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Effects of chronic epilepsy on declarative memory systems
T. Sutula and A. Pitk~inen (Eds.) Progress in Brain Research, Vo|. 135 © 2002 Elsevier Science B.V. All rights reserved
CHAFFER 39
Effects of chronic epilepsy on declarative memory systems C. Helmstaedter* Department of Epileptology, University of Bonn, 53105 Bonn, Germany
Abstract: Memory is systematically affected by temporal lobe epilepsy. Since surgery is a promising alternative to pharmacological treatment the questions which memory system is affected and what the long-term prognosis of memory is are more relevant than ever. We address these issues by cross-sectional and longitudinal analysis of memory performance in large series of patients with temporal lobe epilepsy (TLE). The findings indicate that episodic memory rather than semantic memory is impaired in TLE, in particular in TLE with mesial temporal pathology. With the exception that mesial functions appear increasingly affected by chronic non-mesial TLE, memory decline in TLE is not different from that observed in healthy control subjects. However, since patients perform poorer than controls at any age, normal senescence brings patients to nmesic disability at a younger age. Semantic memory seems unaffected by this process but early cortical lesions appear to interfere with knowledge acquisition. Longitudinal data come to a different conclusion regarding the contribution of epilepsy/seizures to memory decline. Conservative treatment is associated with significant decline in figural memory and 37% of the patients experience some memory decline in the long run. Surgery partly anticipates the decline observed with conservative treatment, but losses are most marked after left temporal lobe surgery. After surgery, quite stable memory or even late recovery from surgery is indicated. Leaving aside the surgical intervention, the data provide evidence that the longitudinal memory outcome in TLE is determined by seizure control, seizure severity, mental reserve capacities, and the retest interval. Thus early and efficient seizure control and the prevention of any cerebral damage from the beginning of epilepsy are demanded.
Introduction Memory is one of the most essential higher brain functions since it provides continuity in time, personal history, and awareness. Theoretically declarative memory, that is the encoding and explicit retrieval of new information, is separated from nondeclarative memory which comprises skill-oriented learning, conditioning and priming processes and which can be driven automatically and implicitly. Neuroanatomically, declarative memory is strongly associated with temporo-mesial structures. It is
* Correspondence to: C. Helmstaedter, University Clinic of Epileptology, Sigmund Freud Strasse 25, 53105 Bonn, Germany. Tel.: -t-49-228-287-6108; Fax: +49228-287-6294; E-mail: [email protected] or C.Helmstaedter @web.de
therefore self-evident that memory deficits represent the major cognitive impairment in focal epilepsies which directly affect these structures, i.e. the temporal lobe epilepsies (TLE) (Hermann et al., 1997). Since TLE represents the majority of chronic focal epilepsies - - about 80% in the Bonn series - and since memory is the function which is directly affected by temporal lobe lesions and functional disturbances, the question of how chronic epilepsy affects declarative memory systems will be discussed in relation to this particular type of epilepsy. Other focal epilepsies (frontal, parietal, occipital, etc.) will not be explicitly addressed but a distinction between mesial and non-mesial, cortical temporal lobe epilepsies will be made. In terms of disease progression and functional reserve capacities the non-mesial temporal lobe epilepsies can be assumed to share many features with other cortically located epilepsies.
440
Declarative memory in temporal lobe epilepsy In recent years great efforts have been made to specify memory problems in TLE and to establish the neuroanatomical and functional basis of these problems (Helmstaedter and Kurthen, 2001). Within the declarative memory system, a basic distinction is made between 'episodic memory' and 'semantic memory' (Tulving, 1984). 'Episodic memory' means the memory for time- and context-dependent information (the car you own) and semantic memory refers to memory for context- and time-independent (world-) knowledge (what a car is in general). As for TLE and 'episodic memory', materialspecific verbal or nonverbal memory impairment can be diagnosed dependent on whether the language dominant or nondominant hemisphere is affected, (Jones-Gotman et al., 1993). In accordance with neurobiological suggestions (Eichenbaum et al., 1992; Squire, 1992), we and other groups have shown that left-sided mesial pathology in TLE correlates well with impairment of verbal long-term consolidation and retrieval. In contrast, cortical temporo-lateral pathology is associated rather with impaired verbal learning, short-term or working memory. This pattern has been demonstrated in detail also by correlation of intracranial, subdurally and intra-hippocampally recorded event-related potentials to measures of memory, by different effects of mesial and cortical pathology on memory, and by different memory outcome after various types of temporal lobe surgery (Elger et al., 1997; Helmstaedter et al., 1997b). For semantic memory in TLE patients, the findings are less consistent. In a study of confrontative naming after temporal lobectomy, Bell et al. (2000) found naming performance deficits dependent on age at acquisition (greater loss of names acquired later) but not on semantic attributes (living/nonliving) of the object names. Studies on semantic word fluency come to inconsistent conclusions as to whether category-specific impairment can be discerned in TLE or not. Jokeit et al. (1998) report categoryspecific impairment in naming as dependent on the lateralization of seizure focus. In contrast, Gleil3ner and Elger (2001) report general but no categoryspecific deficits in semantic fluency in TLE which appeared related to mesial pathology. One of our own studies on relational memory processing demon-
strated that patients with left TLE show increasing memory problems with greater relational (semantic) distances between memory contents (Helmstaedter et al., 1997a). We interpreted this finding as indicative of deficits in semantic relational memory processing. Recently, impairment of remote autobiographical episodic memory has also been reported in TLE (Viskontas et al., 2000). In contrast, personal semantic memory appears unaffected (Bergin et al., 2000). In summary, there is some evidence that patients with TLE indeed have problems with semantic memory processing but it needs to be examined in more detail to which degree deficits in the acquired semantic network and knowledge system architecture or impaired retrieval processes are responsible for these problems. Originally, episodic and semantic memory were thought to represent only two aspects of a unitary declarative memory system which become equally impaired with temporo-mesial lesions. This must be doubted since there is evidence from semantic dementia that semantic memory is more closely related to cortical structures and the permanent repository of knowledge (Garrard and Hodges, 2000). While encoding and retrieval of episodic information strongly depend on mesial functions, semantic knowledge can become independent from hippocampal functional integrity (Nadel et al., 2000). Independence of semantic memory acquisition from hippocampal functioning is suggested by Varhga-Khadem et al. (1997) who found that semantic knowledge had been acquired in spite of the presence of severe episodic memory impairment in single patients with very early damage of mesial structures. From a theoretical point, the dissociation of semantic and episodic memory may be an answer to the ongoing 'chickenegg discussion' of whether impaired episodic memory hinders acquisition of semantic knowledge or vice versa (Squire and Zola-Morgan, 1996; Eichenbaum, 1997; Tulving and Markowitsch, 1998).
Longitudinal studies of memory in chronic TLE Now that epilepsy surgery has become a serious and very successful alternative to medical treatment, patients with chronic epilepsy have a legitimate interest in knowing their cognitive prognosis with the respective treatment.
