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Neuropsychological consequences of epilepsy surgery in frontal lobe epilepsy
Net.'opsycholo~tia, Vol. 36. No. 4 pp. 333 -341, 1998
~
Pergamon
PII: S0028 3932(97)00118 8
¢' 1998 Elsevier Science Ltd. All rights reserved Printed in Great Britain I)02,~ 3932;98 $19.00+0.00
Neuropsychological consequences of epilepsy surgery in frontal lobe epilepsy C. HELMSTAEDTER,*~ U. GLEIBNER,* J. ZENTNERt and C. E. ELGER* *University Hospital of Epileptology, Bonn, Germany: tUniversity Hospital of Neurosurgery, Bonn, Germany
(Receiz'ed 25 Januao" 1997; accepted 1 August 1997)
Abstract--The present study investigated the effect of frontal lobe surgery on "cognitive functions", which have previously been
shown to be discriminative in the evaluation of non-resected patients with frontal lobe epilepsy (FLE). The cognitive outcome was evaluated with particular consideration of the side (left/right), the site (lateral, orbital, mesial, premotor/SMA), the type of surgery (resections vs. resections plus multiple subpial transections; MST), and seizure outcome. The evaluation is based on 33 patients with left (n= 17) or right (n= 16) frontal surgery. Forty-five patients who underwent successful left (n=21) or right (n=24) temporal lobectomy served as controls. The neuropsychological examination covered speed/attention, motor sequencing/coordination, response maintenance/inhibition, short-term memory, and language. With the exception of short-term memory, the chosen tests were discriminative in determining preoperative frontal lobe dysfunctions but they did not differentiate patients with a different lateralization or localization of the frontal focus. At the 3 month follow-up examination, patients with temporal Iobectomy had improved frontal functions, whereas patients with frontal lobe surgery showed a mild deterioration. Within the frontally resected group, completely seizure-free patients had significantly improved short-term memory. Further consideration of the side, site and the type of the frontal resection indicated that patients with premotor/SMA surgery and patients with precentral/central MST had additional impairment after surgery. Premotor/SMA resections led to a deterioration in response maintenance/inhibition and if performed left sided also to deteriorated language functions. The latter impairment could be clearly related to transient aphasia directly after surgery. Irrespective of pareses observed immediately after surgery, patients with MSTs of the precentral/central areas displayed additional problems in motor coordination at the follow-up examination. In this group the seizure outcome was also less favourable. In summing up, frontal lobe surgery does not cause any considerable additional impairment in the short-term followup. However, caution is recommended when surgery or MST affect functional relevant cortex (here the prefrontal/SMA and precentral/central area). Finally, a release of functions associated with frontal areas not affected by surgery is suggested, when seizures are successfully controlled by surgery..!-~ 1998 Elsevier Science Ltd. All rights reserved Key Words: neuropsychology: frontal lobe epilepsy: epilepsy surgery.
inhibition [29, 42], estimations [38], associative learning [34, 35] and anticipation in choice reaction tasks [2]. Historically, these studies suffer from the problem that there were no preoperative data available, and that in most cases only one function was assessed, which was assumed to be representative for frontal lobe functioning in general. Recent approaches, which followed more differentiated functional-anatomical models of the frontal lobes [37, 40] were able to demonstrate specific cognitive impairment in F L E already preoperatively. In our own study of 1996 we explicitly evaluated the question of an impairment of different "frontal subfunctions'" in 23 patients with F L E compared with 38 patients with temporal lobe epilepsy (TLE). In particular we examined memory span, visuomotor speed, selective attention, visuo-perceptual speed, response inhibition, fluency, concept formation/shifts, anticipation/planning behaviour, and m o t o r coordination [16]. These functions were hypo-
Introduction
Due to the complex functional neuronal organization of the frontal lobes and their reciprocal connection to other cortical, limbic and subcortical areas [26, 32], FLE is characterized by a broad interindividual variety of seizure semiology [l, 4, 5, 45] and often shows inter- and intrahemispherically widespread and rapidly propagating epileptic activity [7, 13, 33, 44]. As observed with seizure semiology, a broad variety of cognitive impairment has also been reported in frontal lobe epilepsy. Most data about cognitive impairment in F L E stems from early studies in postoperative patients indicating impairment mainly in performance on concept formation, response +Address for correspondence: Sigmund Freud Strasse 25, 53105 Bonn, Germany. Tel: +49 228 287 6383; Fax: +49 228 287 6294; E-mail: psych(/~mailer.meb.uni-bonn.de 333
334
C. Helmstaedter et al./Neuropsychological consequences of epilepsy surgery in frontal lobe epilepsy
thesized to cover different aspects of frontal lobe functioning. As expected, patients with F L E showed a poorer performance than patients with T L E on all evaluated measures. Factor analysis of the tests indicated that four individual "frontal subfunctions" (speed/attention, short-term memory, motor coordination, response maintenance and inhibition) could be differentiated. In particular a cognitive pattern of impaired motor coordination and/or response inhibition characterized the patients with FLE. Problems in short-term memory and speed/attention were shared with TEE patients. However, none of the tests turned out to differentiate the site or lateralization of frontal lobe focus. A recent study by Upton and T h o m p s o n [41] followed a very similar approach. Parallel to our study, no effects of the lateralization or localization of the frontal lobe epilepsy were obtained and of all the tested functions only m o t o r impairment turned out to be a consistent and discriminative feature in FLE. Because functional concepts evaluated in both studies were very much the same, divergent findings may be explained by different patient selection criteria and different test procedures. Having tests available which help diagnose frontal lobe impairment in epilepsy preoperatively, this study evaluated the cognitive consequences of frontal lobe surgery on these functions. In order to cross-validate the preoperative applicability of the tests, a sample of patients with FLE was evaluated which had only a minimal over-
lap with the sample of our preceeding study. We evaluated possible effects of the side of surgery (left/right), the site of surgery (lateral, orbital, mesial, premotor/SMA), the type of surgery (resection vs. resection with additional multiple subpial transections), and seizure outcome on frontal lobe functions.
Material
and methods
Patients with FLE
Subjects consisted of 33 patients (21 male/12 female) who underwent either left (n = 17) or right (n= 16) frontal lobe surgery (Table 1). Site and type of the frontal resections were individually tailored according to the neuroradiological findings, preoperative or intraoperative electrocorticography (ECOG) examinations, and, if required, functional mapping (electrocortical stimulation via subdural strip or grid electrodes). All but two of the patients with FLE had lesions as determined by magnetic resonance imaging (MRI) (12 tumours, 19 other benign structural changes). With the exception of three right frontal lobectomies, all resections were circumscribed topectomies including the lesion and the surrounding zone of maximum interictal/ictal epileptic activity (see also [47]). Seven left lesionectomies (two lateral and five premotor/SMA resections) and two right resections (one lobectomy and one premotor/SMA resection) were extended by multiple subpial transections (MST) when areas were involved in epilepsy that had been demonstrated to be eloquent cortex by electrical cortical stimulation. All MSTs affected the primary motor cortex.
Table 1. Characteristics of the evaluated groups Subject characteristics
Gender Age (years) Age at onset of epilepsy (years) Duration of epilepsy (years) Lesion: Tumour* Benign malformations* Hippocampal sclerosis No finding Site of surgery: 2/3 anterior resections Lateral Orbital Mesial Premotor/SMA Lobectomy Outcome: Seizure free
(m/f) (m/S.D.) (m/S.D.) (m/S.D.)
R-FLE 16
L-FLE 17
R-TLE 21
L-TLE 24
10/6 30.8 (1 I) 14.7 (12) 17.0 (8)
11/6 28,9 (10) 15,2 (11) 13.6 (9)
12/9 29.4 (10) 13.3 (7) 16.0 (12)
16./8 30.2 (11) 9.8 (8) 20.1 (12)
3 12 1
9 7 1
2 7
8 7
6 3 4 ( 1') 3 (1 ')
6 (2')
7 (43%)
11 (64%)
12
9
-
-
21
24 -
1
-
-
2 8 (5')
-
-
21
24
*Astrocytoma and oligodendroglioma grades I and II etc. ~Cortical dysplasia, DNT, heterotopia etc. 'Number of patients who had resective surgery plus subpial transections reaching into eloquent cortical areas as determined by electrical cortical stimulation. R-FLE, right frontal lobe epilepsy; L-FLE, left frontal lobe epilepsy; R-TLE, right temporal lobe epilepsy; L-TLE, left temporal lobe epilepsy.
