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Neuropsychological aspects of frontal lobe epilepsy
~
Pergamon
0028-3932(95)00121--2
Neuropsychologia, Vol. 34, No. 5, pp. 399-406, 1996 Copyright ~(~ 1996 Elsevier Science Ltd. All rights reserved Printed in Great Britain 0028 3932/96 $15.00+0.00
Neuropsychological aspects of frontal lobe epilepsy C. HELMSTAEDTER,*t B. KEMPER~: and C. E. ELGER* * University Clinic of Epileptology, Bonn, Germany; and ~ University Clinic of Psychiatry, MUnster, Germany (Received 26 Januao' 1995; accepted 4 July 1995)
Abstract--While most neuropsychological studies in focal epilepsies are concerned with temporal lobe epilepsy (TLE), only few investigations aim cognitive functioning in unresected patients with frontal lobe epilepsy (FLE). Following functional models arising from lesional studies, we evaluated patients with TLE (21 left, 17 right) and FLE (6 left, 17 right) with respect to attention and speed, motor coordination, verbal/nonverbal fluency, concept formation, response inhibition, anticipatory behavior and memory span. The following results were obtained. When compared to TLE, FLE was associated with significantly poorer results in almost all tests, fluency tests being the exception. No group differences were found with respect to the lateralization of the epileptic focus or the presence or absence of cerebral lesions. Factor analysis of the tests indicated that different subfunctions (speed, STM, motor coordination, response maintenance and inhibition) were assessed. A particular cognitive pattern of impaired motor coordination or response inhibition appeared to be characteristic for patients with FLE. Key Words: frontal lobe; epilepsy; neuropsychology.
sions seemingly do not profit from information provided in advance in choice reaction tasks [2]. Our own pilot study performed on nonresected patients with frontal and temporal lobe epilepsy indicated attentional deficits to be a significant problem in patients with frontal lobe epilepsy [20]. Furthermore, the findings of this study indicated that patients with FLE also showed memory deficits which could hardly be differentiated from those observed in patients with temporal lobe epilepsy. In contrast, Delaney et al. (1980) found no differences in measures of memory when patients with unilateral frontal lobe foci were compared to healthy controls [11]. Apart from studies on unresected or resected patients with frontal lobe epilepsy, there is a long history of clinical and experimental studies in patients with frontal lesions indicating a broad variety of cognitive and behavioral disorders [44]. Summing up these findings, the frontal lobe can be supposed to be involved particularly in attention, movement programming, spontaneity, conceptualization and planning behavior. Thus, it is hypothesized to mediate "executive behavior" in situations which require new solutions, strategies and decision making [40-44]. In general the frontal lobe is assumed to control, evaluate and modify subordinate nervous system activities [15, 26, 27, 37]. Whether lateralized lesions lead to material specific cognitive deficits is still controversial. Stuss and Benson (1986, pp. 226-228) provide a comprehensive overview on this issue indicating that the functional left/right frontal asymmetry largely follows the
Introduction
Despite the significant progress in structural and functional imaging techniques, the diagnosis of frontal lobe epilepsy still remains a challenging problem in epileptology. Different reasons account for this problem. First of all, FLE is characterized by a broad interindividual variety of seizure semiology [1, 5, 47]. Furthermore, interictually and ictually recorded EEGs frequently show widespread and/or rapidly propagating epileptic activity involving the contralateral frontal lobe and other brain regions [8, 13, 33, 46, 47]. A reasonable explanation for these clinical and electroencephalographic phenomena can be seen in the complex functional organization of the frontal lobes and its reciprocal connection to other cortical, limbic and subcortical areas [24, 32]. While neuropsychological studies in patients with temporal lobe epilepsy provided valuable results regarding memory processing and the functional organization of the temporolimbic system [12, 18], comparable efforts in FLE are rare. Most available data stems from already resected patients indicating impairment preferentially in performance on concept formation, response inhibition [29], estimations [43] and conditional associative learning [35, 36]. Furthermore, patients with left or right frontal excit Address for correspondence: University Clinic of Epileptology, Sigmund Freud Str. 25, 53105 Bonn, Germany; fax: 49-228-287-4328. 399
400
C. Helmstaedter et al./Neuropsychological aspects of frontal lobe epilepsy
k n o w n m a t e r i a l specificity o f the language d o m i n a n t / n o n d o m i n a n t hemisphere [44]. A critical p o i n t o f m o s t o f the studies referred to is that only one cognitive function was assessed, implicitly suggesting that it is representative o f frontal lobe functioning in general. In c o n t r a s t to these studies a n d extending the question o f o u r 1992 study [20], the present study e v a l u a t e d different aspects o f attention, m o t o r c o o r d i n a t i o n , response inhibition, c o n c e p t f o r m a t i o n a n d p l a n n i n g b e h a v i o r in nonresected patients with F L E . The assessed functions were a s s u m e d to cover different aspects o f the c o m p l e x functional a n d n e u r o a n a t o m i c a l o r g a n i z a t i o n o f the frontal lobe [15]. In particular, we e v a l u a t e d w h e t h e r patients with F L E can be differentiated from patients with T L E by m e a n s o f a specific p a t t e r n o f cognitive i m p a i r m e n t . F u r t h e r m o r e , we questioned whether there is evidence to s u p p o r t the a s s u m p tion o f one " c e n t r a l executive f u n c t i o n " or w h e t h e r frontal lobe function needs to be subdifferentiated [44]. Finally, we q u e s t i o n e d whether lateralized epileptic foci m a y lead to m a t e r i a l specific deficits in v e r b a l / n o n v e r b a l tasks.
Methods Subjects Subjects consisted of 61 patients with either FLE (n = 23) or TLE (n = 38). All patients were pharmacoresistent and candidates for epilepsy surgery. All patients underwent extensive interictal and ictal video/EEG-ECoG monitoring. Twenty-one patients had a left temporal lobe epilepsy, 17 patients suffered from a right temporal lobe epilepsy. Thirteen FLE and 12 TLE had circumscribed lesions as indicated by high-resolution MRI. According to postoperative histological findings lesions within the TLE group were hippocampal sclerosis (n = 5), grade I ganglioglioma or glioneuronal hamartia (n -- 4), grade II astrocytoma (n -- 3). Lesions within the FLE group were grade I ganglioglioma (n = 4), cavernoma (n = 3), heterotopia (n = 2), grade I oligodendroglioma (n = 2), necrosis (n = 1), abscess (n = 1). Within the group of FLE, six patients had seizures originating within the left frontal lobe, in 17 patients the seizure onset was right frontal. Seven patients of the FLE group showed strong bilateral ictal and interictal epileptic activity with an accentuation over one hemisphere, in four patients the epilepsy could not be lateralized on the basis of EEG recordings because interictal and ictal activity were undecidable bifrontal. These four patients were classified as being right frontal according to the localization of their lesion. No specific cerebral lesion was associated with bifrontal epileptic activity. The group of FLE patients was too small to consider further differences regarding the site of the epileptic foci in the central, premotor, polar, lateral or orbital region (see Table 1). Apart from a significantly higher seizure frequency in patients with FLE, patients with FLE and TLE did not significantly differ according to demographic or clinical data (Table 2). According to the W A D A test all patients were left hemisphere language dominant. Neuropsychological testing was performed only when the blood serum levels of the anticonvulsive medication were within therapeutic ranges.
Table 1. Localization of the primary epileptogenic zone in FLE patients by means of the EEG/ECoG monitoring and/or MRI-findings. LFLE/ RFLE = left/right frontal lobe epilepsy RFLE N=17
Group Central/premotor Lateral Orbital Polar Global Bifrontal
4 l 1 1 7 4*
LFLE N=6 2 3 1
* The classification of these patients into the RFLE group followed the right frontal localization of structural lesions.
Neuropsychological tests (see Fig. 1) Vocabulao,. The MWT-B (Mehrfachwahl Wortschatz Test) [22] is a vocabulary test which requires the recognition of words of increasing difficulty and not necessarily the knowledge of the individual terms used. This test has been shown to be highly representative for the general educational level of subjects and it serves as an estimator of general intelligence [22]. It should be noted that none of the patients suffered from aphasic language problems which could interfere with the performance on this or other language-based tasks. Immediate verbal and nonverbal memory span. The subtest digit span (forward and backward) of the WAIS [46] was chosen to examine immediate verbal memory span. The Corsi Block test [30] was modified and served as the nonverbal counterpart of the digit span. Corsi Block testing followed the instructions of the WAIS for digit span. Visuomotor speed and selective attention. A letter cancellation test (d2 test) [9] was applied to assess the capacity for sustained selective attention and visuomotor speed. The total number of scanned items minus the number of errors was the objective of the evaluation (GZ-F).
