN,
628
A. HUFNAGEL and
C. E.
ELGER
only. Significant differences were seen with learning trial 6, as well as with subtraction of trials 556 (information loss by interference). Learning trials l-5, the delayed free recall (trial 7) as well as the cued recall trial did not show significant differences. The results indicated, that verbal memory performance in LTLE patients was better with reduced medication (Student’s t-test: trial 6: t=7.84; d.f.= 12; P-cO.001; trials 556: t= 3.93; d.f.= 12; P < 0.01). The data for the different learning trials with different medication are illustrated in Fig. 1.
16 14 12 10 8 6 4 2 0
I
2
3
4
5
Interf.
6
7 Dr
CR
6420
5-6 0 +
full medication
significant
a
difference
reduced
medication
(~~0.01)
N = 13
Fig. I. Auditory Verbal Learning Test (AVLTtperformance of therapy-resistant patients with complex partial seizures of left temporal lobe origin (LTLE) under the conditions of full and reduced medication. Significant improvement with drug reduction only for trial 6 and subtraction oftrials 5 -6 (P
DISCUSSION Anticonvulsants are well known to be likely to reduce the cognitive abilities in epileptic patients as well as in normal controls [ 12,15,29,32-341. In general, they are said to interfere diffusely with vigilance, psychomotor speed and memory performance. These global effects on cognition are particularly true in normal subjects, who primarily suffer from reduction of attention and vigilance [3], depending on drug and dosage. However, in a previous study
ANTICONVULSANT
DRUGS
AFFECT VERBAL
MEMORY
PROCESSING
629
[lo] we were able to show that in epileptic patients with intractable complex partial seizures of temporal lobe origin, anticonvulsant drugs can cause circumscribed cognitive deficits and that these effects are related to the lateralization of the seizure focus. This applies in particular for verbal memory peformance. In the present study, being based on a higher number of investigated subjects, we were able to describe these effects with greater precision. It was possible to demonstrate, that with variation of medication levels and without significant change of attentional measures verbal memory performance was not affected in a diffuse manner, but at a very particular, circumscribed step of mnemonic information processing. In order to elucidate these questions we have used the AVLT, a word list learning format being based on a storage hypothesis of memory, as suggested by MUNGAS for neuropsychological investigation of memory in epileptics [25,30]. The use of this paradigm in left temporal lobe epileptics pre- and postsurgically had shown in a previous study [31], that with the resection of the left temporal lobe all aspects of verbal memory, except immediate memory span, deteriorated significantly. By contrast, our study now demonstrated that verbal memory was not affected globally by anticonvulsants, but very specifically. Under the reduction of medication our patients with left temporal lobe epilepsy significantly improved only for the aspect of retention and retrieval of verbal material after interference. The appropriate performance in the cued recall trial under both conditions rather suggested that our patients, even under full medication, were still able to retain acquired verbal information but that the deficits in trial 6 of the paradigm and in the subtraction of trials 5 and 6 under the condition of full medication were primarily due to inadequate retrieval abilities. Further evidence for this assumption of intact retention of verbal information results from the fact that our patients’ performance did not differ significantly under either conditions in regards to delayed free recall after 30 min. Therefore, the major finding of this study was that it demonstrated anticonvulsive drug effects to modulate only the ability to retrieve newly learned verbal material, following the interference-filled delay, while all the other parameters of memory processing within the AVLT-paradigm remained unchanged. With a storage hypothesis of memory in mind our data may be interpreted in the sense that the processor for retrieving memory traces seems most likely to be susceptible to anticonvulsant drug effects, whereas immediate memory span and long-term retention of verbal information are not significantly affected. Furthermore, our findings suggest that particularly interference effects in memory processing seem to be aggravated by anticonvulsant medication. From previous investigations [S, 361 we know, that interference has a strong and pathological effect in memory disorders associated with medial temporal lobe/limbic dysfunctions. Furthermore current neuropsychological concepts of memory stress the