C. Helmstaedter et al./Neuropsychological consequences of epilepsy surgery in frontal lobe epilepsy MST is a relatively new surgical technique to control seizures originating from eloquent cortex. Its working mechanism is not yet fully understood, but in general transsection of the horizontal fibres is thought to prevent the horizontal spread of seizure activity [21, 31 ].
Patients with TLE A group of 45 patients (28 male/17 female) who underwent left (n=21) or right (n=24) 2/3 anterior temporal lobectomy served as controls (Table 1). As for the FLE patients the followup interval was 3 months. The most frequent pathological finding in these patients was hippocampal sclerosis (47%), followed by benign malformations (31%) and tumours (22%). In anterior 2/3 temporal lobectomy, the extent of the temporolateral resection was 4 cm along the superior and middle temporal gyrus and 5 cm along the inferior temporal gyrus. The hippocampus and the parahippocampal gyrus were usually resected en bloc and the resection reached the middle of the cerebral peduncle at its widest diameter [48]. In order to exclude an extratemporal involvement in the TLE group, we only selected patients for this control group who had temporal lesions and were completely seizure free 3 months after surgery.
Health)' sub/ects In order to get an estimation of the patients impairment, and in order to standardize the test data for direct comparison with each other, test data of 22 (11 men, 11 women) healthy subjects served as controls. The mean age of these subjects was 28.8 years (S.D.=4.6years) and the mean IQ of this group was 104 (S.D,= 11.5).
Neuropsyehological assessment All patients were evaluated preoperatively and 3months postoperatively by use of a short version of the test battery which was introduced in our study from 1996 [16] to evaluate patients with frontal lobe epilepsy. Factor analysis of the tests of the 1996 battery showed that four executive/frontal subfunctions can be differentiated ("speed~attention", "shortterm memory", "response maintenance/inhibition"and "motor coordination"). However, the original test battery included redundant measures. Response inhibition for example was assessed by colour word interference and furthermore by inversely reading "a"s and "b"s (for the latter tests see below). For economic reasons, time-consuming tests with redundant measures were now removed from the battery. The tests selected for the present study were representative for the four factors, that is, the test scores had high factor loadings on the corresponding factor. The following tests were applied: • The subtest digit span (forward and backward) of the WAIS [43] was chosen to examine immediate verbal memory span. The Corsi block test after Milner [30, 24] was modified and served as the non-verbal counterpart of the digit span. Corsi block testing followed the instructions of the WAIS for digit span. • A letter cancellation test (d2 test) was applied to assess the capacity for sustained selective attention and visuomotor speed [8]. The test requires detection and cancellation of the letter "'d" with two apostrophes (d') which is randomly distributed in 14 rows with similar distractor items (i.e. p', d', etc.). The time to perform each row was limited to 20 sec.
335
The total number of scanned items minus the number of errors (misses and false cancellations) was the objective of the evaluation. • The c.I. test (cerebraler Insutfizienz test) consists of two subtests. The first subtest assesses visuo-perceptual speed and demands counting squares out of a table with various other symbols (stars, circles, etc.) as fast as possible. The second subtest assesses interference effects. It requires inverse reading of two rows of"A" and "B" (AABAB... as BBABA... ). For both subtests the time needed to perform the tasks was the object of the evaluation [23]. • The word-fluency test, a subtest of a German intelligence test (LPS: Leistungs Priif System), assesses phonematic fluency. Patients are asked to find as many words as possible beginning with a designated letter (F, R, and K) in a time interval of [rain. The test demands lexical search and requires initiation and spontaneity [19]. • A maze test [9] 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. • Similar to the manual copying 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 repeated fluidly at least 20 times. The performance on these three tasks was rated as follows: 1, No impairment: correct and fluid performance: 2, Mild impairment: correct but not fluid performance: movements are slow or with frequent interruptions or pauses: 3, Impairment: see no. 2 plus perseverations, inadequate strength or interference. Interference was concluded in the unimanual task when the single movements could not be separated and appeared to be mixed. In the bimanual task interference was concluded when irradiations of the movement of one hand to the other hand were observed (one hand shows a mixture of two movements or both hands do the same). 4, Strong impairment: performance was impossible or broke down completely after a few repetitions. Table 3 provides the raw data of the patient groups and the group of healthy controls. For data reduction the test results of the patients were standardized according to the normative test data of the 22 healthy control subjects. Furthermore, composite scores were computed for the individual frontal subfunctions by subtotaling the test scores for the four factors which resulted from the analysis of the original test battery [16]. The result was a standardized value (mean = 100, S.D. = 10) for each function. This had the advantage of data reduction, the scores could be directly compared with each other by means of a cognitive profile, and the relative impairment compared with the healthy subjects could be concluded. The different test scores were subtotalled for the individual functions as follows: • speed:attention (speed in maze testing; scanned items minus errors in the letter cancellation/d2 test; speed in symbol counting/c.I, test: number of words achieved in the word fluency test): • short-term memory (digit span; Corsi block span): • response maintenance/inhibition(errors in maze testing; time needed to perform the interference test/c.l, test); • motor coordination (points achieved in performing uni- and bimanual alternating sequences). Stalisti~ ,~" Preoperative differences between FLE and TLE were evaluated b~ univariate analysis of variance (ANOVA). Post-
336
C. Helmstaedter et al./Neuropsychological consequences of epilepsy surgery in frontal lobe epilepsy
operative performance change in both groups was evaluated with consideration of the preoperative ability status as a covariate (ANCOVA) because comparable studies in patients with TLE consistently show highly significant correlations between postoperative changes and the preoperative ability status. Separate statistics (ANOVAS) were computed within the FLE group to evaluate the possible effects of the type of the resection, the seizure outcome, and the side and the site of the lesion/focus. Because of the heterogeneity of the resections, we restricted the evaluation of the site of resection to the cognitive consequences of MST and premotor/SMA resections. Finally, we took into consideration that some patients with FLE showed neurological symptoms directly after surgery. Comparisons of patients with and without these complications were performed in order to evaluate whether long-lasting residuals can be determined by the test performance. Results At the 3 m o n t h follow-up examination 43% of the right and 64% of the left frontally resected patients were completely seizure free. The nine patients who had subpial transections were less likely to become seizure free (30%) than the remaining 24 patients who had sole resective surgery (60%), but this difference did not become statistically significant. Forty-two per cent of the frontally resected patients (n= 14) demonstrated neurological symptoms directly alter surgery (57% premotor/SMA, 22% lateral, 7% orbital, 14% lobectomy) which had receded almost completely at the 3month follow-up examination. Premotor/SMA resections were accompanied with motor aphasia plus paresis (n=3), transcortical aphasia plus paresis (n= 1), cortical dysarthria (n=2), pure paresis (n = 1), and severe psychomotor slowing (n = 1). One of the lateral resections led to a motor aphasia, and two lateral resections led to pareses. The one patient with an orbital resection showed anosmia after surgery. Two of the three lobectomies were followed by a severe psychomotor slowing (Table 2).
D(fferences between patients with FLE and TLE Univariate analysis (ANOVA) showed that, preoperatively, patients with F L E scored lower than patients
with T L E in all measures except short-term memory IF ranging from 4.9 to 21.0 with P<0.05] (Fig. 1). Group comparisons on the basis of difference scores (postoperative value minus preoperative value) showed that patients with T L E improved in response maintenance/inhibition, patients with FLE remained largely unchanged [A NCOVA with F = 15.9, P < 0.001 ]. Patients with T L E also showed slight gains regarding motor coordination [F= 3.6, P = 0.06] and significant gains regarding speed/attention [F=7.4, P<0.01]. Frontal lobe resections in contrast to temporal resections led to a deterioration in these functions (Fig. 2). Covariance analysis indicated that in both groups there were highly significant negative correlations between the preoperative ability status and the postoperative change in performance. Preoperatively poor scoring patients tended to improve and preoperatively high scoring patients tended to deteriorate alter surgery (r at least 0.5 with P<0.01 for each correlation).