Table 2. Subjects characteristics of patients with frontal (FLE) and temporal lobe epilepsy (TLE)
Sex Age IQ (MWT-B) Lesion (M R1) Age at onset of epilepsy (yrs) Duration of epilepsy (yrs) Seizure frequency (per month)
FLE patients RFLE = 17/ LFLE -- 6
TLE patients RTLE = 17/ LTLE = 21
m/f m/sd m/sd yes
19/4 29/10 99/12 13
20/18 27/11 98/7 12
m/sd
13/7
13/9
m/sd
17/8
14/8
m/sd
37/93
17/18"
FLE = frontal lobe epilepsy, LFLE = left frontal lobe epilepsy, RFLE = right frontal lobe epilepsy, LTE -- left temporal epilepsy, RTE ~ right temporal epilepsy, *p < 0.01.
C. Helmstaedter et al./Neuropsychological aspects of frontal lobe epilepsy
Digit Span verbal memory span
Wechsler, 1964
Corsi-Block-Teat visual-spatial memory span
Milner, 1971
Le~er cancellation-Teat
Brickenkamp, 1978
foreward
backward
582 6439
629 3279etc.
,/ ~
selective attention
. Lehrl, 1984
Perret, 1974
word
blue
(color red
interference/ response inhibition
5-Point-Test
~ .
~
0 *
AABABBAB
(part III)
Word Fluency (F, R, K)
~
I-I0 * • i-] 0
interference/ response inhibition Stroep-Test
~
~l~pd~ffpd
psychomotorspeed c. I.-Test symbol counting/ perceptual speed
401
Horn, 1983 Regard et al., 1982
red
green
green
blue)
F
R
Fisch
Reise
Kiste
o o
[~---~,
~-~
K
figural fluency
Visual Verbal-Test conceptformation & shift
Feldmann and Dragow, 1978
Maze-Test anticipation & planing
Chapuis, 1992
Motor Sequencies coordination, sequencing
Luria, 1973
a
b
c
d
Q
L
L
I
concepts (a b c~ b c d)
(left/right/bimanual)
I
~
fist, edge, palm alternating between fist and palm
Fig. 1. Tests (examples of the test material and cognitive constructs) which were suggested to assess frontal lobe functions.
Visuo perceptual speed and response inhibition. The c.I. test (Test zur raschen Objektivierung cerebraler Insuflizienz) [23] consists of two subtests. The first subtest assesses visuo-perceptual speed and demands counting squares out of a table with various other symbols as fast as possible. The second subtest assesses interference effects. It requires the patient to inversely read two rows of "A '° and "B" ( A A B A B . . . as B B A B A . . . ) . For both subtests the time needed to perform the tasks was the object of the evaluation. In contrast to the subtest "interference" of the c.I. test, the short and modified version of the Stroop test [34] assesses a more complex ability of response inhibition. The three subtests consist of: (1) naming the color of colored dots; (2) naming the color of words which do not refer to colors (example: if, and, rare, u p . . . ) ; (3) naming the color (not reading) of color words (example: the word "red" written in green ink). We evaluated the time taken to perform each of the three subtasks and the difference between parts II and III. Verbal and nonverbal/figural fluency. A word fluency test (subtest 6 of the LPS) [17], which is similar to the FAS [7] assessed phonematic fluency. It demands lexical search of words beginning with the letters F, R, or K and requires initiation and spontaneity,
A modified "Five-Point test" [39] served as the nonverbal counterpart of word fluency. It is performed in three different trials. On the first trial the five dots have to be connected to result in three lines, on the second trial in four lines and on the third trial in five lines. One minute was given for each trial. The total number of correct figures and the total number of errors (rule breaks and perseverations) were chosen for further analysis. Concept formation and concept shiJ?. The Visual-Verbal test [14] was applied to assess concept formation and response inhibition. The test consists of 42 cards. On each card four figures are presented (a/b/c/d). Two triples out of the four figures are similar with respect to either color, form, structure similarities or position (abe and bed, for example). The patient had to identify the two triples and had to name the concepts. Responses were rated as correct when both pointing and naming were correct. The total number of correct responses and the total number of correct pairs were evaluated. Anticipation and planning. A Maze test [10] was used to provide data about foresight/anticipation and feedback guided decision making. The patient had to trace three mazes of increasing difficulty with a pencil. The total time taken in all mazes and total number of errors were the measures of interest.
402
C. Helmstaedter et al./Neuropsychological aspects of frontal lobe epilepsy
Motor coordination and sequencing. Similar to tasks of Luria [27], the patients were asked to copy sequences of left/right unimanual hand movements (fist/edge/palm) and a complex series of bimanual-alternating sequences of hand movements (alternating at the same time between fist/palm with the right and the left hand). The sequences had to be continued over at least 20 repetitions. The performance on these tasks was rated as follows: 1 = no impairment when sequences and alternations were correctly and fluently performed; 2 = mild impairment when sequences and alternations were too slow and/or performed with interruptions; 3 = impairment when movements and the sequences were performed with significant interference--unimanual: the different movements cannot be separated and appear to be mixed, and/or perseveration of a single movement within the sequence; bimanual: irradiation of the left hands movement to the right hand and vice versa (one hand shows a mixture of two movements or both hands do the same, and/or perseverations), perseverations, and inadequate strength; 4 = strong impairment: when the unimanual execution of a sequence was impossible or broke down after a few repetitions; when the coordination of bimanual alternating sequences was impossible or broke down after a few repetitions.
Results M A N O V A with a three factorial model with "patient g r o u p " (frontal/temporal) and "focus lateralization" (left/right hemisphere focus) and cerebral lesion (yes/no) as independent and "tests" (all parameters) as dependent variables revealed only a significant effect o f "patient g r o u p " (Hotellings = 0.89, F = 2.12, d f = 38, p = 0.02). Neither the effects of "focus lateralization" (Hotellings = 0.40, F = 0.95, df = 38, p = 0.51) and "lesion" (Hotellings = 0.27, F = 0.65, df = 38, p = 0.82) nor one o f the interactions reached statistical significance.
Differences between patients with T L E and F L E Post hoc group differences were c o m p u t e d by the use of univariate analysis o f variance with subsequent Tukey tests (see Table 3). Furthermore, the performance of the F L E and T L E group was evaluated with respect to normative test data o f healthy controls. Means and standard deviations were available from test manuals for most o f the tests, or had alternatively been evaluated in healthy controls for our own diagnostic purposes. All test performances were transformed into standard values (mean 100, S.D. = 10). Patients with F L E showed significantly poorer performance on nearly all tasks concerning p s y c h o m o t o r speed and attention. They needed significantly more time than patients with T L E when counting the squares in the c.I. test (F = 5.27, p < 0.05) and needed significantly more time to perform the interference tasks o f the c.l test (F = 14.76,p < 0.001). In the Stroop test the frontal group required more time in each trial (first trial F -- 6.69, p < 0.05; second trial F = 8.40, p < 0.01; third trial F = 7.51,p < 0.01). N o significant group differences were found with
Table 3. The groups performance (mean/S.D.) on tests which were suggested to assess frontal lobe functions Groups
FLE N = 23
Digit span Forward 5.30/0.92 Backward 3.69/1.25 Corsi Block test Forward 5.13/1.01 Backward 4.52/0.94 d2-1etter cancellation GZ-F 311.26/94.89 c.l. test Per. speed 19.39/5.06 Interference 28.08/11.30 Stroop test Time I 15.26/3.54 Time II 19.82/5.12 Time IIl 33.00/8.82 Difference I/III 12.10/9.72 Word fluency Correct words 25.47/7.22 Five-Point test Correct figures 26.34/11.77 Errors (%) 10.78/14.7 Visual-Verbal test Correct items 51.59/14.58 Correct pairs 23.34/10.36 Maze test Total time 364.36/195.10 Total errors 15.08/8.78 Motor sequencing Uni. right 2.17/1.19 Uni. left 2.17/1.30 Bimanual compl. 2.82/1.14
TLE N = 38 6.23/1.36 4.60/1.53
7.29** 5.13"
5.92/0.92 5.31/0.90
11.82"* 10.20"*
367.05/102.6
2.27
15.92/4.65 20.26/4.68
5.27* 14.76"**
12.84/3.20 16.02/4.22 26.02/6.94 9.13/8.04
6.96* 8.40** 7.51"* 1.62
29.07/8.95
1.30
30.23/8.73 5.06/8.90
2.80 8.08**
64.00/9.01 29.89/6.68
11.03"* 6.11"
295.34/132.1 9.23/6.27
2.51 14.66"**
1.26/0.76 1.23/0.67
8.45** 7.68**
1.68/0.90
14.55"**
*p < 0.05; **p < 0.01; ***p < 0.001.
