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Circumscribed improvement of cognitive performance in temporal lobe epilepsy patients with intractable seizures following reduction of anticonvulsant medication
/ Epilepsy
1989;2:147-153
0 1989‘Demos Publications
Circumscribed Improvement of Cognitive Performance in Temporal Lobe Epilepsy Patients with Intractable Seizures Following Reduction of Anticonvulsant Medication H. F. Durwen,
C. E. Elger, C. Helmstaedter,
and H. Penin
During the presurgical evaluation of patients with intractable complex partial seizures, neuropsychometric testing was performed under conditions of full and reduced medication in order to determine the influence of anticonvulsants on cognitive performance. While attentional parameters remained completely unchanged, verbal memory performance improved significantly under reduced medication in patients with left temporal lobe epilepsy (LTLE) only, whereas patients with right temporal lobe epilepsy (RTLE) did not differ significantly under both conditions. However, a reverse, but not significant, pattern with improvement of nonverbal memory under reduced medication was only observed in RTLE subjects. The data suggest circumscribed effects of anticonvulsant medication on cognition in relation to the localization of the seizure focus. Key Words: Temporal lobe epilepsy-Cognition-Memory-AnticonvulsantsIntractable complex partial seizures.
Neuropsychological investigations of patients with unilateral temporal lobe resection for control of ntractable seizures have clearly revealed a significant relationship between left temporal lobe resection and Yrerbal learning deficits, as well as between right :emporal lobe resection and impairment of nonverbal earning (14). In a number of studies on memory, deficits associated with temporal lobe epilepsy (TLE) n nonsurgical cases or prior to surgery were found to ,e less clearly attributed to the lateralization of the bcus (5-7). However, with the development of ;ubtle psychometric test instruments, some studies lave shown lateralized functional disturbances with verbal memory deficits in cases with a left temporal ecus and nonverbal memory deficits associated with he right temporal lobe focus (B-10). Therefore, in
From the Department of Epileptology, Bonn University, sonn, F.R.G. Address correspondence and reprint requests to Dr. H. ;. Durwen at Universit’dts Nervenklinik, Epileptologie, Sigmund Freud-Strasse 25, 5300 Bonn 1, F.RG.
the presurgical workup of TLE patients with intractable seizures, the results of a sophisticated neuropsychological evaluation may help to lateralize and localize the areas of major pathology and therewith the primary epileptic focus (9,11-13). Furthermore, they may serve as a basis to predict postoperative outcome and will be used as reference for postsurgical control of cognitive performance (2,14-16). To date, there seems to be no clear idea to what extent the described deficits result from interictal electrophysiological dysfunction, from an underlying pathological substrate, or from pharmacological interferences. It has been shown that anticonvulsant medications are apt to reduce the cognitive abilities in epileptic patients as well as in normal controls (17-22). In general, they are said to interfere diffusely with vigilance, memory performance, and psychomotor speed. To our knowledge, however, there is no neuropsychological investigation, particularly none in the presurgical workup of TLE patients with intractable seizures, that looks in detail into the possible effects 1 EPILEPSY, VOL. 2, NO. 3, 1989
147
H. F. DURWEN ETAL.
of anticonvulsant medication on cognition. Neuropathologicai studies have demonstrated a correlation between the extent of cell loss in temporal lobe structure resected during epilepsy surgery and specific neuropsychological deficits. Interictal activity of limbic structures and neuropsychological deficits have been evaluated only unsystematically (23). It is the aim of the present study to determine the influence of the anticonvulsant medications on the cognitive and memory performance of patients with pharmacoresistant TLE who underwent the presurgical evaluation. To that purpose, the patients had a neuropsychological test battery under full medication and during the reduction of the anticonvulsant drugs, which is necessary in the presurgical workup.
Materials and Methods Subjects The subject pool consisted of referrals to our inpatient monitoring unit. All patients had intractable complex partial seizures of temporal lobe origin. 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 EEG pathology, all patients were evaluated by continuous closed-circuit TV/EEG monitoring scalp and, in most cases, sphenoidal electrodes. The study sample consisted of 13 patients. In six patients, the seizure focus was localized in the left hemisphere (LTLE) and in seven patients in the right hemisphere (RTLE). All patients were clearly lefthemisphere-dominant for handedness (24) that correlates in 96% with left-hemispheral dominance for language (25). Two patients had a handedness score (23) of -i-2 and i-8, respectively. They both had a WADA procedure and clearly showed a left hemisphere dominance for language. Furthermore, all patients underwent tachistoscopic hemifield stimulation with verbal material, which also revealed a left hemispheral dominance for language processing in each patient (26). Information concerning the demographic features of the subjects is shown in Table 1.
Test instruments All subjects in the program were administered a short version of our basic psychometric test battery, including the Benton Visual Retention Test (BVRT) (27), a German adaptation of the Rey Auditory Verbal Learning Test (AVLT) (28), and a standardized 148
1 EPILEPSY, VOL. 2, NO. 3, 1989
Table 1.