D(JJbrences between diJJerent frontal resections All further statistical analyses referred only to the FLE group focussing on possible effects of the side (left vs, right), the site (lateral vs. premotor/SMA), the type of the resection (lesionectomy vs. lesionectomy plus subpial transections), and seizure outcome (completely seizure free vs. not seizure free). Preoperatively, no significant effects of the side or the site of the lesion/focus could be observed. However, as a trend right-FLE patients tended to perform worse than left-FLE patients (Table 3 and Table 4). First of all analysis of the postoperative changes showed a significant effect of the seizure outcome on short-term memory. Patients who were seizure free at the follow-up examination improved and patients who were not seizure free deteriorated [F=7.3, P<0.01]. When considering side, site and type of the resection, there was a trend for left SMA/premotor resected patients to show deteriorated performance in language testing. Language testing was not a part of the test battery originally in use with FLE and was additionally introduced because, in
Table 2. Neurological sequelae/complications after frontal lobe surgery Neurological sequelae of t¥ontal lobe surgery Sequelae Side of surgery Lateral Mesial Orbital Premotor/SMA Lobectomy
Paresis
Dysarthria or aphasia
Paresis plus aphasia
r/l 1/ 1 // 1//
r/1 / 1* -//-/2' -/
r/l / / -/ -/3* 1~ /-
r, Right; 1, left. *Motor aphasia; *dysarthria; ;trans-cortical aphasia.
Severe psychomotor slowing r/I /-/. . /1/2/-
.
Anosmia
.
r/l -/ / 1/ -/-/
C. Helmstaedter et al./Neuropsychological consequences of epilepsy surgery in frontal lobe epilepsy
337
preoperative differences between patients with frontal (n=33) and temporal (n=45) lobe epilepsy standarized values 110 100
90 8O 70 p
....... F
p
F
resp,inhib.
speed
it0i, i Fi0ii mot.coord,
s.t.m.
Fig. 1. Preoperative differences between patients with frontal and patients with temporal lobe epilepsy in speed/attention, response maintenance/inhibition, motor coordination, and short-term memory.
changes in performance after Iobectomy
frontal (n=33) and temporal (n=45) 10
difference scores (adjusted means)
8
showed an improvement in this function [F=9.62, P < 0.01 ]. Resections with additional MSTs (n = 9) tended to have a negative effect on motor coordination [F= 3.7, P = 0.06]. Patients with or without paresis directly after surgery could not be differentiated by any testing at the 3 month follow-up examination.
6
Discussion
-2
-4
-
speed
resp.inhib, mot.coord,
s.t,m.
Fig. 2. Performance change after frontal and temporal lobe surgery. Changes are reported as difference scores (3 month follow-up value minus preoperative value) which were corrected by the preoperative ability slatus (covariance analysis).
some patients, aphasic symptoms were observed after frontal lobe resections. Accordingly, a statistically significant deterioration in language was observed particularly for those five patients who had left frontal resections and transient motor or transcortical aphasia directly after surgery. Residuals of these aphasic symptoms at the 3 month follow-up evaluation were reflected when changes in language functions in patients with aphasia were compared with those without. Deterioration was especially observed in comprehension [F=26.5, P<0.01] as assessed by the Token test [10], as a trend in verbal fluency [F= 3.4, P = 0.07], and in verbal reasoning [F= 3.9, P = 0.05] as assessed by a subtest of a German intelligence test [3]. Irrespective of the side of surgery, resections within the premotor/SMA area were accompanied by a deterioration in response maintenance/inhibition whereas patients with other resections
The present study evaluated the cognitive outcome of frontal lobe surgery in patients with pharmacoresistant frontal lobe epilepsies, with attention to cognitive mental functions which had previously been shown to be indicative of frontal lobe dysfunction in non-resected frontal lobe epilepsies [16]. The non-resected group of our recent study and the surgical group under study here overlapped only by five patients. Furthermore, the group studied here was larger and consisted of a comparable number of left and right frontal patients. The presurgical results confirm the diagnostic value of the applied neuropsychological measures in terms of a cross-validation. In line with the results of our previous study, patients with FLE showed deficits particularly in motor coordination and response maintenance/inhibition. This is consistent with Upton and Thompson [41], who reported that motor impairment is a consistent and discriminant feature in FLE. In further agreement with Upton and Thompson we did not find conclusive evidence that the lateralization or the localization of the frontal lesion/focus results in different impairment. There was only an unspecific trend of patients with right FLE to be more severely impaired than patients with left FLE. The postoperative cognitive outcome of the evaluated groups first of all turned out to be strongly and inversely related to the preoperative ability status. Comparable observations have been made in studies addressing the
338
C. Helmstaedter et al./Neuropsychological consequences of epilepsy surgery in frontal lobe epilepsy Table 3. Pre- and postoperative performance of the patient groups and reference data from the group of healthy controls n
Controls 22
R-FLE 16
L-FLE 17
R-TLE 21
L-TLE 24
Digit span Pre Post
(m/S.D.)
6.2(1.2)
5.9(1.2) 5.6(1.1)
5.8(1.1) 5.9(1.0)
5.8(1.1) 5.9(1.0)
6.3(1.1) 5.6(1.1)
Corsi block Pre Post
(m/S,D.)
5.9(1.1)
5.2(1.6) 5.0(0.8)
5.2(0.8) 5.6(0.9)
5.3(0.8) 5.5(0.6)
5.5(0.8) 5.8(0.7)
(m/S.D.)
440 (84)
309 (74) 345(93)
340 (99) 371 ( 1 1 5 )
384 (70) 430(83)
396 (57) 456(60)
c.I. test/visuo-perceptual speed (sec) Pre (m/S.D.) Post
14.4(2.2)
19(6.6) 22(17)
19.6(7.3) 21.1 (7.6)
17.0(4.2) 16.3(6.5)
17.2(4.3) 15.8(4.4)
c.I. test/interference (sec) Pre (m/S.D.) Post
18.1 (4.8)
25 (9.2) 25(7.2)
21.3 (4.4) 25.8(9.4)
22.4 (4.8) 19.9(4.8)
22.0 (4.6) 18.0(4.2)
41 (10)
27(7.2) 26(8.1)
24(4.3) 22(10.4)
27.8(9.1) 26.4(9.7)
29.5(8.7) 30(6.7)
208(104)
412(179) 403(194)
314(114) 340(184)
294(141) 299(192)
325(165) 247(122)
6.0 (4)
12.7 (8.2) 8.9(4.9)
9.6 (6.5) 7.7(5.3)
9.8 (7.2) 6.1 (4.2)
8.2 (5.4) 5.7(3.6)
7.6(2.9) 7.2(2.5)
6.5(3.2) 7.0(3.7)
4.3(0.6) 4.8(1.2)
4.9(1.1) 4.5(0.7)
d2 Pre Post
LPS word fluency Pre Post
(m/S.D.)
Maze test/speed (see) Pre (m/S.D.) Post Maze test (errors) Pre Post
(m/S.D.)
Manual copying task (unimanual plus bimanual) Pre (m/S.D.) 3(1) Post
R-FLE right frontal lobe epilepsy; L-FLE left frontal lobe epilepsy; R-TLE right temporal lobe epilepsy; LTLE left temporal lobe epilepsy. m(S.D.) mean (standard deviation).