importance of the left medial temporal lobe-the hippocampus formation in particular-for the ability to retrieve new verbal information, whereas the performance in immediate memory seems to be indpendent of these structures [ 1,6,27,28,30,38]. With these previous findings in mind, our data in terms of localizing aspects would rather suggest, that the hippocampus formation of the temporal lobe most likely is particularly sensitive to anticonvulsant drug effects and mediates the observed deficits in memory performance. However, it remains unclear at present, what underlying mechanisms allow the anticonvulsants to modify memory processing in such a specific manner and whether this can be observed with all anticonvulsants or if they are specific to certain pharmacological substrates. In any case, these observations raise important questions concerning the
630
H. F. DURWEN, A. HUFNAGEL and C. E. ELGER
interaction of antiepileptic drugs with epileptogenic neuronal aggregates in brain areas responsible for memory functions. The assumption of a possible particular interaction between the anticonvulsants and epileptogenic tissue is further supported by the fact, that until now such very specific effects have not been observed in normal control subjects [3], One possible explanation for the observed phenomena may be the lack of sufficient neuronal activation under full medication in these particular areas due to either loss of neuronal cells by morphological pathology, the modification of the neuronal excitability characteristics within the epileptogenic process or perhaps both. It may be that the remaining and/or epileptogenic neurons in the temporal network of memory function, especially in the amygdala-hippocampus region, may be particularly sensitive to medication effects; thus the generation of seizures may be suppressed by medication, but on the other hand it may also have a very strong inhibitory influence on the regular functions that otherwise may still take place in these systems. Since in patients with temporal lobe epilepsy the hippocampus provides a frequent localization for seizure foci, it would not be surprising to find memory deficits as described above. However, it has to be emphasized that not all our patients had their major electrophysiological and/or morphological pathology exactly in the region under consideration and that at least an equal number of patients had pathological findings in the temporolateral area. Further research will have to clarify, of what particular nature the influences are which the primary electrophysiological and/or morphological pathologies have on the modulative effects of anticonvulsant drugs on memory, where they have to be located in relation to the amygdala-hippocampus formation, whether this area as a functional bottleneck may be much more involved in the epileptogenic process than one would conclude from the localization of the primary pathology or whether patients with neither electrophysiological nor morphological disturbances in that region are not affected at all or by specific mnemonic deficits of a different kind. Acknowledgements-We are grateful to the BMA (Bundesministrium fiir Arbeit und Soziales) for the support research project. We thank L. Sarvan for her help in preparing this text for publication in English.
of this
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CO?&3932 92 S5.00+0.00 ,N 1992 Pergamon Pres, Lid
ANTICONVULSANT DRUGS AFFECT PARTICULAR STEPS OF VERBAL MEMORY PROCESSING-AN EVALUATION OF 13 PATIENTS WITH INTRACTABLE COMPLEX PARTIAL SEIZURES OF LEFT TEMPORAL LOBE ORIGIN H. F. DURWEN,*~ A. HUFNAGEL$ and C. E. ELGER: tDepartment
of Neurology, Ruhr-University, Bochum, F.R.G.; and IDepartment (Received
Knappschafts-Krankenhaus (Director: Prof. Dr W. Gehlen), of Epileptology, Bonn University, Bonn, F.R.G.
19 November
1990: accepted 3 December
1991)
Abstract-Thirteen patients with intractable complex partial seizures of left temporal lobe origin were tested for verbal memory performance under the conditions of full and reduced anticonvulsant medication. As suggested by previous investigations memory performance improved significantly with the reduction of anticonvulsants. However, our observations refute assumptions that the effects of antiepileptic drugs act primarily by non-specific mechanisms affecting attention and/or memory diffusely. Our data rather suggest that very specific and circumscribed steps of verbal memory processing, particularly retrieval abilities after interference, are affected by anticonvulsants. The possible implications of these findings in relation to morphological and electrophysiological aspects in patients with temporal lobe epilepsy are discussed.
