Epilepsia, 48(1):124–132, 2007 Blackwell Publishing, Inc. C 2007 International League Against Epilepsy
The Localization and Lateralization of Memory Deficits in Children with Temporal Lobe Epilepsy ∗ †‡§Linda M. Gonzalez, ∗ †§Vicki A. Anderson, ¶Stephen J. Wood, †§L. Anne Mitchell and †§A. Simon Harvey
∗ Australian Centre for Child Neuropsychology Studies, Murdoch Children’s Research Institute, Melbourne, †The University of Melbourne, Melbourne, ‡Monash University, Victoria, §Royal Children’s Hospital, Melbourne; ¶ Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne, Melbourne; and Austin Health, Melbourne, Australia
Summary: Purpose: It is often reported that children with temporal lobe epilepsy (TLE) experience nonlateralized memory impairments. However, many of these studies have been exploratory and not based on memory theory. Further, differences between mesial and lateral subgroups have not been adequately examined. This study aimed to discern more specific patterns of memory impairment in children with TLE. Methods: Forty-three children (5–16 years) with lesional TLE participated. Subjects were categorized in terms of lesion laterality (left, n = 21; right, n = 22) and intratemporal location (mesial, n = 31; lateral, n = 12). Verbal and nonverbal memory tasks were administered that reflected associative, allocentric and recognition paradigms. Results: Facial recognition was poorer in right TLE (p = 0.03). There were no differences between left and right groups on any
other memory task, even when comparisons were restricted to cases with mesial involvement. Irrespective of laterality, clear differences were observed between mesial and lateral lesion subgroups (arbitrary associative learning, p = 0.01; complex figure recall, p = 0.03). The lateral lesion subgroup displayed intact memory function relative to normative standards. Conclusions: Memory is more frequently impaired in children with mesial as opposed to lateral TLE. Tasks with an associative component discriminated between these subgroups, supporting an associative model of hippocampal function. With the exception of facial recognition, memory deficits were not lateralized. Therefore, the nature of memory impairment experienced by children with TLE cannot be extrapolated from adult models. Key Words: Temporal lobe epilepsy—Children—Laterality.
INTRODUCTION
examined the lateralization and localization of memory deficits in children with TLE. The small pediatric literature has focused primarily on differences in memory function between groups with left and right seizure onset. In contrast to adult research, most pediatric studies report that verbal memory is equally impaired in left and right groups (Szab´o et al., 1998; Williams et al., 1998; Adams et al., 1990; Cohen, 1992a; Lewis et al., 1996; Lendt et al., 1999; Mabbott and Smith, 2003; Nolan et al., 2004). There are a small number of studies reporting verbal memory impairment in left TLE, however these studies either did not match the groups for seizure frequency (Fedio and Mirsky, 1969), or emphasized differences between left TLE and controls (Jambaqu´e et al., 1993), which weakens the conclusion that verbal memory is compromised in left but not right TLE. Although the pediatric literature appears to suggest that childhood TLE results in a nonlateralized pattern of verbal memory impairment, it could be argued that these null findings represent limitations in the memory tasks employed, as the adult TLE literature suggests that not all
Memory dysfunction is a common morbidity associated with temporal lobe epilepsy (TLE). An extensive adult literature suggests that verbal memory deficits are associated with left TLE, whereas nonverbal memory is more vulnerable in right TLE, although this effect is not consistently reported (see Bell and Davies, 1998 for review). This “material-specific” pattern of memory impairment suggests that the left and right temporal lobes are specialized in their capacity to support verbal and nonverbal memory, respectively. Further, this literature suggests that the severity of memory impairment is influenced by the extent to which mesial structures are involved (Helmstaedter et al., 1997). Although habitual temporal seizures commonly begin in childhood, relatively fewer studies have Accepted September 5, 2006. Address correspondence and reprint requests to Dr. Linda M. Gonzalez, Ph.D., Department of Psychology, Royal Children’s Hospital, Flemington Rd, Parkville, Victoria, Australia, 3052. E-mail:
[email protected] doi: 10.1111/j.1528-1167.2006.00907.x
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MEMORY IN CHILDREN WITH TLE measures of verbal memory are equally sensitive to laterality effects. Some studies have found novel or arbitrary associative learning paradigms more sensitive than other memory tasks in left TLE (Saling et al., 1993; Wilde et al., 2001). The degree of impairment has been found to correlate with severity of hippocampal sclerosis (Rausch and Babb, 1993; Zaidel et al., 1998; Wood et al., 2000). This relationship suggests that at least one function of the hippocampus is to associate or bind unrelated information (Cohen and Eichenbaum, 1993). With the exception of Adams and colleagues (1990), pediatric TLE studies have not used associative learning paradigms to examine verbal memory. Although Adams et al. included this measure, they did not differentiate between the ability to learn arbitrary and semantically related items, which adult researchers have identified as critical, in keeping with the associative model of hippocampal function (Saling et al., 1993). Thus evidence for a nonlateralized pattern of verbal memory impairment would be strengthened through demonstrating null findings using an associative learning paradigm that separated related and unrelated