Table 4. Pre- and postoperative frontal/executive subfunctions reported as standard values (mean= 100, S.D. = 10) L-FLE 17
R-TLE 21
L-TLE 24
Speed/attention (standard values) Pre (m/S.D.) 88.7 (9) Post 84.6 (22)
87.0 (10) 84.2 (15)
91.4 (9) 92.5 (8)
92.2 (8) 96.8 (8)
Short-term memory (standard values) Pre (m/S.D.) 95.0 (5) Post 94.2(3)
94.3 (5) 95.3 (5)
95.1 (4) 96.0(3)
97.2 (5) 98.1 (3)
Response maintenance/inhibition (standard values) Pre (m/S.D.) 85.7(15) 90.1(7) Post 91.5(7) 90.0(11)
91.5(11) 97.2(6)
95.3(7) 101.2(6)
Motor coordination (standard values) Pre (m/S.D.) 77.4 (22) Post 80.9 (18)
96.7(7) 93.4 (8)
96.8(9) 98.6 (6)
n
R-FLE 16
86.9(18) 83.6 (24)
*Standardized values. R-FLE, right frontal lobe epilepsy; L-FLE, left frontal lobe epilepsy; R-TLE, right temporal lobe epilepsy; L-TLE, left temporal lobe epilepsy. m(S.D.) mean (standard deviation).
C. Helmstaedter et al./Neuropsychological consequences of epilepsy surgery in frontal lobe epilepsy postoperative memory outcome after temporal lobectomies in TLE. This finding can be interpreted to reflect the resection of functioning tissues in addition to lesional tissues in order to achive seizure control [11, 15, 17]. However, because we observed this regression in both FLE and TLE patients, this relationship can also be interpreted in terms of a statistical regression to the mean due to test repetition. When the postoperative performance changes were evaluated by considering the preoperative ability status in group comparisons, the data provided evidence that temporal lobe resections result in a general improvement in "frontal functions", whereas frontal lobe resections led to mild losses in psychomotor speed and motor coordination. The finding of a postoperative improvement in patients with TLE confirms earlier suggestions that "frontal-like" symptoms in TLE probably reflect irradiation of dysfunctions along fronto-temporal pathways that will disappear after surgery by successful control of seizures and epileptic activity [18]. In FLE patients, postoperative seizure control was accompanied by an improvement in short-term memory. This improvement in memory could also be explained by a release phenomenon. This seems likely, particularly because prefrontal areas which are thought to be involved in working memory were mostly not affected by surgery. Considering side, site and the type of the frontal resections, especially premotor/SMA resections and lobectomies showed a high risk (about 70%) of neurological deficits directly after surgery. Two of the three lobectomies led to severe psychomotor slowing, which was observed only in one of the other resections. In premotor/SMA resections the most prominent postoperative impairment was a SMA-deficiency syndrome with aphasia, when surgery was performed within the language-dominant hemisphere, and/or motor arm/leg/ facial impairment after surgery in either hemisphere. It should be noted that the SMA deficiency syndrome is predominantly an impairment of the initiation of behaviour. Consistent with previous reports in patients with SMA lesions, the predominant symptom of aphasia was a speech arrest or transcortical aphasia [6, 22, 28]. Although most operative sequelae were transient, residuals of postoperative aphasia in terms of unspecifically deteriorated language functions could still be observed at the 3 month follow-up examination. The aphasic residuals were not only concerned with impairment in verbal fluency, but also with impaired comprehension and verbal reasoning. This finding can not be consistently explained by a purely expressive speech disorder. Recent functional imaging studies suggest a participation of the frontal lobe in receptive language functions, but the small sample size and lack of experience with SMA resections do not allow an interpretation of our findings as being SMA-specific [20, 36, 39]. Taken together with the deterioration in response maintenance/inhibition, the observations after premotor/SMA resections are otherwise consistent with the known role of the SMA in the
339
initiation/inhibition and programming of motor responses [12, 14, 25, 43]. Irrespective of whether there were motor problems initially after surgery, increased problems in motor coordination at the 3 month follow-up were observed, particularly in those patients who had subpial transections directly affecting the primary motor cortex. Subpial transections in the sensorimotor cortex have been reported to be successful in controlling seizures and lead only to transient but not to persistent neurological/neuropsychological impairment [46]. At least within the first 3 months postoperatively the present data do not support this suggestion. Whereas poorer seizure control can be explained by the remaining epileptogenic tissue, the outcome in motor functioning may reflect different plasticity to compensate for impairment of unilaterally disposed primary motor functions compared with bilaterally disposed premotor/SMA functions. In conclusion, the data confirm the discriminant validity of the neuropsychological assessment of frontal functions in patients with focal epilepsies. The postoperative evaluation reveals satisfactory clinical and cognitive outcome in frontal lobe surgery in general. A good cognitive outcome was observed in patients, who were seizure free after surgery and in whom surgery did not affect the eloquent cortex. A less favourable outcome in terms of direct postoperative neurological impairment and residual problems in language, response maintenance/inhibition and motor coordination resulted from premotor/SMA resections and/or subpial transections into primary motor areas, respectively. Considering that these results were obtained at the 3month follow-up evaluation, further functional improvement, particularly in seizure-free patients, could still be expected.
References
1. Ajmone-Marsan, C. Seizures originating from the orbital cortex of the frontal lobe. Epilepsia, 1988, 29, Suppl. 208. 2. Alivisatos, B. and Milner, B., Effects of frontal or temporal lobectomy on the use of advance information in a choice reaction time task. Neuropsychologia, 1989, 27, 495-503. 3. Amthauer, R., Intelligenz-Struktur-Test IST 70. Hogrefe, G6ttingen Toronto Z~irich, 1973. 4. Bancaud, J. and Talairach, J., Clinical semiology of frontal lobe seizures. In Advances in Neurology: frontal lobe seizures and Epilepsie, eds P. Chauvel, A. V. Delgado-Escueta, E. Halgren and J. Bancaud, Vol. 57. Raven, New York, 1992, pp. 3-58. 5. Benton, A. L. and Hamsher, K. de S., Multilingual Aphasia Examinations. University of Iowa, Iowa City, 1978. 6. Bogousslavsky, J., Assal, G. and Regli, F., Infarct in the area of the left anterior cerebral artery. II. Language disorders. Revue Neurologique (Paris'), 1987, 143, 121-127.
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C. Helmstaedter et al./Neuropsychological consequences of epilepsy surgery in frontal lobe epilepsy
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24. Lezak, M. D., Neuropsychological assessment. New York, Oxford University Press, 1983. 25. Lira, S. H., Dinner, D. S., Pillay, P. K., Ltiders, H., Morris, H. H., Klein, G., Wyllie, E. and Awad, I. A., Functional anatomy of the human supplementary sensorimotor area: results of extraoperative elctrical stimulation. Electroencephalography and Clinical Neurophysiology, 1994, 91,179-193. 26. Ludwig, B., Ajmone-Marson, C. and Van Buren, J., Cerebral seizures of probable orbitofrontal origin. Epilepsia, 1975, 16, 151-158. 27. Luria, A. R., The Working Brain. Penguin Press, London, 1973. 28. Masdeu, J. C., Schoene, W. C. and Funkenstein, H., Aphasia following infarction of the left supplementary motor area. Neurology, 1978, 28, 12201223. 29. Milner, B. Some effects of frontal lobectomy in man. In The Frontal Granular Cortex, eds J. M. Warren and K. Akert. McGraw-Hill, New York, 1964, pp. 313-334. 30. Milner, B. Interhemispheric differences in the localization of psychological processes in man. British Medical Bulletin, 1971,27, 272-277. 31. Morrell, F., Whisler, W. W. and Bleck, T. P., Multiple subpial transection: a new approach to the surgical treatment of focal epilepsy. Journal of Neurosurgery, 1989, 70, 231 239. 32. Nauta, W. J. H. The problem of the frontal lobe: a reinterpretation. Journal of Psychiatry Research, 1971, 8, 167-187. 33. Pedley, T. A., Tharp, B. R. and Hermann, K., Clinical and electroencephalographic characteristics of midline parasagittal foci. Annals of Neurology, 1981, 9, 142-149. 34. Petrides, M. Deficits on conditional associative learning tasks after frontal- and temporal-lobe lesions in man. Neuropsyehologia, 1985, 5, 601-614. 35. Petrides, M. and Milner, B., Deficits on subjectordered tasks after frontal and temporal lobe lesions in man. Neuropo, chologia, 1982, 3, 249-262. 36. Schaffler, L., Luders, H. O., Dinner, D. S., Lesser, R. P. and Chelune, G. J., Comprehension deficits elicited by electrical stimulation of Broca's area. Brain, 1993, 116, 695-715. 37. Shallice, T., From Neuropsvchology to Mental Structure. Cambridge University Press, Cambridge, 1988. 38. Smith, M. L, and Milner, B., Differential effects of frontal-lobe lesions on cognitive estimation and spatial memory. Neuropsychologia, 1984, 22, 697-705. 39. Stromswold, K., Caplan, D., Alpert, N. and Rauch, S., Localization of syntactic comprehension by positron emission tomography. Brain and Language, 1996, 52(3), 452-473. 40. Stuss, T. D. and Benson, T., The Frontal Lobes. Raven Press, New York, 1986. 41. Upton, D. and Thompson, P. J., Epilepsy in the frontal lobes: neuropsychological characteristics. Journal of Epilepsy, 1996, 9, 215 222. 42. Verfaellie, M. and Heilmann, K. M., Response preparation and response inhibition after lesions of the medial frontal lobe. Archives o["Neurology, 1987, 44, 1265-1271.
