Memory performance on the California Verbal Learning Test of children with benign childhood epilepsy with centrotemporal spikes

Epilepsy & Behavior 13 (2008) 600–606

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Memory performance on the California Verbal Learning Test of children with benign childhood epilepsy with centrotemporal spikes Chiara Vago a, Sara Bulgheroni a, Silvana Franceschetti b, Arianna Usilla a, Daria Riva a,* a b

Developmental Neurology Division, Istituto Nazionale Neurologico C. Besta, Via Celoria 11, 20133 Milan, Italy Department of Neurophysiology and Epileptology, Istituto Nazionale Neurologico C. Besta, Via Celoria 11, Milan, Italy

a r t i c l e

i n f o

Article history: Received 12 March 2008 Revised 7 July 2008 Accepted 7 July 2008 Available online 15 August 2008 Keywords: BECTS Learning Memory EEG

a b s t r a c t Verbal learning and retrieval, as well as the use of learning strategies, were assessed in 24 children with benign epilepsy with centrotemporal spikes (BECTS) and 16 controls, using the California Verbal Learning Test—Children’s Version. Neuropsychological data were correlated with EEG features. Compared with age-matched controls, the children with BECTS younger than 10 exhibited significant learning difficulties and were less efficient in using a semantic clustering strategy, whereas no such difference emerged for subjects older than 10. This suggests that the capacity for spontaneous use of a more efficient strategy matures later in children with BECTS. Moreover, the majority of those younger than 10 had multifocal anomalies, suggesting that the difficulties encountered might be caused by the presence of additional foci. Ó 2008 Elsevier Inc. All rights reserved.

1. Introduction Benign epilepsy with centrotemporal spikes (BECTS) is the most frequent epilepsy in school-aged children, accounting for 15% of all childhood epilepsy [1]. The location of interictal epileptic activity may vary and involves mainly the temporal or rolandic regions. Moreover, spikes are often multifocal with a bilateral, asynchronous presentation, and they may even be ipsilateral to the side of the body affected by ictal phenomena [2]. Seizures commonly occur in children aged between 3 and 13, and the EEG spikes fade away spontaneously during puberty at the latest [3]. BECTS is traditionally thought to occur in children with a normal neurological picture and normal cognitive or behavioral performance [4]. In recent years, however, a growing body of evidence suggests that subclinical epileptiform activity produces mild neuropsychological impairment in several areas. Deficiencies have emerged in attention [5–7], visuoperceptual [6,8] and memory [9–11] skills, visuomotor coordination [5,6], verbal abilities [6,12–15], and executive functions [6,9,16]. Although previous studies have analyzed memory functions in children with BECTS, the results were ambiguous, as memory is not a unitary cognitive function. It is split into short- and long-term memory: the first is the limited-capacity store for retaining information for a brief period and performing mental operations on the

* Corresponding author. Divisione di Neurologia Dello Sviluppo, Istituto Nazionale Neurologico C. Besta, Via Celoria 11, 20133 Milan, Italy. Fax: + 39 02 7063.5350. E-mail address: [email protected] (D. Riva). 1525-5050/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2008.07.003

content of this store [17]; the second is the permanent or more stable storage of memories and is split into explicit and implicit memory [18]. Explicit memory is involved in intentional and/or conscious recall and recognition of previous experience or information; implicit memory has no conscious reference to previous experience and refers to heterogeneous abilities, such as priming, skill learning or procedural memory, and habit formation. Explicit memory can be further broken down into two subsystems: episodic memory (the ability to explicitly recollect previously encountered information) and semantic memory (the recall of meanings, understandings, and other factual knowledge). Another factor that might explain the ambiguous results of previous studies is that different tests were used to assess the same memory component. Using the Children’s Auditory Verbal Learning Test 2, Staden et al. [13] measured lower auditory verbal learning ability, but intact immediate and delayed recall in a group of children with BECTS. Other authors, employing the Rey Auditory–Verbal Learning Test, reported that children with BECTS did worse in auditory verbal learning [9,11] and also in long-term recall [9]. By use of a sequential short-term memory task, Weglage et al. [19] found that children with BECTS had significantly impaired IQ and short-term memory. Pinton et al. [8] found no loss of verbal memory competence as measured by a story recall task. Finally, Northcott et al. [10], using the Wide Range Assessment of Memory and Learning, found a specific deficit in general indexes of verbal and visual memory, but not in short- and long-term tasks. We chose to administer the Italian adaptation of the California Verbal Learning Test—Children’s Version (CVLT-C) [20]. The CVLT-C follows the typical procedure of tasks used to assess expli-

