1. No category

doi:10.1093/brain/awh494
Brain (2005), 128, 1546–1555
Three to four years after diagnosis: cognition
and behaviour in children with ‘epilepsy only’.
A prospective, controlled study
K. J. Oostrom,1,3 H. van Teeseling,1 A. Smeets-Schouten,1,4 A. C. B. Peters2 and
A. Jennekens-Schinkel1on behalf of the Dutch Study of Epilepsy in Childhood (DuSECh)
University Medical Center Utrecht, Wilhelmina Children’s Hospital, Departments of Neuropsychology1 and
Child Neurology2, The Netherlands.
Present addresses: 3University Hospital Vrije Universiteit, Department of Medical Psychology, Amsterdam and
Medical Spectrum Twente, Division of Psychology, Enschede, The Netherlands
4
Correspondence to: K. J. Oostrom, PhD, University Hospital Vrije Universiteit, Department of Medical Psychology,
Children’s Section, PO Box 7057, 1007 MB Amsterdam, The Netherlands
E-mail: kj.oostrom@vumc.nl
Keywords: child; epilepsy; cognition; behaviour; psychosocial
Received October 21, 2004. Revised February 25, 2005. Accepted March 1, 2005. Advance Access publication April 7, 2005
Introduction
At least 70% of childhood epilepsies consist of idiopathic
or cryptogenic epilepsy, also referred to as non-symptomatic
epilepsy. We refer to this well-defined subset of epilepsies
as ‘epilepsy only’ (EO) (Sillanpa¨a¨ et al., 1998). The majority
#
of these children are otherwise healthy, have normal intelligence, attend mainstream schools and become seizure-free
within the first 2 years after diagnosis, either spontaneously
or with anti-epileptic drug (AED) treatment (Berg et al., 1995).
The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
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A 3.5-year follow-up study of cognition and behaviour in 42 children with newly diagnosed idiopathic or cryptogenic epilepsy (‘epilepsy only’) attending mainstream education and 30 healthy gender-matched classmate
controls was carried out to identify differences between groups, to detect factors that contribute to the
difference and its change over time, and to establish the proportion of poorly performing children. The neuropsychological battery covered the major domains of cognition, mental and motor speed and academic
language skills. Children were tested at the time of diagnosis (before any anti-epileptic drug treatment started)
and 3, 12 and approximately 42 months later. Parents and teachers completed behaviour checklists, for which
the scoring was adapted to prevent any influence of epilepsy-related ambiguity. Based on parental interviews
at the time of diagnosis, children with epilepsy were categorized as having longstanding behavioural and/or
learning problems, as belonging to a troubled family, as being exposed to ‘off-balance’ parenting starting at the
time of epilepsy onset and/or as reacting maladaptively to the changes in relation to the onset of epilepsy.
Throughout follow-up, the group of children with epilepsy only performed less well than healthy classmates on
measures of learning, memory span for words, attention and behaviour. After controlling for school delay,
proactive interference (number of responses to the same images as in the learning trials, but now presented in
reordered locations) was the only remaining variable that distinguished the group of children with epilepsy only.
Group-wise, no changes in cognitive and behavioural differences over time were found, but instability in
individual performances appeared to characterize children with epilepsy only. Rather than intrinsically
epilepsy-related variables, such as idiopathic versus cryptogenic aetiology, seizure control or anti-epileptic
drug treatment, the child’s prediagnostic learning and behavioural histories and the parents’ ability to continue
their habitual parenting in the face of the diagnosis of epilepsy only were shown by both group-wise and caseby-case analyses to be important for understanding the cognitive and behavioural functioning of the children
with epilepsy only.
Cognition and behaviour in mild epilepsy
Subjects and methods
Subjects
Sixty-nine children with EO had been enrolled consecutively between
January 1997 and November 1998 and they had agreed to participate
three times in the first year after diagnosis. Inclusion criteria at study
entry had been at least two unprovoked non-febrile seizures or status
epilepticus, idiopathic or cryptogenic aetiology (ILAE, 1989), age
between 7 and 16 years, and attendance of mainstream education.
Exclusion criteria had been any associated neurological disorder
(identified by history, physical examination or neuroimaging),
having been diagnosed with another chronic physical disease or
previous use of AEDs. In case of doubt with respect to the nonsymptomatic nature of the epilepsy, the physician had made clear to
the parents and the child that neuroimaging (MRI) was needed to
rule out a minor chance of an underlying structural cause for the
child’s epilepsy. Only after having communicated the normal result
of MRI did the doctor introduce the present study.
Because one of the patients could not find a suitable classmate in
time, the control group consisted of 68 children, matched for gender
1547
and educational level, who provided data to control for normal
development and the effects of retesting. Excluded were classmates
with chronic conditions such as (slight) asthma or a history of
neurological conditions, as they may influence cognition and/or
behaviour. Further details on recruitment and characteristics of
the initial cohort have been reported previously (Oostrom et al.,
2003). The findings reported here concern the subset of children
who positively reacted to a telephone request for participation in
a fourth assessment. The group under study included 42 children
with EO and 30 gender-matched healthy classmate controls.
Idiopathic versus cryptogenic aetiology and syndrome classification were based on data recorded by the children’s neurologists at
diagnosis, according to a standard protocol formulated by the Dutch
Study of Epilepsy in Childhood (DuSECh) (Arts et al., 1999), which
were double-checked and, if necessary, changed after a year (Stroink
et al., 2004). In this study there was no standard protocol for discontinuation of medications after a seizure-free interval. However,
most child neurologists collaborating in DuSECh consider medication withdrawal after a 2-year seizure-free interval.
The study was approved by the ethics and research committees of
the participating hospitals. All children participated on the basis of
written informed consent by their parents. Older children (aged 12
years and over) also gave their own informed assent.
The multicentre study was prospective, longitudinal, and controlled. All children were assessed within 48 h after diagnosis, before
they started AED treatment (if prescribed), and reassessed 3, 12 and
42 (±6) months after first assessment.
