Subclinical epileptiform activity in children with electrical status epilepticus during sleep: Effects on cognition and behavior before and after treatment with levetiracetam

Epilepsy & Behavior 27 (2013) 40–48

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Subclinical epileptiform activity in children with electrical status epilepticus during sleep: Effects on cognition and behavior before and after treatment with levetiracetam Helge Bjørnæs a,⁎, Kristin A. Bakke a, Pål Gunnar Larsson b, Einar Heminghyt a, Elisif Rytter a, Line M. Brager-Larsen c, Ann-Sofie Eriksson a a b c

National Centre for Epilepsy, Oslo University Hospital, Norway Department of Neurosurgery, Oslo University Hospital, Norway Vestre Viken Hospital Thrust, Drammen, Norway

a r t i c l e

i n f o

Article history: Received 1 August 2012 Revised 2 December 2012 Accepted 8 December 2012 Available online 31 January 2013 Keywords: Electrical Status Epilepticus during Sleep (ESES) EEG Levetiracetam Learning and memory Vigilance Behavior Spike index

a b s t r a c t We performed a double-blind placebo-controlled crossover study of the effects of spike activity during sleep and when awake on learning, long-term memory, vigilance and behavior before and after treatment with levetiracetam in children with electrical status epilepticus during sleep. At baseline, verbal learning declined with increasing spike activity, but there were no relations between spike activity and memory, vigilance or behavior. Levetiracetam was effective in reducing sleep-related spike activity, but on a group level, this had no clear effects on behavior, vigilance or learning and memory. Our results do not allow firm conclusions whether to treat nocturnal epileptiform activity or not; larger samples and longer follow-up may be needed. © 2012 Elsevier Inc. All rights reserved.

1. Introduction Patry et al. [1] described six children with epileptic seizures and/or cognitive deficits who all demonstrated a dramatic increase in epileptiform activity during non-REM (NREM) sleep. They termed this activity “electrical status epilepticus induced by sleep, ESES”. Since then, a number of studies have addressed nocturnal epileptiform activity in children and linked it closely to the diagnoses of epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS) [2], the Landau–Kleffner syndrome [3], and benign childhood epilepsy with centrotemporal spikes (BCECTS) [4–7]. Nocturnal epileptiform activity is also reported in a substantial proportion of children with autism [8], ADHD [9,10], and language problems [11]. Many of these children have never had epileptic seizures. Nocturnal epileptiform activity is now considered by many researchers as an epileptic encephalopathy with a specter of consequences on cognition and behavior that differs in form, degree and prognosis depending on the amount, age at onset, duration, localization, and treatment of the activity [12–19]. ⁎ Corresponding author at: National Centre for Epilepsy, PO Box 53, 1306 Bærum Postterminal, Norway. Fax: + 47 67501188. E-mail address: [email protected] (H. Bjørnæs). 1525-5050/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2012.12.007

In its most extreme form, the CSWS syndrome, young children experience a dramatic global developmental regression with loss of most earlier acquired cognitive abilities, including language [14]. A somewhat less pervasive regression is seen in the Landau–Kleffner syndrome, where children develop severe aphasia or even, in some instances, generalized auditive agnosia [20]. In both syndromes, behavior deteriorates over time. Negative effects on cognition and behavior are described even in benign childhood epilepsies with centrotemporal spikes [21–23]. As one possible explanation of the devastating effect of epileptiform activity during NREM sleep, Tassinari et al. hypothesized that spike activity would interfere with the consolidation of memory traces and, thus, “wipe out” what was acquired during the day, the so-called “Penelope Syndrome” [24]. In the paper of Patry et al. [1], all the children had the EEG phenomenon ESES, and according to the definition of ESES, had more than 85% of their NREM sleep potentially disturbed by spike activity. However, the criterion of 85% or more is arbitrarily chosen, and many children with nocturnal spike activity during NREM sleep – perhaps most of them – donot fulfill the criterion [25,26]. Little is known about the effects on cognition and behavior of nocturnal spike activity in children. In addition, children may have different vulnerabilities to the potentially deteriorating effects of spiking during NREM sleep — implying,