C. Vago et al. / Epilepsy & Behavior 13 (2008) 600–606

cit memory: patients are shown a series of stimuli to remember and are later given a recall or recognition task requiring them to think back to the study episode to produce or select a suitable response [21]. This test assesses verbal information learning and retrieval efficiency after both short and long delays in the context of an everyday memory task. To our knowledge, there have been no published reports on use of the CVLT-C in children with BECTS to analyze the learning curve and ability to cluster semantically related items, while also considering recall performance after short- and long-delay. We also consider the number of learning and recall errors, as well as performance in a recognition task. We compare the results obtained in a group of patients with typical active BECTS with the results of a control group, and the relationship between selected EEG characteristics and the BECTS group’s performance.

2. Method 2.1. Participants C. Besta National Neurological Institute in Milan is a center of excellence for the study of childhood epilepsy. In this prospective, single-institution, cross-sectional study, 52 children with typical BECTS were enrolled and followed up between 2003 and 2005. The study was approved by the Institute’s ethics committee. Patients were selected according to the following inclusion criteria: (1) age >6 years; (2) uneventful pregnancy and delivery, normal neonatal status and early psychomotor development, normal neurological findings; (3) no mental delay (full scale IQ > 80), no associated disorders, including language, learning, or specific developmental disorders, and no major behavioral disorders; (4) right-handedness with no family history of left-handedness as determined by the Briggs and Nebes Handedness Inventory [22]; (5) serial awake and sleep EEG recordings showing the typical BECTS pattern in at least three consecutive recordings; (6) no brain lesions or structural anomalies on MRI; (7) parental consent to participation in the study and willingness of the children to cooperate. Twenty-four subjects (including 8 girls) took part in the study. At the time of our neuropsychological assessment, their mean age was 9 years 5 months (range: 7 years to 12 years 7 months). The number of seizures recorded in their medical history up to the assessment varied from 3 to 10 (median = 4). BECTS had been diagnosed when the children were a mean of 7 years old (range: 3 years 2 months to 11 years), and the time elapsing between their diagnosis and our evaluation ranged from 1 year 5 months to 9 years 4 months. At the time of our assessment, only five children were on antiepileptic medication (carbamazepine in 3 cases, valproate in 2). A control group of 16 children (5 girls) were collected from among the patients’ healthy classmates of the same gender and socioeconomic status, with no known learning, language, or neurological problems. Their mean age was 10 years (range: 7 years 5 months to 13 years). The school records of patients and controls were within the normal range for their class. 2.2. EEG characterization Serial EEG recordings were available for all patients; interictal EEG abnormalities were assessed on the latest EEG polygraphic recording, which was always obtained within 2 months of the neuropsychological assessment. A digitized EEG was recorded using 20 electrodes (10–20 International System) together with polygraphic derivations (electro-oculography, spirography, and submental EMG) and included 20 min in the awake state with the eyes closed,