Parental interviews
At the first assessment, a well-trained psychologist (A.S.-S., K.J.O.)
conducted extensive semistructured interviews with the patients’
parents. The interviewer asked preformatted questions addressing
the medical, mental and social histories of their child. The interviews
were transcribed and processed according to Chi’s guidelines (Chi,
1997). Every phrase containing information that pertained to one
of the interview variables was labelled according to the key content
of the utterance (e.g. ‘fear of stigma’, ‘worry about the future’,
‘experience of child’s death’). Analyses of 42 interviews resulted
in a grid consisting of a row for every label (79 in total) and a
column for every interviewee. Then, labels could be grouped into
five broader dichotomous domains (called ‘interview variables’)
(Box 1) (Oostrom et al., 2001a). If, per interview, more than half
of the labels within a domain reflected the presence of a difficulty
the case was allocated to the negative category for that domain
(e.g. family, ‘problems’; parenting, ‘off balance’; child’s reaction,
‘maladaptive’); if labels did not reflect difficulties/problems, the
case was allocated to the positive (‘no problems’, ‘in balance’ or
‘adaptive’) category of that interview variable. At follow-up assessments, parents were interviewed briefly in order to trace changes in
the psychosocial context of the patients.
Neuropsychological assessment
The comprehensive neuropsychological assessment covered major
domains of cognition, academic language skills, and motor and
mental speed (see Box 2 for tests, dependent variables and their
definitions). Available instruments that were downward extensions
of adult psychological tests not suitable for children were adapted.
If no proper tests were available, new tasks were developed; these
pertained to Word Span forwards and backwards and aspects of
learning and memory (learning locations; Schouten et al., 2002),
several aspects of attention (balloon piercing; Oostrom et al., 2002),
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Nevertheless, the school career of children with EO is at risk
(Austin et al., 1999; Bailet and Turk, 2000). We previously
reported that, notwithstanding average intelligence levels,
no less than 22% of children with EO had repeated a year
at school either prior to or in the first year after the diagnosis
(Schouten et al., 2001). That is appreciably more than the 11%
reported for mainstream primary schools in The Netherlands
in the corresponding period (van de Grift, 2000). Moreover,
in the group of children researched, special educational
assistance had been required for more children who were
later diagnosed with EO (51%) than for their healthy
classmates (27%). Consequences may be lifelong, as epidemiological follow-up studies involving adults who stopped
having seizures and were able to discontinue AED treatment
report lasting educational and psychosocial deprivation
(Jalava et al., 1997). However, there may be a cultural
influence, as Wakamoto and colleagues could not establish
social disadvantages in Japanese persons who had had nonsymptomatic epilepsy in childhood and who had normal
intelligence (Wakamoto et al., 2000).
Seeking to understand the educational risks, the present
authors studied cognition and behaviour during the first
year after diagnosis and reported poorer scores across several
measures in patients with EO than in healthy gender-matched
classmate controls (Oostrom et al., 2003). Group-wise, cognitive and behavioural differences existed already at baseline;
the proportion of children with deficits did not change during the first year after diagnosis, but the children who had
the deficits did change. Moreover, psychosocial context rather
than characteristics of the epilepsy were related to patients’
deficits. This prompted an extension of the study. In the
present article we report the course of cognitive and behavioural differences between children with EO and healthy
controls during the first 3–4 years after diagnosis. Again,
the impact of epilepsy variables and that of variables pertaining to psychosocial context are evaluated.
Brain (2005), 128, 1546–1555
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Brain (2005), 128, 1546–1555
Box 1 Interview variables
and behaviour regulation (Computerised Colour Trails I and II;
Oostrom et al., 2002).
The patient and control child were assessed simultaneously in a
van that was equipped with two assessment rooms and that was
stationed in the grounds of the hospital where the child with epilepsy
was treated.
Behaviour questionnaires
At every assessment parents and teachers were asked to complete behaviour checklists [CBCL (Achenbach and Edelbrock,
1991) and TRF (Achenbach, 1991)]. Ratings on the seven items
that were identified as possibly eliciting ambiguous answers, because
the rater could interpret the items in terms of both epilepsy and
behaviour, were treated as missing values (Perrin et al., 1991;
Oostrom et al., 2001b). For the interested reader, the items were:
‘confused or seems to be in a fog’ (13), ‘daydreams or gets lost in
his/her thought’ (17), ‘nervous movements or twitching’ (46), ‘stares
blankly’ (80), ‘strange behaviour’ (84), ‘wets self during the day’
(107) and ‘wets the bed’ (108). Raw scores rather than T-scores
were used for data analysis in order to maximize differences within
the normal range (Perrin et al., 1991). Only the Total Problems scale
was studied due to concerns about the construction of the CBCL and
TRF scales (Hartman et al., 1999).
Statistical analysis
Data were analysed by means of SPSS 10.0 for Windows. We used x2
analyses to test the interdependency of categorical data that were
subsequently used as between subject factors in general linear
model repeated measures analyses of variance (GLM–ANOVA;
full factorial) with neuropsychological and behavioural data as
dependent variables and time after diagnosis as within-subject factor.
Box 2 Neuropsychological Assessment Battery
Domains
Tests/tasks (parameter)
General Intelligence
Coloured Progressive Matrices. Computerised (c-CPM) (Raven
et al., 1990; Schufried, 1996a) (children aged <11 years) [norm
score (IQ)]
Standard Progressive Matrices. Computerised (c-SPM) (Raven
et al., 1992; Schufried, 1995) (children aged 11 years) [norm
score (IQ)]
Vocabulary (Wechsler Intelligence Scale for Children—
Revised, Dutch edition) (WISC-RN) (Bruyn et al., 1986) (standard
score)
Attention
Colour Trails I and II. Computerized adaptation of Color Trails
(Maj et al., 1993) (Oostrom et al., 2002) In Part I the child was
requested to connect, sequentially and as fast as possible,
numbered circles that were scattered over the touch-screen
randomly. All odd numbers were printed in a yellow circle; all
even numbers were printed in a pink circle. In Part II each number
was printed twice: once in a pink and once in a yellow circle. The
child was requested to connect circles in consecutive order from
1 to 25, by alternating between pink and yellow circles. The times
needed for Parts I and II and the difference in performance time
between Parts I and II were recorded electronically (ms).
Balloon Piercing (Oostrom et al., 2002). Seated in front of the
touch screen the child watched a sequence of 375 yellow balloons
entering the screen with randomly varying interstimulus intervals
and wandering over the screen according to a fixed pattern
of tracks. The balloons were provided with complete (target)
or incomplete (distracter) faces (ratio 3 : 10). The child had to
eliminate the targets as quickly as possible by piercing them
(a touch on the target made the balloon pop). The time (ms)
for piercing targets was recorded. The task lasted 10.3 min.