Srlbject churncteristics Handedness
Case/sex/age
(years)
LTLE l/F/29 2/F/24 3/M/20 4/M/18 5/F/15 6/F/26 Mean 22 (age, years) RTLE l/M/43 2/F/29 3/M/35 4/F/35 5/F/33 6/M/24 7/F/35 Mean 28 (age, years)
(scores)
Familial left handedness
flO0 +100 +92 f42 f50 +2
+ -
f64
$100 flO0 +100 +100 t8 +58 +83
-
+72
German test for sustained attention (d2-Aufmerksamkeits-Belastungstest nach Brickenkamp) (29). Furthermore, we used the Digit Span (forward and backward) as well as the Corsi Block Test (forward and backward). Psychomotor speed was assessed by the Tapping Test. Versions C and D of the BVRT were used, registering the number of correct and error responses. The AVLT consists of five presentations with free recall of a 15-word list (list A), one presentation and free recall of a second 15-word list for interference (list B), and a sixth as well as a seventh free recall trial of the first list. The test measured immediate memory span with the first trial, provided a learning curve and also measured retention following the interpolated interference activity. Finally, the seventh trial controlled the delayed free recall after 30 min. The correct answers of each trial were registered for further statistical analysis. The d2-Aufmerksamkeits-Belastungstest nach Brickenkamp is based on a target selection paradigm, comparable to a letter cancellation task. The capacity for sustained attention as well as psychomotor speed were registered. Digit Span and Corsi Block Test 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.
INFLUENCE
Table 2.
Case LTLE 1
OF ANTICONVULSANTS
ON COGNZTIVE PERFORMANCE
Serum levels of anticonvulsants before and after reduction of medication Drugs
Full medication (wg/mU
4.7 6.7
Carbamazepine Phenytoin
8.4 2.1
4.1 0.0
Carbamazepine
8.5
6.9
Phenytoin
25.0
4.1
Carbamazepine Valproic acid
10.4 24.2
10.7 0.0
Carbamazepine Phenobarbital
4.4 16.2
8.4 -
Valproic acid Phenytoin Carbamazepine
44.6 7.7
-
Carbamazepine Valproic acid
12.4 61.2
-
3
Carbamazepine Valproic acid
8.3 35.2
7.1 29.4
4
Carbamazepine Phenobarbital
4.7 48.6
5
Carbamazepine
7.7
6
Phenobarbital Valproic acid Carbamazepine
20.3 33.4 4.8
33.4 5.6
Carbamazepine
9.6
6.6
6
RTLE 1
2
7
Phenytoin Phenobarbital
Reduced medication b-W-4
15.5 20.3
2
IN TLE PATZENTS
Procedure The complete psychometric test battery was individually administered by a neuropsychologist. The first presentation occurred on admission under full medication. On the same day, the patients had closed-circuit TV/EEG monitoring and a blood sample drawn to determine the serum level of the anticonvulsants. A few days after admission, the anticonvulsant medication was individually reduced, in order to enhance the likelihood of registering ictal events. With reduced medication, each patient had a second neuropsychological evaluation and again, on the same day, closed-circuit TV/EEG monitoring and a blood sample drawn to determine the serum level of the anticonvulsants in each patient (Table 2). The procedures were always performed at the same time during the morning. Furthermore, in
7.5 7.6
-
order to prevent learning effects, we used altemative, counterbalanced forms in the two psychometric sessions. The two EEG recordings of each patient were read independently by an interpreter, who did not know the patients’ names or the particular conditions under which the EEG had been registered. In this first study, the reduction of medication occurred due to the clinical needs and did not focus on particular serum levels or different groups of anticonvulsants.
Statistical Analysis Group comparisons of LTLE and RTLE patients were performed for each variable under consideration, using analysis of variance (ANOVA) and the Wilcoxon Rank-Sum Test. 1 EPILEPSY, VOL. 2, NO. 3, 1989
149
H. F. DURWEN ETAL.
Results In order to evaluate the possible effects of drug reduction on the level of vigilance in our patients, we analyzed the measures of attention, sustained attention, and psychomotor speed: Digit Span and Corsi Block Test, d2-Aufmerksamkeits-Belastungstest nach Brickenkamp (sustained attention), as well as the Tapping Test. The results of these tests are presented in detail in Table 3 (Part A). Separate comparisons for RTLE and LTLE patients with full and reduced medication were performed. Using ANOVA and the Wilcoxon Rank-Sum Test, there was no statistically significant difference between different medica-
tion levels for all variables of attention or psychomotor speed. The second part of our test battery consisted of the BVRT, which is thought to test right temporal lobe nonverbal memory functions. The results are presented in Table 3 (Part 8). Using ANOVA and the Wilcoxon Rank-Sum Test for both RTLE and LTLE patients, there were no significant differences for all variables of the BVRT with different medication. However, considering mean scores and standard deviation for numbers of correct responses and errors in RTLE and LTLE patients revealed that the performance of the RTLE group showed a tendency towards improvement under reduced medication,
RTLE (seven patients) Full medication
Part A d2-Aufmerksamkeits-Belastungstest (raw scores) Psychomotor speed (Arbeitstempo) Capacity for sustained attention (Aufmerksamkeits-Belastbarkeit) Digit Span (raw scores) Forward Backward Corsi Block Test (raw scores) Forward Backward Tapping Test (raw scores) Right hand Left Hand Part B BVRT (raw scores) Correct responses Errors Part C AVLT (raw scores) Trial 1 (list a) Trial 2 (list a) Trial 3 (list a) Trial 4 (list a) Trial 5 (list a) List b recall Trial 6 (list a) Trial 7 (delayed free recall, list a) RWilcoxon 150
Rank-Sum
Test: p < 0.05.