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intermittent photic stimulation and hyperventilation, and at least one non-REM sleep cycle. The EEG signal was evaluated using longitudinal bipolar and A1 + A2 referential montages. In accordance with our inclusion criteria, the EEG invariably revealed broad diphasic spikes in all patients, often followed by a slow wave that occurred in isolation or in clusters [23]. Depending on location and maximum negativity (using referential derivations), diphasic spikes were classified as midtemporal (T3/C4), central (C3/C4), or parietal (P3/P4). The location of the discharges was defined as right-sided (R) or left-sided (L). The spikes were classed as multifocal when, within the same recording, their location clearly varied in the same hemisphere or occurred homotopically or heterotopically on the other hemisphere. Rolandic spike complex frequency was assessed while awake and during non-REM sleep, and was classified as absent = 0; rare (fewer than 10 spikes/min) = 1; intermediate (more than 10 spikes, isolated and/or in brief clusters lasting 10–50% of the recording time) = 2; or high (lasting more than 50% of the recording time) = 3. Any epileptic activity with different morphological characteristics or distribution was noted. The awake EEG recordings revealed rare interictal spikes in 13 of 24 children, whereas drowsiness and sleep invariably activated the onset of centrotemporal spikes in all cases. Epileptiform activity was quantified visually rather than by applying pattern recognition methods to detect and quantify spikes because visual inspection is a reliable method for detecting and quantifying rolandic spikes, given their specific morphological features and time course. Moreover, using automated methods is sometimes troublesome, especially when performed on sleep traces, and, in principle, they are no more reliable than visual methods. 2.3. Neuropsychological measures 2.3.1. Wechsler Intelligence Scale for Children—Revised The Wechsler Intelligence Scale for Children—Revised [24], adapted and standardized on an Italian sample by Orsini [25], yielded a full intelligence quotient (FIQ) consisting of verbal (VIQ) and performance (PIQ) subtests. 2.3.2. CVLT-C 2.3.2.1. Monday list. A list of 15 words, 5 each from three semantic categories (fruit, clothing, and toys), are presented orally by the examiner. At the end of each repetition, subjects have to recall as many words as possible in any order. The following indexes were recorded: (1) number of correct words recalled in each of the five trials; (2) total number of words correctly recalled in all five trials; (3) learning index (the difference between trials 5 and 1); (4) percentage of recall consistency for trials 1–5, calculated as (number of times an item correctly recalled on list A in trials 1–4 was recalled at the next trial/total number of items correctly recalled on list A in trials 1–4)  100; (5) number of semantic clusters (i.e., a correct word is reported after another correct word from the same category). We corrected the number of semantic clusters actually recorded by the number of clusters obtainable by chance, in accordance with Vicari et al. [26]. To calculate the number of clusters that can be obtained by chance for a given number of words and categories recalled from the list [27], we used the equation

ER ¼

n21 þ n21 þ    n2k 1 N

where ER is the number of expected (chance) clusters, n12, n22, and nk2 are the numbers of items recalled from the various categories, and N is the total number of items recalled. We calculated the clus-

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tering score as the difference between the number of observed clusters and the number of expected clusters. 2.3.2.2. Thursday list and proactive interference. A second 15-word interference list, which had to be recalled once, was then introduced. Proactive interference is measured as the difference between the number of correct words recalled in trial 1 of the Monday List and the number of words from the Thursday List correctly recalled. 2.3.2.3. Short-delay recall. After this task, short-delay recall of the Monday List was tested freely (short-delay free recall) and then with semantic cues (short-delay cued recall). 2.3.2.4. Long-delay recall. Following a 20-min delay, long-delay recall of the Monday List was measured, again both freely (long-delay free recall) and with semantic cues (long-delay cued recall). 2.3.2.5. Errors. We considered as errors: (1) intrusions (‘‘recalled” words that were not actually on the list) and (2) perseverations (repetitions of responses already given in the same trial). The total numbers of errors made in learning trials and delayed tests were calculated for both indexes. 2.3.2.6. Recognition task. This test uses a yes/no procedure in which 45 words are presented, including 15 target words from the Monday List. The level of performance is reflected in the number of hits (yes on a target item) and the number of correct rejections (no on a distractor).

3. Results 3.1. Data analysis Both the BECTS group and the control group were divided into subgroups by age: <10 (group 1: 15 children with BECTS and 7 control subjects) and >10 (group 2: 9 children with BECTS and 9 control subjects). The numbers of males and females in the two BECTS subgroups were comparable to those in the age-matched control groups (two-tailed Fisher’s exact test, P = 1 for both groups). We decided to divide the subjects into two groups because the spontaneous use of semantic organizational strategies to facilitate learning emerges at a relatively late stage of development and improves with age [20]. It has also been demonstrated that there is a progressive increase with age in the capacity to spontaneously organize study material more effectively [26], with a significant increase in reliance on semantic clustering from about age 10 onward [28]. We conducted: – A t test for independent samples to compare the performance of subjects with BECTS and contol subjects and a t test for paired samples to compare data within subjects. – A mixed analysis of variance (ANOVA) for repeated measures to analyze the learning curves for Monday List trials 1–5 and clustering score across five trials. – The Mann–Whitney nonparametric test to compare the results of subjects with BECTS and control subjects in terms of errors and recognition indexes, as these variables are not normally distributed. – A one-way ANOVA to compare neuropsychological performance according to EEG features and a least significant difference post hoc analysis to investigate which groups differed from each other (Patients were grouped by side of epileptic spikes and unifocal versus multifocal spike location.)