C. Helmstaedter et al./Neuropsychological consequences of epilepsy surgery in frontal lobe epilepsy 43. Wechsler, D. Die Messung der Intelligenz Erwachsener. Textband zum Hamburg- Wechsler-Intelligenztest. Hans Huber Verlag, Bern, Stuttgart, 1964. 44. Williamson, P. D., Spencer, D. D., Spencer, S. S., Novelly, R. A. and Mattson, R. H., Complex partial seizures of frontal lobe origin. Annals (?['Neurology, 1985, 18, 497 504. 45. Williamson, P. D., Wieser, H. G. and DelgadoEscueta, A. V., Clinical characteristics of partial seizures. In Surgical Treatment oJ' the Epilepsies, ed. J. Engel. Raven Press, New York, 1987, pp. 101 123. 46. Wyler, A. R., Wikus, R. J. and Vossler, D. G., Multiple subpial transections for partial seizures in
341
sensorimotor cortex. Neurosurgel:v. 1995, 37, 1122 1127. 47. Zentner. J., Hufnagel, A., Ostertun, B., Wolf, H. K., Behrens, E., Campos, M. G., Solymosi, L., Elger, C. E., Wiestler, O. D. and Schramm, J., Surgical treatment of extratemporal epilepsy: clinical, radiologic, and histophatologic findings in 60 patients. Epilepsia, 1996, 37, 1072-1080. 48. Zentner, J., Hufnagel, A., Wolf, H. 0 K., Ostertun. B., Behrens, E., Campos, M. G., Solymosi, L., Elger, C. E., Wiestler, O. D. and Schramm, J., Surgical treatment of temporal lobe epilepsy: clinical radiological and histopathological findings in 178 patients. Journal Of Neurology, Neurosurgery and P.~3"chiatry, 1995, 58, 666-673.
~
Pergamon
PII: S0028 3932(97)00118 8
¢' 1998 Elsevier Science Ltd. All rights reserved Printed in Great Britain I)02,~ 3932;98 $19.00+0.00
Neuropsychological consequences of epilepsy surgery in frontal lobe epilepsy C. HELMSTAEDTER,*~ U. GLEIBNER,* J. ZENTNERt and C. E. ELGER* *University Hospital of Epileptology, Bonn, Germany: tUniversity Hospital of Neurosurgery, Bonn, Germany
(Receiz'ed 25 Januao" 1997; accepted 1 August 1997)
Abstract--The present study investigated the effect of frontal lobe surgery on "cognitive functions", which have previously been
shown to be discriminative in the evaluation of non-resected patients with frontal lobe epilepsy (FLE). The cognitive outcome was evaluated with particular consideration of the side (left/right), the site (lateral, orbital, mesial, premotor/SMA), the type of surgery (resections vs. resections plus multiple subpial transections; MST), and seizure outcome. The evaluation is based on 33 patients with left (n= 17) or right (n= 16) frontal surgery. Forty-five patients who underwent successful left (n=21) or right (n=24) temporal lobectomy served as controls. The neuropsychological examination covered speed/attention, motor sequencing/coordination, response maintenance/inhibition, short-term memory, and language. With the exception of short-term memory, the chosen tests were discriminative in determining preoperative frontal lobe dysfunctions but they did not differentiate patients with a different lateralization or localization of the frontal focus. At the 3 month follow-up examination, patients with temporal Iobectomy had improved frontal functions, whereas patients with frontal lobe surgery showed a mild deterioration. Within the frontally resected group, completely seizure-free patients had significantly improved short-term memory. Further consideration of the side, site and the type of the frontal resection indicated that patients with premotor/SMA surgery and patients with precentral/central MST had additional impairment after surgery. Premotor/SMA resections led to a deterioration in response maintenance/inhibition and if performed left sided also to deteriorated language functions. The latter impairment could be clearly related to transient aphasia directly after surgery. Irrespective of pareses observed immediately after surgery, patients with MSTs of the precentral/central areas displayed additional problems in motor coordination at the follow-up examination. In this group the seizure outcome was also less favourable. In summing up, frontal lobe surgery does not cause any considerable additional impairment in the short-term followup. However, caution is recommended when surgery or MST affect functional relevant cortex (here the prefrontal/SMA and precentral/central area). Finally, a release of functions associated with frontal areas not affected by surgery is suggested, when seizures are successfully controlled by surgery..!-~ 1998 Elsevier Science Ltd. All rights reserved Key Words: neuropsychology: frontal lobe epilepsy: epilepsy surgery.
inhibition [29, 42], estimations [38], associative learning [34, 35] and anticipation in choice reaction tasks [2]. Historically, these studies suffer from the problem that there were no preoperative data available, and that in most cases only one function was assessed, which was assumed to be representative for frontal lobe functioning in general. Recent approaches, which followed more differentiated functional-anatomical models of the frontal lobes [37, 40] were able to demonstrate specific cognitive impairment in F L E already preoperatively. In our own study of 1996 we explicitly evaluated the question of an impairment of different "frontal subfunctions'" in 23 patients with F L E compared with 38 patients with temporal lobe epilepsy (TLE). In particular we examined memory span, visuomotor speed, selective attention, visuo-perceptual speed, response inhibition, fluency, concept formation/shifts, anticipation/planning behaviour, and m o t o r coordination [16]. These functions were hypo-
Introduction
Due to the complex functional neuronal organization of the frontal lobes and their reciprocal connection to other cortical, limbic and subcortical areas [26, 32], FLE is characterized by a broad interindividual variety of seizure semiology [l, 4, 5, 45] and often shows inter- and intrahemispherically widespread and rapidly propagating epileptic activity [7, 13, 33, 44]. As observed with seizure semiology, a broad variety of cognitive impairment has also been reported in frontal lobe epilepsy. Most data about cognitive impairment in F L E stems from early studies in postoperative patients indicating impairment mainly in performance on concept formation, response +Address for correspondence: Sigmund Freud Strasse 25, 53105 Bonn, Germany. Tel: +49 228 287 6383; Fax: +49 228 287 6294; E-mail: psych(/~mailer.meb.uni-bonn.de 333
334
C. Helmstaedter et al./Neuropsychological consequences of epilepsy surgery in frontal lobe epilepsy
thesized to cover different aspects of frontal lobe functioning. As expected, patients with F L E showed a poorer performance than patients with T L E on all evaluated measures. Factor analysis of the tests indicated that four individual "frontal subfunctions" (speed/attention, short-term memory, motor coordination, response maintenance and inhibition) could be differentiated. In particular a cognitive pattern of impaired motor coordination and/or response inhibition characterized the patients with FLE. Problems in short-term memory and speed/attention were shared with TEE patients. However, none of the tests turned out to differentiate the site or lateralization of frontal lobe focus. A recent study by Upton and T h o m p s o n [41] followed a very similar approach. Parallel to our study, no effects of the lateralization or localization of the frontal lobe epilepsy were obtained and of all the tested functions only m o t o r impairment turned out to be a consistent and discriminative feature in FLE. Because functional concepts evaluated in both studies were very much the same, divergent findings may be explained by different patient selection criteria and different test procedures. Having tests available which help diagnose frontal lobe impairment in epilepsy preoperatively, this study evaluated the cognitive consequences of frontal lobe surgery on these functions. In order to cross-validate the preoperative applicability of the tests, a sample of patients with FLE was evaluated which had only a minimal over-
lap with the sample of our preceeding study. We evaluated possible effects of the side of surgery (left/right), the site of surgery (lateral, orbital, mesial, premotor/SMA), the type of surgery (resection vs. resection with additional multiple subpial transections), and seizure outcome on frontal lobe functions.