items. The laterality of nonverbal memory in children with TLE would also be clarified through consideration of theoretical issues. Nonverbal memory is a complex construct that encompasses a range of more specific processes including allocentric memory (spatial learning independent of egocentric or person-specific cues), facial recognition, navigation, recall of object location and memory for geometric designs. There is no unifying theory of nonverbal memory, with different theorists proposing different mechanisms to support specific skills. For example, O’Keefe and Nadel (1978) proposed that the hippocampus supports nonverbal memory through the formation of allocentric cognitive maps, whereas Cohen and Eichenbaum (1993) suggest that associative processes underpin this aspect of memory. Extrahippocampal structures have also been identified as important to aspects of nonverbal memory, with the fusiform face area integral to facial recognition (Sergent et al., 1992). The multicomponential nature of nonverbal memory may explain some of the variability within the adult TLE literature, as deficits in allocentric memory (Abrahams et al., 1997; Feigenbaum and Morris, 2004) and facial recognition (Milner, 1968; Chiaravalloti and Glosser, 2004) are more consistent than impairments in other aspects of nonverbal memory, such as recall of geometric designs (Barr et al., 1997). The pediatric TLE literature is also inconsistent in terms of the presence and nature of nonverbal memory impairment with some (Jambaqu´e et al., 1993; Lewis et al., 1996; Nolan et al., 2004) but not other studies (Adams et al., 1990; Cohen, 1992a; Williams et al., 1998; Lendt et al., 1999) reporting differences (right < left). The basis for this variability is not understood, although it is possible that some aspects of nonverbal memory are more vulnerable
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than others. In support of this view, Mabbott and Smith (2003) found that facial recognition, but not recall of a complex geometric design, was selectively impaired in right TLE. Similarly, Beardsworth and Zaidel (1994) found deficits in facial recognition, but did not administer additional memory tasks to examine the specificity of this finding. It remains to be determined whether other aspects of nonverbal memory are also selectively impaired. Although most pediatric studies have focused on the laterality of memory impairment in children with TLE, it is also important to consider the influence of mesial or lateral localization within the temporal lobe. In terms of memory function, mesial structures are integral to the formation and retention of new information (Cohen and Eichenbaum, 1993), whereas the neocortex is thought to store long term memories through a process of consolidation (Alvarez and Squire, 1994; Murre, 1996). As mesial and neocortical structures support specific memory functions children with mesial and lateral TLE may exhibit different types of memory impairment, as has been demonstrated for adults (Helmstaedter et al., 1997). Although lateral TLE is relatively common in childhood (Duchowny et al., 1992; Harvey et al., 1997), Nolan and colleagues (2004) are the only investigators to have compared memory in children with mesial and lateral TLE. Although no differences were reported between these subgroups, these authors relied on measures administered in a clinical setting, rather than a protocol developed from theoretical principles. The current study investigated the lateralization and localization of memory in children with TLE. Although previous pediatric studies suggest that TLE during childhood generally results in nonlateralized memory deficits, it could be argued that such null findings reflect the limitations of assessment tasks. This study investigated whether nonlateralized memory deficits persist on theoretically driven measures. Consistent with prior research, it was expected that facial recognition would be selectively impaired in right TLE. It was unclear whether lateralized deficits would be observed for other aspects of memory. In terms of localization, differences were anticipated between mesial and lateral lesion subgroups, with hippocampal involvement expected to be particularly detrimental for memory function. METHOD Participants Forty-three children and adolescents with lesional TLE, aged between 5–16 years, participated in this study. Subjects were recruited over a six-year period (1999–2004), through the Royal Children’s Hospital (n = 37), and the Austin Hospital (n = 6), Melbourne, Australia. The primary inclusion criteria were a clinical diagnosis of TLE referable to a unilateral temporal lobe lesion identified on imaging (MRI, n = 42; CT, n = 1). Diagnoses were Epilepsia, Vol. 48, No. 1, 2007
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L. M. GONZALEZ ET AL. TABLE 1. Demographic and seizure variables for clinical groups
Age (years) Socioeconomic status∗ Males Left hand dominant Antecedent event Age at habitual seizure onset Duration of epilepsy Number anticonvulsants Extratemporal involvement †
Right n = 22
Left n = 21
Mesial n = 31
Lateral n = 12
Right mesial n = 14
Left mesial n = 17
11.41 (3.11) 4.62 (1.34) 15 3 11 6.74 (3.65) 4.67 (4.04) 1.32 (0.89) 9
12.75 (2.59) 4.50 (1.26) 8 2 10 6.77 (4.51) 5.98 (4.04) 1.52 (0.60) 4
12.04 (2.81) 4.57 (1.44) 15 3 18 5.41 (3.57) 6.63 (4.39) 1.42 (0.67) 12
12.12 (3.30) 4.32 (0.65) 8 2 3 10.23 (3.08) 1.89 (1.40) 1.42 (1.00) 1
11.55 (3.14) 4.69 (1.62) 9 2 8 5.54 (3.80) 6.01 (4.45) 1.21 (0.70) 8
12.44 (2.54) 4.47 (1.31) 6 1 10 5.30 (3.48) 7.14 (4.41) 1.59 (0.62) 4
∗ Determined by Daniel’s (1983) Scale of Occupational Prestige, which rates parent employment on a seven-point scale. A low score is indicative of greater prestige. †Evidence of extratemporal abnormalities on MRI.