INTRODUCTION PREVIOUSNEUROPSYCHOLOGICAL evaluations of right-handed patients with left temporal lobe infarct [2,7] or unilateral left temporal lobe resection for control of intractable seizures [ 19, 20, 371 have clearly revealed a significant relationship between the left temporal lobe and functions of verbal memory and learning. However, the literature on memory deficits associated with temporal lobe epilepsy (TLE) in non-surgical cases or prior to surgery has been less clear. Several studies did not find there to be significant differences in memory performance between patients with TLE, other seizure disorders or normal control subjects [17, 18, 221. Other investigations revealed memory deficits in temporal lobe epilepsy, however they failed to relate them to the lateralization of the seizure focus [9, 13, 311. Particularly in recent years and with the development of subtle psychometric test instruments, some studies have shown lateralized functional disturbances with verbal memory deficits in cases with left temporal seizure focus and non-verbal memory deficits associated with right temporal lobe focus 18, 11, 141. In a previous study [lo] we were able to confirm these findings of circumscribed cognitive deficits in relation to the lateralization of the seizure focus, in particular for verbal memory performance. While patients with right TLE had no deficits of verbal memory, patients with left TLE showed significant impairment. Our results, however, suggested that to a major extent these defined deficits were due to the anticonvulsant drug effect. With moderate * Address Krankenhaus
for correspondance: In der Schornau,
Dr H. F. Durwen, Neurologische 4630 Bochum-Langendreer. F.R.G. 623
Klinik der Ruhr-Universitat,
Knappschafts-
624
H. F.
DLKWEN,
A. HUFNAGLL and C. E. ELGEK
reduction of the anticonvulsants the patients with left TLE improved significantly in their verbal memory abilities, while performance of patients with right TLE remained unchanged. The aim of the present study was to clarify, whether the improvement of verbal memory in patients with left TLE under reduced medication was an overall effect, affecting memory performance in general, or whether it was possible to identify certain steps of learning and memory processing which were particularly susceptible to the anticonvulsant drug effects. In an attempt to answer this question a word list learning paradigm with the theoretical framework of a storage hypothesis of memory was used.
MATERIAL
AND METHODS
Subject.\ All subjects of this investigation were patients who suffered from intractable complex partial seizures of left temporal lobe origin and had been referred to our in-patient monitoring unit. The primary reason for admission was to assess the patients’ suitability for focal resection of the epileptogenic lesion. In order to conclusively localize the area of major electrophysiological pathology, all patients underwent continuous closed circuit TV/EEG monitoring with scalp and sphenoidal electrodes. In addition, five patients had electrocorticography with strip electrodes. The study sample consisted of 13 patients with intractable complex partial seizures of clearly left temporal lobe origin (LTLE) established by the presurgical work-up. The exact localization of the seizure focus as being temporolateral or temporomesial was defined by the locus of seizure onset using strip or surface and sphenoidal electrodes. With surface and sphenoidal electrodes it was required in addition, that interictal epileptogenic activity was restricted to one of both areas. According to the OLUFIELU handedness questionnaire 1251 all patients had a clear left hemispherical motor dominance, that corrlates in 96”/, with a left hemisphere dominance for language and verbal memory processing [Zl]. This was further approved by tachistoscopic hemifield stimuation with verbal material 1391 and the WADAtest procedure [35] carried out in eight cases who were operated on electively and/or had a temporolateral seizure focus. The subject pool of this study consisted of four males and nine females. The mean age was 25.7 years (SD 8.9; range 1650 years). The handedness score according to the OLDFIELD questionnaire [25] was + 82.2 (SD 3 1.2; range +2 to + 100). Two patients had familial left-handedness. Seizure parameters and neurological variables are shown in Table I.