1 EPILEPSY, VOL. 2, NO. 3, 1989
LTLE (six patients)
Reduced
medication
Full medication SD
Reduced
medication
Mean
SD
Mean
SD
Mean
SD
Mean
404.4
73
423.0
67
423.2
124
459.7
119
393.7
70
408.3
60
407.3
112
448.7
113
6.1 5.0
1.7 1.6
6.1 4.2
1.6 1.5
5.3 4.3
1.0 1.0
5.5 5.1
0.8 1.7
5.6 5.1
1.5 1.1
5.1 5.0
1.1 1.0
5.3 5.5
1.2 1.6
5.6 6.0
0.8 0.6
58.9 52.4
9.8 12.2
57.5 54.3
10.3 8.6
60.7 56.3
9.6 9.3
66.6 61.5
10.2 12.8
5.5 6.9
2.0 2.6
6.9 5.4
2.1 3.8
7.7 3.3
1.2 1.6
7.7 2.7
2.4 2.4
7.3 9.8 10.9 12.5 12.4 7.3 9.9 8.7
2.1 2.0 2.3 1.8 2.4 1.8 2.9 1.9
6.0 9.1 10.3 12.0 12.3 7.1 10.1 10.0
2.4 2.7 1.7 2.1 1.6 1.6 2.1 2.6
7.1 8.3 10.3 10.7 11.5” 5.5 8.6” 8.5”
2.3 2.2 1.5 1.5 1.0 1.0 2.7 3.7
6.5 10.3 11.7 13.2 14.2” 6.8 12.7’ 13.2,’
1.4 1.8 2.3 2.5 1.2 3.4 1.6 2.0
INFLUENCE
OF ANTZCONVULSANTS
16
ON COGNlTIVE
PERFORMANCE
1N TLE PATIENTS
medication and drug reduction. Most of the patients had interictally nonspecific and/or specific focal EEG pathology that worsened with the reduction of the anticonvulsants. The results are summarized in more detail in Table 4.
I-
12 8
Discussion
4 0
II
I *
lull medlutlon
Ill
IV -o-
V
Intert.
red medlutlon
VI VII l control8
16,
1
f: 8. 4.
01 ’ I *
I II
lull medhtlon
Ill
IV -o-
V
red. medloatlon
Interf.
VI *
VII controlr
whereas the performance of the LTLE group remained almost unchanged. The third part of our test battery consisted of the AVLT, a left hemisphere verbal memory test. The results for all variables are presented in detail in Table 3 (Part C). Comparing the performances with full and reduced medication levels, there were significant group effects in LTLE patients but not in RTLE patients. Significant differences were seen with learning trials V and VI, as well as with the delayed free recall (ANOVA-trial V: F, 17.29; df, 1; p < 0.01; trial VI: F, 9.47; df, 1; p < 0.01; delayed free recall: F, 6.28; df, 1; p < 0.05), while learning trials I-IV were not significantly different. Verbal memory performance in LTLE patients was better with reduced medication (Wilcoxon Rank-Sum Test-two-tailed-trial V: p < 0.05; trial VI: p < 0.05; Wilcoxon Rank-Sum Testdelayed free recall-p < 0.05). The results for the different learning trials with different medication are illustrated in Fig. 1. The EEG showed a relatively wide range of interindividual variability with full
Despite the fact that the EEG as a rule showed signals of an increased cerebral pathology in the majority of patients on a focal level, we observed either an invariance or improvement of partial cognitive functions after reduction of anticonvulsive medication. Previous psychological investigations had already shown that anticonvulsants, in particular barbiturates (30) and phenytoin (20), interfere with the cognitive performance in epileptics (17,18,22) as well as in normal controls (19,21). Most of these studies reported diffuse defects, such as reduction of vigilance, psychomotor speed, general memory performance, and the capacity of mental processing. Our results, however, demonstrate that moderate reduction of anticonvulsants can cause circumscribed improvement of some cognitive functions. While the control parameters for sustained attention and psychomotor speed remained unchanged, there was a significant improvement of verbal memory function, particularly on the level of data acquisition and retrieval. The most interesting finding, however, was that improvement of verbal memory performance with reduced medication occurred only in the group of LTLE patients, whereas in RTLE patients there was no significant effect. Compared to our normal controls (Fig. l), the verbal memory performance of the LTLE patients under reduced medication returned to a normal level. As we pointed out earlier, all our patients were left-hemisphere-dominant for language. Therefore, from a neuropsychological point of view, the improvement in verbal memory testing happened only for those patients who had their maximum of primary pathological activity in that area (left temporal lobe) that represented the function under consideration. One explanation may be that epileptogenic neurons in the temporal network of memory function may be particularly sensitive to medication effects; thus, the generation of seizures may be suppressed with medication. On the other hand, there may also be a strong inhibitory influence on the regular physiological functions of these particular systems. Furthermore, our results imply that the morphological substrate at, or close to, the major EEG focus is functionally still intact and that a major part of the observed preoperative neuropsychologi1 EPILEPSY, VOL. 2, NO. 3, 1989
151
H. F. DURWEN ET AL.
Table 4.