made by a pediatric neurologist, typically on the basis of EEG, MRI, clinical history, and seizure semiology. This approach of basing diagnosis on an epileptogenic lesion coupled with expert neurological opinion is similar to that adopted in several other cohort studies (Camfield and Camfield, 1994; Sillanpaa et al., 1995; Harvey et al., 1997; Sztriha et al., 2002; Berg et al., 2003; Arts et al., 2004). Twenty six participants underwent video EEG monitoring, which indicated unilateral temporal lobe seizure origin in all cases. Across the entire sample, only four participants had independent bilateral temporal interictal discharges, which may be a marker of contralateral dysfunction. Stringent exclusion criteria were employed including epileptic encephalopathy, symptomatic visual field defect, hemiparesis, prior temporal lobe surgery, moderate intellectual disability (IQ ≤ 60), pervasive developmental disorder, and severe behavioral disturbance. Mild intellectual impairment (n = 5) was permitted as lower functioning individuals are commonly seen in clinical practice and other authors have achieved meaningful memory assessment in this group (Nolan et al., 2004). Subjects were classified into three subgroups: right (n = 22) versus left (n = 21); mesial (n = 31) versus lateral (n = 12); and right mesial (n = 17) versus left mesial (n = 14). The characteristics of these groups are summarized in Table 1. Seizure frequency was categorized on an inverse ordinal scale where 1 = daily; 2 = weekly; 3 = monthly; 4 = quarterly; 5 = yearly; 6 = no current seizures, which was defined as no events within the last two years. Across the total sample approximately 25% of participants had been seizure free for more than two years, whereas 65% of cases experienced seizures at least on a monthly basis. Antecedent events included prolonged febrile convulsions, cerebral infections and illness in the perinatal period. Each child’s imaging was visually inspected to characterize the nature and extent of the lesion. This analysis was primarily performed by a pediatric neurologist, with a neuroradiologist reviewing a subset of cases. A group of 23 cases were identified where the abnormality was confined to the mesial region, defined as the hipEpilepsia, Vol. 48, No. 1, 2007
pocampus proper and parahippocampal gyrus. This group comprised 19 cases of MTS, two cases where MTS was associated with dysplasia and two low-grade tumors. In lateral cases (n = 12) there was a lesion in at least one of the superior, middle, inferior temporal or fusiform gyri. Mesial structures were intact. This subgroup comprised five low-grade tumors, four dysplasias and three vascular events. A further eight cases involved both mesial and lateral structures. These cases were combined with the mesial subgroup given that hypotheses predict that mesial involvement is critical to memory dysfunction. There were five low-grade tumors, one vascular event, one dysplasia and one case of herpes simplex encephalitis in this group. The overall mesial group comprised 31 cases. Thirty participants (70%) had circumscribed temporal lesions. On MRI, there was evidence of minor extratemporal involvement in the ipsilateral hemisphere in the remaining 13 (30%) subjects. For such subjects to be included it was required that: the primary lesion was in the temporal lobe; the contralateral cortex had a normal appearance and ipsilateral involvement was not in a region or to an extent that would be expected to influence the cognitive functions under investigation. Extratemporal involvement included: lesions extending to involve a focal frontal (n = 3), occipital (n = 3) or parietal (n = 1) cortical region; subcortical white matter abnormality (n = 2); insular involvement (n = 1) or cerebellar abnormality (n = 2). There was one case where MTS was associated with very mild ipsilateral hemispheric atrophy. Descriptive statistics are provided for each subgroup in Table 1. Subjects in the left and right groups were matched for all variables, with the exception of gender, chi-square (1, N = 43) = 3.91, p = 0.05. Mesial and lateral groups were not matched for age at seizure onset, F (2, 39) = 21.31, p < 0.001, duration of epilepsy, F (2, 39) = 12.63, p =0.001, or presence of extratemporal involvement, χ 2 (1, N = 43) = 3.79, p = 0.05. The left and right mesial groups were matched on all variables, although there was a trend for right mesial TLE to be associated with extratemporal involvement, chi-square (1, N = 43) = 3.66, p = 0.06.