Learning
Learning Locations (computerized non-verbal task). Learning
locations of visually presented images of natural objects in a
4 · 4 matrix (Schouten et al., 2002) [total immediate (immed.)
recall: summed number of correctly recalled locations in each
of the five successive, identical learning trials (maximum = 80);
response times: electronically recorded time elapsed between
stimulus presentation and the child’s touching the location of
choice during the learning phase (ms); proactive interference
(interf.): number of responses after one presentation of the
same images as in the learning trials, but now presented in reordered locations (the higher the number of correctly recalled
locations, the lower the sensitivity to proactive interference)1].
Memory
Word span forward and backward: repeating orally presented
sequences of nouns with imaginable theme (Schouten et al.,
2002) (number of items in largest correctly repeated sequence).
Learning Locations (computerized non-verbal task). Learning
of visually presented images of natural objects (4 · 4 matrix)
(Schouten et al., 2002) (delayed recall: the number of correctly
recalled locations after a delay of 30 min filled with other tasks).
Speed
Reaction Time (Vienna Test System) (Schufried, 1996b) simple and
choice conditions, light, beep, light + light, light + beep targets
[electronically recorded mean time (RT) (ms) of correct reactions].
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Qualitative analysis of the interviews (Chi, 1997) yielded the
following five dimensions, to which contextual problems were
linked (coding between parentheses).
1. Longer existing behavioural problems dating from before the
diagnosis of epilepsy, i.e. difficult behaviour perceived by the
parent as still present but dating from before the first recognition
of signs and symptoms of epilepsy (yes/no). E.g. Being an outsider
at school, noticeably sad, noticeably hyperactive and dominant.
2. Long-standing learning problems, i.e. disappointing school
results perceived by the parent as still present but dating from
before the first recognition/appearance of signs and symptoms of
epilepsy (yes/no). E.g. Due to lack of concentration, to school
absenteeism or with no clear cause.
3. Family trouble, such as marital distress, divorce, psychopathology in another member of the family (yes/no).
4. Parents’ perceptions of discontinuity in their parenting habits in
relation to the onset of epilepsy and hearing about the diagnosis
(thrown off balance/not thrown off balance). E.g. Being emotionally overwhelmed by the signs and symptoms and diagnosis, undifferentiated fear, excessive fear of stigmatisation, steering clear of
relevant information.
5. Parent’s perception of the child’s maladaptive reaction
to changes caused by/associated with the onset of epilepsy
(maladaptive/adaptive). E.g. Excessive feelings of shame and withdrawal interfering with going to school or other social activities,
excessive fear of recurrence of seizures or of adverse effects of
anti-epileptic drugs, death wish or benefit from being ill.
K. J. Oostrom et al.
Cognition and behaviour in mild epilepsy
Box 2 Continued
Manual tapping [electronically recorded number of taps per 30 s
(dominant hand)].
Academic linguistic skills (standard educational packages; selection
based on the child’s educational level) (Bulthuis-deVeer, 1970;
Schippers and Sixma, 1974)
Reading [errors (% of number of text words)].
Writing to dictation [errors (% of number of dictated words)].
Behaviour
Child Behavior Checklist (CBCL), Dutch version (Verhulst et al.,
1996), adapted scoring (Oostrom et al., 2001) on the Total Problems scale: raw scores obtained through standard computerized
processing (Achenbach et al., 1991).
Teacher’s Report Form (TRF), Dutch version (Verhulst et al.,
1997), adapted scoring (Oostrom et al., 2001) (Raw scores on
the Total Problems scale obtained through standard computerised processing (Achenbach, 1991)].
1
Uncorrected raw score was used because the score in the
proactive interference trial was independent of prior learning.
Results
Group analyses
Characteristics of the groups studied
Statistically significantly more patients (82%) than controls
(62%) decided to reparticipate (x 2 = 11.43, P = 0.01).
Comparison of epilepsy-related, demographic, school and
interview variables did not yield any statistically significant
differences between reparticipating children with EO and
dropouts. Nor did reparticipating control children differ
from dropouts in demographic or school variables.
Characteristics of the children are displayed in Table 1.
Epilepsy was localization-related in 11 children with idiopathic epilepsy (ILAE 1.1.a) and in 19 children with cryptogenic epilepsy (ILAE 1.3.a) (eight frontal, four temporal,
and seven with no definable focus). Generalized epilepsies
included childhood absence epilepsy (ILAE 2.1.d) in seven
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and other generalized epilepsy syndromes (ILAE 2.1.h) in five
children. Immediately after the first neuropsychological
assessment, 25 children started AED treatment (12 with cryptogenic epilepsy and 13 with idiopathic epilepsy), of whom
seven were withdrawn from medication (four after being free
of seizures within 3 months of treatment; two within 6 months
of treatment; one girl decided to withdraw in spite of ongoing
sporadic tonic–clonic insults). Of the 17 children who did
not immediately start AED medication after diagnosis, seven
initiated treatment within the first 2 years; of the remaining
10 children, five children were free of seizures within at
the most 18 months after diagnosis and the other five continued to have seizures at low frequency. Interdependencies
between parameters of epilepsy appeared not to be statistically
significant.
In the interviews, parents of 11 children with EO claimed
freedom from any contextual problem. Single clues for contextual problems (Box 1) were found in 15 children and
multiple clues were found in 16 children. Overall, the parents
of 21 children (50%) were thrown off balance as far as their
habitual parenting was concerned and they attributed this to
the diagnosis of EO or to the epilepsy in a wider sense (e.g.
clearly distorted expectations regarding the child’s future
including marriage and driving licence, overprotectiveness
due to excessive fear of adverse AED effects or fear of
recurrence of seizures), eight children (19%) were themselves
maladapted (e.g. excessive feelings of shame and withdrawal,
interfering with going to school or other social activities),
11 (26%) belonged to socially or relationally disrupted
families, 12 (29%) had behavioural problems antedating
the diagnosis of epilepsy and eight (19%) had learning problems antedating the diagnosis of epilepsy.