respect to the d2 letter cancellation test (F---2.27, p > 0.05) or with respect to the fluency tasks (verbal: F = 1.30, p > 0.05; figural: F = 2.80, p > 0.05). H o w ever, F L E patients made more errors in the figural fluency task ( F = 8.08,p < 0.01). G r o u p differences were also observed with respect to verbal/nonverbal m e m o r y span. F L E patients performed significantly poorer than T L E patients on digit span (forward F = 7.29, p < 0.01; backward F = 5.13, p < 0.05) and the Corsi block test (forward F = 11.82, p < 0.01; backward F = 10,20, p < 0 . 0 1 ) . Subjects with F L E identified significantly less correct concepts (F = 11.03, p < 0.01) and less correct pairs of concepts ( F = 6.11, p < 0.05) in the Visual-Verbal test. A highly significant group effect was obtained with the Maze test. Patients with F L E made significantly more errors than patients with T L E (F = 14.66, p < 0.001). N o significant differences were f o u n d with respect to the time needed to trace through the mazes (F = 2.51, p > 0.05). In the tasks o f m o t o r coordination and sequencing patients with F L E scored significantly poorer in sequencing unilateral hand movements (right: F = 8.45, p < 0.01; left: F = 7.68, p < 0.01). The group difference became even more sig-
C. Helmstaedter et al./Neuropsychological aspects of frontal lobe epilepsy
403
nificant with respect to bilateral alternating hand movements (F = 14.55, p < 0.001). When standardized values were considered, the T L E group showed an impaired performance (mean standard value < 90) with respect to word fluency, concept formation (VVT) and the Stroop test. The F L E group showed an impaired performance (mean standard value < 90) on all tests except for verbal/visual memory span and letter cancellation.
ference test and the number of correct concepts on the Visual-Verbal test. These tests have in common the maintenance of response sets and response inhibition. G r o u p comparisons on the basis of their factor scores showed that only factor II (motor control) and IV (response inhibition) differentiated significantly between frontal and temporal patients (factor I1, F = 7.18, p = 0.009; factor IV, F = 9.22, p = 0.003). No lateralization effects could be obtained.
Content analysis of the test batter),
Patterns of impairment
Because F L E patients showed a generally poorer performance than T L E patients it seemed reasonable that the chosen tests were not independent from each other, i.e. the generally poorer performance might reflect the degradation of one underlying "central executive" function. Therefore a factorial analysis was performed including all test parameters. Factor analysis resulted in a fourfactor solution (eigenvalues > 1) explaining 71% of the variance. Varimax rotation resulted in the matrix which is demonstrated in Table 4. Only variables with factor loadings of at least 0.5 were considered in the analysis. Accordingly, the first factor was constituted from variables of different tasks on attention and parameters which depended on time. This can be explained as representing psychomotor speed and attention. The second factor obviously represented programming and coordination of m o t o r sequences, the third verbal/ nonverbal memory span. The fourth factor was constituted by failure scores on the Five-Point test and the Maze test as well as by the time to perform the inter-
Cluster analysis to subgroup patients based on factor scores resulted in three clusters indicating three cognitive patterns. Cluster 1 reflected a p o o r performance preferentially on factor II (motor coordination), cluster 2 was associated with a poor performance only on factor I (speed/attention), and cluster 3 reflected poor performance preferentially on factor IV (response inhibition). The distribution of subgroup patients in these clusters is provided in Table 5. While cluster I! mainly appeared in T L E patients (79%), cluster ! and III were associated with F L E (82%). Nine F L E patients showed the pattern Table 5. Performance clusters and group membership Prominent impairment
Cluster I motor coordination
Cluster II speed/ attention
Cluster Ill response inhibition
Group Temporal Frontal
3 7
35 9
7
Table 4. Varimax rotated factor matrix resulting from factor analysis of all test parameters Tests
Factors 1
Maze test (time) Stroop (time) Five-Point test (correct) Word fluency Letter cancellation Symbol counting (time) Mot. Seq. right Mot. Seq. bil. alternating Mot. Seq. left Digits forward Digits backward Corsi backward Corsi forward Five-Point test (errors) Maze test (errors) Interference (time) VVT (correct) Interpretation:
2
3
4
~0.86 - 0.84 0.71 0.61 0.57 -0.56 0.89 0.81 0.76 0.80 0.78 0.64 (0.47) --0.82 --0.74 --0.61 0.60 psychomotor speed, attention
motor memory coordination span
responseinhibition
404
C. Helmstaedter et al./Neuropsychological aspects of frontal lobe epilepsy
of TLE patients, three TLE patients the pattern of FLE patients. (chi 2 = 21.58, 2 df, p < 0.0001). The distribution particularly of patients with FLE on these clusters could not be related to EEG characteristics, the localization of foci or the type and localization of underlying lesions.
Discussion
The present study evaluated whether specific cognitive deficits can be determined which reliably indicate frontal lobe dysfunctions in nonresected patients with frontal lobe epilepsies. Based on studies on patients with other frontal lobe pathology, tests were selected which were thought to assess frontal subfunctions and largely cover the complex functional organization of the frontal lobe. Factor analysis of the tests in use confirmed that four distinct functions could be determined: "speed/attention (I)", "motor programming and coordination (II)", "memory span (III)", "response maintenance and inhibition (IV)". However, only factors II and IV, "motor programming and coordination" and "response maintenance and inhibition" differentiated significantly between FLE and TLE patients. Thus, the observed motor impairment parallels those deficits described by Luria [25] in patients with frontal lobe pathology. The problems in concept formation, planning behavior and response inhibition are in line with the reported impairment of higher executive functions in lesional patients. It should be noted, however, that although two distinct functions could be determined which discriminate between FLE and TLE, both functions have in common the impairment of the regulation, monitoring and utilization of cues and feedback to guide one's action [15, 27, 37, 41]. Factors I and III failed to discriminate between FLE and TLE. Functions of "speed/attention" were found to be equally impaired in FLE and TLE. Particularly the results on fluency deviated from findings in lesional patients [6, 19, 29, 34, 38]. Only errors made in the figural fluency task discriminated between FLE and TLE patients. One possible explanation for this result is provided by the factor analysis which indicated two aspects of the tasks. The active production of correct responses loaded on the unspecific speed/attention factor while errors loaded on the response inhibition factor and therefore appear to reflect the monitoring aspect of the task. Another explanation for the findings on fluency might be seen in the selection of patients with temporal lobe epilepsy as control. Hermann et al. (1988) pointed out that patients with TLE can show "frontal-like" performance probably caused by the propagation of "neural noise" from pathways which link the temporal lobe and the limbic system with frontal areas. Their argument was based on the finding that patients with TLE showed preoperative deficits in concept formation and shifting between concepts which disappeared after successful epilepsy surgery [16].
Although patients with FLE showed a poorer performance in "verbal and nonverbal memory span" than patients with TLE, a finding which might be explained by the hypothesized involvement of the frontal lobe in working memory [3, 4], the result had no clinical relevance when the data of FLE patients was compared to normative test data. Compared to results in lesional patients we also did not see the expected lateralization effects. On the one hand, the lack of lateralization effects may be due to the small group of patients with left FLE. On the other hand, one might argue, that the assessed cognitive functions are not under the exclusive control of either the left or the right hemisphere. Milner [31] emphasized that the laterality of functions disturbed by frontal lesions is far less striking than that observed from more posterior lesions. The often widespread, bilateral and fast propagating epileptic activity may serve as another reasonable explanation for the obtained results. In addition to the group differences obtained on group means and factor scores, three different patterns of cognitive performance could be determined, one predominantly associated with TLE (79%), and two predominantly associated with FLE (82%). While the pattern associated with TLE was associated with impaired performance in speed/attention, the two patterns associated with FLE indicates that there was one group of patients characterized by marked difficulties in learning, coordination and maintenance of alternating uni- and bilateral motor sequences, and another group which was characterized by problems in concept formation, planning behavior and response inhibition. However, not all patients with FLE could be characterized by one of the two frontal patterns. Nine patients with FLE neither showed an impairment in motor functions nor in functions of response maintenance or inhibition, and instead displayed the pattern seen in TLE patients. Although the clusters suggested different localizations of dysfunctions within the frontal lobe, cluster membership of FLE patients could not be further explained by EEG characteristics or lesions. However, it is reasonable that larger and better selected subgroups of FLE patients might reveal a neuropsychological differentiation between patients with different sites of epileptic foci within the frontal lobe. In conclusion, the present study gives evidence that impaired motor programming and coordination, together with impaired response inhibition in more complex tasks, characterize about two-thirds of the patients with FLE. These findings fit well into current models of frontal lobe functioning. The results give evidence that a differentiation of frontal subfunctions might better reflect frontal lobe functioning than the suggestion of a superordinate central executive function. Deficits in the remaining functions, particularly in attention and fluency were observed in TLE as well, which is most likely due to the strong functional interconnections between frontal and temporal/temporomesial structures and irradiating
C. Helmstaedter et al./Neuropsychological aspects of frontal lobe epilepsy epileptic dysfunction. Future research on larger and better selected patient subgroups must show whether different patterns of impairment can be related to different sites of epileptic foci within the frontal lobe.