MEMORY IN CHILDREN WITH TLE Measures The present study comprised measures of verbal and nonverbal memory, attentional capacity and an estimate of intellectual function. Verbal memory Verbal paired associates (VPA) (Wechsler Memory Scale–Revised; WMS-R; Wechsler, 1987) was administered as a measure of verbal memory. This task involved presenting eight pairs of words, four with a semantic relationship and four arbitrary, over three trials. Recall was assessed after a 30-min delay. Performance was analyzed separately for semantic (“easy”) and arbitrary (“hard”) items for the learning condition (sum trials 1–3) and delayed recall, as these measures may be differentially compromised by mesial lesions (Saling et al., 1993). Nonverbal memory Given that nonverbal memory is a heterogeneous construct, a range of measures were employed to capture the various aspects of this domain. 1. The Nine Box Maze Test—Child Version (NBMTCV; Pentland et al., 2003, adapted from Abrahams et al., 1997). The NBMT-CV, which was developed to tap allocentric and associative aspects of nonverbal memory, is a hidden-object task where a range of familiar objects are hidden in identical opaque plastic bins positioned in a circular array on a square table. The child moves to a different position around the table before recalling what items were hidden (object recall), which bins were used (location recall) and the association between object and location (i.e., where was each object hidden). The task comprises a fivebox trial (5BM) where two objects are hidden in five bins. Children progress to the nine-box trial (9BM) once they have achieved an errorless trial on the 5BM condition (up to a maximum of three attempts). Four objects are hidden in the 9BM condition, two new and two constant across trials. Four nine-box trials are administered, regardless of success. In all trials the child receives credit for correct responses across each of the following domains: object recall, location recall and object-location association. In the 5BM condition these measures are combined to yield a total score (range = 0–24). Each of the domains are analyzed separately in the 9BM trial (range = 0–16). The 9BM total score represents the sum of these domains. 2. Faces subtest from the Children’s Memory Scale (CMS; Cohen, 1992b). This facial recognition task requires subjects to learn a set of novel faces and identify these images from a set of foils presented immediately after presentation and after a 30-min delay. Raw scores were converted to scaled scores, as per the CMS manual. 3. Doors subtest from the Doors and People test (Baddeley et al., 1994). The Doors Test (DT) was included to capture nonverbal recognition. The task involves presenting two individual sets of 12 photographs of doors (Parts A & B). The examiner provides a verbal label for each door, such as “garage door,” which is intended to control
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the verbal strategies adopted by the subject. The subject then identifies these targets from three foils. Part B is more difficult and is only administered if the subject achieves a score of 10 or more on Part A. The overall composite score was analyzed in this study. 4. The Rey Complex Figure Test (RCFT; Rey, 1941). This widely used measure of nonverbal memory requires the subject to copy and recall a complex geometric design. This study assessed incidental recall 3 min after the initial copy condition. The dependent variable was percentage retained on delay. Attentional capacity This study included a composite measure of attention, which provided a broad estimation of the capacity to register new information. This measure was a composite of the forwards and backwards conditions of Digit Span (Wechsler, 1991) and Block Span (Milner, 1971) and was derived from a single factor Principal Components Analysis. If differences were apparent, it was considered necessary to covary this measure in significant memory analyses, as a means of minimizing the likelihood that impaired “memory” performances were actually due to attentional dysfunction. Intelligence Intellectual ability was included as a means of controlling for the possibility that differences in memory performance reflect broader cognitive processes. Thus intelligence, like attentional capacity, was considered a descriptive measure that enhanced interpretation of memory data. Intelligence was estimated through the dyad of Block Design and Vocabulary. Sattler (1992) suggests that this is a particularly useful short form on the Wechsler Intelligence Scale for Children—Third Edition (WISC-III; Wechsler, 