Table 1. Seizure parameters and neurological variables in I3 patients with left temporal lobe epilepsy Seizure type (CP = complex partial seizures): CP 7 patients CP + secondary 6 patients generalization Seizure frequency Mean SD Range
per month (on admission): 14.8 13.7 3 -50
Etiology: Cryptogenic Posttraumatic Vascular Tumorous Age at seizure onset: Mean (years) SD Range (years)
4 patients 2 patients 1 patient 6 patients 13.7 6.1 I 22
ANTICONVULSANTDRUGSAFFECTVERBAL
Morphological
and electrophysiological
MEMORY
625
PROCESSING
characteristics
All 13 patients clearly showed a left temporal EEG focus. In five cases the focus had a temporomesial and in eight cases a temporolateral localization. Of the five patients with temporomesial EEG focus two patients also had a temporomesial lesion in the CT scan, one patient had a temporolateral lesion and two subjects had a normal CT. Of the eight patients with a temporolateral EEG focus two patients also had a temporolateral lesion in the CT scan, four patients had a temporomesial lesion and two subjects had a normal CT. Considering the localization of electrophysiological and morphological pathology combined, nine patients had either one aspect or both in the temporolateral as well as in the temporomesial region. The morphological and electrophysiological data are presented in more detail in Table 2.
Table 2. Localization of EEG focus and CT lesion in 13 patients with intractable complex partial seizures of left temporal lobe origin EEG focus Temporomesial Temporolateral
CT scan Normal Temporomesial Temporolateral Total
lesion lesion
2 2
1 5
2 4 2 8
Total 4 6 3 13
Test instruments A short version of our basic psychometric test battery was administered to all subjects in that particular investigation and included attentional parameters, psychomotor speed as well as measures for verbal memory. The battery consisted of the Corsi Block Test (forward and backward), Digit Span (forward and backward), d2--Aufmerksamkeits-Belastungstest by BRICKENKAMP [4], tapping test and finally of the REY Auditory Verbal Learning Test (AVLT) for verbal memory 1261. The AVLT was used in a German version and consisted of five presentations with free recall of a 15-word list (list a), measuring immediate memory span in trial 1and providing a learning curve by trials 2 5 and giving information about the patient’s learning capacity. Thereafter, a second 15-word list (list b) for interference effects was presented and immediately recalled, followed by a sixth free recall, a delayed free recall after 30 min and a cued recall of the initial word list, thus providing information on retrieval and retention abilities. Subtraction of the performance score in trial 6 from the score in trial 5 reflected an information loss by interference and provided information on the patient’s capacity for retention and retrieval. The cued recall trial as a recognition trial helped to clarify the nature of the patient’s recall problem; adequate performance in the cued recall trial rather suggested a retrieval than a retention problem of memory. The scores for each trial as well as the calculated score (556) were registered for further statistical analysis. The d22AufmerksamkeitssBelastungstest by Brickenkamp is based on a target selection paradigm, comparable to a letter cancellation task, and measures the capacity for sustained attention as well as psychomotor speed. While measuring the span of immediate recall Corsi Block Test as well as Digit Span were used as attentional parameters within this context. They were presented twice and a mean score was calculated. Furthermore the Tapping Test was performed twice for each hand and a mean score calculated for each side. Procedurr A neuropsychologist administered individually the complete psychometric test battery twice. One presentation took place under the condition of full medication. On the same day a blood sample was drawn to determine the serum levels ofthe anticonvulsants. As pointed out in Table 3, levels ofanticonvulsants were not within toxic ranges under condition of full medication. In order to enhance the chances of registering an ictal event, which is required during presurgical work-up of epilepsy patients, there was also a condition of reduced anticonvulsant medication, according to the individual needs of each patient. With reduced medication each patient had a second neuropsychological evaluation and again, on the same day, a blood sample drawn to determine the serum levels of the anticonvulsants (Table 3). On average, there was a 5-day interval between the two test sessions. The test procedures were carried out always at the same time during the morning. Furthermore, in order to avoid practice effects, we used alternative and counterbalanced forms of the AVLT in the two psychometric sessions. As pointed out in an earlier paper [IO] practice effects were most unlikely, because verbal memory performance benefited from drug reduction only in patients with a left temporal seizure focus, whereas performance in RTLE patients remained unaffected under both conditions. None of the patients of this series had clinical seizures either during the testing itself or at least 12 h before.