Scoring of interictalgeneralized and focal specific and nonspecific EEG activities underfull and reduced anticonvulsant medication for each patient of the LTLE and RTLE groups” Reduced
Full medication Nonspecific Case
activities
Generalized
LTLE 1 2 3 4 5 6 RTLE 1 2 3 4 5 6 7
Focal
Specific activities Generalized
Focal
Generalized
activities Focal
Specific activities Generalized
Focal
xx
X X
xx
X
X
xx
X
X
X X
X xx
xx
xx
xx
xx
X
X
xx
xx
xx
xx
X
xx
X
xx X
X
X X
X
“x, mild; xx, moderate;
X
X
X xx X
xxx, severe.
cal deficits may be due to drug effects. This may, to some degree at least, also explain why in other studies (31) there was considerable variability in performance among TLE patients with complex partial seizures. Other reasons for such inter- and intraindividual variabilities may be the severity of the underlying seizure disorder, as well as the actual electrophysiological state during testing. With reduction of medication, the system may regain its behavioral flexibility most of the time, but at the expense of intermittent disturbances by epileptogenic interferences; with further reduction of medication, however, this interference may increase so dramatically that at a certain level the cognitive performance starts to worsen again. In our study and with our moderate reduction of anticonvulsants, we may not have reached this point yet. We expected to observe the same drug-related phenomena with our right hemisphere, nonverbal memory tests. But even if we failed to demonstrate significant differences with RTLE and LTLE patients, we saw a tendency towards the expected direction. Whereas the results for the two different conditions were almost invariable in the LTLE group, the RTLE patients showed an obvious change toward improvement of nonverbal memory under reduced medication. This failure to demonstrate significant effects may be due to the fact that the BVRT is much less sensitive for 152
Nonspecific
medication
1 EPILEPSY, VOL. 2, NO. 3, 1989
cognitive changes than the AVLT. These observations have already been claimed by other studies (32). Other explanations, such as the possible heterogeneity of the two study groups, different levels of drug reduction between groups, or a different sensitivity of right and left TLE foci for anticonvulsants, however, have to be looked into. Besides these aspects, further studies also have to clarify the question of whether these effects are seen with all anticonvulsants or if they are specific to certain pharmacological substrates. Finally, future investigations with a more extensive test battery will have to reveal if this phenomenon of a circumscribed cognitive improvement also exists outside of the temporal lobe. Nevertheless, our study, using a sensitive psychometric instrument, was able to demonstrate that even moderate reductions of anticonvulsants improve cognitive performance. This is in agreement with existing reports in the literature. Furthermore, our data suggest that such cognitive improvements can be circumscribed and that they are related to the areas with the major EEG focus. Despite the worsened EEG patterns, the related cognitive performance improved, which means that within a certain range, EEG and cognitive performance do not change in a parallel fashion and that electrophysiological pathology does not necessarily
INFLUENCE
OF ANTICONVULSANTS
mply functional inactivity on a behavioral level. Fuure studies comparing electrophysiology and neurorsychology will have to investigate these relationhips further. Acknowledgment: We thank the Federal Minister or Labor and Social Affairs for financial support. We hank L. Sarvan for her help in preparing this text for bublication in English.
15.
16. 17. 18.
References Meyer V, Yates A. Intellectual changes following temporal lobectomy for psychomotor epilepsy. J Neurol Neurosurg Psychiatry 1955;18:44-52. Mimer 8. Psychological deficits produced by temporal lobe excision. Res Pub1 Assoc Res Nerv Ment Dis 1958;36: 244-57. Milner B. Memory and the medial temporal regions of the brain. In: Pribram RI-I, Broadbent DE, eds. Biology of memory. New York: Academic Press, 1970:29-50. Weingarten H. Verbal learning in patients with temporal lobe lesions. 1 Verb Learn Verb Behau 1968;7: 520-6. Mirsky A, Primac D, Marsan C, Rosvold H, Stevens JR. Comparison of the psychological test performance of patients with focal and non-focal epilepsy. Exp Neural 1960;2:75-89. Mayeux R, Brandt J, Rosen J, Benson DF. Interictal memory and language impairment in temporal lobe epilepsy. Neurology 1980;30:120-5. Dennerell RD. Cognitive deficits and lateral brain dysfunction in temporal lobe epilepsy. Epilepsia 1964;5: 177-91. Fedio I’, Mirsky A. Selective intellectual deficits in children with temporal lobe or centrencephalic epilepsy. Neuropsychologia 1969;3:287-300. Delaney RC, Rosen AJ, Mattson RH. Novelly RA. Memory function in focal epilepsy: a comparison of nonsurgical, unilateral, temporal lobe and frontal lobe samples. Cortex 1980;16:103-17. Hermann BP, Wyler AR, Richey E, Rea J. Memory function and verbal learning ability in patients with complex partial seizures of temporal lobe origin. Epilepsin 1987;28:547-54. Taylor LB. Localization of cerebral lesions by psychological testing. Chin Neurosurg 1969;16:269-87. Delaney RC. Screening for organicity: the problem of subtle neuropsychological deficit and diagnosis. J Clin Psycho1 1982;4:843-6. KIove H, Matthews CG. Neuropsychological studies of patients with epilepsy. In: Reitan RM, Davison LA, eds. Clinical neuropsychology-currenf status and upplication. New York: John Wiley and Sons, 1974:237-66. Bengzon ARA, Rasmussen T, Gloor I’, Dassault J, Stephens M. Prognostic factors in the surgical treat-
19. 20.
21.
22.
23. 24. 25. 26.
27. 28. 29. 30.
31.
32.