1991) as both subtests are reliable and have a high correlation with Full Scale IQ (r = 0.74; r = 0.79, respectively). The WISC-III was administered for the majority of participants (n = 40). Two participants were aged 5 years at the time of testing and were administered the relevant subtests from the Wechsler Preschool and Primary Scale of Intelligence—Revised (Wechsler, 1989). One subject had recently been administered the Wechsler Abbreviated Scale of Intelligence (Wechsler, 1999) for clinical purposes and those results were utilized. Procedure Approval for the study was obtained through the Human Ethics Committees at the Royal Children’s Hospital and Austin Hospital. Parents provided consent, as did children aged 12 years and older. Younger children assented to involvement. Subjects were identified retrospectively through a review of medical files and prospectively through consultation with treating physicians, attendance at epilepsy case conferences and review of MRI reports. Subjects were assessed individually. Epilepsia, Vol. 48, No. 1, 2007
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Statistical analysis Test variables were converted to z-scores derived from unpublished normative data collected by our research group (n = 320) or existing normative data for Faces and IQ measures. There were no gender effects in our normative data for the variables analyzed in this study. Normative data were only available for children aged 5–6; 8–9; 11– 12 and 15–16 years. In the instance where the child’s age fell between these bands the comparative data set closest to their chronological age was employed. Normative data was available for 34 children (79%), with interpolated values employed for the remaining nine (21%) participants. The normative data indicated very few group differences between 8–16 years, suggesting performance on these measures is largely stable from mid childhood. Thus seven year olds are potentially the age group where interpolated data is less appropriate. There was only one participant in this age group. The distribution of all variables was examined. Total recall on the 5BM and number of easy pairs recalled on delay were consistently skewed for all subgroups. The nonparametric Mann–Whitney U test was employed to examine group differences on these variables. Analysis of covariance (ANCOVA) was employed for all other measures as a means of controlling for differences identified in seizure and demographic variables. Gender was covaried for comparisons between the composite left and right group. Age at seizure onset and extratemporal involvement were controlled for mesial and lateral comparisons. Duration of epilepsy also differed between these groups but was not covaried as it was significantly correlated with age at seizure onset, r = 0.76, p < 0.001. Extratemporal involvement was covaried for left and right mesial comparisons, given the trend towards significance. Given the small sample size and use of covariates, there is some possibility of increased Type II statistical error. To guard
against this possibility Cohen’s d was calculated to examine trends towards significance, with effect sizes ≥ ± 0.67 considered clinically significant and indicative of a meaningful trend. Although informative, this between-group approach does not consider the pattern of individual performance across tasks. These data were considered pertinent in order to delineate the nature of memory impairment for children with mesial and lateral TLE more precisely. As a means of capturing these individual data, the performance of each individual on Hard Pairs Delay and Faces Delay was dichotomized as “intact” (z-scores ≥ −1) or “impaired”’ (z-scores < −1). These ratings were then employed to classify the memory profile of each individual as “material specific” (impaired in one domain concordant with laterality), “reversed” (impaired in one domain discordant with laterality), “global” (impaired in both domains), or “intact” (no memory disturbance). Differences in the distribution of these profiles were explored through chi-square. RESULTS Laterality effects Descriptive and inferential statistics are given in Table 2 for each of the dependent variables. After controlling for differences in gender, ANCOVA revealed that the left and right TLE groups were comparable on all measures with the exception of delayed facial recognition, F (1, 40) = 4.96, p = 0.03, where the right group performed more poorly than the left. The effect size for Easy Pairs Delay approached clinical significance (d = −0.66) with the right group performing more poorly. Lateral versus mesial TLE Table 2 also provides data for comparison of the mesial and lateral groups, which was achieved through ANCOVA