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for instance, that the same amount of spiking may have different effects on cognition and behavior in different children. Consequently, we wanted to study the relationship between amount of spiking during NREM sleep, on the one hand, and cognition and behavior, on the other. Moreover, even though spiking activity is more pronounced during NREM sleep than during REM sleep, in many children, it is not absent in REM sleep [27,28]. Studies of sleep deprivation in healthy people have suggested that NREM sleep and REM sleep have different effects on memory: While deprivation of NREM sleep seems to affect mainly consolidation of declarative memory, deprivation of REM sleep tends to hamper consolidation of procedural memory [29,30]. In addition, epileptiform activity may occur also during daytime when the child is awake [31]. Studies of inter-ictal spiking during daytime have led to the recognition of transient cognitive impairment directly related to spike activity [32,33], as well as the lasting impairment of cognitive functions and school performance in some children with excessive daytime spike activity [34,35]. Presumably, cognition and behavior may be affected by spike activity during one or more of these states. To get a more complete picture of how spike activity relates to cognition and behavior, we, therefore, included spike indexes for REM sleep and for the awake, daytime condition. In a previous paper, we studied the effect of levetiracetam (LEV) on epileptiform activity during NREM sleep [36] and found a significant mean effect with half of the children obtaining 50% or more reduction in spike activity. The present paper is based on the same study and addresses the effects of epileptiform activity during NREM sleep on cognition and behavior just before the LEV treatment was started, as well as possible changes due to treatment. In addition, we wanted to assess effects on cognition and behavior of epileptiform activity during REM sleep and during waking. More specifically, at baseline, before treatment was started, we wanted to assess whether spike activity during NREM sleep would impair recall on the following morning of memory tasks acquired the evening before, in accordance with the “Penelope syndrome” [24]. We also wanted to study possible negative effects on memory of spike activity during REM sleep and during waking. As epileptiform activity during sleep could lead to poor quality of sleep with effects upon the child's alertness the following morning, we wanted to relate measures of vigilance to spike activity during NREM sleep and REM sleep as well as to spike activity in the awake state. In addition, we hypothesized that degree of spike activity would be reflected in the child's behavior. After treatment with levetiracetam, we wanted to assess whether improvement in spike activity would be beneficial for cognition and behavior. We did not include a study of placebo effects. 2. Material and methods A new method for quantifying spike activity [37] was applied on 24-hour EEG registrations. Spike indexes (SI) defined as percentage of time with less than 3 s between spikes in 10-minute epochs were calculated for the awake state (SI-AW), during NREM sleep (SI-NREM), and during REM sleep (SI-REM). All children referred to the children's department at the National Centre for Epilepsy have a 24-hour ambulatory EEG recording. The reasons for referring children to the Centre may not always be epileptic seizures, but concerns about attention, behavior, school performance, or to investigate possible EEG abnormalities in children with ADHD or autism. Thus, children who had a 24-hour EEG recording with a spike index of at least 30% during NREM sleep and who had at least a fourfold increase in SI-NREM from awake state were consecutively considered for inclusion. In addition, children had to be between 5 and 10 years of age and have an IQ over 50. They should have been seizure free for at least six weeks prior to inclusion. Twenty-three children fulfilled these criteria and

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were invited to participate in the study. We found this randomization to either LEV or placebo ethical for the following reasons: Seventeen of the children had paediatric diagnoses (ADHD, Asperger syndrome o.a.) but no diagnoses of epilepsy. Eleven of them were treated with methylphenidate and continued on this medication throughout the study. Only four children had epilepsy and were receiving antiepileptic drugs. In these children, LEV (or placebo) were given as add on medications. Following inclusion, the children were blindly randomized to either treatment with levetiracetam (LEV) first or placebo first. The patients, then, had a 24-hour ambulatory EEG recording and a baseline neuropsychological assessment, as outlined below (T1), followed by a four-week titration period with either LEV or placebo. Levetiracetam was titrated up to 20–25 mg/kg. The titration period was followed by an eight-week treatment period. Then, a four-week wash-out/titration period followed before the children were changed from LEV to placebo or vice versa for eight weeks. Twenty-four-hour EEG recordings and neuropsychological testing were performed at the end of both treatment periods (T2 and T3). The effect of levetiracetam (LEV) treatment on the epileptiform activity during NREM sleep is reported elsewhere [35] and will be only briefly summarized in the present paper. Electroencephalograms were successfully recorded at baseline in 21 patients. The children were tested using the Norwegian version of the Wechsler Abbreviated Scale of Intelligence (WASI) [38] on the day they were going to have the baseline (T1) EEG recording. We had decided to exclude children with IQ substantially below 70 from further cognitive testing but not from analyses of treatment effects on the epileptiform activity and on behavior. One patient with total IQ of 62 was excluded, leaving 20 for further testing. On the same day, during late afternoon, those included for cognitive assessment were tested with three brief memory tests consisting of a 10-word list learning task and tests for learning/recognition of 16 faces and five abstract designs. Immediate performance was scored: For the 10-word list, we recorded number of words recalled in the best trial during acquisition, “best trial”, and for faces and designs number of items correctly recognized during acquisition. On the following morning, the children were tested for recall of the 10 words, and for recognition of the faces and designs among foils. Scores were number of items correctly recalled (words) or recognized (faces and designs), respectively. Percent remembered was calculated by dividing the score in the morning by the respective score during acquisition in the evening, multiplied by 100. This score reflects how well the learned material is preserved during the night and is regarded as an estimate of the efficiency of the consolidation process. In addition, they were tested with three tests supposed to measure attention, concentration and vigilance: a simple reaction time task, a choice reaction time task, and a semantic word fluency task (for short we name these tests “vigilance tests;” for closer description of the test methods, see Appendix A). The test procedures were repeated at T2 and T3 with parallel versions of the memory tests but with the same vigilance tests. At baseline, the test results were deemed invalid in two children due to insufficient cooperation, leaving 18 test protocols for the baseline analyses. Additionally, five children dropped out of the testing later on: two discontinued the study because of adverse effects on behavior, one because of a positive effect on behavior while on LEV which the parents would not jeopardize by continuing the study, one refused to participate in testing for the third time, and the test protocol was canceled in one child because there was insecurity about the administration of LEV. Thus, only 13 test protocols remained for analyses of treatment effects. On each of the three test occasions, one of the parents filled in two questionnaires: Norwegian versions of the Strength and Difficulties Questionnaire, SDQ [39,40] and of the Child Health Questionnaire (CHQ) [41,42]. Both questionnaires require description of the children's health conditions and behavior during the last weeks prior to admittance, SDQ rendering scores on 7 clinical scales, CHQ on 15 scales (se Appendix A). Complete data on behavioral measures were available for baseline analyses in 19 children, and for assessment of treatment effects in 17 children.