441
TABLE 1 Longitudinal studies on cognition in focal epilepsies Study
Nr. of groups
Interval
Seizure outcome (seizure free)
JQ
Memory
Selwa et al., 1994
28 conserv. (TLE) 31 surgery (TLE)
1-8 years 2-17 months
conserv, no change surgery 64%
no change in conserv. better after right-sided surgery
no change in conserv. patients improvement after right-sided surgery
Rausch et al., 1994
20 surgery (TLE)
>9 years
Holmes et al., 1998
25 conserv. (partial epilepsies) 47 conserv. (TLE) 114 surgery (TEE)
10 years
improvement 33%
2-10 years
surgery 64%
Helmstaedter et al., 2000
Aikia et al., 2001
20 conserv. (TLE)
conserv. 24%
5 years
100%
In general, the following factors can be suggested to cause mental decline in chronic epilepsy: (1) preexisting structural lesions including surgical defects; (2) progression of the disease underpinning epilepsy; (3) progression of epilepsy (secondary epileptogenesis, kindling, etc.); (4) accumulation of lesions secondary to epilepsy (trauma, intoxication, status epilepticus, etc.); (5) physiological or pathological aging. There are two essential questions regarding the prognosis of memory in TLE. Firstly, what is the risk of memory decline in chronic medically treated epilepsy as compared to the risk of memory decline after successful surgery (to say nothing of those patients who do not become seizure free after surgery), and secondly, what are the additional effects of aging on cognitive function in both groups. We evaluated these questions with a cross-sectional and longitudinal study approach, the latter findings being reported first. (An overview over cross-sectional and longitudinal studies and a discussion of the differences between these approaches are provided by Dodrill, 2002, this volume.) Longitudinal studies, which address the issue of long-term changes of episodic memory performance
improved performance
short- and long-term losses in verbal memory after left-sided surgery logical memory unchanged
worse verbal memory after left- than right-sided surgery stable course after surgery worsened figural memory with conservative treatment stable verbal learning and even improved delayed recall
Non-memory
worsened speed and visual spatial functions improved attention after surgery
in chronic epilepsy span intervals ranging from 2 to 10 years (see Table 1). These studies have indicated quite stable memory performance when patients are treated conservatively with antiepileptic drugs (Selwa et al., 1994; Holmes et al., 1998; ,~iki~i et al., 2001). Our own evaluation (Helmstaedter et al., 2000) of 47 patients with TLE (mean retest interval 56 4- 26 months), indicates significant deterioration of figural memory performance (see Figs. 1 and 2). The study of Holmes et al. (1998) revealed mild deterioration in speed and, interestingly, also in visuo-spatial functions. When classified according to reliability of change indices, our data show that about 20% of the conservatively treated patients significantly decline in verbal or figural memory, only 5 to 10% of the patients had improved memory functions (see Table 2). Taking together both verbal and figural learning, 37% of the conservatively treated patients showed a significant deterioration in memory in the long run. So far the high number of patients who show individual decline in either verbal or figural memory supports the assumption of an accumulation of lesions over time. The finding of a significant deterioration particularly of figural memory is of interest since it directs attention to the widely
442
120
figural memory [standard values]
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100 -
80
70
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60
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conservative
i
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47 51 63 Fig. l. Box plot of figural memory performance (standard value with mean = 100, SD = 10) in design learning in conservatively and operatively treated patients with temporal lobe epilepsy. For conservative patients results at two (initial and long-term follow-up evaluation [2-10 yrs, 56-4-26 months]) and for operated patients results at three test times (preoperative, one year postoperative and long-term follow-up evaluation [2-10 yrs, 58-4-28 months) are displayed. Significance levels result from t-tests for dependent measures. The data indicate significant losses in conservative patients and after right temporal surgery.
neglected right hemisphere. Our current working hypothesis is that this finding may reflect compensatory sacrifice of right hemisphere functions for preservation of verbal functions as observed in patients with right hemisphere language representation and early acquisition of left hemisphere lesions (Helmstaedter et al., 1994). From surgical patients who underwent left amygdalo-hippocampectomy at least we have evidence that, after surgery, right mesial structures compensate verbal memory functions which were associated to the left mesial lobe before surgery (Grunwald et al., 1998).
In contrast to the course of memory function in conservatively treated patients, epilepsy surgery often marks a significant step in regard to cognitive performance. While temporal lobe epilepsy surgery is very successful in permanently controlling seizures, deterioration of memory is very likely when brain tissues are removed which are still involved in memory function (Helmstaedter and Kurthen, 2001). As regards verbal memory, baseline performance together with age at surgery are powerful predictors of the postoperative outcome (Helmstaedter and E1ger, 1996; Davies et al., 1998; Helmstaedter, 1999).
Fig. 2. Box plot of verbal memory performance (standard value with mean = 100, SD = 10) in list learning in conservatively and operatively treated patients with temporal lobe epilepsy: (a) learning over 5 trials; (b) loss of learned items after 1/2 h delay). For conservative patients results at two (initial T1 and long-term follow-up evaluation T3) and for operated patients results at three test times (preoperative T1, one year postoperative T2 and long-term follow-up evaluation T3) are displayed. Significance levels result from t-tests for dependent measures. The data indicate significant losses in verbal learning after left surgery and stable performance at the long-term follow-up. After right-sided surgery reversible loss in verbal delayed recall is indicated.
443
120-
verbal learning trials 1 to 5 [standard value]
i
l
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I
II
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60~T1
Lp
120
100
(a)
~T2
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T3
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right surgery
left surgery
47
51
63
verbal memory loss in free recall [standard value]
||
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60. BT1 ~T2 40
(b) i
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left surgery
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51
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BT3
444 TABLE 2 Long-term memorychange in conservativelyand surgicallytreated patients with TLE Group
Conservative Right-sided surg. LeR-sided surg.
Verbal learning
Figural learning
Total (verbal and figural)
baselinepostop, loss/gain (%)
postop.long-term loss/gain (%)
baselinepostop, loss/gain (%)
postop.long-term loss/gain (%)
baselinepostop, loss/gain (%)
postop.long-term loss/gain (%)
baselinelong-term loss/gain (%)
18/4 37/2
20/6 16/4 8/6
12/6 21/15
22/9 8/16 5/14
25/4 48/0
24/4 10/6
37/9 33/12 44/12
Individual changes according to reliability of change indices (p = 0.1). Postoperative memory changes (baseline-postop.), changes from postoperative to long-term follow-up in surgical patients and from baseline to long-term follow-up in conservative patients (postop.-long-term),and changes from baseline to long-term (baseline-longterm). Numbers indicate the percentage of patients who, according to reliability of change indices, showed significantly deteriorated or improved performancein the respective aspects of memory. Losses due to surgery are most marked when patients are operated at an age beyond of 30 years, when fluent intelligence starts to stagnate and when capacities for behavioral compensation are beginning to deteriorate (regarding fluid/crystallized intelligence see: Cattell, 1957). Much better outcome is achieved when surgery is performed at an age before puberty, when functional plasticity can compensate surgical damage (Helmstaedter, 1999). Accepting that surgery can cause significant additional memory impairment and accepting that episodic memory functions like other functions of 'fluid intelligence' (Cattell, 1957) deteriorate with normal aging (Balota et al., 2000; Zacks et al., 2000), one may hypothesize that in operated patients, even when seizures are controlled, severe amnesic syndromes will become evident with an advanced age. Preliminary long-term follow-up data of memory performance after left temporal lobe surgery which were presented by R. Rausch at the annual AES meeting in 1994, strongly supported this assumption, in that verbal memory was found to have declined further when patients were re-evaluated 10 years after surgery. Our long-term data of 114 operated patients with TLE, however, lead to a different conclusion. The results clearly demonstrate the known initial impact of surgery on memory at the follow-up evaluation one year postoperatively. As can be seen in Fig. 1 figural learning is affected by right temporal surgery and verbal learning (the more cortical aspect) but not loss of learned words in delayed recall (the more
mesial aspect) are affected by left temporal surgery (Fig. 2). Taking together verbal and figural learning, 48% of the left temporal and 25% of the right temporal resected patients showed a significant decline in performance at the one-year postoperative followup evaluation. From this time on, however, relatively stable courses of verbal and figural memory were observed in follow up-intervals up to 10 years (Figs. 1 and 2, Table 2). Individual losses and gains over this period were largely balanced and by part even indicated long-term recovery after surgery. Aggregating verbal and figural memory 24% of the fight temporal resected patients and only 10% of the left temporal resected patients showed further losses in memory. Finally, when considering the whole time interval from baseline to the long-term follow-up evaluation, 44% of the left and 33% of the fight temporal resected patients show a significant memory loss as compared to 37% of the conservatively treated patients (Table 2). Looking at the long-term memory outcome in conservative and operated patients without consideration of the changes caused by surgery, the following variables turn out to be significant predictors of the course of memory performance: baseline performance, degree of seizure control and frequency of secondarily generalized seizures, duration of retest interval, and verbal IQ (estimated by a vocabulary test) (Table 3). Going into more detail, only 17% of the seizure-free patients showed an individually significant memory decline as compared to 21% of
445 TABLE 3 Predictors of long-term changes in memory
Greater loss in (verbal/ nonverbal) memory i
ANOVA
Predictors
t-test
F = 13.1, p < 0.001 R 2 = 0.27
better baseline performance greater number of generalized seizures longer retest interval lower IQ poorer overall seizure control
t = 5.0*** t = 3.5*** t = 2.2* t = 2.2* t = 2.1'
Stepwise regression performed for all patients with TLE (n = 151). *, p < 0.05; ***, p < 0.001. l Difference in non-operated patients: long-term follow-up minus baseline performance. Difference in operated patients: long-term follow-up minus performance 1 year after surgery.