Cognition
The neuropsychological test results of children with EO and
controls are summarized in Table 2. Table 3 shows the results
of statistical analyses. Children with EO performed statistically significantly worse than healthy classmates on measures
of learning (learning locations: proactive interference,
response times, total immediate recall), word span backwards
and sustained attention (balloon piercing) (Table 3, column
‘Medical status’; i.e. patients versus healthy controls). Mixed
design analysis with both medical status and school achievement (i.e. repeated versus did not repeat a grade at school)
as independent variables showed children with EO to be significantly more sensitive to proactive interference, whereas
children who repeated a grade at school once (whether a
patient or a control child) performed worse across measures of intelligence, attention, working memory, writing to
dictation and simple reaction time to light [Table 3, column
‘MS · school achievement (SA) main effects]. The slight
statistical significances of the separate analyses suggest that
the disadvantage of the children with EO is not bound to
idiopathic or cryptogenic aetiology, to seizure control or to
AED treatment (Table 3, columns ‘Aetiology’, ‘Seizure remission’ and ‘AED treatment’).
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Independent epilepsy-related variables were: medical status (epilepsy
versus healthy); the level of aetiological classification (idiopathic
versus cryptogenic); seizure remission (remission versus ongoing
seizures); and AED treatment (AED versus no AED). Variables
that were not intrinsically epilepsy-related were school achievement
(with school delay or remedial teaching versus without school delay)
and five interview variables (see Box 1 for more detail). Since the
modest number of subjects could not support analysis of all variables
as factors in mixed design analyses, for the most part separate analyses were carried out. Age was a covariate in all but age-normed
(CPM/SPM and WISC-R Vocabulary) measures. Tests were twosided, with a 5% significance interval. For multiple comparisons
Bonferroni correction was applied.
In case-by-case analyses, for each parameter the criterion for
underperformance was fixed at 2 SD worse than the mean performance in the control group. If, within the same assessment, underperformance concerned at least two parameters within the same
domain it was considered a deficit in that domain. If a deficit persisted throughout at least 1 year it was called a persistent deficit.
Brain (2005), 128, 1546–1555
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Brain (2005), 128, 1546–1555
K. J. Oostrom et al.
Table 1 Characteristics of children with ‘epilepsy only’ (EO) and controls (healthy classmates)
Children with EO
n
Age at diagnosis (years; mean 6 SD)
IQ at intake (mean 6 SD)
Having repeated a school grade (n) before intake
Having repeated a school grade at 4th assessment (n)
Using AED at 4th assessment
Seizure remission of >1.5 years at 4th assessment
With AED
Without AED
Idiopathic
Cryptogenic
Total
23
8.4 6 1.9
102 6 11
4
6
11
19
9.2 6 3.3
108 6 16
4
6
14
42
8.8 6 2.6
102 6 17
8
12
25
28
19
9
7
9
12
0
Controls
Total
P*
30
8.6 6 2.8
101 6 16
2–4†
3–7‡
72
8.7 6 2.7
104 6 14
10–12†
15–19‡
NS
NS
NS
NS
–
*Patients compared with controls; missing data for †two and ‡four controls. IQ = intelligence quotient; AED = anti-epileptic drug;
NS = not significant.
Behaviour
Mean CBCL and TRF total problems scores are shown in
Table 2. In general, parents as well as teachers reported more
behavioural problems in children with EO than in healthy
controls (Table 3, column ‘Medical status’). Differences could
not be related to school achievement, idiopathic versus cryptogenic aetiology of epilepsy or AED treatment. Parents of
children in seizure remission reported the most behavioural
problems (Table 3, column ‘Seizure remission’).
However, within the group of patients, having or not having reached seizure remission was not statistically significant.
Patients who belonged to troubled families were rated
by parents as having more behavioural problems than
those growing up in happy families. Of course, parents reported more problems in children with a history of behavioural
problems than in children with no history of behavioural
problems.
Time effects
In the complete sample (patients and controls), statistically
significant improvement of test performances (all P values <
0.05) during follow-up was found in computerised colour
trails parts I and II, word span (forwards), balloon piercing
(response time), tapping and learning locations (total
immediate recall and response time). Age was statistically
significant in all relevant measures except for response time
in learning locations and for measures of behaviour. It was
only in both parts of colour trails and in writing to dictation
that medical status seemed important: school repeaters with
EO continued to perform poorly whereas initial differences
between healthy school repeaters and healthy non-repeaters
disappeared over time (Table 3, column ‘MS · school achievement (SA)’).
Cases with persisting deficits
Summated over the four assessments, virtually all patients
(41/42) and controls (28/30) underperformed, that is,
obtained a score that was at least 2 SD worse than the mean
of the controls, on at least one parameter within a domain and
in at least one assessment. No statistically significant difference was found between the number of patients (16/42) and
the number of controls (6/30) qualifying for a deficit, defined
as at least two underperformances within the same domain
(38 and 20% respectively). In the complete sample, statistically significantly more patients (n = 8;19%) than controls
(n = 1; 3%) had persistent deficits (x 2 = 4.58, P = 0.03). Their
characteristics are presented in Table 4.
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When considering only patients, those who repeated a
grade once had statistically significantly worse scores than
those without educational delay on measures of attention
[Colour Trails Part I (P < 0.001, F = 10.21), Part II (P <
0.001, F = 12.26) and interference (P < 0.00, F = 12.74)],
memory [learning locations delayed recall (P < 0.05,
F = 6.29)]), reading (P < 0.05, F = 4.13) and simple reaction
time to light (P < 0.01, F = 7.83). Epilepsy characteristics
(idiopathic versus cryptogenic aetiology of epilepsy, seizure
remission [defined as seizure freedom of at least 1.5 years]
and AED treatment) were statistically insignificant factors.
However, worse scores in measures of attention [response
time for piercing balloons (P < 0.05, F = 5.81)] and learning
locations [total immediate recall (P < 0.00, F = 21.36),
response time (P < 0.05, F = 5.90) and proactive interference
(P < 0.01, F = 7.04)] were found in children who were exposed
to off-balance parenting. As could be expected, children with
long-standing learning problems performed worse than children without learning problems on intelligence [CPM/SPM
(P < 0.00, F = 13.11)], word span backwards (P < 0.04,
F = 4.63), response time when piercing balloons (P < 0.00,
F = 13.12) and reading (P < 0.00, F = 9.11). Patients with
longstanding behavioural problems, and those belonging
to troubled families (P values < 0.00, F values 10.95 and
12.68 respectively) were reported to have more behavioural
problems (CBCL) than patients without a history of longstanding behavioural problems and patients belonging to
happy families.