– Spearman’s nonparametric rank correlation to test the relationship between spike rate, measured on an ordinal scale (0–3), and CVLT-C data. Analyses were based on raw scores; the significance level was set at 0.05. 3.2. EEG findings Table 1 summarizes the main EEG and clinical features. The interictal epileptic spikes had a right location in 16 children (10 in group 1, 6 in group 2) and a left location in 8 (5 in group 1, 3 in group 2). Spike activity was classified as unilateral in 16 cases (8 in group 1, 8 in group 2) and multifocal in 8 (7 in group 1, 1 in group 2). During the awake EEG recording, 13 children had only rare interictal spikes, whereas drowsiness and sleep invariably prompted the onset of rolandic and/or midtemporal spikes. We classified epileptiform activity during sleep as rare in 8 children, intermediate in 5, and high in 11. 3.3. Neuropsychological test results 3.3.1. IQ Both BECTS groups had mean IQ scores within the normal range. In group 1, children with BECTS did not differ from the control group in terms of VIQ and FIQ [BECTS group: FIQ = 105.93 (SD = 14.99), VIQ = 106.67 (10.97); control group: FIQ = 116.71 (8.73), VIQ = 111.71 (8.73)], whereas a significant difference emerged in PIQ [BECTS group: 103.47 (17.51), control group: 118.57 (8.89); t = 2.68, P = 0.014]. No significant correlation was seen between PIQ and CVLT-C indexes. In group 2, there was no difference between the children with BECTS and the control group [BECTS group: FIQ = 110.33 (14.52), VIQ = 105.11 (11.37), PIQ = 114.22 (16.22); control group: FIQ = 119 (13.14), VIQ = 115.78 (11.71), PIQ = 115.83 (12.55)]. 3.3.2. CVLT-C results 3.3.2.1. Monday list. In group 1, the total number of words recalled across five trials was significantly lower for children with BECTS than for control children [t = 2.4, P = 0.027]. A 2  5 mixed analysis of variance showed a main effect of Trial [F(4,80) = 50.12, P < 0.001], as all participants tended to recall more items at later trials, and a main effect of Group [F(1,20) = 4.67, P = 0.043], as the control group recalled more words across the five trials. The Trial  Group interaction was not significant [F(4,80) = 1.51, P = 0.206], suggesting that the pattern learning across the trial was similar for patients and controls (see Fig. 1a). A serial paired t test was conducted specifically to analyze differences between trials within the two groups. Both patients and controls showed a significant increase between the first and second repetitions [BECTS group: t = 5.28, P < 0.001; control group: t = 5.61, P = 0.001] and between the second and third repetitions [BECTS group: t = 3.06, P = 0.009; control group: t = 0.26, P = 0.022], and thereafter only a slight, not statistically significant increase in the number of words recalled per trial. An independent t test showed that the difference between the children with BECTS and the control children was significant only in the fourth and fifth trials [t = 2.3, P = 0.032, and t = 2.78, P = 0.012, respectively]. That patients had a more limited learning capacity than controls over trials 1–5 was confirmed by the significantly lower learning index of the children with BECTS [t = 2.49, P = 0.028]. On the other hand, recall consistency did not differ between two groups across the five trials [t = 1.24, P = 0.231]. In group 2 no significant difference emerged between the BECTS and control groups in the total number of words recalled across the

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C. Vago et al. / Epilepsy & Behavior 13 (2008) 600–606 Table 1 EEG features Partecipant No/sex

Age at exam (yr.mo)

Prominent focus

Associated foci

Other epileptic abnormalities

Classification

1/F 2/M 3/F 4/F 5/M 6/M 7/F 8/M 9/F 10/M 11/F 12/M 13/M 14/M 15/M 16/M 17/M 18/M 19/F 20/M 21/M 22/F 23/M 24/M

10.3 12.7 10.3 9.1 12.5 9.6 9.7 9.0 12.7 11.3 7.11 7.0 11.9 7.6 12.6 7.5 7.4 7.00 11.7 7.11 8.8 8 9.6 8.11

T4 T3 T4 T4 C4 C3 C4 T4 T4 T4 C4 T3 C3 C4 C4 T4 C4 C4 C3 C3 C4/P4 T3 C4 C3

None None C3 None None None Cz T3 None None None None None None None None T4 T3 None T3 None P3 None T4

Rare, isolated generalized SWS during sleep none Rare, isolated generalized SWS during sleep None Rare generalized SWS during ips Rare, isolated generalized SWS during sleep None None None None None None None None None None None None None None None None None None