References
1. Ajmone-Marsan, C. Seizures originating from the orbital cortex of the frontal lobe. Epilepsia 29, 208, 1988. 2. Alivisatos, B. and Milner, B. Effects of frontal or temporal lobectomy on the use of advance in information in a choice reaction time task. Neuropsychologia 27, 495-503, 1989. 3. Baddeley, A. D. and Hitch, G. J. Working memory. In The Psychology of Learning and Moth~ation, Vol. 8, Advances in Research and Theory, G. H. Bower (Editor), pp. 47--89. Academic Press, New York, 1974. 4. Baddeley, A. D. Working memory. Phil. Trans. R. Soc. London 302, 311-324, 1983. 5. Bancaud, J. and Talairach, J. Clinical semiology of frontal lobe seizures. In Advances in Neurology, Vol. 57, Frontal Lobe Seizures and Epilepsy, P. Chauvel, A. V. Delgado-Escueta, E. Halgren and J. Bancaud (Editors), pp. 3-58. Raven, New York, 1992. 6. Benton, A. L. Differential behavioral effect in frontal lobe disease. Neuropsychologia 6, 53-60, 1968. 7. Benton, A. L. and Hamsher, K. de S. Multilingual Aphasia Examinations. University of Iowa, Iowa City, 1978. 8. Brazier, M. A. B. Electrical seizures discharges within the human brain: The problem of spread. In Epilepsy: Its Phenomena in Man, M. A. B. Brazier (Editor), pp. 155-171. Academic Press, Orlando, 1973. 9. Brickenkamp, R. d2- Aufmerksamkeits- Belastungstest. Hogrefe, G6ttingen, 1978. 10. Chapuis, F. Labyrinthtest. Hogrefe, G6ttingen, 1992. 11. Delaney, R. C., Rosen, A. J., Mattson, R. H. and Novelly, R. A. Memory function in focal epilepsy: A comparison of non-surgical, unilateral temporal lobe and frontal lobe samples. Cortex 16, 103-117, 1980. 12. Elger, C. E., Grunwald, Th., Helmstaedter, C. and Kurthen, M. Cortical localization of cognitive functions. In Recent Advances in Epilepsy, 6, T. A. Pedley, S. Brian and S. Meldrum (Editors), pp. 77-93. Churchill Livingstone, Edinburgh, 1995. 13. Fegersten, L. and Roger, A. Frontal epileptogenic foci and their clinical correlations. Electroencephagraph), Clinical Neurophysiology ! 3, 905-913, 1961. 14. Feldman, M. J. and Dragow, J. The VisuaL Verbal Test (VVT). Western Psychological Services, Los Angeles, CA, 1981. 15. Fuster, J. M. The Prefrontal Cortex. Raven Press, New York, 1980. 16. Hermann, B. P., Wyler, A. R. and Richey, E. T. Wisconsin card sorting test performance in patients with complex partial seizures of temporal lobe origin. J. Clin. Exp. Neuropsvchol. 10, 467~476, 1988.
405
17. Horn, W. Leistungsprfif~ystem L-P-S. Hogrefe, G6ttingen, 1983. 18. Jones-Gotman, M., Smith, M. L. and Zatorre, R. J. Neuropsychological testing for localizing and lateralizing the epileptogenic region. In Surgical Treatment of the Epilepsies, J. Engel (Editor), pp. 245-261. Raven Press, New York, 1993. 19. Jones-Gotman, M. and Milner, B. Design fluency: The invention of nonsense drawings after focal cortical lesions. Neuropsychologia 15, 653-674, 1977. 20. Kemper, B., Helmstaedter, C. and Elger, C. E. Kognitive Profile von pr~ichirurgischen Patienten mit Frontal- und Temporallappenepilepsie. In Epilepsie '91, D. Scheffner (Editor), pp. 345-350. Einhorn Presse Verlag, Reinbeck, 1992. 21. Kolb, B. and Milner, B. Performance of complex arm and facial movements after focal brain lesions. Neuropsychologia 19, 505-514, 1981. 22. Lehrl, S. Mehrfachwahl-Wortschatz-lntelligenztest (MWT-B). Straube Verlag, Erlangen, 1976. 23. Lehrl, S. and Fischer, B. C.1-Test zur raschen Objektivierung cerebraler Insu[fienzen. Vless-Test, Ebersberg, 1984. 24. Ludwig, B., Ajmone-Marson, C. and Van Buren, J. Cerebral seizures of probable orbitofrontal origin. Epilepsia 16, 151-158, 1975. 25. Luria, A. R. Higher Cortical Functions in Man. Basic Books, New York, 1966/1980. 26. Luria, A. R. Frontal Lobe syndromes. In Handbook of Clinical Neurology, Vol. 2, P. J. Vinken and G. W. Bruyn (Editors), pp. 725-757. North Holland, Amsterdam, 1969. 27. Luria, A. R. The Working Brain. Penguin Press, London, 1973. 28. Milner, B. Effects of different brain lesions on card sorting: the role of the frontal lobes. Arch. Neuro. (Chicago) 9, 90-100, 1963. 29. Milner, B. Some effects of frontal lobectomy in man. In The Frontal Granular Cortex, J. M. Warren and K. Akert (Editors), pp. 313-334. McGraw-Hill, New York, 1964. 30. Milner, B. Interhemispheric differences in the localization of psychological processes in man. Br. Medical Bull. 27, 272-277, 1971. 31. Milner, B. Hemispheric specialization: Scope and limits. In The Neuroscience." Third Stud), Program, F. O. Schmitt and F. G. Worden (Editors), pp. 75-89. MIT Press, Cambridge, MA, 1974. 32. Nauta, W. J. H. The problem of the frontal lobe: A reinterpretation. J. Psychiat. Res. 8, 167--187, 1971. 33. Pedley, T. A., Tharp, B. R. and Hermann, K. Clinical and electroencephalographic characteristics of midline parasagittal foci. Ann. Neurol. 9, 142 149, 1981. 34. Perret, E. The left frontal lobe of man and the suppression of habitual responses in verbal categorical behavior. Neuropsychologia 12, 323-330, 1974. 35. Petrides, M. and Milner, B. Deficits on subjectordered tasks after frontal and temporal lobe lesions in man. Neuropsychologia 3, 249-262, 1982. 36. Petrides, M. Deficits on conditional associative learning tasks after frontal- and temporal lobe lesions in man. Neuropsychologia 5, 601-614, 1985. 37. Pribram, K. H. The primate frontal cortex-executive
406
38.
39. 40. 41. 42.
C. Helmstaedter et al./Neuropsychological aspects of frontal lobe epilepsy of the brain. In Psychophysiology of the Frontal Lobes, K. H. Pribram and A. R. Luria (Editors), pp. 293-314. Academic Press, New York, 1973. Ramier, A. M. and Hecaen, H. Role respectif des atteintes frontales et de la lateralisation lesionelle dans les deficits de la "fluence verbale". Revue Neurologique 123, 17-22, 1970. Regard, M., Strauss, E. and Knapp, P. Children's production on verbal and non-verbal fluency tasks. Perceptual Motor Skills 55, 839-844, 1982. Shallice, T. and Evans, M. E. The involvement of the frontal lobes in cognitives estimation. Cortex 14, 294-303, 1978. Shallice, T. Specific impairments of planning. Philos. Trans. R. Soc. London B 298, 199-209, 1982. Shallice, T. From Neuropsychology to Mental Structure. Cambridge University Press, Cambridge, 1988.
43. Smith, M. L. and Milner, B. Differential effects of frontal-lobe lesions on cognitive estimation and spatial memory. Neuropsychologia 22, 697-705, 1984. 44. Stuss, T. D. and Benson, T. The FrontalLobes. Raven Press, New York, 1986. 45. Wechsler, D. Die Messung der Intelligenz Erwachsener. Textband zum Hamburg- Wechsler-Intelloenztest. Hans Huber Verlag, Bern, 1964. 46. Williamson, P. D., Spencer, D. D., Spencer, S. S., Novelly, R. A. and Mattson, R. H. Complex partial seizures of frontal lobe origin. Ann. Neurol. 18, 497504, 1985. 47. Williamson, P. D., Wieser, H. G. and DelgadoEscueta, A. V, Clinical characteristics of partial seizures. In Surgical Treatment of the Epilepsies, J. Engel (Editor), pp. 101 123. Raven Press, New York, 1987.