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In all cases except two, the same parent filled in the questionnaires on all three occasions. As we had relatively wide ranges both in spike indexes and in cognitive levels among the children at baseline (see Table 1), we decided to study the relationships between spike indexes and cognition/behavior by means of correlations. Multiple regression analyses were considered but abandoned because the independent variables were closely correlated. Because there were a couple of outliers in the distribution of spike indexes, we decided to use Spearman's rank order correlations which are less sensitive to outliers than Pearson's product-moment correlations [43]. Changes in memory, vigilance and behavior from baseline to the LEV condition were studied as functions of the parallel changes in spike indexes by means of correlations. Spearman's correlations were chosen here as well for the same reasons as mentioned above. This procedure was also supposed to minimize possible effects of slight differences in difficulty between the test versions used at the three occasions (see Appendix A). Corrections for multiple comparisons were made within each table of correlation coefficients by means of the Bonferroni–Holm's procedure [44]. As this procedure is rather strict when applied on comparisons of sets of variables that are more or less correlated, and the samples vary a little in number of patients from one comparison to another, we show both the corrected and uncorrected p-values. Because the present paper includes pre-treatment analyses in addition to analyses of treatment effects, and some children dropped out of the study at different stages and for different reasons, the presented numbers of patients are slightly different from those in our previous study mentioned above [36]. At baseline, brain areas most heavily involved in spike activity during sleep were located to the left hemisphere in five children, to the right hemisphere in eight children, and in five the activity was bilateral. Among those children who later on dropped out of the study, one had a focus in the left hemisphere, three in the right, and one had bilateral spike activity, leaving four left, five right, and four bilateral, respectively. Thus, there is no substantial bias with respect to side of foci. With respect to the anterior–posterior axis, most children (eleven) had foci in the central/temporal regions, four had foci in the central/parietal regions, two in the occipital lobes, and one in the prefrontal area. There were no known structural abnormalities. None of the children had epileptic seizures during the study. The study was approved by the Regional Ethics Committee. 3. Results

Table 2 Baseline learning and memory performance in relation to spike indexes. N = 16–18 SI-NREM

SI-AW

SI-REM

Verbal learning Best learning trial N.o. words following morning Percent remembered

−.68⁎⁎ (*) −.49⁎ (ns) −.32

−.71⁎⁎ (*) −.50⁎ (ns) −.32

−.72⁎⁎ (*) −.49⁎ (ns) −.30

Face recognition Immediate Following morning Percent remembered

−.31 −.30 −.01

−.01 −.21 −.32

−.20 −.25 −.15

Design recognition Immediate Following morning Percent remembered

−.31 −.53⁎⁎ (ns) −.01

−.44 −.55⁎⁎ (ns) −.01

−.44 −.57⁎⁎ (ns) .00

The table shows rank-correlation coefficients between scores on cognitive tests and the spike indexes during non-REM sleep (SI-NREM) when awake (SI-AW) and during REM sleep (SI-REM). In brackets: significance levels after correction for multiple comparisons. N.o., number of. ⁎ p b .05. ⁎⁎ p b .01.

recall of verbal material, and a lower number of designs recognized the following morning, while low spike activity relates to better performance. There are no significant correlations with face recognition and, nota bene, with any of the indexes of consolidation (percent of learned material remembered the following morning, see Appendix A). Only the correlation coefficients between verbal learning, best trial, and spike activity during REM sleep, NREM sleep and when awake remained significant following correction for multiple comparisons (asterisk in brackets, see Table 2). Performance on the tests supposed to measure aspects of attention, vigilance, and reaction speed the morning following overnight EEG recording is shown in Table 3. Here, with the exception of word fluency, positive correlation coefficients mean that high spike indexes are related to poor test performance. The coefficients indicate that high spike activity particularly during SI-REM is associated with slower response speed and more omissions (and vice versa). However, none of these coefficients remained statistically significant after a correction for multiple comparisons. There were no significant correlations (even uncorrected) between the spike indexes and the behavioral measures at baseline (correlation matrix not shown).

3.1. At baseline 3.2. Treatment effects: Mean changes Mean IQ in the group was 90.8 with a range from 69 to 114 (Table 1). The mean SI-NREM was 57.8% with a range from 23% to 88%, mean SI-REM was 20.5% with a range from 5.2% to 62%, and mean SI-AW was 6.1% with a range from 0.2% to 34%. Performance on the memory tests in relation to the three spike indexes is shown in Table 2. The negative correlation coefficients indicate that high spike indexes are related to low test performance and vice versa, which means that high spike activity, particularly during REM and when the child is awake, is related to impaired verbal learning (number of words recalled in best trial during acquisition), poorer Table 1 Intelligence quotient scores (IQ) and EEG at baseline. N = 19–21

Full-scale IQ SI-NREM (%) SI-REM (%) SI-AW (%)

Mean (sd)

Range

90.8 (14.5) 57.8 (19.9) 20.5 (14.6) 6.1 (10.1)

69–114 23–88 5.2–62 0.2–34

3.2.1. Spike indexes (Table 4) Repeated measures ANOVA showed a significant reduction in mean spike activity during sleep on LEV as compared with baseline, reflected in SI-NREM (F = 10.3, p b .001) and SI-REM (F = 4.7, Table 3 Baseline vigilance in the morning in relation to spike indexes. N = 16–18

Word fluency Simple reaction time Percent omissions Choice reaction time Percent comissions Percent omissions

SI-NREM

SI-AW

SI-REM

−.02 .48 .38 .43 .11 .33

−.28 .39 .33 .46 .30 .54⁎ (ns)

−.17 .54⁎ (ns) .39 .63⁎ (ns) .22 .48⁎ (ns)

The table shows rank-correlation coefficients between scores on vigilance tests and the spike indexes during non-REM sleep (SI-NREM) when awake (SI-AW) and during REM sleep (SI-REM). In brackets: significance levels after correction for multiple comparisons. ⁎ p b .01.