R L R R R L R R R R R L L R R R R R L L R L R L

Rate of discharges Awake

Non-REM sleep

0 0 2 1 0 1 1 1 1 1 0 1 0 0 0 1 1 1 0 1 1 1 2 0

1 1 3 2 1 2 1 3 3 3 2 3 1 1 2 3 3 3 1 3 2 3 3 1

F, female; M, male; T, temporal; C, central; P, parietal; SWS, slow wave sharp; ips, intermittent photic stimulation; R, right; L, left; 0, absent spikes; 1, fewer than 10 spikes/ min; 2, more than 10 spikes encompassing 10–50% of the recording time; 3, spikes encompassing more than 50% of the recording time.

b

14

14

13

13

12

12

11

11

Recalled Words

Recalled Words

a

10 9 8

Group 1

7

10 9 8 Group2 7

BECTS 6

BECTS

6 Controls

5 1

2

3

4

5

Trials

Controls

5 1

2

3

4

5

Trials

Fig. 1. Number of recalled words along the five learning trials of the Monday List for patients and controls in group 1 (a) and group 2 (b).

five trials. Analysis of the learning curves revealed a main effect of Trial [F(4,64) = 49.338, P < 0.001], but not of Group [F(1,16) = 0.11, P = 0.917] (see Fig. 1b). The independent t test revealed no significant difference between the children with BECTS and the control children in any of the trials. Instead, patients and controls both showed a significant increase in the number of words recalled between the first and second repetitions [BECTS group: t = 5.28, P < 0.001; control group: t = 5.61, P = 0.001] and between the second and third repetitions [BECTS group: t = 3.06, P = 0.009; control group: t = 0.26, P = 0.022], with only a slight improvement thereafter. 3.3.2.2. Clustering score. In those younger than 10, there was a main effect of Groups [F(1,20) = 0.12, P < 0.001], but not of Trials, with a constant clustering score across the five trials [F(4,80) = 0.48, P = 0.903] (see Fig. 2a). The BECTS group had a

lower clustering score than the control group in the second (t = 3.491, P = 0.029), third (t = 2.105, P = 0.048), and fifth (t = 2.341, P = 0.030) trials. A serial paired t test showed that there was no significant difference in clustering scores in trials 1–5 for either patients or controls. Conversely, there was a main effect of Trial [F(4,64) = 49.338, P < 0.001], but not of Group [F(1,16) = 0.11, P = 0.917] on the clustering scores in group 2, meaning that both patients and controls tended to produce more semantic clusters in later trials, but with no difference between the two groups (see Fig. 2b). The post hoc analysis indicated that the results for the children with BECTS and controls were comparable. Moreover, the increase in clustering scores in subsequent trials was not statistically significant for either the children with BECTS or the controls.

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b

3.0

3.0

2.5

2.5

2.0

2.0

Clustering Score

Clustering Score

a

1.5 1.0 Group1

.5 0.0 -.5 1

2

3

4

1.5 1.0 Group 2

.5

BECTS

0.0

Controls

-.5

BECTS Controls 1

5

2

3

4

5

Trials

Trials

Fig. 2. Clustering scores along the five learning trials of the Monday List for patients and controls in group 1 (a) and group 2 (b).

3.3.2.3. Thursday list and proactive interference. We found no differences in Thursday List recall or proactive interference. 3.3.2.3.1. Recall. We compared the results obtained in patients and controls in short- and long-delay recall, in free and cued conditions. In group 1, control children performed significantly better than children with BECTS in long-delay with semantic cues [t = 2.61, P = 0.017], whereas we found no differences in group 2. 3.3.2.3.2. Errors. The numbers of intrusions and perseverations in learning trials and delayed tests were comparable for children with BECTS and controls, in both groups 1 and 2. 3.3.2.3.3. Recognition. There were no differences between the children with BECTS and control children in either age group with respect to recognition variables, number of hits, and number of correct rejections, Table 2 summarizes the CVLT-C results for patients and controls in groups 1 and 2.