Pergamon
0028-3932(95)00121--2
Neuropsychologia, Vol. 34, No. 5, pp. 399-406, 1996 Copyright ~(~ 1996 Elsevier Science Ltd. All rights reserved Printed in Great Britain 0028 3932/96 $15.00+0.00
Neuropsychological aspects of frontal lobe epilepsy C. HELMSTAEDTER,*t B. KEMPER~: and C. E. ELGER* * University Clinic of Epileptology, Bonn, Germany; and ~ University Clinic of Psychiatry, MUnster, Germany (Received 26 Januao' 1995; accepted 4 July 1995)
Abstract--While most neuropsychological studies in focal epilepsies are concerned with temporal lobe epilepsy (TLE), only few investigations aim cognitive functioning in unresected patients with frontal lobe epilepsy (FLE). Following functional models arising from lesional studies, we evaluated patients with TLE (21 left, 17 right) and FLE (6 left, 17 right) with respect to attention and speed, motor coordination, verbal/nonverbal fluency, concept formation, response inhibition, anticipatory behavior and memory span. The following results were obtained. When compared to TLE, FLE was associated with significantly poorer results in almost all tests, fluency tests being the exception. No group differences were found with respect to the lateralization of the epileptic focus or the presence or absence of cerebral lesions. Factor analysis of the tests indicated that different subfunctions (speed, STM, motor coordination, response maintenance and inhibition) were assessed. A particular cognitive pattern of impaired motor coordination or response inhibition appeared to be characteristic for patients with FLE. Key Words: frontal lobe; epilepsy; neuropsychology.
sions seemingly do not profit from information provided in advance in choice reaction tasks [2]. Our own pilot study performed on nonresected patients with frontal and temporal lobe epilepsy indicated attentional deficits to be a significant problem in patients with frontal lobe epilepsy [20]. Furthermore, the findings of this study indicated that patients with FLE also showed memory deficits which could hardly be differentiated from those observed in patients with temporal lobe epilepsy. In contrast, Delaney et al. (1980) found no differences in measures of memory when patients with unilateral frontal lobe foci were compared to healthy controls [11]. Apart from studies on unresected or resected patients with frontal lobe epilepsy, there is a long history of clinical and experimental studies in patients with frontal lesions indicating a broad variety of cognitive and behavioral disorders [44]. Summing up these findings, the frontal lobe can be supposed to be involved particularly in attention, movement programming, spontaneity, conceptualization and planning behavior. Thus, it is hypothesized to mediate "executive behavior" in situations which require new solutions, strategies and decision making [40-44]. In general the frontal lobe is assumed to control, evaluate and modify subordinate nervous system activities [15, 26, 27, 37]. Whether lateralized lesions lead to material specific cognitive deficits is still controversial. Stuss and Benson (1986, pp. 226-228) provide a comprehensive overview on this issue indicating that the functional left/right frontal asymmetry largely follows the
Introduction
Despite the significant progress in structural and functional imaging techniques, the diagnosis of frontal lobe epilepsy still remains a challenging problem in epileptology. Different reasons account for this problem. First of all, FLE is characterized by a broad interindividual variety of seizure semiology [1, 5, 47]. Furthermore, interictually and ictually recorded EEGs frequently show widespread and/or rapidly propagating epileptic activity involving the contralateral frontal lobe and other brain regions [8, 13, 33, 46, 47]. A reasonable explanation for these clinical and electroencephalographic phenomena can be seen in the complex functional organization of the frontal lobes and its reciprocal connection to other cortical, limbic and subcortical areas [24, 32]. While neuropsychological studies in patients with temporal lobe epilepsy provided valuable results regarding memory processing and the functional organization of the temporolimbic system [12, 18], comparable efforts in FLE are rare. Most available data stems from already resected patients indicating impairment preferentially in performance on concept formation, response inhibition [29], estimations [43] and conditional associative learning [35, 36]. Furthermore, patients with left or right frontal excit Address for correspondence: University Clinic of Epileptology, Sigmund Freud Str. 25, 53105 Bonn, Germany; fax: 49-228-287-4328. 399
400
C. Helmstaedter et al./Neuropsychological aspects of frontal lobe epilepsy
k n o w n m a t e r i a l specificity o f the language d o m i n a n t / n o n d o m i n a n t hemisphere [44]. A critical p o i n t o f m o s t o f the studies referred to is that only one cognitive function was assessed, implicitly suggesting that it is representative o f frontal lobe functioning in general. In c o n t r a s t to these studies a n d extending the question o f o u r 1992 study [20], the present study e v a l u a t e d different aspects o f attention, m o t o r c o o r d i n a t i o n , response inhibition, c o n c e p t f o r m a t i o n a n d p l a n n i n g b e h a v i o r in nonresected patients with F L E . The assessed functions were a s s u m e d to cover different aspects o f the c o m p l e x functional a n d n e u r o a n a t o m i c a l o r g a n i z a t i o n o f the frontal lobe [15]. In particular, we e v a l u a t e d w h e t h e r patients with F L E can be differentiated from patients with T L E by m e a n s o f a specific p a t t e r n o f cognitive i m p a i r m e n t . F u r t h e r m o r e , we questioned whether there is evidence to s u p p o r t the a s s u m p tion o f one " c e n t r a l executive f u n c t i o n " or w h e t h e r frontal lobe function needs to be subdifferentiated [44]. Finally, we q u e s t i o n e d whether lateralized epileptic foci m a y lead to m a t e r i a l specific deficits in v e r b a l / n o n v e r b a l tasks.
Methods Subjects Subjects consisted of 61 patients with either FLE (n = 23) or TLE (n = 38). All patients were pharmacoresistent and candidates for epilepsy surgery. All patients underwent extensive interictal and ictal video/EEG-ECoG monitoring. Twenty-one patients had a left temporal lobe epilepsy, 17 patients suffered from a right temporal lobe epilepsy. Thirteen FLE and 12 TLE had circumscribed lesions as indicated by high-resolution MRI. According to postoperative histological findings lesions within the TLE group were hippocampal sclerosis (n = 5), grade I ganglioglioma or glioneuronal hamartia (n -- 4), grade II astrocytoma (n -- 3). Lesions within the FLE group were grade I ganglioglioma (n = 4), cavernoma (n = 3), heterotopia (n = 2), grade I oligodendroglioma (n = 2), necrosis (n = 1), abscess (n = 1). Within the group of FLE, six patients had seizures originating within the left frontal lobe, in 17 patients the seizure onset was right frontal. Seven patients of the FLE group showed strong bilateral ictal and interictal epileptic activity with an accentuation over one hemisphere, in four patients the epilepsy could not be lateralized on the basis of EEG recordings because interictal and ictal activity were undecidable bifrontal. These four patients were classified as being right frontal according to the localization of their lesion. No specific cerebral lesion was associated with bifrontal epileptic activity. The group of FLE patients was too small to consider further differences regarding the site of the epileptic foci in the central, premotor, polar, lateral or orbital region (see Table 1). Apart from a significantly higher seizure frequency in patients with FLE, patients with FLE and TLE did not significantly differ according to demographic or clinical data (Table 2). According to the W A D A test all patients were left hemisphere language dominant. Neuropsychological testing was performed only when the blood serum levels of the anticonvulsive medication were within therapeutic ranges.
Table 1. Localization of the primary epileptogenic zone in FLE patients by means of the EEG/ECoG monitoring and/or MRI-findings. LFLE/ RFLE = left/right frontal lobe epilepsy RFLE N=17
Group Central/premotor Lateral Orbital Polar Global Bifrontal
4 l 1 1 7 4*
LFLE N=6 2 3 1
* The classification of these patients into the RFLE group followed the right frontal localization of structural lesions.
Neuropsychological tests (see Fig. 1) Vocabulao,. The MWT-B (Mehrfachwahl Wortschatz Test) [22] is a vocabulary test which requires the recognition of words of increasing difficulty and not necessarily the knowledge of the individual terms used. This test has been shown to be highly representative for the general educational level of subjects and it serves as an estimator of general intelligence [22]. It should be noted that none of the patients suffered from aphasic language problems which could interfere with the performance on this or other language-based tasks. Immediate verbal and nonverbal memory span. The subtest digit span (forward and backward) of the WAIS [46] was chosen to examine immediate verbal memory span. The Corsi Block test [30] was modified and served as the nonverbal counterpart of the digit span. Corsi Block testing followed the instructions of the WAIS for digit span. Visuomotor speed and selective attention. A letter cancellation test (d2 test) [9] was applied to assess the capacity for sustained selective attention and visuomotor speed. The total number of scanned items minus the number of errors was the objective of the evaluation (GZ-F).