ON COGNITIVE
PERFORMANCE
IN TLE PATlENTS
ment of temporal lobe epileptics. Neurology 1968;18: 717-31. Wannamaker BB, Matthews CG. Prognostic implications of neuropsychological test performance for surgical treatment of epilepsy. ] Nerv Ment Dis 1976;163: 2943. Rausch R, Crandall PH. Psychological status related to surgical control of temporal lobe seizures. Epilepsiu 1982;23:191-202. Shorvon SD, Reynolds EH. Reduction of polypharmacy for epilepsy. Brit Med 1 1979;2:102>5. Thompson PJ, Trimble MR. Anticonvulsant drugs and cognitive functions. Epilepsiu 1982;23:53144. Hutt SJ, Jackson PM, Belsham AB, Higgins G. Perceptual motor behaviour in relation to blood phenobarbital level. Dev Med Child Neural 1968;10:626-32. Thompson PJ, Huppert FA, Trimble MR. Phenytoin and cognitive function; effects on normal volunteers and implication for epilepsy. Br J C/in Psycho1 1981; 20:155-62. Trimble MR, Thompson PJ, Huppert F. Anticonvulsant drugs and cognitive abilities. In: Canger R, Angeleri F, Penry JK, eds. Advances in epileptology: The XIth Epilepsy International Symposium. New York: Raven Press, 1980:199-204. Gallassi R, Morreale A, Lorusso S, Procaccianti G, Lugasesi E, Baruzzi AL. Carbamazepine and phenytoin-comparison of cognitive effects in epileptic patients during monotherapy and withdrawal. Arch Neural 1988;45:8924. Wieser H-G, Elger CE. Methods of presurgicul euuluution of epileptic patients. Berlin: Springer, 1987. Oldfield RC. The assessment and analysis of handedness: The Edinburgh Inventory. Neuropsychologiu 1971;9:97. Milner B. Psychological aspects of focal epilepsy and its neurosurgical management. Actu Neural 1975;8:299. Young AW. Methodological and theoretical basis of visual hemifield studies. In: Beaumont JG, ed. Divided visual field studies of cerebral organization. New York: Academic Press, 1981. Benton AL The revised visual retention test, 4th ed. New York: Psychological Corporation, 1974. Rey A. L’examen clinique en psychologique. Paris: Presses Universitaires de France, 1964. Brickenkamp R Aufmerksamkeits-Belastungs-Test (d2), 6. Auflage, Hogrefe, Gijttingen, FRG, 1978. Camfield CS, Caplin S, Doyle AB, Shapiro SH, Cummings C, Camfield PR. Side effects of phenobarbital in toddlers; behavioural and cognitive aspects. J Pediutr 1979;95:361-5. Hermann BP, Wyler AR, Steenman H, Richey ET. The interrelationship between language function and verbal learning/memory performance in patients with complex partial seizures. Cortex 1988;24:245-53. Ivnik RJ, Sharbrough FW, Laws ER. Anterior temporal Iobectomy for the control of partial complex seizures. Information for counseling patients. Mayo Clin Proc 1988;63:783-93.
j EPILEPSY, VOL. 2, NO. 3, 1989
153
1989;2:147-153
0 1989‘Demos Publications
Circumscribed Improvement of Cognitive Performance in Temporal Lobe Epilepsy Patients with Intractable Seizures Following Reduction of Anticonvulsant Medication H. F. Durwen,
C. E. Elger, C. Helmstaedter,
and H. Penin
During the presurgical evaluation of patients with intractable complex partial seizures, neuropsychometric testing was performed under conditions of full and reduced medication in order to determine the influence of anticonvulsants on cognitive performance. While attentional parameters remained completely unchanged, verbal memory performance improved significantly under reduced medication in patients with left temporal lobe epilepsy (LTLE) only, whereas patients with right temporal lobe epilepsy (RTLE) did not differ significantly under both conditions. However, a reverse, but not significant, pattern with improvement of nonverbal memory under reduced medication was only observed in RTLE subjects. The data suggest circumscribed effects of anticonvulsant medication on cognition in relation to the localization of the seizure focus. Key Words: Temporal lobe epilepsy-Cognition-Memory-AnticonvulsantsIntractable complex partial seizures.
Neuropsychological investigations of patients with unilateral temporal lobe resection for control of ntractable seizures have clearly revealed a significant relationship between left temporal lobe resection and Yrerbal learning deficits, as well as between right :emporal lobe resection and impairment of nonverbal earning (14). In a number of studies on memory, deficits associated with temporal lobe epilepsy (TLE) n nonsurgical cases or prior to surgery were found to ,e less clearly attributed to the lateralization of the bcus (5-7). However, with the development of ;ubtle psychometric test instruments, some studies lave shown lateralized functional disturbances with verbal memory deficits in cases with a left temporal ecus and nonverbal memory deficits associated with he right temporal lobe focus (B-10). Therefore, in
From the Department of Epileptology, Bonn University, sonn, F.R.G. Address correspondence and reprint requests to Dr. H. ;. Durwen at Universit’dts Nervenklinik, Epileptologie, Sigmund Freud-Strasse 25, 5300 Bonn 1, F.RG.