3.4. Relationship to EEG features Spike ratio during the awake and sleep EEG recordings showed no significant correlation with patients’ scores in either age group. We divided the patient groups according to the prominent EEG spike location (right vs left, multifocal vs unifocal) and compared the CVLT-C results obtained in the children with BECTS and controls. In group 1, comparison of the subjects with BECTS with a right or left focus versus control children revealed no significant difference in CVLT-C results. The comparison between controls and patients with unifocal or multifocal spikes revealed a significant difference in cued long-delay results [F(2,19) = 4, P = 0.045] and a trend toward a decreased number of words recalled from the Monday List [F(2,19) = 2.38, P = 0.051]. Post hoc analysis indicated that patients with multifocal EEG spikes

Table 2 CVLT-C data

Monday list Trial 1 Trial 2 Trial 3 Trial 4 Trial 5 Learning score Recall consistency Clustering score Trial 1 Clustering score Trial 2 Clustering score Trial 3 Clustering score Trial 4 Clustering score Trial 5 Thursday list Correct words Proactive interference Short delay Free Cued Long delay Free Cued Errors Intrusions Perseverations Recognition Hits Correct rejection

Patients Group 1- M (sd)

Control Group 1- M (sd)

Patients Group 2- M (sd)

Control Group 2- M (sd)

5.6 (1.59) 7.8 (1.42) 9 (2.14) 9.47 (1.81) 9.73 (1.91) 4.13 (1.64) 75.46 (7.36) 0.02 (1.08) 0.18 (0.71) 0.09 (1.24) 0.02 (1.30) 0.01 (1.21)

5.86 (1.77) 8.86 (1.57) 10.14 (1.68) 11.14 (0.9) 11.86 (0.9) 6 (1.63) 79.41 (6.09) 0.75 (0.63) 1.16 (1.07) 1.09 (0.84) 1.03 (1.73) 1.48 (1.46)

7.33 (1.32) 10.11 (1.27) 11.89 (2.03) 12.33 (1.22) 12.89 (1.36) 5.56 (1.81) 86.14 (8.5) 0.43 (0.87) 0.07 (0.8) 0.65 (0.98) 1.57 (1.72) 2.57 (1.29)

7.22 (2.82) 10 (2.12) 11.56 (1.74) 12.44 (1.88) 13 (1.80) 5.77 (3.41) 82.56 0.94 (1.78) 1.03 (0.86) 1.39 (0.8) 1.74 (0.99) 2.63 (0.85)

5.53 (1.96) 0.06 (1.91)

5.29 (1.60) 0.57 (1.71)

7 (1.87) 0.33 (1.8)

8.78 (2.28) 1.56 (3)

8.67 (2.23) 8.53 (2.07)

10.43 (1.13) 10.14 (0.9)

12.11 (2.18) 11.67 (1.58)

12 (2.18) 12.22 (1.72)

9.33 (1.91) 8.67 (1.72)

10.57 (1.27) 10.71 (1.70)

12.22 (1.64) 12.11 (1.54)

12.44 (2.01) 12.44 (2.01)

4.27 (4.28) 6.27 (4.43)

2.57 (2.51) 8.57 (6.57)

2.44 (3.09) 5.56 (3)

2.11 (2.08) 4.78 (1.39)

13.67 (1.59) 28.2 (1.66)

14 (0.82) 28.86 (1.57)

14.67 (0.71) 29.67 (0.71)

14.89 (0.33) 30 (0)

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fared significantly worse than controls in both the above-mentioned measures. In group 2, the comparison between controls and patients with BECTS with right or left foci revealed no significant differences. We were unable to compare subjects with multiple foci against those with a single focus and controls because of the small number of cases with multifocal anomalies in our series.