TABLE 2. Mean z-scores, standard deviations and effect sizes of memory variables for left versus right TLE, mesial versus lateral TLE and right versus left mesial TLE Right n = 22 5BM total score 9BM object recall 9BM location recall 9BM associative recall 9BM total score Faces immediate Faces delay DT total RCFT proportion retained VPA easy pairs learned VPA hard pairs learned VPA easy pairs delay VPA hard pairs delay Attention composite Estimated IQ
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−0.74 (2.30) −0.48 (1.30) −0.99 (1.67) −0.65 (1.69) −0.79 (1.58) −0.77 (1.27) −1.00 (1.08) −1.13 (1.38) −1.19 (1.64) −1.21 (1.56) −1.15 (1.26) −1.20 (2.62) −1.65 (2.08) −0.23 (1.19) −0.49 (1.32)
Left n = 21 −0.01 (0.74) 0.19 (1.30) −0.51 (1.28) −0.31 (1.29) −0.23 (1.11) −0.11 (1.14) −0.22 (0.99) −1.35 (1.22) −1.05 (1.46) −1.09 (1.23) −1.28 (1.08) 0.32 (1.91) −1.93 (1.89) −0.24 (0.71) −0.40 (1.34)
Effect size −0.42 −0.50 −0.32 −0.23 −0.41 −0.53 −0.71 0.17 −0.10 −0.01 0.11 −0.66 0.14 0.01 −0.07
Mesial n = 31 −0.63 (2.01) −0.20 (1.39) −0.95 (1.63) −0.79 (1.54) −0.76 (1.46) −0.55 (1.23) −0.72 (1.08) −1.47 (1.30) −1.52 (1.28) −1.25 (1.24) −1.45 (1.07) −1.00 (2.53) −2.26 (1.97) −0.14 (1.04) −0.65 (1.18)
Lateral n = 12 0.24 (0.29) −0.03 (1.20) −0.27 (0.97) 0.32 (1.07) 0.12 (0.93) −0.19 (1.27) −0.33 (1.13) −0.64 (1.11) −0.01 (1.66) −0.90 (1.76) −0.60 (1.22) −0.16 (1.54) −0.57 (1.35) 0.38 (0.79) 0.09 (1.53)
Effect size −0.50 −0.13 −0.46 −0.74 −0.64 −0.29 −0.35 −0.64 −0.99 −0.25 −0.73 −0.36 −0.86 −0.52 −0.42
Right mesial n = 14 −1.28 (2.76) −0.67 (1.25) −1.31 (1.95) −1.20 (1.71) −1.23 (1.70) −0.93 (1.28) −1.14 (1.08) −1.24 (1.52) −1.64 (1.25) −1.17 (1.43) −1.37 (1.21) −1.68 (2.90) −2.14 (2.30) −0.42 (1.36) −0.58 (1.10)
Left mesial n = 17
Effect size
−0.09 (0.81) 0.19 (1.41) −0.65 (1.29) −0.45 (1.33) −0.37 (1.15) −0.24 (1.14) −0.37 (0.98) −1.66 (1.09) −1.43 (1.34) −1.31 (1.11) −1.51 (0.97) −0.44 (2.11) −2.36 (1.75) 0.07 (0.66) −0.71 (1.28)
−0.59 −0.64 −0.41 −0.48 −0.59 −0.56 −0.71 0.32 −0.16 0.11 0.13 −0.49 0.11 −0.47 0.11
MEMORY IN CHILDREN WITH TLE with age at seizure onset and extratemporal involvement as covariates. The mesial group performed significantly more poorly than the lateral group on the RCFT Proportion Retained, F (1, 39) = 4.88, p = 0.03, and Hard Pairs recalled on delay, F (1, 39) = 7.39, p = 0.01. The mesial group also tended to perform below the lateral group on the 9BM associative measure, F (1, 39) = 3.44, p = 0.07, and Hard Pairs learned, F (1, 39) = 3.75, p = 0.06. Both these measures were associated with clinically significant effect sizes, d = −0.74 and d = −0.73, respectively. As the mesial group comprised some cases (n = 23) with circumscribed mesial lesions and other more “lobar” cases (n = 8), analyses were repeated comparing only the circumscribed mesial and lateral subgroups. These groups differed on age at seizure onset, t(33) = −4.81, p < 0.001, which was covaried. These analyses revealed a similar pattern of results to those described for the whole mesial group. The performance of the pure mesial group was significantly below the lateral subgroup on Hard Pairs recalled on delay, F (1, 32) = 4.64, p = 0.04. Clinically significant effect sizes were observed for the RCFT Proportion Retained, d = −0.86, F (1, 31) = 1.69, p = 0.20, 9BM associative measure, d = −0.71, F (1, 32) = 2.48, p = 0.13 and Hard Pairs learned, d = −0.82, F (1, 32) = 2.70, p = 0.11. Descriptive statistics presented in Table 2 for mesial and lateral groups suggested that the mean performance of the lateral group fell within the average range on memory tasks, as all z-scores fell above −1. However, these group data do not account for the possibility that some individual participants with lateral TLE may still have performed poorly on these tasks. Memory profiles, based on performance on Hard Pairs Delay and Faces Delay, were examined to further explore this possibility. These data are presented in Table 3. Although the lesion by memory group analysis was not significant, chi-square (3, N = 43) = 6.27, p = 0.09, there was a trend for the lateral group to primarily comprise intact cases. This trend was borne out in Chi-squared analysis only including lateral cases, chi-square (3, N = 43) = 11.33, p = 0.01. Eight of the 12 lateral cases (66%) exhibited intact memory function. There was no difference in the frequency of memory profiles for the mesial group, indicating that all patterns were represented, chi-square (3, N = 43) = 4.26, p = 0.23.