the presurgical workup of TLE patients with intractable seizures, the results of a sophisticated neuropsychological evaluation may help to lateralize and localize the areas of major pathology and therewith the primary epileptic focus (9,11-13). Furthermore, they may serve as a basis to predict postoperative outcome and will be used as reference for postsurgical control of cognitive performance (2,14-16). To date, there seems to be no clear idea to what extent the described deficits result from interictal electrophysiological dysfunction, from an underlying pathological substrate, or from pharmacological interferences. It has been shown that anticonvulsant medications are apt to reduce the cognitive abilities in epileptic patients as well as in normal controls (17-22). In general, they are said to interfere diffusely with vigilance, memory performance, and psychomotor speed. To our knowledge, however, there is no neuropsychological investigation, particularly none in the presurgical workup of TLE patients with intractable seizures, that looks in detail into the possible effects 1 EPILEPSY, VOL. 2, NO. 3, 1989
147
H. F. DURWEN ETAL.
of anticonvulsant medication on cognition. Neuropathologicai studies have demonstrated a correlation between the extent of cell loss in temporal lobe structure resected during epilepsy surgery and specific neuropsychological deficits. Interictal activity of limbic structures and neuropsychological deficits have been evaluated only unsystematically (23). It is the aim of the present study to determine the influence of the anticonvulsant medications on the cognitive and memory performance of patients with pharmacoresistant TLE who underwent the presurgical evaluation. To that purpose, the patients had a neuropsychological test battery under full medication and during the reduction of the anticonvulsant drugs, which is necessary in the presurgical workup.
Materials and Methods Subjects The subject pool consisted of referrals to our inpatient monitoring unit. All patients had intractable complex partial seizures of temporal lobe origin. 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 EEG pathology, all patients were evaluated by continuous closed-circuit TV/EEG monitoring scalp and, in most cases, sphenoidal electrodes. The study sample consisted of 13 patients. In six patients, the seizure focus was localized in the left hemisphere (LTLE) and in seven patients in the right hemisphere (RTLE). All patients were clearly lefthemisphere-dominant for handedness (24) that correlates in 96% with left-hemispheral dominance for language (25). Two patients had a handedness score (23) of -i-2 and i-8, respectively. They both had a WADA procedure and clearly showed a left hemisphere dominance for language. Furthermore, all patients underwent tachistoscopic hemifield stimulation with verbal material, which also revealed a left hemispheral dominance for language processing in each patient (26). Information concerning the demographic features of the subjects is shown in Table 1.
Test instruments All subjects in the program were administered a short version of our basic psychometric test battery, including the Benton Visual Retention Test (BVRT) (27), a German adaptation of the Rey Auditory Verbal Learning Test (AVLT) (28), and a standardized 148
1 EPILEPSY, VOL. 2, NO. 3, 1989
Table 1.
Srlbject churncteristics Handedness
Case/sex/age
(years)
LTLE l/F/29 2/F/24 3/M/20 4/M/18 5/F/15 6/F/26 Mean 22 (age, years) RTLE l/M/43 2/F/29 3/M/35 4/F/35 5/F/33 6/M/24 7/F/35 Mean 28 (age, years)
(scores)
Familial left handedness
flO0 +100 +92 f42 f50 +2
+ -
f64
$100 flO0 +100 +100 t8 +58 +83
-
+72
German test for sustained attention (d2-Aufmerksamkeits-Belastungstest nach Brickenkamp) (29). Furthermore, we used the Digit Span (forward and backward) as well as the Corsi Block Test (forward and backward). Psychomotor speed was assessed by the Tapping Test. Versions C and D of the BVRT were used, registering the number of correct and error responses. The AVLT consists of five presentations with free recall of a 15-word list (list A), one presentation and free recall of a second 15-word list for interference (list B), and a sixth as well as a seventh free recall trial of the first list. The test measured immediate memory span with the first trial, provided a learning curve and also measured retention following the interpolated interference activity. Finally, the seventh trial controlled the delayed free recall after 30 min. The correct answers of each trial were registered for further statistical analysis. The d2-Aufmerksamkeits-Belastungstest nach Brickenkamp is based on a target selection paradigm, comparable to a letter cancellation task. The capacity for sustained attention as well as psychomotor speed were registered. Digit Span and Corsi Block Test 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.
INFLUENCE
Table 2.
Case LTLE 1
OF ANTICONVULSANTS
ON COGNZTIVE PERFORMANCE
Serum levels of anticonvulsants before and after reduction of medication Drugs
Full medication (wg/mU
4.7 6.7
Carbamazepine Phenytoin
8.4 2.1
4.1 0.0
Carbamazepine
8.5
6.9
Phenytoin
25.0
4.1
Carbamazepine Valproic acid
10.4 24.2
10.7 0.0
Carbamazepine Phenobarbital
4.4 16.2
8.4 -
Valproic acid Phenytoin Carbamazepine
44.6 7.7
-
Carbamazepine Valproic acid
12.4 61.2
-
3
Carbamazepine Valproic acid
8.3 35.2
7.1 29.4
4
Carbamazepine Phenobarbital
4.7 48.6
5
Carbamazepine
7.7
6
Phenobarbital Valproic acid Carbamazepine
20.3 33.4 4.8
33.4 5.6
Carbamazepine
9.6
6.6
6
RTLE 1
2
7
Phenytoin Phenobarbital
Reduced medication b-W-4
15.5 20.3
2
IN TLE PATZENTS
Procedure The complete psychometric test battery was individually administered by a neuropsychologist. The first presentation occurred on admission under full medication. On the same day, the patients had closed-circuit TV/EEG monitoring and a blood sample drawn to determine the serum level of the anticonvulsants. A few days after admission, the anticonvulsant medication was individually reduced, in order to enhance the likelihood of registering ictal events. With reduced medication, each patient had a second neuropsychological evaluation and again, on the same day, closed-circuit TV/EEG monitoring and a blood sample drawn to determine the serum level of the anticonvulsants in each patient (Table 2). The procedures were always performed at the same time during the morning. Furthermore, in
7.5 7.6
-
order to prevent learning effects, we used altemative, counterbalanced forms in the two psychometric sessions. The two EEG recordings of each patient were read independently by an interpreter, who did not know the patients’ names or the particular conditions under which the EEG had been registered. In this first study, the reduction of medication occurred due to the clinical needs and did not focus on particular serum levels or different groups of anticonvulsants.