those with 2-12 seizures per year and 38% of those with more than 12 seizures per year. Summarizing the long-term data, the results show that a considerable number of conservatively treated patients experience memory decline in the long run. Mean group data indicate that in this group major losses are observed in figural memory performance. Surgery partly anticipates the changes observed with conservative treatment by causing a marked decline in verbal learning or figural learning directly after surgery. In the following years a significantly more stable performance is indicated than with conservative treatment. However, immediate and longitudinal losses after left temporal lobe surgery exceed those observed with conservative treatment. The spontaneous course of memory in TLE is determined by seizure control, seizure severity, cognitive reserve capacities, and the time interval. In this respect it is important to note that 64% of the operated patients became seizure free as compared to 23% of the conservatively treated patients and that only 20% of those who were seizure free remained on a polytherapy as compared to more than 70% of those who still had seizures. Cross-sectional studies on m e m o r y in chronic TLE
Longitudinal studies cover relatively short time intervals as compared to an average lifespan. Hence
inferences on longer intervals must be drawn from cross-sectional evaluations. There is a large number of cross-sectional studies addressing the question of mental deterioration in chronic epilepsy. These studies mostly focus on intelligence indicating that an earlier onset of epilepsy and a longer duration of epilepsy may be associated with poor intellectual attainment. A recent study by Jokeit and Ebner (1999) demonstrated that with a duration of epilepsy exceeding 30 years, mental decline can be expected, and that this deterioration can be delayed in patients with higher levels of education. Although not explicitly discussed by the authors, their findings suggest that this relation becomes particularly evident with measures of 'fluid intelligence' since the relation between 'duration of epilepsy' and 'intellectual decline' becomes more pronounced when the WAIS short-form IQ is subtracted from 'crystallized vocabulary IQ' (Jokeit et al., 2000). From a methodological point of view the conclusion of a superiority of the factor 'duration of epilepsy' over the factor 'age' is questionable because regression analyses were calculated using IQ data, which are already corrected for age (see also Hermann et al., 2002, this volume, and Jokeit and Ebner, 2002, this volume). In 1995, the Bozeman Epilepsy Consortium, which represents eight major epilepsy centers in the USA, examined the contribution of age, age at seizure onset, duration of epilepsy, focus laterality and other variables not only to IQ but also to memory performance in 1141 patients with pharmacoresistant epilepsy. In contrast to Joker and Ebner (1999) and Jokeit et al. (2000), this study revealed earlier onset of epilepsy as the only factor of poor performance in both domains (Strauss et al., 1995). One must be cautious when trying to predict longitudinal courses of performance on the basis of cross-sectional data because one needs to control possible cohort effects. With respect to epilepsy, improvement of diagnosis and treatment regimens, as well as the introduction of the 'new' AEDs must be taken into account as potential causes of cohort effects. In any case, with temporal lobe epilepsies and mesial temporal lobe epilepsy in particular we face the additional problem that most of these epilepsies start early in life and that the duration of epilepsy is therefore strongly correlated with chronological age. In contrast, when patient samples with a wider range
446 of epilepsy onsets are evaluated, a different etiology of epilepsies must be considered and controlled for. In order to solve this methodological problem we conducted a study on aging and episodic/semantic memory in a homogeneous group of patients with left mesial temporal lobe epilepsy (with hippocampal sclerosis/atrophy) and compared age regression of memory in these patients with that obtained in patients with non-mesial temporal lobe epilepsy (i.e. no hippocampal sclerosis/atrophy). Furthermore, in contrast to other cross-sectional studies, age regressions in the patient groups were compared with those in an age-matched group of healthy subjects (see also Helmstaedter and Elger, 1999a,b; Helmstaedter, 2000). We hypothesized, that effects of chronic epilepsy on memory, i.e. accelerated memory decline, may be evidenced by different age regressions in patients and healthy control subjects. The study comprised 63 patients with mesial (mTLE) and 87 patients with non-mesial left temporal lobe epilepsies (nmTLE) who were evaluated with respect to word list learning (episodic memory), passive vocabulary (semantic knowledge), and semantic decision making. Memory and vocabulary were also evaluated in 125 age-matched healthy volunteers (see Table 4). Verbal episodic memory was assessed by the VLMT (Verbaler Lern- und Merkf~ihigkeits test) a German test which in analogy to the AVLT requires serial list learning and recall over five trials, recall after distraction, 30 min delayed recall and recognition (Helmstaedter et al., 2001a). Vocabulary was assessed by the Mehrfachwahl-WortschatzIntelligenztest (MWT-B) which requires selection of words with increasing difficulty and decreasing frequency of occurrence out of alternative non-words (Lehrl, 1978). Verbal reasoning was assessed by a sub-test of a German intelligence test (IST = Intelligenz-Struktur-Test), which requires selection of a word out of five alternatives which have another connotation or do not belong to the same semantic field as the target word (e.g. sitting, lying, going, kneeling, standing) (Amthauer, 1973). For a better comparability, all scores were transformed into standard values (mean 100, SD 10). Group differences between patients with mTLE and nmTLE were calculated by multivariate analysis of variance. Data analysis (MANOVA) indicated that, as a trend, mTLE patients performed more poorly on
TABLE 4 Subject characteristics
n
Sex (m/f) Age (years) Handedness right - left - ambidextrous Age at onset of epilepsy (years) Duration of epilepsy (years) Pathology: no finding HS tumor - DNT - cort. dyspl. - other -
Patients mTLE
Patients Healthy F/X 2 n m T L E controls significance
63 34/29 32/9.2
87 125 37/50 80/45 27.8/8.4 27.2/8.7
84% 9% 7% 9.8/7.6
64% 10% 6% 12.6/7.2
-
5.3**
22.6/11.6 15.2/9.3-
18.5"*
23%
-
-
-
1.9 n.s. 9.8** 0.01 n.s.
1 0 0 %
-
-
5% 10% 19%
m
m
4 3 %
m
-
m
n.s., not significant; **, p < 0.01.
the tests than nmTLE patients (F = 2.24, p = 0.054). Univarate analysis showed highly significant group differences in measures of episodic verbal learning and memory ( F between 5.6 and 8.2 with pvalues between <0.05 and 0.01) but not for vocabulary (F = 1.1, p = 0.31) or reasoning ( F = 0.001, p = 0.95). Mean standard values ranging between 90 and 100 indicate that semantic knowledge is relatively preserved in left TLE (Table 5). Poor intercorrelations between performance on episodic and semantic memory indicated that these measures were independent rather than redundant. Age regressions show that episodic memory performance (learning and recognition) deteriorates equally with aging in healthy persons and patients (Table 5 and Fig. 3). In contrast, semantic functions are positively correlated to age indicating gains over time. Only in nmTLE patients delayed recall was negatively related to age. Since learning is more closely associated with cortical structures and delayed recall is more closely associated with mesial structures, the latter appear at particular risk of becoming increasingly affected in chronic nmTLE. In nmTLE but not in mTLE, semantic memory is related positively to the age at onset of epilepsy in-
447
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chronological age [yrs.] Fig. 3. Age regressions of verbal memory (learning over 5 trials) and vocabulary in (a) 63 patients with left mesial (from Helmstaedter and Elger, 1999a) and (b) 87 patients with left non-mesial (cortical) temporal lobe epilepsy as compared to age regressions obtained in 125 healthy subjects. Results show comparable regressions despite principal differences in performance levels.
448 TABLE 5 Group performance and correlations to chronological age and age at the onset of epilepsy Performance
Group
n
Mean/SD
Standardvalue (m = 100; SD = 10)
Correlationto age
98.2/11 98.7/12 (104/14)
98.9 99.2 100 93.6 92.4 100
0.45** 0.09 n.s. (0.22*) 0.34** 0.18 n.s. (-)
0.01 n.s. 0.38** (-) 0.26* 0.22* (-)
84.6 90.6 100 82.2 87.6 100 90.0 99.5 100
0.37** 0.29** (0.34**) 0.01 n.s. 0.28** (0.00 n.s.) 0.23* 0.33** (0.23*)
0. l 1 0.16 (-) 0.00 0.12 (-) 0.03 0,12 (-)
Correlation to onset of epilepsy J
Measures of semantic knowledge
Vocabulary (IQ) Reasoning
mTLE 61 nmTLE 87 (controls) (125) mTLE 61 nmTLE 87 (-) (-)
(-)
Measures of episodic verbal memory
Learning Delayed recall (loss) Recognition memory
mTLE 61 42.5/8.1 nmTLE 87 47.3/8.3 (controls) (125) (53.6/8.4) mTLE 61 4.2/2.1 nmTLE 87 3.2/2.2 (controls) (125) (1.6/1.8) mTLE 61 12.5/4.0 nmTLE 87 12.9/2.3 (controls) (125) (12.6/2.6)
l Pearson correlation coefficient (r) with levels of (two-tailed) significance: n,s., not significant; *, p < 0.05; **, p < 0.01. dicating that less semantic knowledge has been acquired by patients with earlier onset cortical lesions (Table 5 and Fig. 4). These results are of importance in four respects. The data firstly emphasize the decisive contribution of the mesial structures and hippocampal damage to the impairment of episodic memory in TLE (Hermann et al., 1997). Semantic memory, in contrast, appears rather unaffected by TLE. Secondly, there is evidence that episodic memory declines over time in patients and healthy subjects as well and that age regressions are not different. That is to say that patients perform more poorly than controls at any age and that it is the interaction of cerebral damage with normal aging rather than progressive epilepsy which brings patients closer to disabling memory impairment at older age. However, this concerns the more cortical aspects of verbal memory so far. An exception must probably be made for patients with nonmesial temporal lobe epilepsies, in whom chronic epilepsy may lead to progressive affection of mesial functions. Thirdly, there is no evidence from our data that episodic memory impairment affects the acquisition of semantic knowledge. This finding is in line
with Varhga-Khadem et al. (1997) who suggest that episodic and semantic memory differentially depend on mesial structures. Finally, there is evidence that early onset of cortical lesions but not of mesial lesions hinders knowledge acquisition. This finding provides further evidence for the aforementioned suggestion that episodic and semantic memory are driven by different brain structures or systems.