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In order to explore the basis for variability within the lateral group, those lateral cases with intact memory function were compared to lateral cases exhibiting any type of memory abnormality (“material specific,” “reversed,” or “global”). Different types of abnormality were combined due to small numbers. Lateral cases with impaired memory did not differ from intact lateral cases in terms of age at seizure onset, t(10) = 1.10, p = 0.30, seizure severity, t(10) = 1.32, p = 0.20, and number of medications, t(10) = 0.39, p = 0.70. Visual inspection of the data did not suggest that memory profile was related to number of lateral gyri involved or etiology. Right versus left mesial There were no significant differences between the left and right mesial group, once extratemporal involvement had been controlled. The right mesial group tended to perform more poorly than the left on delayed faces recall, F (1, 28) = 4.00, p = 0.06, 9BM object recall, F (1, 28) = 3.41, p = 0.08, and 9BM total score, F (1, 28) = 3.11, p = 0.09. DISCUSSION This study revealed that mesial TLE is more frequently associated with memory impairment than lateral TLE, which is consistent with adult studies (Burgerman et al., 1995; Helmstaedter et al., 1997). Deficits within the mesial group were pronounced on verbal and nonverbal memory tasks with an associative component, supporting this model of hippocampal function (Cohen and Eichenbaum, 1993). Despite the use of theoretically derived memory measures, there were no lateralized differences between right and left TLE groups on verbal or nonverbal memory tasks, with the exception of facial recognition. The right TLE group performed more poorly on facial recognition, which is consistent with previous pediatric studies (e.g., Mabbott and Smith, 2003) and suggests that this is a distinct aspect of nonverbal memory. These findings contribute towards delineating the specific nature of memory impairment associated with TLE during childhood and the clinical factors that predispose individuals to such deficits. Lesion location As predicted, results suggest that intratemporal lesion location influences memory function in children with
TABLE 3. Memory classification∗ for individual participants with mesial and lateral TLE
Mesial Lateral
“Material specific” n
“Reverse” n
“Intact” n
“Global” n
12 2
4 1
8 8
7 1
∗ Based on performance on Faces Delay and VPA Hard Pairs Delay Material specific, verbal memory impaired in left TLE, nonverbal memory impaired in right TLE; Reverse, verbal memory impairment in right TLE; nonverbal memory in left TLE; Intact no memory impairment; Global, verbal and nonverbal memory impaired.
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TLE. At a group level, mesial TLE was associated with poorer memory function than lateral TLE on RCFT proportion retained and delayed recall of VPA hard pairs. The mesial group also tended to perform more poorly than the lateral group on the 9BM associative measure and the learning trials of VPA hard pairs. These effects persisted once age at seizure onset and extratemporal involvement had been covaried. For all other measures the mean of the mesial group fell below the lateral group. These results appear to be inconsistent with those of Nolan et al. (2004), who did not find group differences between their mesial and lateral TLE sample. This discrepancy may be partly related to differences in protocol, as the current study suggests that only a selection of memory tasks discriminate between mesial and lateral TLE. Although the RCFT was common between this study and Nolan et al., the specific dependent variable employed was different. The current study employed a proportional measure, which accounted for the accuracy of the original copy, whereas the Nolan et al. examined delayed recall independent of initial performance. In support of this view, when differences between the mesial and lateral groups were analyzed on the same measure as employed by Nolan et al. results were on the cusp of significance, F(1, 36) = 4.07, p = 0.05. In the current study all the measures that tap associative processes (specifically hard pairs from the VPA and object-location association from the NBMT-CV) were sensitive to mesial/lateral differences. These findings appear to be consistent with an associative model of hippocampal function (Cohen and Eichenbaum, 1993) and parallel adult studies which suggest that associative measures are particularly sensitive to the presence and severity of mesial involvement (e.g., Wood et al., 2000). However, the proportional measure of the RCFT also discriminated between lateral/mesial subgroups, which is not typically thought of as an associative task. Although it could be argued that this measure does tap associative processes through the binding of specific visual details, this may be an overly liberal application of the associative theory, which could effectively be applied to all memory tasks. These results suggest that memory function differs in children with mesial and lateral TLE, but the basis of this difference is more complex than the ability to form novel associations. The current study provided some data to suggest that the connectivity between mesial and lateral structures may be an important consideration in understanding the nature of memory impairment in these subgroups. Group differences were attenuated when cases with more extensive “lobar” lesions involving both regions were excluded. These attenuated findings could be related to decreased statistical power, given the reduced sample size, or alternatively suggest that those cases with “lobar” lesions exhibit particularly poor memory function, indicating an interaction Epilepsia, Vol. 48, No. 1, 2007