H. Bjørnæs et al. / Epilepsy & Behavior 27 (2013) 40–48 Table 4 Treatment effects on the spike indexes.

Table 6 Treatment effects: Vigilance before and after treatment with LEV.

N = 17

SI-NREM (%) SI-REM (%) SI-AW (%)

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N = 11–13 Baseline

Placebo

LEV

F

p

57.1 (4.7) 20.7 (3.8) 6.3 (2.6)

47.2 (6.0) 16.0 (3.1) 3.6 (1.1)

34.1 (7.3) 11.9 (3.5) 3.5 (1.2)

10.3 4.7 1.2

b.001 b.05 ns

The table shows mean spike indexes and standard deviations (in brackets) at the baseline, placebo, and levetiracetam conditions, and results of repeated measures analyses of variance (F and p-values).

p b .05). The reduction in spike activity when awake did not reach statistical significance. Post hoc tests showed that the reduction in SI-NREM from baseline to placebo was not significant, while the reduction from the placebo condition to the LEV condition was significant (p b .05), and also, of course, the reduction from the placebo condition to the LEV condition (p b 0.001). Decomposition of the changes in SI-REM showed that the only significant reduction was from baseline to the LEV condition (p b 0.05) (Bonferroni's post hoc test). On an individual basis, while on LEV, eight children (47%) had more than 50% reduction in SI-NREM and 3 (18%) had a normalized EEG. The same figures are applicable to the changes in SI-REM and also to the changes in SI-AW, all compared with the baseline level. The same three children had normalized EEG during all arousal conditions. 3.2.2. Memory tests (Table 5) After correcting for multiple comparisons, there were no significant changes in performance from baseline to the LEV condition. 3.2.3. Vigilance tests (Table 6) There were no significant changes from baseline to the LEV condition with respect to measures of vigilance. 3.3. Treatment effects: Changes in cognition and behavior as a function of changes in spike indexes

Word fluency (n.o. words) Simple reaction time (ms) Percent omissions Choice reaction time (ms) Percent commissions Percent omissions

Table 5 Treatment effects: Memory performance before and after treatment with LEV.

LEV Mean (sd)

F

p

23.0 (3.1) 457 (27) 3.1 (1.2) 615 (28) 18.5 (4.2) 6.4 (2.1)

22.1 (3.2) 483 (26) 3.5 (1.5) 589 (26) 23.1 (3.2) 4.7 (1.2)

0.3 4.7 0.5 2.4 0.3 1.5

ns ns ns ns ns ns

The table shows mean test results (raw scores) and standard deviations (in brackets) on vigilance tasks at the baseline and at levetiracetam conditions, and results of repeated measures analyses of variance (F and p-values). N.o., number of.

LEV and corresponding changes in SI-AW; however, the negative signs indicated that improvements in spike activity were related to impairments in behavior. These findings were not expected. Observation of the scatterplots underlying the correlations revealed that the correlations were heavily influenced by three outliers, case nos. 3, 4, and 21, despite the use of Spearman's correlations (see Fig. 1). As this gave a false expression of the effects on behavior of changes in spike activity, we removed these outliers from the analyses. The new correlation matrix gave two significant correlations indicating a slight positive effect on the SDQ family impact score of improvements in spike activity during NREM and when awake. After correction for multiple comparisons, none of these correlations remained statistically significant (last mentioned matrix is not shown).

Table 7 Treatment effects: Changes in spike indexes vs. changes in behavior. N = 12–15 Clinical scales

3.3.1. Behavioral measures (Table 7) Initially, we obtained several significant correlations between measures of changes in behavior from baseline to treatment with

Baseline Mean (sd)

SI-NREM

SI-AW

SI-REM

Strengths and Difficulties Questionnaire Total difficulty -.06 Emotional symptoms .06 Conduct problems .14 Hyperactivity .02 Peer problems -.28 Prosocial scale -.22 Family impact .14

-.07 -.02 .29 -.30 -.18 .07 -.28

.11 -.15 .07 -.22 -.09 -.26 -.08

Child Health Questionnaire Global health Physical functioning Social limitations, emotional Social limitations, physical Bodily pain/discomfort Behavior Global behavior Mental health Self-esteem General health perception Change in health Parental impact, emotional Parental impact, time Family activities Family cohesion

-.19 -.31 .20 -.59⁎ (ns) -.37 .16 -.11 -.43 -.40 -.28 -.71⁎⁎ (ns) -.13 -.61⁎ (ns) -.33 -.20

-.13 -.43 .11 -.42 -.21 -.13 -.41 -.25 .20 .13 -.47 -.24 -.53 -.28 .13

N = 12–13 Baseline Mean (sd)

LEV Mean (sd)

F

p

Verbal learning Best learning trial (n.o. words) N.o. words following morning Percent remembered

8.9 (0.5) 7.1 (0.8) 77.0 (5.7)

9.3 (0.5) 7.8 (0.7) 83.3 (5.8)

1.4 4.7 1.6

ns ns ns

Face recognition Immediate Following morning Percent remembered

13.2 (0.7) 12.4 (0.8) 94.2 (3.3)

13.6 (0.6) 13.4 (0.6) 98.6 (3.1)

0.3 2.3 0.9

ns ns ns

Design recognition Immediate Following morning Percent remembered

3.5 (0.4) 3.0 (0.5) 92.6 (15.2)

4.1 (0.3) 3.8 (0.4) 96.5 (9.7)

3.5 11.1 0.1

ns b.01 (ns) ns

The table shows mean test results (raw scores) and standard deviations (in brackets) on memory tasks at the baseline and at levetiracetam conditions, and results of repeated measures analyses of variance (F and p-values; in brackets: significance levels after correction for multiple comparisons). Max obtainable score on “verbal learning best trial” and “n.o. words following morning” is 10. Max obtainable score immediately and “following morning” on “Face recognition” is 16, and on “Design recognition” 5. N.o., number of.