Material
and methods
Patients with FLE
Subjects consisted of 33 patients (21 male/12 female) who underwent either left (n = 17) or right (n= 16) frontal lobe surgery (Table 1). Site and type of the frontal resections were individually tailored according to the neuroradiological findings, preoperative or intraoperative electrocorticography (ECOG) examinations, and, if required, functional mapping (electrocortical stimulation via subdural strip or grid electrodes). All but two of the patients with FLE had lesions as determined by magnetic resonance imaging (MRI) (12 tumours, 19 other benign structural changes). With the exception of three right frontal lobectomies, all resections were circumscribed topectomies including the lesion and the surrounding zone of maximum interictal/ictal epileptic activity (see also [47]). Seven left lesionectomies (two lateral and five premotor/SMA resections) and two right resections (one lobectomy and one premotor/SMA resection) were extended by multiple subpial transections (MST) when areas were involved in epilepsy that had been demonstrated to be eloquent cortex by electrical cortical stimulation. All MSTs affected the primary motor cortex.
Table 1. Characteristics of the evaluated groups Subject characteristics
Gender Age (years) Age at onset of epilepsy (years) Duration of epilepsy (years) Lesion: Tumour* Benign malformations* Hippocampal sclerosis No finding Site of surgery: 2/3 anterior resections Lateral Orbital Mesial Premotor/SMA Lobectomy Outcome: Seizure free
(m/f) (m/S.D.) (m/S.D.) (m/S.D.)
R-FLE 16
L-FLE 17
R-TLE 21
L-TLE 24
10/6 30.8 (1 I) 14.7 (12) 17.0 (8)
11/6 28,9 (10) 15,2 (11) 13.6 (9)
12/9 29.4 (10) 13.3 (7) 16.0 (12)
16./8 30.2 (11) 9.8 (8) 20.1 (12)
3 12 1
9 7 1
2 7
8 7
6 3 4 ( 1') 3 (1 ')
6 (2')
7 (43%)
11 (64%)
12
9
-
-
21
24 -
1
-
-
2 8 (5')
-
-
21
24
*Astrocytoma and oligodendroglioma grades I and II etc. ~Cortical dysplasia, DNT, heterotopia etc. 'Number of patients who had resective surgery plus subpial transections reaching into eloquent cortical areas as determined by electrical cortical stimulation. R-FLE, right frontal lobe epilepsy; L-FLE, left frontal lobe epilepsy; R-TLE, right temporal lobe epilepsy; L-TLE, left temporal lobe epilepsy.
C. Helmstaedter et al./Neuropsychological consequences of epilepsy surgery in frontal lobe epilepsy MST is a relatively new surgical technique to control seizures originating from eloquent cortex. Its working mechanism is not yet fully understood, but in general transsection of the horizontal fibres is thought to prevent the horizontal spread of seizure activity [21, 31 ].
Patients with TLE A group of 45 patients (28 male/17 female) who underwent left (n=21) or right (n=24) 2/3 anterior temporal lobectomy served as controls (Table 1). As for the FLE patients the followup interval was 3 months. The most frequent pathological finding in these patients was hippocampal sclerosis (47%), followed by benign malformations (31%) and tumours (22%). In anterior 2/3 temporal lobectomy, the extent of the temporolateral resection was 4 cm along the superior and middle temporal gyrus and 5 cm along the inferior temporal gyrus. The hippocampus and the parahippocampal gyrus were usually resected en bloc and the resection reached the middle of the cerebral peduncle at its widest diameter [48]. In order to exclude an extratemporal involvement in the TLE group, we only selected patients for this control group who had temporal lesions and were completely seizure free 3 months after surgery.
Health)' sub/ects In order to get an estimation of the patients impairment, and in order to standardize the test data for direct comparison with each other, test data of 22 (11 men, 11 women) healthy subjects served as controls. The mean age of these subjects was 28.8 years (S.D.=4.6years) and the mean IQ of this group was 104 (S.D,= 11.5).
Neuropsyehological assessment All patients were evaluated preoperatively and 3months postoperatively by use of a short version of the test battery which was introduced in our study from 1996 [16] to evaluate patients with frontal lobe epilepsy. Factor analysis of the tests of the 1996 battery showed that four executive/frontal subfunctions can be differentiated ("speed~attention", "shortterm memory", "response maintenance/inhibition"and "motor coordination"). However, the original test battery included redundant measures. Response inhibition for example was assessed by colour word interference and furthermore by inversely reading "a"s and "b"s (for the latter tests see below). For economic reasons, time-consuming tests with redundant measures were now removed from the battery. The tests selected for the present study were representative for the four factors, that is, the test scores had high factor loadings on the corresponding factor. The following tests were applied: • The subtest digit span (forward and backward) of the WAIS [43] was chosen to examine immediate verbal memory span. The Corsi block test after Milner [30, 24] was modified and served as the non-verbal counterpart of the digit span. Corsi block testing followed the instructions of the WAIS for digit span. • A letter cancellation test (d2 test) was applied to assess the capacity for sustained selective attention and visuomotor speed [8]. The test requires detection and cancellation of the letter "'d" with two apostrophes (d') which is randomly distributed in 14 rows with similar distractor items (i.e. p', d', etc.). The time to perform each row was limited to 20 sec.