Cross-sectional results on age regression of m e m o r y before and after surgery The results of our cross-sectional study suggest that memory impairment in TLE and in mesial TLE in particular becomes evident early in the course of the disease and that further memory decline can be expected to continue at the same rate as in healthy individuals. Studies in newly diagnosed patients with focal epilepsy support the suggestion of an initial lesion (Pulliainen et al., 2000; Aiki~i et al., 2001). Thus the cross-sectional data demand prevention of any further cerebral damage which might accelerate progressive mental aging from the beginning of epilepsy.
449
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chronological a g e [yrs.] Fig. 5. Age regressionof verbal memory(learningover 5 trials) in 245 patients with left temporal lobe epilepsybeforeand one year after epilepsy surgeryas comparedto age regression of verbal memoryin 125 healthy controlpersons. While the preoperativeage regression parallels that in controls, the significantlysteeperpostoperativeregressionindicatesacceleratedmemorydecline. Since temporal lobe epilepsy surgery often achieves seizure control at the risk of additional memory impairment, the obvious question is of whether additional brain damage due to surgery may change the long-term prognosis of memory at an older age (Helmstaedter et al., 2001b). Fig. 5 demonstrates data from a large sample of 245 patients with left temporal resections. 62% of these patients were completely seizure free (Engel category: Ia) and losses in verbal memory were highly significant (learning over 5 trials: t = 6.9, p < 0.0001). Age regression of verbal memory performance changes significantly from before surgery (r = -0.287, p < 0.001) to one year after surgery (r--0.387, p < 0.001), i.e. postoperatively, age regression is significantly steeper than the preoperative one (p < 0.01). Age regressions in the healthy group and preoper-
ative patients run largely in parallel, confirming the findings which have above been reported for smaller groups of patients with mesial and nonmesial TLE (Helmstaedter and Elger, 1999a). The difference between the pre- and postoperative age-related memory decline shows that memory performance of a 33year-old non-operated patient with left temporal lobe epilepsy is equivalent to that of a 60-year-old healthy subject. After surgery, performance of a 21-year-old patient corresponds to that of a 60-year-old control person! Thus, when bringing the fact that losses after surgery are greater in older patients together with the fact that memory declines with aging, it seems that surgery not only changes the performance level but also accelerates cognitive aging. This example impressively demonstrates how additional lesions in the course of chronic epilepsy can change the longterm prognosis of memory.
451
Summary TLE typically affects declarative memory. Following Tulving's differentiation of episodic and semantic memory, it is the time- and context-dependent episodic memory, which is particularly found to be impaired. Episodic memory appears strongly linked to the functional integrity of the temporo-mesial structures. There is evidence that in TLE patients also impairment of semantic memory processing can be observed, but different from episodic memory impairment it seems to be more related to cortical temporal lesions and less if any to mesial hippocampal damage. Conclusive with these suggestions, the presented data show that functions indicative for semantic memory are less affected in TLE than episodic memory. Chronological age, age at epilepsy onset, and duration of epilepsy have obviously a different impact on episodic and semantic memory as dependent on whether epilepsy originates in cortical or mesial structures. As regards the long-term prognosis of semantic memory in TLE, cross-sectional data show that gains in semantic knowledge can be achieved over time despite of episodic memory impairment. Early acquisition of cortical lesions or early onset of non-mesial epilepsy, however, seem to interfere with the acquisition of semantic knowledge. This finding is consistent with those demonstrating poorer intelligence with earlier onset epilepsy. Cross-sectional data provide striking evidence that there is a progressive decline of episodic verbal memory which preferentially affects the more cortical aspects of verbal learning and memory. However, contrary to findings on intelligence, this decline appears to result from an interaction of early cerebral damage with normal aging rather than from progressive epilepsy. Thus, the more severe the initial damage the earlier disabling memory problems can be expected. An exception must probably be made for non-mesial TLE in which increasing affection of the mesial aspects of memory with longer duration is indicated. Different from the cross-sectional data the longitudinal data suggest deterioration of memory in the course of chronic TLE due to uncontrolled and more severe seizures. Dependent on seizure frequency 17% to 38% the patients experience significant memory decline in a time interval ranging from 2 to 10 years. Complete and per-
manent seizure control can be achieved in more than 60% of the operated patients but additional memory impairment due to surgery and associated changes of the long-term prognosis of memory with aging necessitate a careful and individual counseling of the patient. With conservative treatment 37% of the patients experience a significant decline in memory. Surgery anticipates the memory decline observed with conservative treatment, but left temporal surgery specifically and permanently impairs verbal memory. Deterioration of verbal memory after left temporal resection significantly exceeds that in conservative treatment. Regarding the relevance of this finding one may well discuss that verbal memory impairment is of greater importance for every day life than figural memory. The brain has limited capacities to restitute and compensate damage and the final conclusion from the presented findings is as simple as it could be: memory can be protected with achievement of early and efficient seizure control and with the prevention of any kind of cerebral damage from the beginning of epilepsy. Thus early neuroprotection and more safe and memory sparing treatment will be important future issues in the treatment of chronic TLE.
Acknowledgements This work was supported by the Deutsche Forschungsgemeinschaft DFG: EL 122-6.
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452 Cattell, R.B. (1957) Personality and Motivation; Structure and Measurement. World Book, Yonkers-on-Hudson, NY. Davies, K.G., Bell, B.D., Bush, A.J. and Wyler, A.R. (1998) Prediction of verbal memory loss in individuals after anterior temporal lobectomy. Epilepsia, 39(8): 820-828. Dodrill, C.B. (2002) Progressive cognitive decline in adolescents and adults with epilepsy. In: T. Sutula and A. Pitk~inen (Eds.), Do Seizures Damage the Brain. Progress in Brain Research, Vol. 135. Elsevier, Amsterdam, pp. 399-407. Eichenbaum, H. (1997) How does the brain organize memories?. Science, 277: 330-332. Eichenbaum, H., Cohen, N.J., Otto, T. and Wible, C. (1992) Memory representation in the hippocampus: functional domain and functional organization. In: L.R. Squire, G. Lynch, N.M. Weinberger and J.L. McGaugh (Eds.), Memory: Organization and Locus of Change. Oxford University Press, New York, pp. 163-204. Elger, C.E., Grunwald, Th., Lehnertz, K., Kutas, M., Helmstaedter, C., Van Roost, D., Mangun, G.R. and Heinze, H.J. (1997) Human temporal lobe potentials in verbal learning and memory. Neuropsychologia, 35: 657-668. Garrard, P. and Hodges, J.R. (2000) Semantic dementia: clinical, radiological and pathological perspectives. J. Neurol., 247: 409-422. GleiBner, U. and Elger, C.E. (2001) The hippocampal contribution to verbal fluency in patients with temporal lobe epilepsy. Cortex, 37(1): 55-63. Grunwald, T., Lehnertz, K., Helmstaedter, C., Kutas, M., Pezer, N., Kurthen, M., Van Roost, D. and Elger, C.E. (1998) Limbic ERPs predict verbal memory after left-sided hippocampectomy. Neuroreport, 9(15): 3375-3378. Helmstaedter, C. (1999) Prediction of memory reserve capacity. Adv. Neurol., 81: 271-279. Helmstaedter, C. (2000) Cognitive impairment in temporal-lobe epilepsy - - reply. Lancet, 355(9208): 1019. Helmstaedter, C. and Elger, C.E. (1996) Cognitive consequences of two-thirds anterior temporal lobectomy on verbal memory in 144 patients: a three-month follow-up study. Epilepsia, 37(2): 171-180. Helmstaedter, C. and Elger, C.E. (1999a) The phantom of progressive dementia in epilepsy. Lancet, 354(9196): 2133-2134. Helmstaedter, C. and Elger, C.E. (1999b) Episodic memory and semantic knowledge in left temporal lobe epilepsy with and without mesial hippocampal sclerosis. Epilepsia, 40(Suppl. 7): 48. Helmstaedter, C. and Kurthen, M. (2001) Memory and epilepsy: characteristics, course, and influence of drugs and surgery. Curr. Opin. Neurol., 14(2): 211-216. Helmstaedter, C., Kurthen, M., Linke, D.B. and Elger, C.E. (1994) Right hemisphere restitution of language and memory functions in right hemisphere language-dominant patients with left temporal lobe epilepsy. Brain, 117(4): 729-737. Helmstaedter, C., Gleissner, U., Di Perua, M. and Elger, C.E. (1997a) Relational verbal memory processing in patients with temporal lobe epilepsy. Cortex, 33(4): 667-678. Helmstaedter, C., Lehnertz, K., Grunwald, Th., Gleigner, U., Schramm, J. and Elger, C.E. (1997b) Differential involvement
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453 lowing left temporal lobe surgery. Epilepsia, 35(Suppl. 8): 81. Selwa, L.M., Berent, S., Giordani, B., Henry, T.R., Buchtel, H.A. and Ross, D.A. (1994) Serial cognitive testing in temporal lobe epilepsy: longitudinal changes with medical and surgical therapies. Epilepsia, 35(4): 743-749. Squire, L.R. (1992) Memory and the hippocampus: a synthesis from findings with rats, monkeys and humans. Psychol. Rev., 99(2): 195-231. Squire, L.R. and Zola-Morgan, S. (1996) Structure and function of declarative and nondeclarative memory systems. Proc. Natl. Acad. Sci. USA, 93: 13515-13522. Strauss, E., Loring, D., Chelune, G., Hunter, M., Hermann, B.P., Perrine, K., Westerveld, M., Trenerry, M. and Barr, W. (1995) Predicting cognitive impairment in epilepsy: findings from the Bozeman Epilepsy Consortium. J. Clin. Exp. Neuropsychol., 17(6): 909-917.