.04 -.22 -.05 -.07 -.11 .11 -.04 -.20 .29 .06 -.30 .06 -.24 .02 .14

The table shows rank-correlation coefficients between difference scores from baseline to the levetiracetam condition on scales from questionnaires describing the children's behavior, and difference scores representing changes from baseline to levetiracetam in spike indexes during non-REM sleep (SI-NREM), when awake (SI-AW), and during REM sleep (SI-REM). In brackets: significance levels after correction for multiple comparisons. ⁎ p b .05. ⁎⁎ p b .01.

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H. Bjørnæs et al. / Epilepsy & Behavior 27 (2013) 40–48 Table 9 Treatment effects: Changes in spike indexes vs changes in vigilance. N = 11–13 SI-NREM Word fluency Simple reaction time Percent omissions Choice reaction time Percent comissions Percent omissions

.60⁎ (ns) −.54 −.14 .02 −.29 .00

SI-AW

SI-REM

.32 −.46 −.81⁎⁎ (ns) .34 −.03 −.04

.58⁎ (ns) −.47 −.37 .02 .05 .27

The table shows rank-correlation coefficients between difference scores from the baseline to the levetiracetam conditions on vigilance tests, and difference scores representing changes from baseline to levetiracetam in spike indexes during non-REM sleep (SI-NREM), when awake (SI-AW) and during REM sleep (SI-REM). In brackets: significance levels after correction for multiple comparisons. ⁎ p b .05. ⁎⁎ p b .01.

Fig. 1. Representative scatterplot showing correlations between treatment effects of levetiracetam on epileptiform activity when awake (SI-AW) (x-axis) and changes in Child Health Questionnaire scales, here exemplified by the scale “Self-esteem” (y-axis). Changes in both variables are defined as difference scores relative to baseline.

3.3.2. Memory tests (Table 8) Five of the 18 children who had cognitive assessment at baseline did not complete one or both of the two test sessions during treatment conditions. However, this did not bias the sample with respect to the statistical analyses performed as the dropouts were not significantly different from the 13 remaining children on any of the baseline measures of age, spike activity, spike focus location, IQ, memory, vigilance or behavior (Student's t-test for independent samples). Unexpectedly, the correlation coefficients between SI-AW and SI-REM on the one hand and face recognition immediately and in the following morning on the other indicated that improvements in spike activity were related to impaired test performance. One of these correlations, between SI-NREM and face recognition the following morning, remains significant even after correction for multiple comparisons. Observation of the corresponding scatterplot shows that one of the patients who showed a paradoxical behavioral

response to improvements in spike activity (case no. 4) also contributed heavily to this inverse relationship. However, changes in spike activity had no effects on measures of verbal learning or design recognition. 3.3.3. Vigilance tests (Table 9) The results were somewhat inconsistent. Improvements in spike activity were related to better word fluency but to more omissions on the simple test for reaction time. However, after correction for multiple comparisons, there were no significant correlations left. 4. Discussion We have chosen to use a new method for the calculation of spike indexes [37]. The spike indexes are calculated as the percentage of time with less than 3 s between the spikes in consecutive 10-minute epochs. This is the only published method for semi-automated assessment. It returns values with high reliability that may easily be reproduced and with low subjective influence which will make it easier to compare results from different studies and patients. The indexes seem to correspond well with visual assessment of amount of spike activity [37,45]. 4.1. Baseline results

Table 8 Treatment effects: Changes in spike indexes vs changes in memory performance. N = 11–13 SI-NREM

SI-AW

SI-REM

Verbal learning Best learning trial N.o. words following morning Percent remembered

−.50 .48 −.56

.21 −.18 .22

−.20 −.41 −.38

Face recognition Immediate Following morning Percent remembered

−.72⁎⁎ (ns) −.82⁎⁎⁎ (*) −.03

.02 −.26 .18

−.66⁎ (ns) −.63⁎ (ns) −.19

Design recognition Immediate Following morning Percent remembered

.10 −.40 −.04

.15 .24 .11

.22 −.17 .30

The table shows rank-correlation coefficients between difference scores from baseline to the levetiracetam condition on the memory tests, and the difference scores representing changes from baseline to levetiracetam in spike indexes during non-REM sleep (SI-NREM), when awake (SI-AW), and during REM sleep (SI-REM). In brackets: significance levels after correction for multiple comparisons. ⁎ p b .05. ⁎⁎ p b .01. ⁎⁎⁎ p b .001.

Most of the children selected for this study had relatively modest amounts of epileptiform activity during sleep, i.e., in the range well below 85% and with a mean SI-NREM of 57.8%, as indicated in Table 1. Actually, only three had spike activity of 85% or more during NREM sleep. Yet, the spike activity seemed to impair the learning of verbal material. As the epileptiform activity during sleep was recorded after the learning phase, the impairment is probably due to the conjoint effects of epileptiform activity during the preceding night and day. This reasoning presupposes that the amount of nocturnal and diurnal epileptiform activities is relatively constant, at least from one night (and day) to the next. Larsson et al. [46] showed that amount of epileptiform activity recorded during a full-night sleep was comparable to the amount found during sleep at sleepdeprived EEG recording at daytime, indicating relative stability at least over a few hours. It is not well-known why nocturnal epileptiform activity may entail cognitive impairments. Several possible explanations have been proposed. It is reasonable to assume that the abnormal patterns of neuronal firing during sleep may disturb the quality of sleep, thus mimicking sleep deprivation, which has clear effects on measures of alertness, attention, and vigilance in healthy people [47]. In accordance with this, increased daytime sleepiness was recently reported in children with benign rolandic epilepsy [48]. We had no indications