335
The total number of scanned items minus the number of errors (misses and false cancellations) was the objective of the evaluation. • The c.I. test (cerebraler Insutfizienz test) consists of two subtests. The first subtest assesses visuo-perceptual speed and demands counting squares out of a table with various other symbols (stars, circles, etc.) as fast as possible. The second subtest assesses interference effects. It requires inverse reading of two rows of"A" and "B" (AABAB... as BBABA... ). For both subtests the time needed to perform the tasks was the object of the evaluation [23]. • The word-fluency test, a subtest of a German intelligence test (LPS: Leistungs Priif System), assesses phonematic fluency. Patients are asked to find as many words as possible beginning with a designated letter (F, R, and K) in a time interval of [rain. The test demands lexical search and requires initiation and spontaneity [19]. • A maze test [9] 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. • Similar to the manual copying 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 repeated fluidly at least 20 times. The performance on these three tasks was rated as follows: 1, No impairment: correct and fluid performance: 2, Mild impairment: correct but not fluid performance: movements are slow or with frequent interruptions or pauses: 3, Impairment: see no. 2 plus perseverations, inadequate strength or interference. Interference was concluded in the unimanual task when the single movements could not be separated and appeared to be mixed. In the bimanual task interference was concluded when irradiations of the movement of one hand to the other hand were observed (one hand shows a mixture of two movements or both hands do the same). 4, Strong impairment: performance was impossible or broke down completely after a few repetitions. Table 3 provides the raw data of the patient groups and the group of healthy controls. For data reduction the test results of the patients were standardized according to the normative test data of the 22 healthy control subjects. Furthermore, composite scores were computed for the individual frontal subfunctions by subtotaling the test scores for the four factors which resulted from the analysis of the original test battery [16]. The result was a standardized value (mean = 100, S.D. = 10) for each function. This had the advantage of data reduction, the scores could be directly compared with each other by means of a cognitive profile, and the relative impairment compared with the healthy subjects could be concluded. The different test scores were subtotalled for the individual functions as follows: • speed:attention (speed in maze testing; scanned items minus errors in the letter cancellation/d2 test; speed in symbol counting/c.I, test: number of words achieved in the word fluency test): • short-term memory (digit span; Corsi block span): • response maintenance/inhibition(errors in maze testing; time needed to perform the interference test/c.l, test); • motor coordination (points achieved in performing uni- and bimanual alternating sequences). Stalisti~ ,~" Preoperative differences between FLE and TLE were evaluated b~ univariate analysis of variance (ANOVA). Post-
336
C. Helmstaedter et al./Neuropsychological consequences of epilepsy surgery in frontal lobe epilepsy
operative performance change in both groups was evaluated with consideration of the preoperative ability status as a covariate (ANCOVA) because comparable studies in patients with TLE consistently show highly significant correlations between postoperative changes and the preoperative ability status. Separate statistics (ANOVAS) were computed within the FLE group to evaluate the possible effects of the type of the resection, the seizure outcome, and the side and the site of the lesion/focus. Because of the heterogeneity of the resections, we restricted the evaluation of the site of resection to the cognitive consequences of MST and premotor/SMA resections. Finally, we took into consideration that some patients with FLE showed neurological symptoms directly after surgery. Comparisons of patients with and without these complications were performed in order to evaluate whether long-lasting residuals can be determined by the test performance. Results At the 3 m o n t h follow-up examination 43% of the right and 64% of the left frontally resected patients were completely seizure free. The nine patients who had subpial transections were less likely to become seizure free (30%) than the remaining 24 patients who had sole resective surgery (60%), but this difference did not become statistically significant. Forty-two per cent of the frontally resected patients (n= 14) demonstrated neurological symptoms directly alter surgery (57% premotor/SMA, 22% lateral, 7% orbital, 14% lobectomy) which had receded almost completely at the 3month follow-up examination. Premotor/SMA resections were accompanied with motor aphasia plus paresis (n=3), transcortical aphasia plus paresis (n= 1), cortical dysarthria (n=2), pure paresis (n = 1), and severe psychomotor slowing (n = 1). One of the lateral resections led to a motor aphasia, and two lateral resections led to pareses. The one patient with an orbital resection showed anosmia after surgery. Two of the three lobectomies were followed by a severe psychomotor slowing (Table 2).
D(fferences between patients with FLE and TLE Univariate analysis (ANOVA) showed that, preoperatively, patients with F L E scored lower than patients
with T L E in all measures except short-term memory IF ranging from 4.9 to 21.0 with P<0.05] (Fig. 1). Group comparisons on the basis of difference scores (postoperative value minus preoperative value) showed that patients with T L E improved in response maintenance/inhibition, patients with FLE remained largely unchanged [A NCOVA with F = 15.9, P < 0.001 ]. Patients with T L E also showed slight gains regarding motor coordination [F= 3.6, P = 0.06] and significant gains regarding speed/attention [F=7.4, P<0.01]. Frontal lobe resections in contrast to temporal resections led to a deterioration in these functions (Fig. 2). Covariance analysis indicated that in both groups there were highly significant negative correlations between the preoperative ability status and the postoperative change in performance. Preoperatively poor scoring patients tended to improve and preoperatively high scoring patients tended to deteriorate alter surgery (r at least 0.5 with P<0.01 for each correlation).
D(JJbrences between diJJerent frontal resections All further statistical analyses referred only to the FLE group focussing on possible effects of the side (left vs, right), the site (lateral vs. premotor/SMA), the type of the resection (lesionectomy vs. lesionectomy plus subpial transections), and seizure outcome (completely seizure free vs. not seizure free). Preoperatively, no significant effects of the side or the site of the lesion/focus could be observed. However, as a trend right-FLE patients tended to perform worse than left-FLE patients (Table 3 and Table 4). First of all analysis of the postoperative changes showed a significant effect of the seizure outcome on short-term memory. Patients who were seizure free at the follow-up examination improved and patients who were not seizure free deteriorated [F=7.3, P<0.01]. When considering side, site and type of the resection, there was a trend for left SMA/premotor resected patients to show deteriorated performance in language testing. Language testing was not a part of the test battery originally in use with FLE and was additionally introduced because, in
Table 2. Neurological sequelae/complications after frontal lobe surgery Neurological sequelae of t¥ontal lobe surgery Sequelae Side of surgery Lateral Mesial Orbital Premotor/SMA Lobectomy
Paresis
Dysarthria or aphasia
Paresis plus aphasia
r/l 1/ 1 // 1//
r/1 / 1* -//-/2' -/
r/l / / -/ -/3* 1~ /-
r, Right; 1, left. *Motor aphasia; *dysarthria; ;trans-cortical aphasia.
Severe psychomotor slowing r/I /-/. . /1/2/-
.
Anosmia
.
r/l -/ / 1/ -/-/
C. Helmstaedter et al./Neuropsychological consequences of epilepsy surgery in frontal lobe epilepsy
337
preoperative differences between patients with frontal (n=33) and temporal (n=45) lobe epilepsy standarized values 110 100
90 8O 70 p
....... F
p
F
resp,inhib.
speed
it0i, i Fi0ii mot.coord,
s.t.m.
Fig. 1. Preoperative differences between patients with frontal and patients with temporal lobe epilepsy in speed/attention, response maintenance/inhibition, motor coordination, and short-term memory.
changes in performance after Iobectomy
frontal (n=33) and temporal (n=45) 10
difference scores (adjusted means)
8
showed an improvement in this function [F=9.62, P < 0.01 ]. Resections with additional MSTs (n = 9) tended to have a negative effect on motor coordination [F= 3.7, P = 0.06]. Patients with or without paresis directly after surgery could not be differentiated by any testing at the 3 month follow-up examination.
6
Discussion
-2
-4
-
speed
resp.inhib, mot.coord,
s.t,m.
Fig. 2. Performance change after frontal and temporal lobe surgery. Changes are reported as difference scores (3 month follow-up value minus preoperative value) which were corrected by the preoperative ability slatus (covariance analysis).
some patients, aphasic symptoms were observed after frontal lobe resections. Accordingly, a statistically significant deterioration in language was observed particularly for those five patients who had left frontal resections and transient motor or transcortical aphasia directly after surgery. Residuals of these aphasic symptoms at the 3 month follow-up evaluation were reflected when changes in language functions in patients with aphasia were compared with those without. Deterioration was especially observed in comprehension [F=26.5, P<0.01] as assessed by the Token test [10], as a trend in verbal fluency [F= 3.4, P = 0.07], and in verbal reasoning [F= 3.9, P = 0.05] as assessed by a subtest of a German intelligence test [3]. Irrespective of the side of surgery, resections within the premotor/SMA area were accompanied by a deterioration in response maintenance/inhibition whereas patients with other resections
The present study evaluated the cognitive outcome of frontal lobe surgery in patients with pharmacoresistant frontal lobe epilepsies, with attention to cognitive mental functions which had previously been shown to be indicative of frontal lobe dysfunction in non-resected frontal lobe epilepsies [16]. The non-resected group of our recent study and the surgical group under study here overlapped only by five patients. Furthermore, the group studied here was larger and consisted of a comparable number of left and right frontal patients. The presurgical results confirm the diagnostic value of the applied neuropsychological measures in terms of a cross-validation. In line with the results of our previous study, patients with FLE showed deficits particularly in motor coordination and response maintenance/inhibition. This is consistent with Upton and Thompson [41], who reported that motor impairment is a consistent and discriminant feature in FLE. In further agreement with Upton and Thompson we did not find conclusive evidence that the lateralization or the localization of the frontal lesion/focus results in different impairment. There was only an unspecific trend of patients with right FLE to be more severely impaired than patients with left FLE. The postoperative cognitive outcome of the evaluated groups first of all turned out to be strongly and inversely related to the preoperative ability status. Comparable observations have been made in studies addressing the
338
C. Helmstaedter et al./Neuropsychological consequences of epilepsy surgery in frontal lobe epilepsy Table 3. Pre- and postoperative performance of the patient groups and reference data from the group of healthy controls n
Controls 22
R-FLE 16
L-FLE 17
R-TLE 21
L-TLE 24
Digit span Pre Post
(m/S.D.)