Table 2. Subjects characteristics of patients with frontal (FLE) and temporal lobe epilepsy (TLE)
Sex Age IQ (MWT-B) Lesion (M R1) Age at onset of epilepsy (yrs) Duration of epilepsy (yrs) Seizure frequency (per month)
FLE patients RFLE = 17/ LFLE -- 6
TLE patients RTLE = 17/ LTLE = 21
m/f m/sd m/sd yes
19/4 29/10 99/12 13
20/18 27/11 98/7 12
m/sd
13/7
13/9
m/sd
17/8
14/8
m/sd
37/93
17/18"
FLE = frontal lobe epilepsy, LFLE = left frontal lobe epilepsy, RFLE = right frontal lobe epilepsy, LTE -- left temporal epilepsy, RTE ~ right temporal epilepsy, *p < 0.01.
C. Helmstaedter et al./Neuropsychological aspects of frontal lobe epilepsy
Digit Span verbal memory span
Wechsler, 1964
Corsi-Block-Teat visual-spatial memory span
Milner, 1971
Le~er cancellation-Teat
Brickenkamp, 1978
foreward
backward
582 6439
629 3279etc.
,/ ~
selective attention
. Lehrl, 1984
Perret, 1974
word
blue
(color red
interference/ response inhibition
5-Point-Test
~ .
~
0 *
AABABBAB
(part III)
Word Fluency (F, R, K)
~
I-I0 * • i-] 0
interference/ response inhibition Stroep-Test
~
~l~pd~ffpd
psychomotorspeed c. I.-Test symbol counting/ perceptual speed
401
Horn, 1983 Regard et al., 1982
red
green
green
blue)
F
R
Fisch
Reise
Kiste
o o
[~---~,
~-~
K
figural fluency
Visual Verbal-Test conceptformation & shift
Feldmann and Dragow, 1978
Maze-Test anticipation & planing
Chapuis, 1992
Motor Sequencies coordination, sequencing
Luria, 1973
a
b
c
d
Q
L
L
I
concepts (a b c~ b c d)
(left/right/bimanual)
I
~
fist, edge, palm alternating between fist and palm
Fig. 1. Tests (examples of the test material and cognitive constructs) which were suggested to assess frontal lobe functions.
Visuo perceptual speed and response inhibition. The c.I. test (Test zur raschen Objektivierung cerebraler Insuflizienz) [23] consists of two subtests. The first subtest assesses visuo-perceptual speed and demands counting squares out of a table with various other symbols as fast as possible. The second subtest assesses interference effects. It requires the patient to inversely read two rows of "A '° and "B" ( A A B A B . . . as B B A B A . . . ) . For both subtests the time needed to perform the tasks was the object of the evaluation. In contrast to the subtest "interference" of the c.I. test, the short and modified version of the Stroop test [34] assesses a more complex ability of response inhibition. The three subtests consist of: (1) naming the color of colored dots; (2) naming the color of words which do not refer to colors (example: if, and, rare, u p . . . ) ; (3) naming the color (not reading) of color words (example: the word "red" written in green ink). We evaluated the time taken to perform each of the three subtasks and the difference between parts II and III. Verbal and nonverbal/figural fluency. A word fluency test (subtest 6 of the LPS) [17], which is similar to the FAS [7] assessed phonematic fluency. It demands lexical search of words beginning with the letters F, R, or K and requires initiation and spontaneity,
A modified "Five-Point test" [39] served as the nonverbal counterpart of word fluency. It is performed in three different trials. On the first trial the five dots have to be connected to result in three lines, on the second trial in four lines and on the third trial in five lines. One minute was given for each trial. The total number of correct figures and the total number of errors (rule breaks and perseverations) were chosen for further analysis. Concept formation and concept shiJ?. The Visual-Verbal test [14] was applied to assess concept formation and response inhibition. The test consists of 42 cards. On each card four figures are presented (a/b/c/d). Two triples out of the four figures are similar with respect to either color, form, structure similarities or position (abe and bed, for example). The patient had to identify the two triples and had to name the concepts. Responses were rated as correct when both pointing and naming were correct. The total number of correct responses and the total number of correct pairs were evaluated. Anticipation and planning. A Maze test [10] was used to provide data about foresight/anticipation and feedback guided decision making. The patient had to trace three mazes of increasing difficulty with a pencil. The total time taken in all mazes and total number of errors were the measures of interest.
402
C. Helmstaedter et al./Neuropsychological aspects of frontal lobe epilepsy
Motor coordination and sequencing. Similar to tasks of Luria [27], the patients were asked to copy sequences of left/right unimanual hand movements (fist/edge/palm) and a complex series of bimanual-alternating sequences of hand movements (alternating at the same time between fist/palm with the right and the left hand). The sequences had to be continued over at least 20 repetitions. The performance on these tasks was rated as follows: 1 = no impairment when sequences and alternations were correctly and fluently performed; 2 = mild impairment when sequences and alternations were too slow and/or performed with interruptions; 3 = impairment when movements and the sequences were performed with significant interference--unimanual: the different movements cannot be separated and appear to be mixed, and/or perseveration of a single movement within the sequence; bimanual: irradiation of the left hands movement to the right hand and vice versa (one hand shows a mixture of two movements or both hands do the same, and/or perseverations), perseverations, and inadequate strength; 4 = strong impairment: when the unimanual execution of a sequence was impossible or broke down after a few repetitions; when the coordination of bimanual alternating sequences was impossible or broke down after a few repetitions.
Results M A N O V A with a three factorial model with "patient g r o u p " (frontal/temporal) and "focus lateralization" (left/right hemisphere focus) and cerebral lesion (yes/no) as independent and "tests" (all parameters) as dependent variables revealed only a significant effect o f "patient g r o u p " (Hotellings = 0.89, F = 2.12, d f = 38, p = 0.02). Neither the effects of "focus lateralization" (Hotellings = 0.40, F = 0.95, df = 38, p = 0.51) and "lesion" (Hotellings = 0.27, F = 0.65, df = 38, p = 0.82) nor one o f the interactions reached statistical significance.
Differences between patients with T L E and F L E Post hoc group differences were c o m p u t e d by the use of univariate analysis o f variance with subsequent Tukey tests (see Table 3). Furthermore, the performance of the F L E and T L E group was evaluated with respect to normative test data o f healthy controls. Means and standard deviations were available from test manuals for most o f the tests, or had alternatively been evaluated in healthy controls for our own diagnostic purposes. All test performances were transformed into standard values (mean 100, S.D. = 10). Patients with F L E showed significantly poorer performance on nearly all tasks concerning p s y c h o m o t o r speed and attention. They needed significantly more time than patients with T L E when counting the squares in the c.I. test (F = 5.27, p < 0.05) and needed significantly more time to perform the interference tasks o f the c.l test (F = 14.76,p < 0.001). In the Stroop test the frontal group required more time in each trial (first trial F -- 6.69, p < 0.05; second trial F = 8.40, p < 0.01; third trial F = 7.51,p < 0.01). N o significant group differences were found with
Table 3. The groups performance (mean/S.D.) on tests which were suggested to assess frontal lobe functions Groups
FLE N = 23
Digit span Forward 5.30/0.92 Backward 3.69/1.25 Corsi Block test Forward 5.13/1.01 Backward 4.52/0.94 d2-1etter cancellation GZ-F 311.26/94.89 c.l. test Per. speed 19.39/5.06 Interference 28.08/11.30 Stroop test Time I 15.26/3.54 Time II 19.82/5.12 Time IIl 33.00/8.82 Difference I/III 12.10/9.72 Word fluency Correct words 25.47/7.22 Five-Point test Correct figures 26.34/11.77 Errors (%) 10.78/14.7 Visual-Verbal test Correct items 51.59/14.58 Correct pairs 23.34/10.36 Maze test Total time 364.36/195.10 Total errors 15.08/8.78 Motor sequencing Uni. right 2.17/1.19 Uni. left 2.17/1.30 Bimanual compl. 2.82/1.14
TLE N = 38 6.23/1.36 4.60/1.53
7.29** 5.13"
5.92/0.92 5.31/0.90
11.82"* 10.20"*
367.05/102.6
2.27
15.92/4.65 20.26/4.68
5.27* 14.76"**
12.84/3.20 16.02/4.22 26.02/6.94 9.13/8.04
6.96* 8.40** 7.51"* 1.62
29.07/8.95
1.30
30.23/8.73 5.06/8.90
2.80 8.08**
64.00/9.01 29.89/6.68
11.03"* 6.11"
295.34/132.1 9.23/6.27
2.51 14.66"**
1.26/0.76 1.23/0.67
8.45** 7.68**
1.68/0.90
14.55"**
*p < 0.05; **p < 0.01; ***p < 0.001.