H. F. DURWEN, A. HUFNACEL and C. E. ELGER
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Table 3. Serum levels of anticonvulsants under full and reduced in 13 patients with left temporal lobe epilepsy
No.
Initials
Drugs
Full med. @g/ml)
medication
Red. med. (pgiml)
(1)
Sch.M.
Phenytoin Phenobarbital
15.5 20.3
4.7 6.7
(2)
L.B.
Carbamazepin Phenytoin
8.4 2.1
4.1 0.0
(3)
M.J.
Carbamazepin
8.5
6.9
(4)
G.M.
Phenytoin
25.0
4.1
(5)
D.J.
Carbamazepin Valproic Acid
10.4 24.2
10.7 0.0
(6)
Sch.G.
Carbamazepin Phenobarbital
4.4 16.2
8.4 0.0
(7)
G.S.
Carbamazepin Phenytoin
4.5 13.7
3.8 0.0
(8)
D.I.
Phenobarbital
20.3
14.6
(9)
Z.R.
Phenytoin Phenobarbital
12.0 21.1
5.1 0.0
(10)
B.A.
Carbamazepin
10.9
6.8
(11)
K.D.
Carbamazepin Phenytoin Valproic Acid
7.2 3.7 49.2
6.2 0.0 0.0
(12)
Sch.U.
Carbamazepin Phenytoin Phenobarbital
6.2 7.1 12.2
5.8 3.2 0.0
(13)
1.K
Carbamazepin Vatproic Acid
5.0 38.1
6.5 0.0
Most of the patients in this first evaluation only had moderate reduction of the anticonvulsants depending on the increase of seizure frequency and the risk of developing generalized seizures. For ethical reasons, therefore. the reduction of medication at this time occurred on the basis of clinical needs and did not focus on particular serum levels of different groups of anticonvulsants. Sfafislical
anulysis
A group comparison of LTLE patients between the conditions of full and reduced medication each variable under consideration, using Student’s f-test (two-tailed) for paired variables.
was performed
for
RESULTS Attentional
measures
Previous investigations [32-341 have shown that anticonvulsants can affect attention as well as psychomotor speed and thus cognitive performance in general. Therefore, in order to look out for significant effects of anticonvulsants on vigilance and thus indirectly on higher cognitive functions like memory performance even under the condition of moderate drug reduction, we used a comprehensive attentional test battery to monitor attention, sustained attention and psychomotor speed, including Digit Span (forward and backward), Corsi Block Test (forward and backward) d2-Aufmerksamkeits-Belastungstest by Brickenkamp (psychomotor speed and capacity for sustained attention) as well as the finger tapping test.