6.2(1.2)
5.9(1.2) 5.6(1.1)
5.8(1.1) 5.9(1.0)
5.8(1.1) 5.9(1.0)
6.3(1.1) 5.6(1.1)
Corsi block Pre Post
(m/S,D.)
5.9(1.1)
5.2(1.6) 5.0(0.8)
5.2(0.8) 5.6(0.9)
5.3(0.8) 5.5(0.6)
5.5(0.8) 5.8(0.7)
(m/S.D.)
440 (84)
309 (74) 345(93)
340 (99) 371 ( 1 1 5 )
384 (70) 430(83)
396 (57) 456(60)
c.I. test/visuo-perceptual speed (sec) Pre (m/S.D.) Post
14.4(2.2)
19(6.6) 22(17)
19.6(7.3) 21.1 (7.6)
17.0(4.2) 16.3(6.5)
17.2(4.3) 15.8(4.4)
c.I. test/interference (sec) Pre (m/S.D.) Post
18.1 (4.8)
25 (9.2) 25(7.2)
21.3 (4.4) 25.8(9.4)
22.4 (4.8) 19.9(4.8)
22.0 (4.6) 18.0(4.2)
41 (10)
27(7.2) 26(8.1)
24(4.3) 22(10.4)
27.8(9.1) 26.4(9.7)
29.5(8.7) 30(6.7)
208(104)
412(179) 403(194)
314(114) 340(184)
294(141) 299(192)
325(165) 247(122)
6.0 (4)
12.7 (8.2) 8.9(4.9)
9.6 (6.5) 7.7(5.3)
9.8 (7.2) 6.1 (4.2)
8.2 (5.4) 5.7(3.6)
7.6(2.9) 7.2(2.5)
6.5(3.2) 7.0(3.7)
4.3(0.6) 4.8(1.2)
4.9(1.1) 4.5(0.7)
d2 Pre Post
LPS word fluency Pre Post
(m/S.D.)
Maze test/speed (see) Pre (m/S.D.) Post Maze test (errors) Pre Post
(m/S.D.)
Manual copying task (unimanual plus bimanual) Pre (m/S.D.) 3(1) Post
R-FLE right frontal lobe epilepsy; L-FLE left frontal lobe epilepsy; R-TLE right temporal lobe epilepsy; LTLE left temporal lobe epilepsy. m(S.D.) mean (standard deviation).
Table 4. Pre- and postoperative frontal/executive subfunctions reported as standard values (mean= 100, S.D. = 10) L-FLE 17
R-TLE 21
L-TLE 24
Speed/attention (standard values) Pre (m/S.D.) 88.7 (9) Post 84.6 (22)
87.0 (10) 84.2 (15)
91.4 (9) 92.5 (8)
92.2 (8) 96.8 (8)
Short-term memory (standard values) Pre (m/S.D.) 95.0 (5) Post 94.2(3)
94.3 (5) 95.3 (5)
95.1 (4) 96.0(3)
97.2 (5) 98.1 (3)
Response maintenance/inhibition (standard values) Pre (m/S.D.) 85.7(15) 90.1(7) Post 91.5(7) 90.0(11)
91.5(11) 97.2(6)
95.3(7) 101.2(6)
Motor coordination (standard values) Pre (m/S.D.) 77.4 (22) Post 80.9 (18)
96.7(7) 93.4 (8)
96.8(9) 98.6 (6)
n
R-FLE 16
86.9(18) 83.6 (24)
*Standardized values. R-FLE, right frontal lobe epilepsy; L-FLE, left frontal lobe epilepsy; R-TLE, right temporal lobe epilepsy; L-TLE, left temporal lobe epilepsy. m(S.D.) mean (standard deviation).
C. Helmstaedter et al./Neuropsychological consequences of epilepsy surgery in frontal lobe epilepsy postoperative memory outcome after temporal lobectomies in TLE. This finding can be interpreted to reflect the resection of functioning tissues in addition to lesional tissues in order to achive seizure control [11, 15, 17]. However, because we observed this regression in both FLE and TLE patients, this relationship can also be interpreted in terms of a statistical regression to the mean due to test repetition. When the postoperative performance changes were evaluated by considering the preoperative ability status in group comparisons, the data provided evidence that temporal lobe resections result in a general improvement in "frontal functions", whereas frontal lobe resections led to mild losses in psychomotor speed and motor coordination. The finding of a postoperative improvement in patients with TLE confirms earlier suggestions that "frontal-like" symptoms in TLE probably reflect irradiation of dysfunctions along fronto-temporal pathways that will disappear after surgery by successful control of seizures and epileptic activity [18]. In FLE patients, postoperative seizure control was accompanied by an improvement in short-term memory. This improvement in memory could also be explained by a release phenomenon. This seems likely, particularly because prefrontal areas which are thought to be involved in working memory were mostly not affected by surgery. Considering side, site and the type of the frontal resections, especially premotor/SMA resections and lobectomies showed a high risk (about 70%) of neurological deficits directly after surgery. Two of the three lobectomies led to severe psychomotor slowing, which was observed only in one of the other resections. In premotor/SMA resections the most prominent postoperative impairment was a SMA-deficiency syndrome with aphasia, when surgery was performed within the language-dominant hemisphere, and/or motor arm/leg/ facial impairment after surgery in either hemisphere. It should be noted that the SMA deficiency syndrome is predominantly an impairment of the initiation of behaviour. Consistent with previous reports in patients with SMA lesions, the predominant symptom of aphasia was a speech arrest or transcortical aphasia [6, 22, 28]. Although most operative sequelae were transient, residuals of postoperative aphasia in terms of unspecifically deteriorated language functions could still be observed at the 3 month follow-up examination. The aphasic residuals were not only concerned with impairment in verbal fluency, but also with impaired comprehension and verbal reasoning. This finding can not be consistently explained by a purely expressive speech disorder. Recent functional imaging studies suggest a participation of the frontal lobe in receptive language functions, but the small sample size and lack of experience with SMA resections do not allow an interpretation of our findings as being SMA-specific [20, 36, 39]. Taken together with the deterioration in response maintenance/inhibition, the observations after premotor/SMA resections are otherwise consistent with the known role of the SMA in the
339
initiation/inhibition and programming of motor responses [12, 14, 25, 43]. Irrespective of whether there were motor problems initially after surgery, increased problems in motor coordination at the 3 month follow-up were observed, particularly in those patients who had subpial transections directly affecting the primary motor cortex. Subpial transections in the sensorimotor cortex have been reported to be successful in controlling seizures and lead only to transient but not to persistent neurological/neuropsychological impairment [46]. At least within the first 3 months postoperatively the present data do not support this suggestion. Whereas poorer seizure control can be explained by the remaining epileptogenic tissue, the outcome in motor functioning may reflect different plasticity to compensate for impairment of unilaterally disposed primary motor functions compared with bilaterally disposed premotor/SMA functions. In conclusion, the data confirm the discriminant validity of the neuropsychological assessment of frontal functions in patients with focal epilepsies. The postoperative evaluation reveals satisfactory clinical and cognitive outcome in frontal lobe surgery in general. A good cognitive outcome was observed in patients, who were seizure free after surgery and in whom surgery did not affect the eloquent cortex. A less favourable outcome in terms of direct postoperative neurological impairment and residual problems in language, response maintenance/inhibition and motor coordination resulted from premotor/SMA resections and/or subpial transections into primary motor areas, respectively. Considering that these results were obtained at the 3month follow-up evaluation, further functional improvement, particularly in seizure-free patients, could still be expected.
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