Abbreviations: see Box 2.
101 (16)
10.3 (2.9)
Controls
Mean (SD)
104 (15)
9.7 (2.7)
Patients
Mean (SD)
104 (15)
9.8 (2.7)
Controls
Mean (SD)
103 (13)
9.4 (2.2)
104 (17)
10.1 (2.6)
94 (15)
8.2 (2.2)
97 (15)
9.6 (2.6)
Controls
Mean (SD)
Patients
Mean (SD)
Patients
Mean (SD)
Controls
Mean (SD)
42 6 6 months later
12 months
3.6 (1.2)
3.2 (0.8)
13.3 (2.7)
562
487
674
691
140
3.9 (3.1)
14.7 (15.3)
14.3 (11.5)
8.1 (9.3)
(1.2)
(1.0)
(2.6)
(104)
(111)
(120)
(151)
(25)
(3.0)
(13.8)
(21.9)
(21.2)
(118)
(102)
(101)
(86)
(23)
54 (12)
2338 (632)
6.1 (2.1)
(12)
(677)
(2.5)
(86)
(93)
(168)
(469)
(23)
23.0 (21.3)
21.1 (22.3)
5.0 (5.3)
9.8 (8.4)
521
467
767
759
140
12.9 (2.9)
4.3 (1.3)
2.8 (0.8)
58 (12)
2170 (693)
5.5 (2.7)
(93)
(84)
(112)
(108)
(31)
10.7 (9.4)
7.1 (10.3)
4.9 (4.4)
13.5 (8.2)
528
453
647
654
135
14.2 (1.6)
4.3 (1.0)
3.1 (0.8)
62 (9)
1774 (296)
6.9 (2.9)
13.9 (2.8)
517
445
640
652
142
13.1 (2.8)
542
477
641
658
143
3.7 (3.3)
12.5 (12.6)
8.7 (9.5)
10.9 (11.8)
4.0 (3.3)
14.2 (13.4)
25.4 (22.4)
26.9 (22.7)
(82)
(77)
(101)
(108)
(21)
4.5 (1.1)
3.4 (1.1)
4.5 (1.0)
3.1 (0.9)
(114)
(90)
(93)
(104)
(22)
63 (11)
1792 (335)
6.9 (3.0)
60 (10)
2050 (773)
5.8 (2.4)
(183)
(86)
(94)
(112)
(28)
18.2 (14.7)
23.8 (19.2)
5.4 (3.8)
13.1 (10.4)
521
437
604
599
147
13.7 (2.0)
4.7 (0.9)
3.4 (0.9)
60 (12)
2068 (788)
6.7 (3.3)
(89)
(89)
(86)
(106)
(29)
11.9 (12.2)
5.6 (4.7)
4.5 (3.5)
10.8 (9.0)
479
423
575
575
149
14.6 (1.4)
5.0 (0.9)
3.8 (1.0)
65 (6)
1613 (442)
7.9 (3.3)
(65 225) 128 116 (55 017) 118 909 (46 935) 113 817 (45 206) 113 755 (41 927) 104 269 (39 399) 93 153 (33 471) 85 435 (26 219)
(10 2287) 223 501 (96 773) 203 423 (122 307) 202 305 (102 005) 195 734 (80 645) 190 214 (85 332) 167 128 (68 323) 131 592 (38 137)
(74 023) 79 388 (75 054) 101 456 (116 131) 88 488 (68331)
81 979 (53296) 85 945 (57858) 73 976 (47320) 46 157 (23662)
(1194)
3662 (1011)
3731 (1063)
3443 (650)
3651 (983)
3218 (473)
3463 (787)
3181 (539)
(17)
(2.8)
Patients
Mean (SD)
Test/task
3 months
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General intelligence
c-CPM/c-SPM (IQ)
102
Vocabulary (standard score)
9.8
Attention
c-Colour trails (ms)
Part I
136 835
Part II
224 314
Interference (II–I)
79 468
Balloon piercing
4000
Learning
Learning locations
Total immediate recall (no.)
53
Response time
2314
Proactive interference (no.)
5.0
Memory
Word span (no.)
Forwards
3.8
Backwards
2.9
Learning locations (no.)
Delayed recall
12.4
Speed (ms)
Reaction times
544
Simple Rtlight
486
Simple Rtbeep
670
Choice Rtlight+light
666
Choice Rtlight+beep
Manual tapping (no.)
139
Academic linguistic skills (% errors)
Reading
4.2
Writing to dictation
14.1
Behaviour (total score)
CBCL
27.1
TRF
21.4
At diagnosis
Domain
Table 2 Results of neuropsychological assessment in children with EO and healthy classmates, shown separately for each assessment
Cognition and behaviour in mild epilepsy
Brain (2005), 128, 1546–1555
1551
0.01, 8.38
0.00, 17.17
0.03, 4.86
0.05, 4.19
0.03, 5.07
0.01, 6.45
0.03, 4.78
0.01, 6.89
13.88
16.07
13.58
4.70
0.04, 4.78
0.01, 17.94
0.04, 8.84
0.03, 4.92
0.00,
0.00,
0.00,
0.03,
0.05, 4.19
SA†
Seizure remission
AED treatment
0.02, 3.74
0.03, 3.48
0.02, 3.55
0.03, 3.59
0.03, 3.59‡
0.04, 3.33‡
0.04, 3.32
0.01, 4.90
0.02, 4.34
0.02, 4.49
0.02, 4.12‡
0.03, 3.76
0.01, 4.65
MS · SA MS · SA · time Idiopathic£ Cryptogenic¥ Remission¶ Ongoing seizures No AED AED$
Main effect (to the disadvantage of )
Aetiology
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‡
Brain (2005), 128, 1546–1555
Differences are to the disadvantage of: *children with EO; †who once repeated a grade at school; £with idiopathic epilepsy; ¥with cyptogenic epilepsy; ¶in seizure remission; $using AED;
this significant difference can not be interpreted as adverse AED-effect because differences already existed at pre-treatment baseline and no interaction effects with time were found.
AED = anti-epileptic drug; EO = ‘epilepsy only’; MS = medical status; SA = school achievement; RT = reaction time. For other abbreviations see Box 2.