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of tiredness during the day in the children in our study, but this was not explicitly assessed. Normal sleep on the preceding night seems to be important for learning and memory [49]. As mentioned above, it is also hypothesized that ESES may interfere with the process of memory consolidation, which is very active during sleep, leading to an exaggerated forgetting of what was acquired during the day, called the Penelope syndrome [24]. In the present study, we did not find support for this hypothesis. Our presumed indicators of consolidation, i.e., amount remembered in percent of baseline performance, did not correlate with any of the spike indexes. This may also be due to the relatively modest amounts of epileptiform activity during sleep in the children in our study. It may be that the process of consolidation is robust to spike indexes under 85%. Our results are in contrast with the findings of a case study where memory performance of four children with different amounts of nocturnal epileptiform activity was compared with a healthy control group [50]. While the children in the control group could recall more associated word pairs following a night of sleep than immediately after learning in the afternoon, the patients recalled less. When inspecting the presented data, there were, however, no differences in the amount remembered among the patients despite large differences in nocturnal epileptiform activity: With individual spike indexes of 35%, 40%, 90%, and 97%, the amount remembered was about 84%, 70%, 75%, and 87%, respectively. This raises the question whether impaired memory performance following sleep may be related to factors other than disturbed consolidation caused by epileptiform activity. Possibly, one such factor may be impaired learning capacity, as it seems that material that is not well-acquired may not be subject to the consolidating process during sleep [51]. Another such confounding factor may be lasting metabolic changes in the child's brain related to the epileptiform activity. Metabolic disturbances, often including the frontal cortex, were found in daytime functional brain imaging in children with ESES [52,53], even with spike indexes well below 85%. If such metabolic disturbances are common also with spike indexes in the range of the present study, this could have an impact on test performance during the day. Finally, as the nightly epileptiform activity endures over time, there is a risk of suboptimal apoptosis or pruning of neuronal networks and hampered myelinization [54,55] which may lead to long-lasting structural alterations in the developing brain with consequences for cognition. Longer duration of the epileptiform activity is associated with greater impact on cognition and behavior [56]. In order to fully understand impaired cognitive performance in children with subclinical epileptiform activity, these factors ought to be addressed in future studies. We did not find any relationships between measures of vigilance in the morning and spike indexes. This may, again, be due to the relatively moderate amounts of epileptiform activity in the majority of the children in our study.

4.2. Treatment effects 4.2.1. EEG Levetiracetam seems to be an effective drug to reduce or eliminate epileptiform activity during sleep. This applies to spike activity during both NREM sleep and REM sleep. The reduction in spike activity in the awake state did not reach statistical significance. This may be due to a floor effect, as we have found that almost half of the children had SI-AW of less than 1%. Nevertheless, more than 50% of the children experienced more than 50% reduction also, here, and three children obtained a normal EEG also when awake. For further discussion of LEV in the treatment of epileptiform activity, we refer to an earlier paper from our group [35].

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4.2.2. With respect to the effects of treatment on behavior, there were no significant effects of improvement in spike activity on any of the behavioral measures after removal of three outliers (see above). This indicates that changes in the amount of epileptiform activity due to treatment with LEV do not lead to substantial changes in behavior on a group level, at least in a short term. 4.2.3. Discussion of the paradoxical findings Even though the results with respect to cases 3, 4, and 21 (Fig. 1) are not representative for the group and, thus, may be defined statistically as outliers, we have no reason to regard the results as unreliable. The same parent filled in the questionnaires at different occasions, and the EEG recordings were reliable. Patient nos. 3 and 4 showed the greatest improvements in SI-AW, but they were described by their mothers as substantially impaired behaviorally on the CHQ, more than any of the remaining children. Patient no. 4 was described as worse on all CHQ scales and patient no. 3 on 13 out of 15 scales. This paradoxical relationship between improvement in the EEG and deterioration in behavior may be related to the phenomenon called forced normalization (FN) [57,58]. It is assumed that antiepileptic drugs with potent effects on the epileptiform activity, like levetiracetam, may provoke this paradoxical relationship with behavior in some patients [59]. We want to point to this risk when administering levetiracetam to children with epilepsy. In such instances, it would probably be wise not to discontinue the drug altogether, as the paradoxical effect may, hopefully, be reversed with lowering of the dosages, as was seen when FN was provoked by lamotrigine treatment [60]. 4.2.4. Neuropsychological measures Despite significant improvements in nocturnal epileptiform activity from baseline to the LEV condition on a group level, this was not reflected in cognition, neither in memory measures nor in measures of vigilance. Neither did we find significant changes in cognition as a function of changes in the amount of epileptiform activity from baseline to the LEV condition (with one exception, see Table 8). We can only speculate why. It may be that improvements in cognition following improvements in the EEG are cumulative processes that take more time than was available in the present study. It may also be that physiological processes in the brain concomitant to a pathological EEG, like metabolic changes and interference with brain development, as mentioned above, are processes that are slowly improving second to improvements in the EEG. Only long-term follow-up of these children can shed light on these issues. The two children with the greatest treatment effects on daytime EEG, who were described by their parents to have deteriorated in behavior (patient nos. 3 and 4), were also doing worse on one or more neuropsychological tests. Particularly, patient no. 4, who experienced substantial improvements in all EEG parameters, is contributing heavily to the inverse relationships between changes in face recognition in the morning and changes in SI-NREM. Thus, it seems that paradoxical responses to improvements in epileptiform activity may also modify cognition in some patients. 5. Conclusions Interictal epileptiform activity seems to impair verbal learning, even in a group of children with a mean spike index during NREM sleep of 57.8%, substantially below the 85% originally used to define the lower limit of ESES. However, we do not find support for the hypothesis that spike activity interferes with the consolidation of memory traces (the Penelope syndrome). We found LEV to be effective in treating nocturnal epileptiform activity, but as diminished spike activity does not have clear effects on a