between mesial and lateral structures. Although the role of neocortical structures in memory is not fully understood, there is evidence that mesial structures are essential for the consolidation of new information, but through a process of hippocampal-neocortical interactions long term memories come to be stored within the neocortex (Alvarez and Squire, 1994; Murre, 1996). This model would predict that measures of semantic and long-term memory may be impaired in lateral TLE. The possibility that these aspects of memory may be impaired in lateral TLE requires further investigation. Although results of the present study caution against considering TLE as a homogeneous clinical group, it is also important to recognize individual variability within mesial and lateral subgroups. Within the lateral group, individual memory profiles revealed that 4 of the 12 cases with lateral TLE experienced some memory impairment (2 material-specific impairment; 1 reversed memory deficits and 1 global difficulties). The basis for this variability is unknown and is not obviously related to seizure frequency, medications, age at seizure onset, etiology or number of gyri involved. It is possible that individuals with lateral TLE and memory impairment may have a diffuse epileptogenic zone which may compromise mesial temporal function. Further research is also required to identify the basis of variability in individual performance within the mesial group. Although there is still much to be learned about memory function in children with mesial and lateral TLE, particularly in terms of specific risk factors, this study clearly demonstrates that childhood TLE should not be considered a homogeneous disorder. As a group, children with lateral TLE fare much better than those with mesial TLE, with most lateral cases exhibiting intact memory relative to normative standards. From an empirical perspective, these findings highlight the importance of analyzing lateral and mesial cases separately; as a failure to do so potentially diminishes overall group effects and creates a false impression that TLE in childhood is necessarily associated with memory impairment. From a clinical perspective, individual assessment of memory function is essential, given some variability within both clinical groups in terms of the nature of memory impairment. Laterality With the exception of facial recognition, this study did not find evidence for differences in memory function between children with left and right TLE. This finding is consistent with most other pediatric studies (e.g., Mabbott and Smith, 2003), but strengthens this literature through demonstrating this null result on measures with a strong theoretical rationale and in a subset of cases with mesial pathology. Further, our sample contained very few cases with independent left and right discharges, suggesting that the lack of lateralized memory findings is not due to
MEMORY IN CHILDREN WITH TLE bi-temporal seizure activity. It could, however, be argued that the absence of group differences reflects the limited power of the study to detect such an effect (i.e., Type II error), however there were no clinically significant effect sizes, with the exception of facial recognition. The stringent selection criteria and ascertainment of a large sample relative to previous studies all maximized the likelihood that laterality effects would have been detected, if present. Laterality effects were apparent for delayed facial recognition, for the entire sample and mesial subgroup (trend only). Although it could be argued that such an isolated effect represents a spurious or chance result, other pediatric (Beardsworth and Zaidel, 1994; Mabbott and Smith, 2003) and adult studies (e.g., Chiaravalloti and Glosser, 2004) have found facial recognition to be particularly vulnerable in right TLE. This finding is consistent with functional imaging studies which suggest that facial processing is mediated by a discrete area in the right fusiform gyrus (Sergent et al., 1992) and is more strongly lateralized than other nonverbal skills (Kanwisher et al., 1997). There is some evidence that facial recognition involves an interaction between the fusiform face area and mesial structures (Haxby et al., 1996). Thus there are strong theoretical grounds to suggest that facial recognition represents a discrete aspect of nonverbal memory. With the exception of facial recognition, this study combined with previous pediatric research (e.g., Mabbott and Smith, 2003) provides convergent evidence that TLE in childhood is not associated with lateralized memory deficits. This pattern of impairment contrast to the material-specific deficits reported in adult studies, particularly with respect to verbal memory (see Bell and Davies, 1998 for review). The basis of this nonlateralized memory deficit is unclear but may possibly indicate a disruption to the hemispheric specialization of memory. Drawing parallels to Bates and Roe’s (2001) theory of language development, it is possible that early memory is supported by a bitemporal network early in life and that the presence of an epileptogenic lesion disrupts the lateralization of the memory system. Our data provide indirect support for this view as facial recognition appears to be lateralized from infancy (Tzourio-Mazoyer et al., 2002; de Haan et al., 2003) and it may be that this early specialization resulted in an adult-type pattern of impairment for this, but not other, aspects of memory. Further research, including studies of memory lateralization in healthy children, is required to better understand the factors that lead to this nonlateralized pattern of impairment characteristic of children with TLE. Limitations and future directions This study suggests that TLE in childhood results in localized but not lateralized memory deficits. Although this is a theoretically meaningful pattern of results, findings
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must be considered cautiously given the small sizes of lesion subgroups, which prevented more detailed analysis of some variables such as etiology. These results suggest that it may be more informative for future research to focus on differences between mesial and lateral subgroups than between left and right onset. Future work would also be enhanced by inclusion of an extratemporal comparison group, as it is possible that some cognitive changes attributed to the temporal lobe may actually represent nonspecific effects of an epileptogenic lesion in the developing brain. Although further research is required to fully understand the nature of memory impairment associated with TLE during childhood, it is clear that clinical decision making, including surgical planning, should be based on dedicated pediatric research and not extrapolated from adult studies. Acknowledgments: We are grateful for the assistance of the neuropsychologists, neurologists, and neurosurgeons at the Royal Children’s Hospital and Austin Hospital for their assistance in recruiting the participants; particularly Ms. Jacquie Wrennall, Dr. Lloyd Shields, Dr. Rick Leventer, Dr. Mark Mackay, Dr. Ingrid Scheffer, Dr. Michael Hayman, Dr. Peter Rowe, and Ms. Wirginia Maixner. We also acknowledge the financial support of the Perpetual Foundation and Murdoch Childrens Research Institute. We are indebted to the children and families for their involvement.
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