General intelligence
c-CPM/c-SPM IQ
Vocabulary
Attention
c-CT
Part I
Part II
Interference (II–I)
Balloon piercing
Learning
Learning locations
Total immediate recall
Response time
Proactive interference
Memory
Word span forward
Backward
Learning location
Delayed recall
Speed
Reaction times (RT)
Simple RTlight
Simple RTbeep
Choice RTlight+light
Choice RTlight+beep
Manual tapping
Academic linguistic skills
Reading
Writing to dictation
Behaviour
CBCL total score
TRF total score
EO children vs controls* MS*
Main effects
Main effect
Interaction effects
MS · school achievement (SA)
Medical status (MS)
Table 3 Statistically significant differences between (subgroups of) children with EO and healthy controls over time (P value, F value) (blanks:
not statistically significant)
1552
K. J. Oostrom et al.
Cognition and behaviour in mild epilepsy
Brain (2005), 128, 1546–1555
1553
Table 4 Characteristics of the eight children with epilepsy and one control child with persistent cognitive deficits
Patient
Sex (M,F)
Age at intake (years)
IQ at intake
Index seizure
ILAE*
Seizure remission
Deficit
1
2
3
4
5
6
7
8
Control
1
M
F
F
M
M
F
M
F
5
13
11
8
5
5
6
9
104
130
82
107
78
92
98
99
GTC + CPS
GTC
GTC
Absence
CPS
Absence
CPS
CPS
1.1.a
1.3.a
1.3.a
2.1.d
1.3.a
2.1.d
1.3.a
1.3.a
>1.5 years
>2 years†
Ongoing seizures
>1.5 years†
>1.0 years†
>1.5 years†
>1.5 years†
>1.5 years†
Attention, learning
Learning
Behaviour
Attention, academic skills
Learning
Learning, behaviour
Behaviour
Behaviour
M
7
99
–
–
–
Attention
*Engel; 2000, †with AED. GTC = generalized tonic clonic seizure(s); CPS = complex partial seizure(s).
Discussion
Long-term psychosocial and social disadvantages of having
had epilepsy in childhood have been convincingly described
(Jalava et al., 1997; Morgan et al., 2000) but it remains unclear
how these disadvantages arise. The present follow-up study
was performed to prospectively assess cognitive and behavioural functioning in otherwise healthy schoolchildren with
EO, in the first 3–4 years after diagnosis. This was done
by comparing (subgroups of) children with EO with healthy
age- and gender-matched classmates, by comparing within
the epilepsy group those with idiopathic to those with cryptogenic aetiology, those on and off AED and those who had
attained seizure freedom to those who had not, and by caseby-case analyses. Strengths of the study are the relative homogeneity of the epilepsy group as far as level of aetiological
classification (e.g. idiopathic versus cryptogenic) and illness
stage are concerned, developmentally sound assessment procedures, a control for response ambiguity in the behavioural
questionnaires, and a combined qualitative and quantitative
approach, the latter with appropriate processing of qualitative
contextual information. Assets of the assessment van were
that the children did not travel further than usual for hospital
visits, thereby preventing travel-related fatigue of the children,
and that the first assessment of patient and control child could
be arranged flexibly within 48 h after diagnosis. Limitations of
the study were, notwithstanding its multiple-centre approach
and consecutive inclusion, the rather small number of patients
and the sample attrition that resulted from the call-back procedure; however, epilepsy-related biases resulting from the
dropping out of participants were not found. In the light
of the pivotal role that contextual variables proved to play,
we now regret our earlier decision to not interview the parents
of the healthy control children.
Differences between groups are strongly
influenced by school career
Throughout the follow-up, the group of children with EO
lagged behind in both performance times and, particularly
in the domains of learning and attention, content. They also
exhibited more problematic behaviour. However, after
controlling for the possible influence of repeating a grade
at school, the only remaining disadvantage in the cognitive
domains turned out to be increased susceptibility to proactive
interference. Proactive interference is the well-known phenomenon that previous learning inhibits new learning of
similar material. It is closely related to poor concentration
and person-related variables, such as not being certain of
oneself (Torgesen, 1994). Moreover, children with EO who
had once repeated a grade continued to have poor scores in
Colour Trails I and II and continued to make more writing
errors, whereas repeaters without EO caught up with nonrepeaters. In the comparisons with healthy classmates, especially children with cryptogenic epilepsy and those to whom
AED was prescribed, scored more poorly. The latter finding
cannot be explained as an adverse effect of the medication, as
differences between children with and without AED already
existed at the pretreatment baseline. Rather, specialists may be
more apt to prescribe AED to children with EO and school or
learning difficulties than to those whose parents do not have
any complaints about their children’s cognition and/or behaviour. Finally, the parents of children with ongoing seizures
were found to report less behavioural problems than parents
of children in seizure remission. This finding is at variance
with earlier findings in children with new-onset epilepsy,
which were obtained, however, in a less rigidly composed
sample including children with symptomatic epilepsy (Austin
et al., 2002). For the present results, one may speculate that
being seizure-free may in some cases produce a ‘burden of
normality’, as described after epilepsy surgery and other
chronic conditions (Wilson et al., 2001).
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x2 tests of differences between these eight patients with
persistent deficit(s) and the 34 patients without persistent
deficit(s) showed overrepresentation of maladaptive parenting (x 2 = 4.72, P = 0.03), family problems (x 2 = 6.03, P = 0.01)
and behavioural problems prior to the diagnosis (x 2 = 9.57,
P = 0.01) in the eight patients. No statistically significant
relationships were found between persistent deficits and epilepsy characteristics or school achievement.
1554
Brain (2005), 128, 1546–1555
Within the EO group, context rather than
epilepsy variables are associated with
cognitive and behavioural problems
Persistently disadvantaged children
A few studies have addressed clinically significant cognitive
disadvantages or deficits and reported these to be present
in about 20% of the samples under study (Schoenfeld et al.,
1999; Seidel and Mitchell, 1999), which is not dissimilar from
the present finding. The case-by-case approach of the present
study facilitated the evaluation of these disadvantages in
respect of their distribution within the groups under study
and their development over time. In more than 80% of
children with EO cognitive and behavioural problems were
absent or, interestingly, not persistent. Two issues are worthy
of mention. In the almost 20% of children who were found
to have a so-called deficit, poor parenting, unhappy family
situations and prior existence of behavioural problems were
overrepresented. This finding is at least partly in line with
previous research, which found that children with epilepsy
whose parents were perceived as having an overcontrolling
approach had more problems than children with similar types
of epilepsy who did not perceive their parents as overcontrolling (Carlton-Ford et al., 1997). Secondly, non-persistent cognitive and/or behavioural problems were demonstrated in
nearly twice as many children with EO (38%) than in healthy
children (20%).