Tulving, E. (1984) Precis of elements of episodic memory. Behav. Brain Sci., 7: 223-268. Tulving, E. and Markowitsch, H.J. (1998) Episodic and declarative memory: role of the hippocampus. Hippocampus, 8: 198204. Varhga-Khadem, F., Gadian, D.G., Watkins, K.E., Conelly, A., Van Paesschen, W. and Mishkin, M. (1997) Differential effects of early hippocampal pathology on episodic and semantic memory. Science, 277: 376-380. Viskontas, I.V., McAndrews, M.P. and Moscovitch, M. (2000) Remote episodic memory deficits in patients with unilateral temporal lobe epilepsy and excisions. J. Neurosci., 20(15): 5853-5857. Zacks, R.T., Hasher, L. and Li, K.Z.H. (2000) Human memory. In: F.I.M. Craik and T.A. Salthouse (Eds.), The Handbook of Aging and Cognition. Lawrence Erlbaum Associates Publishers, Mahwah, NJ, pp. 293-357.
CHAFFER 39
Effects of chronic epilepsy on declarative memory systems C. Helmstaedter* Department of Epileptology, University of Bonn, 53105 Bonn, Germany
Abstract: Memory is systematically affected by temporal lobe epilepsy. Since surgery is a promising alternative to pharmacological treatment the questions which memory system is affected and what the long-term prognosis of memory is are more relevant than ever. We address these issues by cross-sectional and longitudinal analysis of memory performance in large series of patients with temporal lobe epilepsy (TLE). The findings indicate that episodic memory rather than semantic memory is impaired in TLE, in particular in TLE with mesial temporal pathology. With the exception that mesial functions appear increasingly affected by chronic non-mesial TLE, memory decline in TLE is not different from that observed in healthy control subjects. However, since patients perform poorer than controls at any age, normal senescence brings patients to nmesic disability at a younger age. Semantic memory seems unaffected by this process but early cortical lesions appear to interfere with knowledge acquisition. Longitudinal data come to a different conclusion regarding the contribution of epilepsy/seizures to memory decline. Conservative treatment is associated with significant decline in figural memory and 37% of the patients experience some memory decline in the long run. Surgery partly anticipates the decline observed with conservative treatment, but losses are most marked after left temporal lobe surgery. After surgery, quite stable memory or even late recovery from surgery is indicated. Leaving aside the surgical intervention, the data provide evidence that the longitudinal memory outcome in TLE is determined by seizure control, seizure severity, mental reserve capacities, and the retest interval. Thus early and efficient seizure control and the prevention of any cerebral damage from the beginning of epilepsy are demanded.
Introduction Memory is one of the most essential higher brain functions since it provides continuity in time, personal history, and awareness. Theoretically declarative memory, that is the encoding and explicit retrieval of new information, is separated from nondeclarative memory which comprises skill-oriented learning, conditioning and priming processes and which can be driven automatically and implicitly. Neuroanatomically, declarative memory is strongly associated with temporo-mesial structures. It is
* Correspondence to: C. Helmstaedter, University Clinic of Epileptology, Sigmund Freud Strasse 25, 53105 Bonn, Germany. Tel.: -t-49-228-287-6108; Fax: +49228-287-6294; E-mail: [email protected] or C.Helmstaedter @web.de
therefore self-evident that memory deficits represent the major cognitive impairment in focal epilepsies which directly affect these structures, i.e. the temporal lobe epilepsies (TLE) (Hermann et al., 1997). Since TLE represents the majority of chronic focal epilepsies - - about 80% in the Bonn series - and since memory is the function which is directly affected by temporal lobe lesions and functional disturbances, the question of how chronic epilepsy affects declarative memory systems will be discussed in relation to this particular type of epilepsy. Other focal epilepsies (frontal, parietal, occipital, etc.) will not be explicitly addressed but a distinction between mesial and non-mesial, cortical temporal lobe epilepsies will be made. In terms of disease progression and functional reserve capacities the non-mesial temporal lobe epilepsies can be assumed to share many features with other cortically located epilepsies.
440
Declarative memory in temporal lobe epilepsy In recent years great efforts have been made to specify memory problems in TLE and to establish the neuroanatomical and functional basis of these problems (Helmstaedter and Kurthen, 2001). Within the declarative memory system, a basic distinction is made between 'episodic memory' and 'semantic memory' (Tulving, 1984). 'Episodic memory' means the memory for time- and context-dependent information (the car you own) and semantic memory refers to memory for context- and time-independent (world-) knowledge (what a car is in general). As for TLE and 'episodic memory', materialspecific verbal or nonverbal memory impairment can be diagnosed dependent on whether the language dominant or nondominant hemisphere is affected, (Jones-Gotman et al., 1993). In accordance with neurobiological suggestions (Eichenbaum et al., 1992; Squire, 1992), we and other groups have shown that left-sided mesial pathology in TLE correlates well with impairment of verbal long-term consolidation and retrieval. In contrast, cortical temporo-lateral pathology is associated rather with impaired verbal learning, short-term or working memory. This pattern has been demonstrated in detail also by correlation of intracranial, subdurally and intra-hippocampally recorded event-related potentials to measures of memory, by different effects of mesial and cortical pathology on memory, and by different memory outcome after various types of temporal lobe surgery (Elger et al., 1997; Helmstaedter et al., 1997b). For semantic memory in TLE patients, the findings are less consistent. In a study of confrontative naming after temporal lobectomy, Bell et al. (2000) found naming performance deficits dependent on age at acquisition (greater loss of names acquired later) but not on semantic attributes (living/nonliving) of the object names. Studies on semantic word fluency come to inconsistent conclusions as to whether category-specific impairment can be discerned in TLE or not. Jokeit et al. (1998) report categoryspecific impairment in naming as dependent on the lateralization of seizure focus. In contrast, Gleil3ner and Elger (2001) report general but no categoryspecific deficits in semantic fluency in TLE which appeared related to mesial pathology. One of our own studies on relational memory processing demon-
strated that patients with left TLE show increasing memory problems with greater relational (semantic) distances between memory contents (Helmstaedter et al., 1997a). We interpreted this finding as indicative of deficits in semantic relational memory processing. Recently, impairment of remote autobiographical episodic memory has also been reported in TLE (Viskontas et al., 2000). In contrast, personal semantic memory appears unaffected (Bergin et al., 2000). In summary, there is some evidence that patients with TLE indeed have problems with semantic memory processing but it needs to be examined in more detail to which degree deficits in the acquired semantic network and knowledge system architecture or impaired retrieval processes are responsible for these problems. Originally, episodic and semantic memory were thought to represent only two aspects of a unitary declarative memory system which become equally impaired with temporo-mesial lesions. This must be doubted since there is evidence from semantic dementia that semantic memory is more closely related to cortical structures and the permanent repository of knowledge (Garrard and Hodges, 2000). While encoding and retrieval of episodic information strongly depend on mesial functions, semantic knowledge can become independent from hippocampal functional integrity (Nadel et al., 2000). Independence of semantic memory acquisition from hippocampal functioning is suggested by Varhga-Khadem et al. (1997) who found that semantic knowledge had been acquired in spite of the presence of severe episodic memory impairment in single patients with very early damage of mesial structures. From a theoretical point, the dissociation of semantic and episodic memory may be an answer to the ongoing 'chickenegg discussion' of whether impaired episodic memory hinders acquisition of semantic knowledge or vice versa (Squire and Zola-Morgan, 1996; Eichenbaum, 1997; Tulving and Markowitsch, 1998).