respect to the d2 letter cancellation test (F---2.27, p > 0.05) or with respect to the fluency tasks (verbal: F = 1.30, p > 0.05; figural: F = 2.80, p > 0.05). H o w ever, F L E patients made more errors in the figural fluency task ( F = 8.08,p < 0.01). G r o u p differences were also observed with respect to verbal/nonverbal m e m o r y span. F L E patients performed significantly poorer than T L E patients on digit span (forward F = 7.29, p < 0.01; backward F = 5.13, p < 0.05) and the Corsi block test (forward F = 11.82, p < 0.01; backward F = 10,20, p < 0 . 0 1 ) . Subjects with F L E identified significantly less correct concepts (F = 11.03, p < 0.01) and less correct pairs of concepts ( F = 6.11, p < 0.05) in the Visual-Verbal test. A highly significant group effect was obtained with the Maze test. Patients with F L E made significantly more errors than patients with T L E (F = 14.66, p < 0.001). N o significant differences were f o u n d with respect to the time needed to trace through the mazes (F = 2.51, p > 0.05). In the tasks o f m o t o r coordination and sequencing patients with F L E scored significantly poorer in sequencing unilateral hand movements (right: F = 8.45, p < 0.01; left: F = 7.68, p < 0.01). The group difference became even more sig-
C. Helmstaedter et al./Neuropsychological aspects of frontal lobe epilepsy
403
nificant with respect to bilateral alternating hand movements (F = 14.55, p < 0.001). When standardized values were considered, the T L E group showed an impaired performance (mean standard value < 90) with respect to word fluency, concept formation (VVT) and the Stroop test. The F L E group showed an impaired performance (mean standard value < 90) on all tests except for verbal/visual memory span and letter cancellation.
ference test and the number of correct concepts on the Visual-Verbal test. These tests have in common the maintenance of response sets and response inhibition. G r o u p comparisons on the basis of their factor scores showed that only factor II (motor control) and IV (response inhibition) differentiated significantly between frontal and temporal patients (factor I1, F = 7.18, p = 0.009; factor IV, F = 9.22, p = 0.003). No lateralization effects could be obtained.
Content analysis of the test batter),
Patterns of impairment
Because F L E patients showed a generally poorer performance than T L E patients it seemed reasonable that the chosen tests were not independent from each other, i.e. the generally poorer performance might reflect the degradation of one underlying "central executive" function. Therefore a factorial analysis was performed including all test parameters. Factor analysis resulted in a fourfactor solution (eigenvalues > 1) explaining 71% of the variance. Varimax rotation resulted in the matrix which is demonstrated in Table 4. Only variables with factor loadings of at least 0.5 were considered in the analysis. Accordingly, the first factor was constituted from variables of different tasks on attention and parameters which depended on time. This can be explained as representing psychomotor speed and attention. The second factor obviously represented programming and coordination of m o t o r sequences, the third verbal/ nonverbal memory span. The fourth factor was constituted by failure scores on the Five-Point test and the Maze test as well as by the time to perform the inter-
Cluster analysis to subgroup patients based on factor scores resulted in three clusters indicating three cognitive patterns. Cluster 1 reflected a p o o r performance preferentially on factor II (motor coordination), cluster 2 was associated with a poor performance only on factor I (speed/attention), and cluster 3 reflected poor performance preferentially on factor IV (response inhibition). The distribution of subgroup patients in these clusters is provided in Table 5. While cluster I! mainly appeared in T L E patients (79%), cluster ! and III were associated with F L E (82%). Nine F L E patients showed the pattern Table 5. Performance clusters and group membership Prominent impairment
Cluster I motor coordination
Cluster II speed/ attention
Cluster Ill response inhibition
Group Temporal Frontal
3 7
35 9
7
Table 4. Varimax rotated factor matrix resulting from factor analysis of all test parameters Tests
Factors 1
Maze test (time) Stroop (time) Five-Point test (correct) Word fluency Letter cancellation Symbol counting (time) Mot. Seq. right Mot. Seq. bil. alternating Mot. Seq. left Digits forward Digits backward Corsi backward Corsi forward Five-Point test (errors) Maze test (errors) Interference (time) VVT (correct) Interpretation:
2
3
4
~0.86 - 0.84 0.71 0.61 0.57 -0.56 0.89 0.81 0.76 0.80 0.78 0.64 (0.47) --0.82 --0.74 --0.61 0.60 psychomotor speed, attention
motor memory coordination span
responseinhibition
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C. Helmstaedter et al./Neuropsychological aspects of frontal lobe epilepsy
of TLE patients, three TLE patients the pattern of FLE patients. (chi 2 = 21.58, 2 df, p < 0.0001). The distribution particularly of patients with FLE on these clusters could not be related to EEG characteristics, the localization of foci or the type and localization of underlying lesions.
Discussion
The present study evaluated whether specific cognitive deficits can be determined which reliably indicate frontal lobe dysfunctions in nonresected patients with frontal lobe epilepsies. Based on studies on patients with other frontal lobe pathology, tests were selected which were thought to assess frontal subfunctions and largely cover the complex functional organization of the frontal lobe. Factor analysis of the tests in use confirmed that four distinct functions could be determined: "speed/attention (I)", "motor programming and coordination (II)", "memory span (III)", "response maintenance and inhibition (IV)". However, only factors II and IV, "motor programming and coordination" and "response maintenance and inhibition" differentiated significantly between FLE and TLE patients. Thus, the observed motor impairment parallels those deficits described by Luria [25] in patients with frontal lobe pathology. The problems in concept formation, planning behavior and response inhibition are in line with the reported impairment of higher executive functions in lesional patients. It should be noted, however, that although two distinct functions could be determined which discriminate between FLE and TLE, both functions have in common the impairment of the regulation, monitoring and utilization of cues and feedback to guide one's action [15, 27, 37, 41]. Factors I and III failed to discriminate between FLE and TLE. Functions of "speed/attention" were found to be equally impaired in FLE and TLE. Particularly the results on fluency deviated from findings in lesional patients [6, 19, 29, 34, 38]. Only errors made in the figural fluency task discriminated between FLE and TLE patients. One possible explanation for this result is provided by the factor analysis which indicated two aspects of the tasks. The active production of correct responses loaded on the unspecific speed/attention factor while errors loaded on the response inhibition factor and therefore appear to reflect the monitoring aspect of the task. Another explanation for the findings on fluency might be seen in the selection of patients with temporal lobe epilepsy as control. Hermann et al. (1988) pointed out that patients with TLE can show "frontal-like" performance probably caused by the propagation of "neural noise" from pathways which link the temporal lobe and the limbic system with frontal areas. Their argument was based on the finding that patients with TLE showed preoperative deficits in concept formation and shifting between concepts which disappeared after successful epilepsy surgery [16].
Although patients with FLE showed a poorer performance in "verbal and nonverbal memory span" than patients with TLE, a finding which might be explained by the hypothesized involvement of the frontal lobe in working memory [3, 4], the result had no clinical relevance when the data of FLE patients was compared to normative test data. Compared to results in lesional patients we also did not see the expected lateralization effects. On the one hand, the lack of lateralization effects may be due to the small group of patients with left FLE. On the other hand, one might argue, that the assessed cognitive functions are not under the exclusive control of either the left or the right hemisphere. Milner [31] emphasized that the laterality of functions disturbed by frontal lesions is far less striking than that observed from more posterior lesions. The often widespread, bilateral and fast propagating epileptic activity may serve as another reasonable explanation for the obtained results. In addition to the group differences obtained on group means and factor scores, three different patterns of cognitive performance could be determined, one predominantly associated with TLE (79%), and two predominantly associated with FLE (82%). While the pattern associated with TLE was associated with impaired performance in speed/attention, the two patterns associated with FLE indicates that there was one group of patients characterized by marked difficulties in learning, coordination and maintenance of alternating uni- and bilateral motor sequences, and another group which was characterized by problems in concept formation, planning behavior and response inhibition. However, not all patients with FLE could be characterized by one of the two frontal patterns. Nine patients with FLE neither showed an impairment in motor functions nor in functions of response maintenance or inhibition, and instead displayed the pattern seen in TLE patients. Although the clusters suggested different localizations of dysfunctions within the frontal lobe, cluster membership of FLE patients could not be further explained by EEG characteristics or lesions. However, it is reasonable that larger and better selected subgroups of FLE patients might reveal a neuropsychological differentiation between patients with different sites of epileptic foci within the frontal lobe. In conclusion, the present study gives evidence that impaired motor programming and coordination, together with impaired response inhibition in more complex tasks, characterize about two-thirds of the patients with FLE. These findings fit well into current models of frontal lobe functioning. The results give evidence that a differentiation of frontal subfunctions might better reflect frontal lobe functioning than the suggestion of a superordinate central executive function. Deficits in the remaining functions, particularly in attention and fluency were observed in TLE as well, which is most likely due to the strong functional interconnections between frontal and temporal/temporomesial structures and irradiating
C. Helmstaedter et al./Neuropsychological aspects of frontal lobe epilepsy epileptic dysfunction. Future research on larger and better selected patient subgroups must show whether different patterns of impairment can be related to different sites of epileptic foci within the frontal lobe.