4. Discussion In this study, intelligence performance, competence in learning and retrieval of verbal material, and the ability to use learning strategies were analyzed in a sample of children with BECTS followed up and tested at the same center. We found that: (1) there were no statistical differences between the BECTS and control groups in terms of FIQ and VIQ, but the children with BECTS younger than 10 did significantly less well than their controls with respect to PIQ, which involves mainly visuoperceptual abilities; (2) in group 1, children with BECTS exhibited lower capacity for verbal learning and a lower semantic clustering score; (3) the younger children (group 1) had a selective decrease on semantically cued recall after a 20-min delay, whereas short- and long-delay free recall were intact in both groups; (4) the numbers of intrusions and perseverations in children with BECTS in both age groups were comparable to the results for controls. With respect to point 2, children younger than 10 had mild learning performance difficulties, which became more evident in the last two trials, as confirmed by the fact that the learning index was significantly higher in the control group. Recall consistency was comparable in patients and controls across consecutive presentations of the list, implying that the children with BECTS had no difficulty in formulating or maintaining a learning plan. The younger children with BECTS were less efficient in using a semantic clustering strategy, however: this would seem to explain their inadequacy in learning the list of words presented, as processing verbal information at a deeper, semantic level leads to better recall than processing it at a shallower, phonological or perceptual level [29]. A limited ability to organize information to remember by semantic attributes and to take advantage of semantic cues to facilitate encoding was observed only in the younger children with BECTS; no such difference emerged between children with BECTS and controls older than 10. As mentioned earlier, this strategy emerges relatively late in a child’s development [20]. Albeit with the limits of a cross-sectional, not longitudinal study, this finding seems to suggest that an epileptic focus at the centrotemporal site gives rise to a disturbance that further delays the acquisition of the spontaneous ability to use more efficient encoding and retrieval strategies. Consistent with the above findings, we can speculate that the poor performance on cued recall after a long delay in group 1 might also be attributable to a weaker ability to draw on the semantic cue given explicitly in the instructions. It may be that the central role of semantic retrieval strategies emerges only after a long delay because items should be organized into semantic categories during their retention [30,31]. On the other hand, retrieval efficiency after a short-delay might be more influenced by factors linked to immediate recall, such as rehearsal processes and the contribution of short-term memory [26]. The poor semantic clustering in our younger subjects may suggest a deficit in the use of executive control processes to organize material efficiently. Selecting and implementing organizational strategies geared to improving performance in a task are processes based on the activation of frontal regions [32]. Adults with frontal lobe lesions fare poorly in free recall tests, particularly when the tests depend heavily on the use of memory strategies, such as

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those using multiple learning trials [33] or categorized word lists [34]. Previous studies on children with BECTS found significant impairments in functions managed by the frontal lobe, such as attention, learning strategies, and response organization [11], control of impulsivity and inhibition [35,36], and strategic access to mental lexicon [9,15]. As regards qualitative errors analysis, our children with BECTS did as well as control children in terms of the number of words recalled that were not actually on the list, in both learning trials and delayed tests, meaning that their ability to inhibit irrelevant information was intact. Previous studies reported deficits in some frontal functions, whereas others found them unimpaired in both children [37,38] and adults [39] with frontal epilepsy. Our results also support the idea that, although the epileptic activity is concentrated mainly in the centrotemporal regions, variations in its local extent and contralateral diffusion [40], and any secondary generalization, might also interfere with the development of cortical areas apparently not strictly related to the primary site of the typical focus of BECTS [41]. We analyzed the CVLT-C data in relation to specific features on EEGs obtained within 2 months of the neuropsychological assessment. There was evidence of children with multifocal anomalies having more difficulty with cued recall after a long delay, which is consistent with our earlier findings of subjects with multifocal anomalies having more severe deficiencies in language tests [15], and also with the report from Woolf [42], who found lower cognitive test scores in children with multifocal spikes. It is also worth noting that seven of the eight cases with multifocal anomalies in our sample were younger than 10. No differences emerged in the CVLT-C data in relation to the side of the epileptic focus. Some studies have reported a correlation between neuropsychological impairments and side of epileptic focus [15,43,44], whereas several others have found no such relationship [13,19,37,45]. As emphasized in our previous work [15], BECTS is characterized by a cortical hyperexcitability that may vary with time in location, side, and degree, leading to the transient appearance/disappearance of additional dysfunctional areas. Finally, we failed to demonstrate any significant relation between CVLT-C performance and spike frequency. This would suggest that cortical dysfunctional states depend on a period of hyperexcitability rather than on the time course (and quantity) of the spikes at the time of the test. Our results are consistent with the majority of previous studies [14,42,44], including one in which the neuropsychological assessment was conducted at much the same time as a combined EEG/ MEG examination [42]. In conclusion, our results indicate that children with BECTS exhibit impairments in the ‘‘organizational” and ‘‘strategic” aspects of verbal learning and memory. Response organization, the use of adequate strategies, and frontal lobe functions, in general, mature during the period in which BECTS mainly occurs and would consequently be more susceptible to the related multifocal epileptic activity, which would delay the development of these abilities [11]. Acknowledgments This study was supported by a grant from the Fondazione Mariani per la Neurologia Pediatrica dedicated to ‘‘Neuropsychology of Epilepsy with Centrotemporal Spikes.” The authors thank Frances Coburn and Andrew Bailey for help with the English. References [1] Lundberg S, Eeg-Olofsson O. Rolandic epilepsy: a challenge in terminology and classification. Eur J Paediatr Neurol 2003;7:239–41.

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