Longitudinal studies of memory in chronic TLE Now that epilepsy surgery has become a serious and very successful alternative to medical treatment, patients with chronic epilepsy have a legitimate interest in knowing their cognitive prognosis with the respective treatment.
441
TABLE 1 Longitudinal studies on cognition in focal epilepsies Study
Nr. of groups
Interval
Seizure outcome (seizure free)
JQ
Memory
Selwa et al., 1994
28 conserv. (TLE) 31 surgery (TLE)
1-8 years 2-17 months
conserv, no change surgery 64%
no change in conserv. better after right-sided surgery
no change in conserv. patients improvement after right-sided surgery
Rausch et al., 1994
20 surgery (TLE)
>9 years
Holmes et al., 1998
25 conserv. (partial epilepsies) 47 conserv. (TLE) 114 surgery (TEE)
10 years
improvement 33%
2-10 years
surgery 64%
Helmstaedter et al., 2000
Aikia et al., 2001
20 conserv. (TLE)
conserv. 24%
5 years
100%
In general, the following factors can be suggested to cause mental decline in chronic epilepsy: (1) preexisting structural lesions including surgical defects; (2) progression of the disease underpinning epilepsy; (3) progression of epilepsy (secondary epileptogenesis, kindling, etc.); (4) accumulation of lesions secondary to epilepsy (trauma, intoxication, status epilepticus, etc.); (5) physiological or pathological aging. There are two essential questions regarding the prognosis of memory in TLE. Firstly, what is the risk of memory decline in chronic medically treated epilepsy as compared to the risk of memory decline after successful surgery (to say nothing of those patients who do not become seizure free after surgery), and secondly, what are the additional effects of aging on cognitive function in both groups. We evaluated these questions with a cross-sectional and longitudinal study approach, the latter findings being reported first. (An overview over cross-sectional and longitudinal studies and a discussion of the differences between these approaches are provided by Dodrill, 2002, this volume.) Longitudinal studies, which address the issue of long-term changes of episodic memory performance
improved performance
short- and long-term losses in verbal memory after left-sided surgery logical memory unchanged
worse verbal memory after left- than right-sided surgery stable course after surgery worsened figural memory with conservative treatment stable verbal learning and even improved delayed recall
Non-memory
worsened speed and visual spatial functions improved attention after surgery
in chronic epilepsy span intervals ranging from 2 to 10 years (see Table 1). These studies have indicated quite stable memory performance when patients are treated conservatively with antiepileptic drugs (Selwa et al., 1994; Holmes et al., 1998; ,~iki~i et al., 2001). Our own evaluation (Helmstaedter et al., 2000) of 47 patients with TLE (mean retest interval 56 4- 26 months), indicates significant deterioration of figural memory performance (see Figs. 1 and 2). The study of Holmes et al. (1998) revealed mild deterioration in speed and, interestingly, also in visuo-spatial functions. When classified according to reliability of change indices, our data show that about 20% of the conservatively treated patients significantly decline in verbal or figural memory, only 5 to 10% of the patients had improved memory functions (see Table 2). Taking together both verbal and figural learning, 37% of the conservatively treated patients showed a significant deterioration in memory in the long run. So far the high number of patients who show individual decline in either verbal or figural memory supports the assumption of an accumulation of lesions over time. The finding of a significant deterioration particularly of figural memory is of interest since it directs attention to the widely
442
120
figural memory [standard values]
i-p
Fp
110 -
100 -
80
70
II
test times iT1
60
50
~
[ ~ T2 i
conservative
i
right surgery
i
iT3
left surgery
47 51 63 Fig. l. Box plot of figural memory performance (standard value with mean = 100, SD = 10) in design learning in conservatively and operatively treated patients with temporal lobe epilepsy. For conservative patients results at two (initial and long-term follow-up evaluation [2-10 yrs, 56-4-26 months]) and for operated patients results at three test times (preoperative, one year postoperative and long-term follow-up evaluation [2-10 yrs, 58-4-28 months) are displayed. Significance levels result from t-tests for dependent measures. The data indicate significant losses in conservative patients and after right temporal surgery.
neglected right hemisphere. Our current working hypothesis is that this finding may reflect compensatory sacrifice of right hemisphere functions for preservation of verbal functions as observed in patients with right hemisphere language representation and early acquisition of left hemisphere lesions (Helmstaedter et al., 1994). From surgical patients who underwent left amygdalo-hippocampectomy at least we have evidence that, after surgery, right mesial structures compensate verbal memory functions which were associated to the left mesial lobe before surgery (Grunwald et al., 1998).
In contrast to the course of memory function in conservatively treated patients, epilepsy surgery often marks a significant step in regard to cognitive performance. While temporal lobe epilepsy surgery is very successful in permanently controlling seizures, deterioration of memory is very likely when brain tissues are removed which are still involved in memory function (Helmstaedter and Kurthen, 2001). As regards verbal memory, baseline performance together with age at surgery are powerful predictors of the postoperative outcome (Helmstaedter and E1ger, 1996; Davies et al., 1998; Helmstaedter, 1999).
Fig. 2. Box plot of verbal memory performance (standard value with mean = 100, SD = 10) in list learning in conservatively and operatively treated patients with temporal lobe epilepsy: (a) learning over 5 trials; (b) loss of learned items after 1/2 h delay). For conservative patients results at two (initial T1 and long-term follow-up evaluation T3) and for operated patients results at three test times (preoperative T1, one year postoperative T2 and long-term follow-up evaluation T3) are displayed. Significance levels result from t-tests for dependent measures. The data indicate significant losses in verbal learning after left surgery and stable performance at the long-term follow-up. After right-sided surgery reversible loss in verbal delayed recall is indicated.
443
120-
verbal learning trials 1 to 5 [standard value]
i
l
100-
I
II
i
test times
60~T1
Lp
120
100
(a)
~T2
L p
i
T3
i
conservative
right surgery
left surgery
47
51
63
verbal memory loss in free recall [standard value]
||
80
Lp
test times
60. BT1 ~T2 40
(b) i
i
i
conservative
right surgery
left surgery
47
51
63
BT3
444 TABLE 2 Long-term memorychange in conservativelyand surgicallytreated patients with TLE Group
Conservative Right-sided surg. LeR-sided surg.
Verbal learning
Figural learning
Total (verbal and figural)
baselinepostop, loss/gain (%)
postop.long-term loss/gain (%)
baselinepostop, loss/gain (%)
postop.long-term loss/gain (%)
baselinepostop, loss/gain (%)
postop.long-term loss/gain (%)
baselinelong-term loss/gain (%)
18/4 37/2
20/6 16/4 8/6
12/6 21/15
22/9 8/16 5/14
25/4 48/0
24/4 10/6
37/9 33/12 44/12
Individual changes according to reliability of change indices (p = 0.1). Postoperative memory changes (baseline-postop.), changes from postoperative to long-term follow-up in surgical patients and from baseline to long-term follow-up in conservative patients (postop.-long-term),and changes from baseline to long-term (baseline-longterm). Numbers indicate the percentage of patients who, according to reliability of change indices, showed significantly deteriorated or improved performancein the respective aspects of memory. Losses due to surgery are most marked when patients are operated at an age beyond of 30 years, when fluent intelligence starts to stagnate and when capacities for behavioral compensation are beginning to deteriorate (regarding fluid/crystallized intelligence see: Cattell, 1957). Much better outcome is achieved when surgery is performed at an age before puberty, when functional plasticity can compensate surgical damage (Helmstaedter, 1999). Accepting that surgery can cause significant additional memory impairment and accepting that episodic memory functions like other functions of 'fluid intelligence' (Cattell, 1957) deteriorate with normal aging (Balota et al., 2000; Zacks et al., 2000), one may hypothesize that in operated patients, even when seizures are controlled, severe amnesic syndromes will become evident with an advanced age. Preliminary long-term follow-up data of memory performance after left temporal lobe surgery which were presented by R. Rausch at the annual AES meeting in 1994, strongly supported this assumption, in that verbal memory was found to have declined further when patients were re-evaluated 10 years after surgery. Our long-term data of 114 operated patients with TLE, however, lead to a different conclusion. The results clearly demonstrate the known initial impact of surgery on memory at the follow-up evaluation one year postoperatively. As can be seen in Fig. 1 figural learning is affected by right temporal surgery and verbal learning (the more cortical aspect) but not loss of learned words in delayed recall (the more
mesial aspect) are affected by left temporal surgery (Fig. 2). Taking together verbal and figural learning, 48% of the left temporal and 25% of the right temporal resected patients showed a significant decline in performance at the one-year postoperative followup evaluation. From this time on, however, relatively stable courses of verbal and figural memory were observed in follow up-intervals up to 10 years (Figs. 1 and 2, Table 2). Individual losses and gains over this period were largely balanced and by part even indicated long-term recovery after surgery. Aggregating verbal and figural memory 24% of the fight temporal resected patients and only 10% of the left temporal resected patients showed further losses in memory. Finally, when considering the whole time interval from baseline to the long-term follow-up evaluation, 44% of the left and 33% of the fight temporal resected patients show a significant memory loss as compared to 37% of the conservatively treated patients (Table 2). Looking at the long-term memory outcome in conservative and operated patients without consideration of the changes caused by surgery, the following variables turn out to be significant predictors of the course of memory performance: baseline performance, degree of seizure control and frequency of secondarily generalized seizures, duration of retest interval, and verbal IQ (estimated by a vocabulary test) (Table 3). Going into more detail, only 17% of the seizure-free patients showed an individually significant memory decline as compared to 21% of
445 TABLE 3 Predictors of long-term changes in memory
Greater loss in (verbal/ nonverbal) memory i
ANOVA
Predictors
t-test
F = 13.1, p < 0.001 R 2 = 0.27
better baseline performance greater number of generalized seizures longer retest interval lower IQ poorer overall seizure control
t = 5.0*** t = 3.5*** t = 2.2* t = 2.2* t = 2.1'
Stepwise regression performed for all patients with TLE (n = 151). *, p < 0.05; ***, p < 0.001. l Difference in non-operated patients: long-term follow-up minus baseline performance. Difference in operated patients: long-term follow-up minus performance 1 year after surgery.