These findings fit with and expand on our earlier work,
in which we described multiconditional vulnerability to the
cognitive and/or behavioural problems of children with EO in
the first year after diagnosis (Oostrom et al., 2003). Although
the predominant association of context variables with the
vulnerability of children with EO to cognitive and behavioural
problems may not be specific to children with epilepsy,
it urges researchers and practitioners to go beyond the strictly
medical variables and to explore parental and other contextual risks.
Acknowledgements
We are most grateful to all the children who participated in
our study. We also thank their parents and teachers. We thank
Mrs W. Meijer MA for her contribution in the data collection,
Prof. Dr O. Brouwer for his critical comments on earlier
versions of the manuscript and Mrs M. Schinkel MA for
language editing. The study was supported by the Dutch
Epilepsy Foundation (NEF), JANIVO Foundation, Peugeot
Holland NV and Foundation for the Advancement of Neuropsychological Research in Children (BNOK). Participants
of the Dutch Study of Epilepsy in Childhood (DuSECh) are:
W. F. M. Arts MD PhD (UMC Rotterdam), A. C. B. Peters
MD PhD (UMC Utrecht), O. F. Brouwer MD PhD (UMC
Groningen), C. A. van Donselaar MD PhD (UMC Utrecht/
St Clara Hospital Rotterdam), E. A. J. Peeters MD (Juliana
Children’s Hospital, The Hague), H. Stroink MD PhD
(Hospital St. Elisabeth, Tilburg).
References
Achenbach TM, Edelbrock C. Manual for the child Behavior Checklist 4–18
and 1991 profile. Burlington, VT: University of Vermant Department of
Psychiatry, 1991.
Achenbach TM. Manual for Teacher’s Report Form and 1991 profile.
Burlington, VT: University of Vermant Department of Psychiatry, 1991.
Arts WFM, Geerts TA, Brouwer OF, Peters ACB, Stroink H, Donselaar CA
van. The early prognosis of epilepsy in childhood; the prediction of a poor
outcome. The Dutch Study of Epilepsy in Childhood. Epilepsia 1999; 40:
726–34.
Austin JK, Huberty TJ, Huster GA, Dunn DW. Does academic achievement
in children with epilepsy change over time? Dev Med Child Neurol 1999;
41: 473–9.
Austin JK, Dunn DW, Caffrey HM, Perkins SM, Harezlak J, Rose DF.
Recurrent seizures and behavioural problems in children with first recognized seizures: a prospective study. Epilepsia 2002: 43; 1564–73.
Austin JK, Dunn DW, Johnson CS, Perkins SM. Behavioral issues involving
children and adolescents with epilepsy and the impact of their families:
recent research data. Epilepsy Behav 2004; 5 S3: S33–41.
Bailet LL, Turk WR. The impact of childhood epilepsy on neurocognitive
and behavioural performance: a prospective longitudinal study. Epilepsia
2000; 41: 52–64.
Berg AT, Hauser WA, Shinnar S. The prognosis of childhood-onset epilepsy.
In: Shinnar S, Amir N, Brandski D, editors. Childhood seizures. Basel:
Karger; 1995. p. 93–9.
Bruyn EEJ de, Steene G van der, Haassen PP van. Wechsler Intelligence Scale
for Children—Revised. Nederlandse Uitgave. Lisse: Swets-Zeitlinger; 1986.
Bulthuis-de Veer A. Taal is niet zo moeilijk (1970). Groningen: WoltersNoordhoff; 1970.
Carlton-Ford S, Miller R, Nealeigh N, Sanchez N. The effects of perceived
stigma and psychosocial over-control on the behavioural problems of
children with epilepsy. Seizure 1997; 6: 383–91.
Chi MTH. Quantifying qualitative analysis of verbal data: a practical guide.
J Learn Sci 1997; 6: 271–315.
Engel J Jr. A proposed diagnostic scheme for people with epileptic seizures
and with epilepsy: report of the ILAE Task Force on Classification and
Terminology. Epilepsia 2000; 42: 1–8.
Fastenau PS, Shen J, Dunn DW, Perkins SM, Hermann BP, Austin JK.
Neuropsychological predictors of academic underachievement in pediatric
Downloaded from by guest on October 15, 2014
Throughout the follow-up, neither idiopathic versus cryptogenic aetiology, seizure remission nor use of AED had
clinically meaningful effects with respect to cognition or
behaviour. On the other hand, contextual variables did
turn out to be associated with these disadvantages, offbalance and maladaptive parenting in the earliest months
after diagnosis being especially strongly correlated. Attention
has previously been drawn to the predicament of caregivers.
In particular, maternal adaptation to a child’s epilepsy has
been expounded to be a complex factor in the child’s adaptation (Shore et al., 2004). The relationship between parental
anxiety and the child’s quality of life has also been described
previously (Williams et al., 2003). Quite recently, research by
Austin’s group drew attention to moderating effects of family
mastery on academic achievement in writing and possibly
reading and on behavioural problems (Austin et al., 2004;
Fastenau et al., 2004). We have reported previously that maladaptive parenting has traceable associations with the child’s
neuropsychological performance and school achievement.
The present paper provides evidence that these associations
are still present 3.5 years after diagnosis.
K. J. Oostrom et al.
Cognition and behaviour in mild epilepsy
1555
Schouten A, Oostrom KJ, Peters ACB, Jennekens-Schinkel A. School career of
children with epilepsy, who are otherwise healthy, is at risk prior to the
diagnosis. Dev Med Child Neurol 2001; 43: 575–6.
Schouten A, Oostrom KJ, Pestman WR, Peters ACB, Jennekens-Schinkel A.
Dutch Study Group of Epilepsy in Childhood. Learning and memory of
school children with epilepsy: a prospective controlled longitudinal study.
Dev Med Child Neurol 2002; 44: 803–11.
Schufried G. Standard Progressive Matrices (7.00). Mo¨dling, Dr G. Schufried
Computer Program; 1995.