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group level on cognition and behavior, we are not able to conclude whether to treat or not, based on our data. Further studies with larger groups of patients and longer follow-up are needed, particularly when considering hazards for the developing brain of long-standing spike activity as reported in the literature. 6. Limitations We had many dropouts and missing data mainly because many of these children were behaviorally and emotionally unstable. Even though they were in-patients and met a stable research team, satisfactory cooperation was not easily achieved. Because of the dropouts, we ended up with relatively small groups. This limited the options for more powerful metric statistical procedures. Lack of a control group prevented us from the possibility to compare the study group with healthy children. Instead, we had to assess relations between different degrees of spike activity and performance/behavior within the study group, which limited the power of the statistical methods. We did not have a systematic recording of amount of sleep, but there were no indications that the children were sleepy during the day. Nevertheless, a systematic assessment of sleepiness could perhaps shed more light on the reasons why verbal learning was hampered in the children in our study. Likewise, in addition to the measures of IQ, a comprehensive neuropsychological assessment at baseline would be of value to better understand the concerns about the children's functioning that led to referral to our hospital in the first place. Acknowledgments The study was supported by a grant from UCB, Belgium. The placebo and LEV tablets used in the study were supplied by UCB. Thanks to Kirsten Stabell for valuable contributions in verifying the data and advice during the preparation of the manuscript, to Sverre Andresen for constructing the Face Recognition Test, and to Marit Bjørnvoll for valuable support during the final preparation of the manuscript.

The procedure is repeated until the child can repeat all words. The procedure consists of maximum ten trials. If the criterion is reached before the tenth trial, an additional trial is administered. Scores were number of words repeated in the best trial during acquisition in the evening, and number of words recalled in the following morning. Percent remembered was calculated by dividing the score in the morning by the respective score during acquisition in the evening multiplied by 100. This score reflects how well the learned material is preserved during the night and is regarded as an estimate of the efficiency of the consolidation process. Three parallel versions (A, B and C) of the 10-word lists, regarded to be equally difficult to learn, were used. The 3 versions were presented in the same order to all children, i.e., A was used at T1, B at T2, and C at T3. Face acquisition and recognition Because we wanted to test the children three times with 12 weeks in between, we wanted to use different collections of faces to minimize the learning effect. We were not aware of any standardized test for face recognition with three parallel versions, and we, therefore, constructed such collections of faces (Andresen 2010, unpublished). This was done by downloading a large number of portraits of adults from the web. Three sets of 16 faces were constructed, each with 8 male and 8 female faces. Faces were transformed from color to black and white and cropped to minimize the amount of clothing and background that was visible. The portraits were 14 × 12 cm. In the same way, 96 faces to be used as foils were constructed. The material was printed on A4 paper sheets and kept in files. Acquisition in the evening was performed by presenting one at the time of the 16 target portraits with the instruction to the child to look closely to the pictures. To ensure good attention, they were asked to tell whether the person depicted was a man or a woman. The portraits were exposed for about 5 s each. Recognition was tested immediately after the acquisition phase by showing each target and two foils in a fixed random sequence. The position of the target among foils was randomized. Portraits to be recognized were 7 × 6 cm. The child was asked, “Which of these three faces have I shown you before” and encouraged to point it out. Recognition in the morning was done in the same way, the child was now asked, “Which of these three faces did I show you in the first place?”

Appendix A. Test methods Learning and memory tests Our prime purpose was to study the effects of epileptiform activity during NREM sleep on memory for newly learned material, in order to assess the hypothesis of Tassinari et al. [24] that epileptiform activity during NREM sleep may interfere with consolidation of memory traces. We also wanted to study whether spike activity during the preceding night would affect basic cognitive functioning in the morning. In addition, we wanted to test for effects on cognition of changes in epileptiform activity due to LEV treatment. As this was a doubleblind, placebo-controlled study, we, therefore, had to test the children three times and, accordingly, to use three parallel versions of the memory tests to minimize learning effects. As tests for learning/acquisition and memory, we used a simple test for verbal learning and recall, the 10-word test described by Luria [61], a test of acquisition and recognition of faces (Andresen, 2010, unpublished), and a test for acquisition and recognition of abstract designs [62]. As tests for basic cognitive functioning, we chose a phonetic and a semantic word fluency task, a task for simple reaction time, and a choice reaction time task [63,64]. The 10-word test The test consists of a list of ten common Norwegian words. The words are read out loud to the child who repeats as many as possible.