Statistical Analysis Group comparisons of LTLE and RTLE patients were performed for each variable under consideration, using analysis of variance (ANOVA) and the Wilcoxon Rank-Sum Test. 1 EPILEPSY, VOL. 2, NO. 3, 1989
149
H. F. DURWEN ETAL.
Results In order to evaluate the possible effects of drug reduction on the level of vigilance in our patients, we analyzed the measures of attention, sustained attention, and psychomotor speed: Digit Span and Corsi Block Test, d2-Aufmerksamkeits-Belastungstest nach Brickenkamp (sustained attention), as well as the Tapping Test. The results of these tests are presented in detail in Table 3 (Part A). Separate comparisons for RTLE and LTLE patients with full and reduced medication were performed. Using ANOVA and the Wilcoxon Rank-Sum Test, there was no statistically significant difference between different medica-
tion levels for all variables of attention or psychomotor speed. The second part of our test battery consisted of the BVRT, which is thought to test right temporal lobe nonverbal memory functions. The results are presented in Table 3 (Part 8). Using ANOVA and the Wilcoxon Rank-Sum Test for both RTLE and LTLE patients, there were no significant differences for all variables of the BVRT with different medication. However, considering mean scores and standard deviation for numbers of correct responses and errors in RTLE and LTLE patients revealed that the performance of the RTLE group showed a tendency towards improvement under reduced medication,
RTLE (seven patients) Full medication
Part A d2-Aufmerksamkeits-Belastungstest (raw scores) Psychomotor speed (Arbeitstempo) Capacity for sustained attention (Aufmerksamkeits-Belastbarkeit) Digit Span (raw scores) Forward Backward Corsi Block Test (raw scores) Forward Backward Tapping Test (raw scores) Right hand Left Hand Part B BVRT (raw scores) Correct responses Errors Part C AVLT (raw scores) Trial 1 (list a) Trial 2 (list a) Trial 3 (list a) Trial 4 (list a) Trial 5 (list a) List b recall Trial 6 (list a) Trial 7 (delayed free recall, list a) RWilcoxon 150
Rank-Sum
Test: p < 0.05.
1 EPILEPSY, VOL. 2, NO. 3, 1989
LTLE (six patients)
Reduced
medication
Full medication SD
Reduced
medication
Mean
SD
Mean
SD
Mean
SD
Mean
404.4
73
423.0
67
423.2
124
459.7
119
393.7
70
408.3
60
407.3
112
448.7
113
6.1 5.0
1.7 1.6
6.1 4.2
1.6 1.5
5.3 4.3
1.0 1.0
5.5 5.1
0.8 1.7
5.6 5.1
1.5 1.1
5.1 5.0
1.1 1.0
5.3 5.5
1.2 1.6
5.6 6.0
0.8 0.6
58.9 52.4
9.8 12.2
57.5 54.3
10.3 8.6
60.7 56.3
9.6 9.3
66.6 61.5
10.2 12.8
5.5 6.9
2.0 2.6
6.9 5.4
2.1 3.8
7.7 3.3
1.2 1.6
7.7 2.7
2.4 2.4
7.3 9.8 10.9 12.5 12.4 7.3 9.9 8.7
2.1 2.0 2.3 1.8 2.4 1.8 2.9 1.9
6.0 9.1 10.3 12.0 12.3 7.1 10.1 10.0
2.4 2.7 1.7 2.1 1.6 1.6 2.1 2.6
7.1 8.3 10.3 10.7 11.5” 5.5 8.6” 8.5”
2.3 2.2 1.5 1.5 1.0 1.0 2.7 3.7
6.5 10.3 11.7 13.2 14.2” 6.8 12.7’ 13.2,’
1.4 1.8 2.3 2.5 1.2 3.4 1.6 2.0
INFLUENCE
OF ANTZCONVULSANTS
16
ON COGNlTIVE
PERFORMANCE
1N TLE PATIENTS
medication and drug reduction. Most of the patients had interictally nonspecific and/or specific focal EEG pathology that worsened with the reduction of the anticonvulsants. The results are summarized in more detail in Table 4.
I-
12 8
Discussion
4 0
II
I *
lull medlutlon
Ill
IV -o-
V
Intert.
red medlutlon
VI VII l control8
16,
1
f: 8. 4.
01 ’ I *
I II
lull medhtlon
Ill
IV -o-
V
red. medloatlon
Interf.