ANTICONVULSANT
DRUGS
AFFECT
VERBAL
MEMORY
PROCESSING
627
The results for each single test are presented in detail in Table 4(a). Separate comparisons for each variable of attention and psychomotor speed in LTLE patients with full and reduced medication levels were performed. Using Students r-test (two-tailed) for paired variables there was no statistically significant difference between the two conditions of different medication levels for each variable of attention or psychomotor speed. Table 4. Cognitive test data (attentional parameters and AVLT) of 13 patients with left temporal lobe epilepsy-psychometric testing under full and reduced medication (group mean scores) Full medication Mean SD
Reduced Mean
medication SD
(a) d2 Aufmerksamkeits-Belastungstest Psychomotor speed (Arbeitstempo) Capacity for sustained attention (Aufmerksamkeitsbelastbarkeit)
(raw scores): 389 382
91 87
404 396
109 I06
Digit Span (raw scores): Forward Backward
5.3 4.6
0.8
1.1
5.4 4.9
0.9 I .4
Corsi Block Test (raw scores): Forward Backward
6.0 5.4
I .2 I .3
5.7 5.5
0.9 I .2
61.6 54.9
8.5 9.6
59.6 57.3
6.5 11.1
(raw scores): I (list a) 2 (list a) 3 (list a) 4 (list a) 5 (list a)
7.0 8.8 10.2 Il.1 12.1
I .8 I .8 I .9 2.1 I .5
6.0 9.2 I I .2 12.5 13.2
I .8 2.0 2.0 2.5 2.0
List (b) recall Trial 6 (list a) Trial 7 (list a) (delayed
5.5 8.5t 9.0
I .6 2.9 3.5
6.7 12.0t 10.9
2.6 2.5 2.9
12.9
2.4
13.6
I .8
Tapping Test (raw scores) Right hand Left hand
(b) AVLT Trial Trial Trial Trial Trial
free recall)
Cued recall (list a)
Trial 5-6 (list a) Student’s
Verbal
t-test: *P
3.7*
2.1
I .5*
I .2
tP
memory
As suggested earlier by MUNGAS [24] to test the memory performance in temporal lobe epileptics, we used a word list learning paradigm, in order to evaluate the possible effects of drug reduction on different aspects of verbal memory performance. Alternative and counterbalanced versions of the Auditory Verbal Learning Test by Rey (AVLT) were presented to the patients under the conditions of full and moderately reduced medication. The results for all variables of verbal learning and memory are presented in detail in Table 4(b). Comparing the performances with full and reduced medication levels, there were significant group effects on LTLE patients for particular steps of verbal memory processing
H. F. DUKWEN,
628
A. HUFNAGEL and
C. E.
ELGER
only. Significant differences were seen with learning trial 6, as well as with subtraction of trials 556 (information loss by interference). Learning trials l-5, the delayed free recall (trial 7) as well as the cued recall trial did not show significant differences. The results indicated, that verbal memory performance in LTLE patients was better with reduced medication (Student’s t-test: trial 6: t=7.84; d.f.= 12; P-cO.001; trials 556: t= 3.93; d.f.= 12; P < 0.01). The data for the different learning trials with different medication are illustrated in Fig. 1.
16 14 12 10 8 6 4 2 0
I
2
3
4
5
Interf.
6
7 Dr
CR
6420
5-6 0 +
full medication
significant
a
difference
reduced
medication
(~~0.01)
N = 13
Fig. I. Auditory Verbal Learning Test (AVLTtperformance of therapy-resistant patients with complex partial seizures of left temporal lobe origin (LTLE) under the conditions of full and reduced medication. Significant improvement with drug reduction only for trial 6 and subtraction oftrials 5 -6 (P
DISCUSSION Anticonvulsants are well known to be likely to reduce the cognitive abilities in epileptic patients as well as in normal controls [ 12,15,29,32-341. In general, they are said to interfere diffusely with vigilance, psychomotor speed and memory performance. These global effects on cognition are particularly true in normal subjects, who primarily suffer from reduction of attention and vigilance [3], depending on drug and dosage. However, in a previous study
ANTICONVULSANT
DRUGS
AFFECT VERBAL
MEMORY
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629
[lo] we were able to show that in epileptic patients with intractable complex partial seizures of temporal lobe origin, anticonvulsant drugs can cause circumscribed cognitive deficits and that these effects are related to the lateralization of the seizure focus. This applies in particular for verbal memory peformance. In the present study, being based on a higher number of investigated subjects, we were able to describe these effects with greater precision. It was possible to demonstrate, that with variation of medication levels and without significant change of attentional measures verbal memory performance was not affected in a diffuse manner, but at a very particular, circumscribed step of mnemonic information processing. In order to elucidate these questions we have used the AVLT, a word list learning format being based on a storage hypothesis of memory, as suggested by MUNGAS for neuropsychological investigation of memory in epileptics [25,30]. The use of this paradigm in left temporal lobe epileptics pre- and postsurgically had shown in a previous study [31], that with the resection of the left temporal lobe all aspects of verbal memory, except immediate memory span, deteriorated significantly. By contrast, our study now demonstrated that verbal memory was not affected globally by