References
1. Ajmone-Marsan, C. Seizures originating from the orbital cortex of the frontal lobe. Epilepsia 29, 208, 1988. 2. Alivisatos, B. and Milner, B. Effects of frontal or temporal lobectomy on the use of advance in information in a choice reaction time task. Neuropsychologia 27, 495-503, 1989. 3. Baddeley, A. D. and Hitch, G. J. Working memory. In The Psychology of Learning and Moth~ation, Vol. 8, Advances in Research and Theory, G. H. Bower (Editor), pp. 47--89. Academic Press, New York, 1974. 4. Baddeley, A. D. Working memory. Phil. Trans. R. Soc. London 302, 311-324, 1983. 5. Bancaud, J. and Talairach, J. Clinical semiology of frontal lobe seizures. In Advances in Neurology, Vol. 57, Frontal Lobe Seizures and Epilepsy, P. Chauvel, A. V. Delgado-Escueta, E. Halgren and J. Bancaud (Editors), pp. 3-58. Raven, New York, 1992. 6. Benton, A. L. Differential behavioral effect in frontal lobe disease. Neuropsychologia 6, 53-60, 1968. 7. Benton, A. L. and Hamsher, K. de S. Multilingual Aphasia Examinations. University of Iowa, Iowa City, 1978. 8. Brazier, M. A. B. Electrical seizures discharges within the human brain: The problem of spread. In Epilepsy: Its Phenomena in Man, M. A. B. Brazier (Editor), pp. 155-171. Academic Press, Orlando, 1973. 9. Brickenkamp, R. d2- Aufmerksamkeits- Belastungstest. Hogrefe, G6ttingen, 1978. 10. Chapuis, F. Labyrinthtest. Hogrefe, G6ttingen, 1992. 11. Delaney, R. C., Rosen, A. J., Mattson, R. H. and Novelly, R. A. Memory function in focal epilepsy: A comparison of non-surgical, unilateral temporal lobe and frontal lobe samples. Cortex 16, 103-117, 1980. 12. Elger, C. E., Grunwald, Th., Helmstaedter, C. and Kurthen, M. Cortical localization of cognitive functions. In Recent Advances in Epilepsy, 6, T. A. Pedley, S. Brian and S. Meldrum (Editors), pp. 77-93. Churchill Livingstone, Edinburgh, 1995. 13. Fegersten, L. and Roger, A. Frontal epileptogenic foci and their clinical correlations. Electroencephagraph), Clinical Neurophysiology ! 3, 905-913, 1961. 14. Feldman, M. J. and Dragow, J. The VisuaL Verbal Test (VVT). Western Psychological Services, Los Angeles, CA, 1981. 15. Fuster, J. M. The Prefrontal Cortex. Raven Press, New York, 1980. 16. Hermann, B. P., Wyler, A. R. and Richey, E. T. Wisconsin card sorting test performance in patients with complex partial seizures of temporal lobe origin. J. Clin. Exp. Neuropsvchol. 10, 467~476, 1988.
405
17. Horn, W. Leistungsprfif~ystem L-P-S. Hogrefe, G6ttingen, 1983. 18. Jones-Gotman, M., Smith, M. L. and Zatorre, R. J. Neuropsychological testing for localizing and lateralizing the epileptogenic region. In Surgical Treatment of the Epilepsies, J. Engel (Editor), pp. 245-261. Raven Press, New York, 1993. 19. Jones-Gotman, M. and Milner, B. Design fluency: The invention of nonsense drawings after focal cortical lesions. Neuropsychologia 15, 653-674, 1977. 20. Kemper, B., Helmstaedter, C. and Elger, C. E. Kognitive Profile von pr~ichirurgischen Patienten mit Frontal- und Temporallappenepilepsie. In Epilepsie '91, D. Scheffner (Editor), pp. 345-350. Einhorn Presse Verlag, Reinbeck, 1992. 21. Kolb, B. and Milner, B. Performance of complex arm and facial movements after focal brain lesions. Neuropsychologia 19, 505-514, 1981. 22. Lehrl, S. Mehrfachwahl-Wortschatz-lntelligenztest (MWT-B). Straube Verlag, Erlangen, 1976. 23. Lehrl, S. and Fischer, B. C.1-Test zur raschen Objektivierung cerebraler Insu[fienzen. Vless-Test, Ebersberg, 1984. 24. Ludwig, B., Ajmone-Marson, C. and Van Buren, J. Cerebral seizures of probable orbitofrontal origin. Epilepsia 16, 151-158, 1975. 25. Luria, A. R. Higher Cortical Functions in Man. Basic Books, New York, 1966/1980. 26. Luria, A. R. Frontal Lobe syndromes. In Handbook of Clinical Neurology, Vol. 2, P. J. Vinken and G. W. Bruyn (Editors), pp. 725-757. North Holland, Amsterdam, 1969. 27. Luria, A. R. The Working Brain. Penguin Press, London, 1973. 28. Milner, B. Effects of different brain lesions on card sorting: the role of the frontal lobes. Arch. Neuro. (Chicago) 9, 90-100, 1963. 29. Milner, B. Some effects of frontal lobectomy in man. In The Frontal Granular Cortex, J. M. Warren and K. Akert (Editors), pp. 313-334. McGraw-Hill, New York, 1964. 30. Milner, B. Interhemispheric differences in the localization of psychological processes in man. Br. Medical Bull. 27, 272-277, 1971. 31. Milner, B. Hemispheric specialization: Scope and limits. In The Neuroscience." Third Stud), Program, F. O. Schmitt and F. G. Worden (Editors), pp. 75-89. MIT Press, Cambridge, MA, 1974. 32. Nauta, W. J. H. The problem of the frontal lobe: A reinterpretation. J. Psychiat. Res. 8, 167--187, 1971. 33. Pedley, T. A., Tharp, B. R. and Hermann, K. Clinical and electroencephalographic characteristics of midline parasagittal foci. Ann. Neurol. 9, 142 149, 1981. 34. Perret, E. The left frontal lobe of man and the suppression of habitual responses in verbal categorical behavior. Neuropsychologia 12, 323-330, 1974. 35. Petrides, M. and Milner, B. Deficits on subjectordered tasks after frontal and temporal lobe lesions in man. Neuropsychologia 3, 249-262, 1982. 36. Petrides, M. Deficits on conditional associative learning tasks after frontal- and temporal lobe lesions in man. Neuropsychologia 5, 601-614, 1985. 37. Pribram, K. H. The primate frontal cortex-executive
406
38.
39. 40. 41. 42.
C. Helmstaedter et al./Neuropsychological aspects of frontal lobe epilepsy of the brain. In Psychophysiology of the Frontal Lobes, K. H. Pribram and A. R. Luria (Editors), pp. 293-314. Academic Press, New York, 1973. Ramier, A. M. and Hecaen, H. Role respectif des atteintes frontales et de la lateralisation lesionelle dans les deficits de la "fluence verbale". Revue Neurologique 123, 17-22, 1970. Regard, M., Strauss, E. and Knapp, P. Children's production on verbal and non-verbal fluency tasks. Perceptual Motor Skills 55, 839-844, 1982. Shallice, T. and Evans, M. E. The involvement of the frontal lobes in cognitives estimation. Cortex 14, 294-303, 1978. Shallice, T. Specific impairments of planning. Philos. Trans. R. Soc. London B 298, 199-209, 1982. Shallice, T. From Neuropsychology to Mental Structure. Cambridge University Press, Cambridge, 1988.
43. Smith, M. L. and Milner, B. Differential effects of frontal-lobe lesions on cognitive estimation and spatial memory. Neuropsychologia 22, 697-705, 1984. 44. Stuss, T. D. and Benson, T. The FrontalLobes. Raven Press, New York, 1986. 45. Wechsler, D. Die Messung der Intelligenz Erwachsener. Textband zum Hamburg- Wechsler-Intelloenztest. Hans Huber Verlag, Bern, 1964. 46. Williamson, P. D., Spencer, D. D., Spencer, S. S., Novelly, R. A. and Mattson, R. H. Complex partial seizures of frontal lobe origin. Ann. Neurol. 18, 497504, 1985. 47. Williamson, P. D., Wieser, H. G. and DelgadoEscueta, A. V, Clinical characteristics of partial seizures. In Surgical Treatment of the Epilepsies, J. Engel (Editor), pp. 101 123. Raven Press, New York, 1987.