VI *
VII controlr
whereas the performance of the LTLE group remained almost unchanged. The third part of our test battery consisted of the AVLT, a left hemisphere verbal memory test. The results for all variables are presented in detail in Table 3 (Part C). Comparing the performances with full and reduced medication levels, there were significant group effects in LTLE patients but not in RTLE patients. Significant differences were seen with learning trials V and VI, as well as with the delayed free recall (ANOVA-trial V: F, 17.29; df, 1; p < 0.01; trial VI: F, 9.47; df, 1; p < 0.01; delayed free recall: F, 6.28; df, 1; p < 0.05), while learning trials I-IV were not significantly different. Verbal memory performance in LTLE patients was better with reduced medication (Wilcoxon Rank-Sum Test-two-tailed-trial V: p < 0.05; trial VI: p < 0.05; Wilcoxon Rank-Sum Testdelayed free recall-p < 0.05). The results for the different learning trials with different medication are illustrated in Fig. 1. The EEG showed a relatively wide range of interindividual variability with full
Despite the fact that the EEG as a rule showed signals of an increased cerebral pathology in the majority of patients on a focal level, we observed either an invariance or improvement of partial cognitive functions after reduction of anticonvulsive medication. Previous psychological investigations had already shown that anticonvulsants, in particular barbiturates (30) and phenytoin (20), interfere with the cognitive performance in epileptics (17,18,22) as well as in normal controls (19,21). Most of these studies reported diffuse defects, such as reduction of vigilance, psychomotor speed, general memory performance, and the capacity of mental processing. Our results, however, demonstrate that moderate reduction of anticonvulsants can cause circumscribed improvement of some cognitive functions. While the control parameters for sustained attention and psychomotor speed remained unchanged, there was a significant improvement of verbal memory function, particularly on the level of data acquisition and retrieval. The most interesting finding, however, was that improvement of verbal memory performance with reduced medication occurred only in the group of LTLE patients, whereas in RTLE patients there was no significant effect. Compared to our normal controls (Fig. l), the verbal memory performance of the LTLE patients under reduced medication returned to a normal level. As we pointed out earlier, all our patients were left-hemisphere-dominant for language. Therefore, from a neuropsychological point of view, the improvement in verbal memory testing happened only for those patients who had their maximum of primary pathological activity in that area (left temporal lobe) that represented the function under consideration. One explanation may be that epileptogenic neurons in the temporal network of memory function may be particularly sensitive to medication effects; thus, the generation of seizures may be suppressed with medication. On the other hand, there may also be a strong inhibitory influence on the regular physiological functions of these particular systems. Furthermore, our results imply that the morphological substrate at, or close to, the major EEG focus is functionally still intact and that a major part of the observed preoperative neuropsychologi1 EPILEPSY, VOL. 2, NO. 3, 1989
151
H. F. DURWEN ET AL.
Table 4.
Scoring of interictalgeneralized and focal specific and nonspecific EEG activities underfull and reduced anticonvulsant medication for each patient of the LTLE and RTLE groups” Reduced
Full medication Nonspecific Case
activities
Generalized
LTLE 1 2 3 4 5 6 RTLE 1 2 3 4 5 6 7
Focal
Specific activities Generalized
Focal
Generalized
activities Focal
Specific activities Generalized
Focal
xx
X X
xx
X
X
xx
X
X
X X
X xx
xx
xx
xx
xx
X
X
xx
xx
xx
xx
X
xx
X
xx X
X
X X
X
“x, mild; xx, moderate;
X
X
X xx X
xxx, severe.
cal deficits may be due to drug effects. This may, to some degree at least, also explain why in other studies (31) there was considerable variability in performance among TLE patients with complex partial seizures. Other reasons for such inter- and intraindividual variabilities may be the severity of the underlying seizure disorder, as well as the actual electrophysiological state during testing. With reduction of medication, the system may regain its behavioral flexibility most of the time, but at the expense of intermittent disturbances by epileptogenic interferences; with further reduction of medication, however, this interference may increase so dramatically that at a certain level the cognitive performance starts to worsen again. In our study and with our moderate reduction of anticonvulsants, we may not have reached this point yet. We expected to observe the same drug-related phenomena with our right hemisphere, nonverbal memory tests. But even if we failed to demonstrate significant differences with RTLE and LTLE patients, we saw a tendency towards the expected direction. Whereas the results for the two different conditions were almost invariable in the LTLE group, the RTLE patients showed an obvious change toward improvement of nonverbal memory under reduced medication. This failure to demonstrate significant effects may be due to the fact that the BVRT is much less sensitive for 152
Nonspecific
medication
1 EPILEPSY, VOL. 2, NO. 3, 1989
cognitive changes than the AVLT. These observations have already been claimed by other studies (32). Other explanations, such as the possible heterogeneity of the two study groups, different levels of drug reduction between groups, or a different sensitivity of right and left TLE foci for anticonvulsants, however, have to be looked into. Besides these aspects, further studies also have to clarify the question of whether these effects are seen with all anticonvulsants or if they are specific to certain pharmacological substrates. Finally, future investigations with a more extensive test battery will have to reveal if this phenomenon of a circumscribed cognitive improvement also exists outside of the temporal lobe. Nevertheless, our study, using a sensitive psychometric instrument, was able to demonstrate that even moderate reductions of anticonvulsants improve cognitive performance. This is in agreement with existing reports in the literature. Furthermore, our data suggest that such cognitive improvements can be circumscribed and that they are related to the areas with the major EEG focus. Despite the worsened EEG patterns, the related cognitive performance improved, which means that within a certain range, EEG and cognitive performance do not change in a parallel fashion and that electrophysiological pathology does not necessarily
INFLUENCE
OF ANTICONVULSANTS
mply functional inactivity on a behavioral level. Fuure studies comparing electrophysiology and neurorsychology will have to investigate these relationhips further. Acknowledgment: We thank the Federal Minister or Labor and Social Affairs for financial support. We hank L. Sarvan for her help in preparing this text for bublication in English.
15.
16. 17. 18.
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