anticonvulsants, but very specifically. Under the reduction of medication our patients with left temporal lobe epilepsy significantly improved only for the aspect of retention and retrieval of verbal material after interference. The appropriate performance in the cued recall trial under both conditions rather suggested that our patients, even under full medication, were still able to retain acquired verbal information but that the deficits in trial 6 of the paradigm and in the subtraction of trials 5 and 6 under the condition of full medication were primarily due to inadequate retrieval abilities. Further evidence for this assumption of intact retention of verbal information results from the fact that our patients’ performance did not differ significantly under either conditions in regards to delayed free recall after 30 min. Therefore, the major finding of this study was that it demonstrated anticonvulsive drug effects to modulate only the ability to retrieve newly learned verbal material, following the interference-filled delay, while all the other parameters of memory processing within the AVLT-paradigm remained unchanged. With a storage hypothesis of memory in mind our data may be interpreted in the sense that the processor for retrieving memory traces seems most likely to be susceptible to anticonvulsant drug effects, whereas immediate memory span and long-term retention of verbal information are not significantly affected. Furthermore, our findings suggest that particularly interference effects in memory processing seem to be aggravated by anticonvulsant medication. From previous investigations [S, 361 we know, that interference has a strong and pathological effect in memory disorders associated with medial temporal lobe/limbic dysfunctions. Furthermore current neuropsychological concepts of memory stress the importance of the left medial temporal lobe-the hippocampus formation in particular-for the ability to retrieve new verbal information, whereas the performance in immediate memory seems to be indpendent of these structures [ 1,6,27,28,30,38]. With these previous findings in mind, our data in terms of localizing aspects would rather suggest, that the hippocampus formation of the temporal lobe most likely is particularly sensitive to anticonvulsant drug effects and mediates the observed deficits in memory performance. However, it remains unclear at present, what underlying mechanisms allow the anticonvulsants to modify memory processing in such a specific manner and whether this can be observed with all anticonvulsants or if they are specific to certain pharmacological substrates. In any case, these observations raise important questions concerning the
630
H. F. DURWEN, A. HUFNAGEL and C. E. ELGER
interaction of antiepileptic drugs with epileptogenic neuronal aggregates in brain areas responsible for memory functions. The assumption of a possible particular interaction between the anticonvulsants and epileptogenic tissue is further supported by the fact, that until now such very specific effects have not been observed in normal control subjects [3], One possible explanation for the observed phenomena may be the lack of sufficient neuronal activation under full medication in these particular areas due to either loss of neuronal cells by morphological pathology, the modification of the neuronal excitability characteristics within the epileptogenic process or perhaps both. It may be that the remaining and/or epileptogenic neurons in the temporal network of memory function, especially in the amygdala-hippocampus region, may be particularly sensitive to medication effects; thus the generation of seizures may be suppressed by medication, but on the other hand it may also have a very strong inhibitory influence on the regular functions that otherwise may still take place in these systems. Since in patients with temporal lobe epilepsy the hippocampus provides a frequent localization for seizure foci, it would not be surprising to find memory deficits as described above. However, it has to be emphasized that not all our patients had their major electrophysiological and/or morphological pathology exactly in the region under consideration and that at least an equal number of patients had pathological findings in the temporolateral area. Further research will have to clarify, of what particular nature the influences are which the primary electrophysiological and/or morphological pathologies have on the modulative effects of anticonvulsant drugs on memory, where they have to be located in relation to the amygdala-hippocampus formation, whether this area as a functional bottleneck may be much more involved in the epileptogenic process than one would conclude from the localization of the primary pathology or whether patients with neither electrophysiological nor morphological disturbances in that region are not affected at all or by specific mnemonic deficits of a different kind. Acknowledgements-We are grateful to the BMA (Bundesministrium fiir Arbeit und Soziales) for the support research project. We thank L. Sarvan for her help in preparing this text for publication in English.
of this
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