those with 2-12 seizures per year and 38% of those with more than 12 seizures per year. Summarizing the long-term data, the results show that a considerable number of conservatively treated patients experience memory decline in the long run. Mean group data indicate that in this group major losses are observed in figural memory performance. Surgery partly anticipates the changes observed with conservative treatment by causing a marked decline in verbal learning or figural learning directly after surgery. In the following years a significantly more stable performance is indicated than with conservative treatment. However, immediate and longitudinal losses after left temporal lobe surgery exceed those observed with conservative treatment. The spontaneous course of memory in TLE is determined by seizure control, seizure severity, cognitive reserve capacities, and the time interval. In this respect it is important to note that 64% of the operated patients became seizure free as compared to 23% of the conservatively treated patients and that only 20% of those who were seizure free remained on a polytherapy as compared to more than 70% of those who still had seizures. Cross-sectional studies on m e m o r y in chronic TLE
Longitudinal studies cover relatively short time intervals as compared to an average lifespan. Hence
inferences on longer intervals must be drawn from cross-sectional evaluations. There is a large number of cross-sectional studies addressing the question of mental deterioration in chronic epilepsy. These studies mostly focus on intelligence indicating that an earlier onset of epilepsy and a longer duration of epilepsy may be associated with poor intellectual attainment. A recent study by Jokeit and Ebner (1999) demonstrated that with a duration of epilepsy exceeding 30 years, mental decline can be expected, and that this deterioration can be delayed in patients with higher levels of education. Although not explicitly discussed by the authors, their findings suggest that this relation becomes particularly evident with measures of 'fluid intelligence' since the relation between 'duration of epilepsy' and 'intellectual decline' becomes more pronounced when the WAIS short-form IQ is subtracted from 'crystallized vocabulary IQ' (Jokeit et al., 2000). From a methodological point of view the conclusion of a superiority of the factor 'duration of epilepsy' over the factor 'age' is questionable because regression analyses were calculated using IQ data, which are already corrected for age (see also Hermann et al., 2002, this volume, and Jokeit and Ebner, 2002, this volume). In 1995, the Bozeman Epilepsy Consortium, which represents eight major epilepsy centers in the USA, examined the contribution of age, age at seizure onset, duration of epilepsy, focus laterality and other variables not only to IQ but also to memory performance in 1141 patients with pharmacoresistant epilepsy. In contrast to Joker and Ebner (1999) and Jokeit et al. (2000), this study revealed earlier onset of epilepsy as the only factor of poor performance in both domains (Strauss et al., 1995). One must be cautious when trying to predict longitudinal courses of performance on the basis of cross-sectional data because one needs to control possible cohort effects. With respect to epilepsy, improvement of diagnosis and treatment regimens, as well as the introduction of the 'new' AEDs must be taken into account as potential causes of cohort effects. In any case, with temporal lobe epilepsies and mesial temporal lobe epilepsy in particular we face the additional problem that most of these epilepsies start early in life and that the duration of epilepsy is therefore strongly correlated with chronological age. In contrast, when patient samples with a wider range
446 of epilepsy onsets are evaluated, a different etiology of epilepsies must be considered and controlled for. In order to solve this methodological problem we conducted a study on aging and episodic/semantic memory in a homogeneous group of patients with left mesial temporal lobe epilepsy (with hippocampal sclerosis/atrophy) and compared age regression of memory in these patients with that obtained in patients with non-mesial temporal lobe epilepsy (i.e. no hippocampal sclerosis/atrophy). Furthermore, in contrast to other cross-sectional studies, age regressions in the patient groups were compared with those in an age-matched group of healthy subjects (see also Helmstaedter and Elger, 1999a,b; Helmstaedter, 2000). We hypothesized, that effects of chronic epilepsy on memory, i.e. accelerated memory decline, may be evidenced by different age regressions in patients and healthy control subjects. The study comprised 63 patients with mesial (mTLE) and 87 patients with non-mesial left temporal lobe epilepsies (nmTLE) who were evaluated with respect to word list learning (episodic memory), passive vocabulary (semantic knowledge), and semantic decision making. Memory and vocabulary were also evaluated in 125 age-matched healthy volunteers (see Table 4). Verbal episodic memory was assessed by the VLMT (Verbaler Lern- und Merkf~ihigkeits test) a German test which in analogy to the AVLT requires serial list learning and recall over five trials, recall after distraction, 30 min delayed recall and recognition (Helmstaedter et al., 2001a). Vocabulary was assessed by the Mehrfachwahl-WortschatzIntelligenztest (MWT-B) which requires selection of words with increasing difficulty and decreasing frequency of occurrence out of alternative non-words (Lehrl, 1978). Verbal reasoning was assessed by a sub-test of a German intelligence test (IST = Intelligenz-Struktur-Test), which requires selection of a word out of five alternatives which have another connotation or do not belong to the same semantic field as the target word (e.g. sitting, lying, going, kneeling, standing) (Amthauer, 1973). For a better comparability, all scores were transformed into standard values (mean 100, SD 10). Group differences between patients with mTLE and nmTLE were calculated by multivariate analysis of variance. Data analysis (MANOVA) indicated that, as a trend, mTLE patients performed more poorly on
TABLE 4 Subject characteristics
n
Sex (m/f) Age (years) Handedness right - left - ambidextrous Age at onset of epilepsy (years) Duration of epilepsy (years) Pathology: no finding HS tumor - DNT - cort. dyspl. - other -
Patients mTLE
Patients Healthy F/X 2 n m T L E controls significance
63 34/29 32/9.2
87 125 37/50 80/45 27.8/8.4 27.2/8.7
84% 9% 7% 9.8/7.6
64% 10% 6% 12.6/7.2
-
5.3**
22.6/11.6 15.2/9.3-
18.5"*
23%
-
-
-
1.9 n.s. 9.8** 0.01 n.s.
1 0 0 %
-
-
5% 10% 19%
m
m
4 3 %
m
-
m
n.s., not significant; **, p < 0.01.
the tests than nmTLE patients (F = 2.24, p = 0.054). Univarate analysis showed highly significant group differences in measures of episodic verbal learning and memory ( F between 5.6 and 8.2 with pvalues between <0.05 and 0.01) but not for vocabulary (F = 1.1, p = 0.31) or reasoning ( F = 0.001, p = 0.95). Mean standard values ranging between 90 and 100 indicate that semantic knowledge is relatively preserved in left TLE (Table 5). Poor intercorrelations between performance on episodic and semantic memory indicated that these measures were independent rather than redundant. Age regressions show that episodic memory performance (learning and recognition) deteriorates equally with aging in healthy persons and patients (Table 5 and Fig. 3). In contrast, semantic functions are positively correlated to age indicating gains over time. Only in nmTLE patients delayed recall was negatively related to age. Since learning is more closely associated with cortical structures and delayed recall is more closely associated with mesial structures, the latter appear at particular risk of becoming increasingly affected in chronic nmTLE. In nmTLE but not in mTLE, semantic memory is related positively to the age at onset of epilepsy in-
447
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chronological age [yrs.] Fig. 3. Age regressions of verbal memory (learning over 5 trials) and vocabulary in (a) 63 patients with left mesial (from Helmstaedter and Elger, 1999a) and (b) 87 patients with left non-mesial (cortical) temporal lobe epilepsy as compared to age regressions obtained in 125 healthy subjects. Results show comparable regressions despite principal differences in performance levels.