Design acquisition and recognition We used the abstract designs in the visual memory part of the test of Visual–Perceptual Skills—Revised [62]. The test consists of 16 target designs. After 5 s, presentation of each single target, a recognition sheet with the target among 4 foils, is shown, and the child is asked to identify the target by number or by pointing. As we needed three parallel test versions to minimize learning effects, we presented only five memory items at each test session in the following way: At baseline, we presented targets and recognition sheet nos. 1-4-7-10-13, called version A, at T2 nos. 2-5-8-11-14, called version B, and at T3 nos. 3-6-9-12-15, called version C. Immediate recognition in the evening was recorded. In the morning, the children were shown the five appropriate recognition sheets only and asked to identify the targets. As the targets and foils are successively increasing in complexity in the original test, our three short versions have slightly increasing difficulty. Vigilance tests To assess basic cognitive state in the morning following a full-night EEG recording, we used the following tests: Word fluency The children were asked to produce as many words starting with the letter “s” as possible in 1 min, i.e., phonetic fluency. Then, they

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were asked to name as many animals as possible in 1 min, i.e., semantic fluency. As we realized that some of the youngest children were illiterate or bad readers, only the semantic fluency scores are used. Tests for response speed and response withholding, the ReAct tests [63,64] Simple reaction time. This is a computerized test where a red bird-like target (a “red space monster”) occurs with varying delay intervals within 3-second periods. The child is asked to press the spacebar as fast as possible at each target. The task goes on for 5 min. Mean reaction time and percent omissions were scored. Choice reaction time. The child is again asked to respond as fast as possible each time the “red space monster” occurs on the screen. However, in this version, the targets are replaced by a fixed percent of “kind space monsters” in other colors than red and a yellow “sun”. These non-targets are presented in random order within the same time frames. The child is asked not to respond to any of these. The task goes on for 10 min. Mean reaction time, percent omissions and percent commissions were scored. References [1] Patry G, Lyagoubi S, Tassinari CA. Subclinical “electrical status epilepticus” induced by sleep in children. A clinical and electroencephalographic study of six cases. Arch Neurol 1971;24:242–52. [2] Roulet Perez E, Davidoff V, Despland PA, Deonna T. Mental and behavioural deterioration of children with epilepsy and CSWS: acquired epileptic frontal syndrome. Dev Med Child Neurol 1993;35:661–74. [3] Li M, Hao XY, Qing J, Wu XR. Correlation between CSWS and aphasia in Landau– Kleffner syndrome: a study of three cases. Brain Dev 1996;18:197–200. [4] Deonna T, Roulet-Perez E. Early-onset acquired epileptic aphasia (Landau–Kleffner syndrome, LKS) and regressive autistic disorders with epileptic EEG abnormalities: the continuing debate. Brain Dev 2010;32:746–52. [5] Hughes JR. A review of the relationships between Landau–Kleffner syndrome, electrical status epilepticus during sleep, and continuous spike-waves during sleep. Epilepsy Behav 2011;20:247–53. [6] Danielsson J, Petermann F. Cognitive deficits in children with benign rolandic epilepsy of childhood or rolandic discharges: a study of children between 4 and 7 years of age with and without seizures compared with healthy controls. Epilepsy Behav 2009;16: 646–51. [7] Verrotti A, D'Egidio C, Agostinelli S, Parisi P, Chiarelli F, Coppola G. Cognitive and linguistic abnormalities in benign childhood epilepsy with centrotemporal spikes. Acta Paediatr 2011;100:768–72. [8] Ekinci O, Arman AR, Isik U, Bez Y, Berkem M. EEG abnormalities and epilepsy in autistic spectrum disorders: clinical and familial correlates. Epilepsy Behav 2010;17:178–82. [9] Wannag E, Eriksson AS, Larsson PG. Attention-deficit hyperactivity disorder and nocturnal epileptiform activity in children with epilepsy admitted to a national epilepsy center. Epilepsy Behav 2010;18:445–9. [10] Silvestri R, Gagliano A, Calarese T, et al. Ictal and interictal EEG abnormalities in ADHD children recorded over night by video-polysomnography. Epilepsy Res 2007;75:130–7. [11] Overvliet GM, Besseling RM, Vles JS, et al. Nocturnal epileptiform EEG discharges, nocturnal epileptic seizures, and language impairments in children: review of the literature. Epilepsy Behav 2010;19:550–8. [12] El Shakankiry HM. Epileptiform discharges augmented during sleep: is it a trait with diverse clinical presentation according to age of expression? Epilepsy Res 2010;89:113–20. [13] Seri S, Thai JN, Brazzo D, Pisani F, Cerquiglini A. Neurophysiology of CSWS-associated cognitive dysfunction. Epilepsia 2009;50(Suppl. 7):33–6. [14] Scholtes FB, Hendriks MP, Renier WO. Cognitive deterioration and electrical status epilepticus during slow sleep. Epilepsy Behav 2005;6:167–73. [15] Liukkonen E, Kantola-Sorsa E, Paetau R, Gaily E, Peltola M, Granstrom ML. Long-term outcome of 32 children with encephalopathy with status epilepticus during sleep, or ESES syndrome. Epilepsia 2010;51:2023–32. [16] Paquier PF, Verheulpen D, De Tiege X, Van Bogaert P. Acquired cognitive dysfunction with focal sleep spiking activity. Epilepsia 2009;50(Suppl. 7):29–32. [17] Peltola ME, Liukkonen E, Granstrom ML, et al. The effect of surgery in encephalopathy with electrical status epilepticus during sleep. Epilepsia 2011;52:602–9. [18] Kramer U, Sagi L, Goldberg-Stern H, Zelnik N, Nissenkorn A, Ben-Zeev B. Clinical spectrum and medical treatment of children with electrical status epilepticus in sleep (ESES). Epilepsia 2009;50:1517–24. [19] Yan Liu X, Wong V. Spectrum of epileptic syndromes with electrical status epilepticus during sleep in children. Pediatr Neurol 2000;22:371–9. [20] Stefanatos G. Changing perspectives on Landau–Kleffner syndrome. Clin Neuropsychol 2011;25:963–88.

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