Schufried G. Coloured Progressive Matrices (1.00). Mo¨dling, Dr G. Schufried
Computer Program; 1996a.
Schufried G. Vienna Test System—reaction time apparatus. Computer
program Version AZU/WKZ/Npsy; 1996b.
Shore CP, Austin JK, Dunn DW. Maternal adaptation to a child’s epilepsy.
Epilepsy Behav 2004; 5: 557–68.
Sillanpa¨a¨ M, Jalava M, Kaleva O, Shinnar S. Long-term prognosis of seizures
with onset in childhood. N Engl J Med 1998; 338: 1715–22.
Seidel WT, Mitchell WG. Cognitive and behavioural effects of carbamazepine
in children: data from benign rolandic epilepsy. J Child Neurol 1999;
14: 716–23.
Statistical Package for the Social Sciences (SPSS for Windows) 10.0.7. SPSS,
Chicago, (IL): SPSS; 2000.
Stroink H, van Donselaar CA, Geerts AT, Peters AC, Brouwer OF,
van Nieuwenhuizen O, et al. Interrater agreement of the diagnosis and
classification of a first seizure in childhood. The Dutch Study of Epilepsy in
Childhood. J Neurol Neurosurg Psychiatry 2004; 75: 241–5.
Torgesen JK. Issues in the assessment of executive function. An informationprocessing perspective. In: Lyon GR, editor. Frames of reference for the
assessment of learning disabilities. New views on measurement issues.
Baltimore (MD): Paul Brookes; 1994. p. 143–62.
Verhulst FC, Ende J van der, Koot HM. Handleiding voor de CBCL/
4–18. Rotterdam: Afdeling Kinder- en Jeugdpsychiatrie, Sophia
Kinderziekenhuis/Academisch
Ziekenhuis
Rotterdam/Erasmus
Universiteit Rotterdam; 1996.
Verhulst FC, Ende J van der, Koot HM. Handleiding voor de Teacher’s
Report Form (TRF). Rotterdam: Afdeling Kinder- en Jeugdpsychiatrie,
Sophia Kinderziekenhuis/Academisch Ziekenhuis Rotterdam/Erasmus
Universiteit Rotterdam; 1997.
Wakamoto H, Nagao H, Hayashi M, Morimoto T. Long-term medical,
educational, and social prognoses of childhood-onset epilepsy:
a population-based study in a rural district of Japan. Brain Dev 2000;
22: 246–55.
Williams J, Steel C, Sharp GB, Delos Reyes E, Phillips T, Bates S, et al. Parental
anxiety and quality of life in children with epilepsy. Epilepsy Behav 2003;
4: 483–6.
Wilson S, Bladin P, Saling M. The ‘burden of normality’: concepts of adjustment after surgery for seizures. J Neurol Neurosurg Psychiatry 2001;
70: 649–56.
Downloaded from by guest on October 15, 2014
epilepsy: moderating roles of demographic, seizure and psychosocial
variables. Epilepsia 2004; 45: 1261–72.
Grift W van de. Hoe kan ik de opbrengst van mijn school bepalen? [How can
I assess the output of my school?]. School Manage 2000; 13: 12–22.
Hartman CA, Hox J, Auerbach J, Erol N, Fonseca AC, Mellenbergh GJ, et al.
Syndrome dimensions of the Child Behavior Checklist and the Teacher
Report Form: a critical empirical evaluation. J Child Psychol Psychiatry
1999; 40: 1095–116.
ILAE, Commission on Classification and Terminology of the International
League against Epilepsy. Proposal for revised classification of epilepsy
and epileptic syndromes. Epilepsia 1989; 22: 489–501.
Jalava M, Silanpa¨a¨ M, Camfield C, Camfield P. Social adjustment and competence 35 years after onset of childhood epilepsy: a prospective study.
Epilepsia 1997; 38: 708–15.
Maj M, D’Elia L, Satz P, Janssen R, Zaudig M, Uchiyama C, et al. Evaluation of
two new neuropsychological tests designed to minimize cultural bias in
the assessment of HIV-I seropositive persons: A WHO study. Arch Clin
Neuropsychol 1993; 8: 123–35.
Morgan CLI, Ahmed Z, Kerr MP. Social deprivation and prevalence of epilepsy and associated health usage. J Neurol Neurosurg Psychiatry 2000: 69:
13–17.
Oostrom KJ, Schouten A, Kruitwagen CLJJ, Peters ACB, JennekensSchinkel A. Parents’ perceptions of adversity introduced by upheaval
and uncertainty at the onset of childhood epilepsy. Epilepsia 2001a; 42:
1452–60.
Oostrom KJ, Schouten, Kruitwagen CLJJ, Peters ACB, Jennekens-Schinkel A.
Dutch Study Group of Epilepsy in Childhood. Epilepsy-related ambiguity
in rating the child behavior checklist and the teacher’s report form.
Epileptic Disord 2001b; 3: 39–45.
Oostrom KJ, Schouten A, Kruitwagen CLJJ, Peters ACB, JennekensSchinkel A. Dutch Study Group of Epilepsy in Childhood. Attention
deficits are not characteristic of schoolchildren with newly diagnosed
idiopathic or cryptogenic epilepsy. Epilepsia 2002; 43: 301–10.
Oostrom KJ, Smeets-Schouten A, Kruitwagen CLJJ, Peters ACB, JennekensSchinkel A. Not only a matter of epilepsy: early problems of cognition and
behavior in children with ‘epilepsy only’—a prospective controlled study
starting at diagnosis. Pediatrics 2003; 112: 1338–44.
Perrin EC, Stein REK, Drotar D. Cautions in using the Child Behavior
Checklist/4–18. J Pediatr Psychol 1991; 35: 1091–6.
Raven JC, Court JH, Raven J. Coloured Progressive Matrices (1990 edition).
Oxford: Oxford Psychologists Press; 1990.
Raven JC, Court JH, Raven J. Standard Progressive Matrices (1992 edition).
Oxford: Oxford Psychologists Press; 1992.
Schippers BW, Sixma J. Taal voor het leven (1974). Groningen: WoltersNoordhoff, 1974.
Schoenfeld J, Seidenberg M, Woodard A, Hecox K, Inglese C, Mack K,
Hermann B. Neuropsychological and behavioural status of children
with complex partial seizures. Dev Med Child Neurol 1999; 41: 724–31.
Brain (2005), 128, 1546–1555