448 TABLE 5 Group performance and correlations to chronological age and age at the onset of epilepsy Performance
Group
n
Mean/SD
Standardvalue (m = 100; SD = 10)
Correlationto age
98.2/11 98.7/12 (104/14)
98.9 99.2 100 93.6 92.4 100
0.45** 0.09 n.s. (0.22*) 0.34** 0.18 n.s. (-)
0.01 n.s. 0.38** (-) 0.26* 0.22* (-)
84.6 90.6 100 82.2 87.6 100 90.0 99.5 100
0.37** 0.29** (0.34**) 0.01 n.s. 0.28** (0.00 n.s.) 0.23* 0.33** (0.23*)
0. l 1 0.16 (-) 0.00 0.12 (-) 0.03 0,12 (-)
Correlation to onset of epilepsy J
Measures of semantic knowledge
Vocabulary (IQ) Reasoning
mTLE 61 nmTLE 87 (controls) (125) mTLE 61 nmTLE 87 (-) (-)
(-)
Measures of episodic verbal memory
Learning Delayed recall (loss) Recognition memory
mTLE 61 42.5/8.1 nmTLE 87 47.3/8.3 (controls) (125) (53.6/8.4) mTLE 61 4.2/2.1 nmTLE 87 3.2/2.2 (controls) (125) (1.6/1.8) mTLE 61 12.5/4.0 nmTLE 87 12.9/2.3 (controls) (125) (12.6/2.6)
l Pearson correlation coefficient (r) with levels of (two-tailed) significance: n,s., not significant; *, p < 0.05; **, p < 0.01. dicating that less semantic knowledge has been acquired by patients with earlier onset cortical lesions (Table 5 and Fig. 4). These results are of importance in four respects. The data firstly emphasize the decisive contribution of the mesial structures and hippocampal damage to the impairment of episodic memory in TLE (Hermann et al., 1997). Semantic memory, in contrast, appears rather unaffected by TLE. Secondly, there is evidence that episodic memory declines over time in patients and healthy subjects as well and that age regressions are not different. That is to say that patients perform more poorly than controls at any age and that it is the interaction of cerebral damage with normal aging rather than progressive epilepsy which brings patients closer to disabling memory impairment at older age. However, this concerns the more cortical aspects of verbal memory so far. An exception must probably be made for patients with nonmesial temporal lobe epilepsies, in whom chronic epilepsy may lead to progressive affection of mesial functions. Thirdly, there is no evidence from our data that episodic memory impairment affects the acquisition of semantic knowledge. This finding is in line
with Varhga-Khadem et al. (1997) who suggest that episodic and semantic memory differentially depend on mesial structures. Finally, there is evidence that early onset of cortical lesions but not of mesial lesions hinders knowledge acquisition. This finding provides further evidence for the aforementioned suggestion that episodic and semantic memory are driven by different brain structures or systems.
Cross-sectional results on age regression of m e m o r y before and after surgery The results of our cross-sectional study suggest that memory impairment in TLE and in mesial TLE in particular becomes evident early in the course of the disease and that further memory decline can be expected to continue at the same rate as in healthy individuals. Studies in newly diagnosed patients with focal epilepsy support the suggestion of an initial lesion (Pulliainen et al., 2000; Aiki~i et al., 2001). Thus the cross-sectional data demand prevention of any further cerebral damage which might accelerate progressive mental aging from the beginning of epilepsy.
449
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TLEI
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age at the onset of epilepsy [yrs.] Fig. 4. Regression of the age at the onset of epilepsy and verbal memory (learning over 5 trials) and vocabulary in (a) 63 patients with left mesial and (b) 87 patients with left non-mesial (cortical) temporal lobe epilepsy. Results show poorer performance in vocabulary with an earlier onset of epilepsy in the nonmesial group.
450
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chronological a g e [yrs.] Fig. 5. Age regressionof verbal memory(learningover 5 trials) in 245 patients with left temporal lobe epilepsybeforeand one year after epilepsy surgeryas comparedto age regression of verbal memoryin 125 healthy controlpersons. While the preoperativeage regression parallels that in controls, the significantlysteeperpostoperativeregressionindicatesacceleratedmemorydecline. Since temporal lobe epilepsy surgery often achieves seizure control at the risk of additional memory impairment, the obvious question is of whether additional brain damage due to surgery may change the long-term prognosis of memory at an older age (Helmstaedter et al., 2001b). Fig. 5 demonstrates data from a large sample of 245 patients with left temporal resections. 62% of these patients were completely seizure free (Engel category: Ia) and losses in verbal memory were highly significant (learning over 5 trials: t = 6.9, p < 0.0001). Age regression of verbal memory performance changes significantly from before surgery (r = -0.287, p < 0.001) to one year after surgery (r--0.387, p < 0.001), i.e. postoperatively, age regression is significantly steeper than the preoperative one (p < 0.01). Age regressions in the healthy group and preoper-
ative patients run largely in parallel, confirming the findings which have above been reported for smaller groups of patients with mesial and nonmesial TLE (Helmstaedter and Elger, 1999a). The difference between the pre- and postoperative age-related memory decline shows that memory performance of a 33year-old non-operated patient with left temporal lobe epilepsy is equivalent to that of a 60-year-old healthy subject. After surgery, performance of a 21-year-old patient corresponds to that of a 60-year-old control person! Thus, when bringing the fact that losses after surgery are greater in older patients together with the fact that memory declines with aging, it seems that surgery not only changes the performance level but also accelerates cognitive aging. This example impressively demonstrates how additional lesions in the course of chronic epilepsy can change the longterm prognosis of memory.
451
Summary TLE typically affects declarative memory. Following Tulving's differentiation of episodic and semantic memory, it is the time- and context-dependent episodic memory, which is particularly found to be impaired. Episodic memory appears strongly linked to the functional integrity of the temporo-mesial structures. There is evidence that in TLE patients also impairment of semantic memory processing can be observed, but different from episodic memory impairment it seems to be more related to cortical temporal lesions and less if any to mesial hippocampal damage. Conclusive with these suggestions, the presented data show that functions indicative for semantic memory are less affected in TLE than episodic memory. Chronological age, age at epilepsy onset, and duration of epilepsy have obviously a different impact on episodic and semantic memory as dependent on whether epilepsy originates in cortical or mesial structures. As regards the long-term prognosis of semantic memory in TLE, cross-sectional data show that gains in semantic knowledge can be achieved over time despite of episodic memory impairment. Early acquisition of cortical lesions or early onset of non-mesial epilepsy, however, seem to interfere with the acquisition of semantic knowledge. This finding is consistent with those demonstrating poorer intelligence with earlier onset epilepsy. Cross-sectional data provide striking evidence that there is a progressive decline of episodic verbal memory which preferentially affects the more cortical aspects of verbal learning and memory. However, contrary to findings on intelligence, this decline appears to result from an interaction of early cerebral damage with normal aging rather than from progressive epilepsy. Thus, the more severe the initial damage the earlier disabling memory problems can be expected. An exception must probably be made for non-mesial TLE in which increasing affection of the mesial aspects of memory with longer duration is indicated. Different from the cross-sectional data the longitudinal data suggest deterioration of memory in the course of chronic TLE due to uncontrolled and more severe seizures. Dependent on seizure frequency 17% to 38% the patients experience significant memory decline in a time interval ranging from 2 to 10 years. Complete and per-
manent seizure control can be achieved in more than 60% of the operated patients but additional memory impairment due to surgery and associated changes of the long-term prognosis of memory with aging necessitate a careful and individual counseling of the patient. With conservative treatment 37% of the patients experience a significant decline in memory. Surgery anticipates the memory decline observed with conservative treatment, but left temporal surgery specifically and permanently impairs verbal memory. Deterioration of verbal memory after left temporal resection significantly exceeds that in conservative treatment. Regarding the relevance of this finding one may well discuss that verbal memory impairment is of greater importance for every day life than figural memory. The brain has limited capacities to restitute and compensate damage and the final conclusion from the presented findings is as simple as it could be: memory can be protected with achievement of early and efficient seizure control and with the prevention of any kind of cerebral damage from the beginning of epilepsy. Thus early neuroprotection and more safe and memory sparing treatment will be important future issues in the treatment of chronic TLE.
Acknowledgements This work was supported by the Deutsche Forschungsgemeinschaft DFG: EL 122-6.
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