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Duration of Epilepsy and Cognitive

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Article in Neuropsychology · November 2013

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 Neuropsychology © 2013 American Psychological Association
2014, Vol. 28, No. 2, 212–221 0894-4105/14/$12.00 DOI: 10.1037/neu0000034

Duration of Epilepsy and Cognitive Development in Children:

A Longitudinal Study

Loretta van Iterson Bonne J. H. Zijlstra

SEIN Epilepsy Institute in the Netherlands Foundation and University of Amsterdam
School De Waterlelie

Paul B. Augustijn Aryan van der Leij and Peter F. de Jong

SEIN Epilepsy Institute in the Netherlands Foundation University of Amsterdam
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
This document is copyrighted by the American Psychological Association or one of its allied publishers.

Objective: To study the pattern of cognitive development in relation to duration of epilepsy. Methods:
Participants were 113 children with epilepsy referred because of concerns about their cognitive devel-
opment and tested at least twice at tertiary epilepsy settings. Verbal, Performance, and Full Scale IQ were
measured with Wechsler Intelligence Scales. Various epilepsy and demographic variables were included.
Change over time was modeled with multilevel analysis for longitudinal data with variable measurement
occasion. Results: The Verbal and Full Scales could be fitted best as a downward progressing function.
Earlier in time, decline was likely to be largest; later in time, decline followed a continuous, dwindling
course. A similar trend was seen for the Performance Scale. Initially, Verbal IQ was higher than
Performance IQ but this discrepancy decreased over time. Later onset of epilepsy was associated with an
attenuated decline of the Verbal Scale. None of the other epilepsy variables were related to the course
of cognitive development. Higher parental education was associated with higher IQ, but was not
protective against decline. Conclusions: Verbal IQ, though initially spared, drops. The Performance IQ,
which may have shown its vulnerability earlier in the course of the epilepsy, shows overall smaller
changes. It is suggested that seizures impact synergistically on an affected brain, which leads to
progressive cognitive decline. Earlier onset of epilepsy is associated with relatively higher VIQ, larger
VIQ ⬎ PIQ discrepancies and more decline.

Keywords: cognitive decline, pediatric epilepsy, duration of epilepsy, multilevel analysis, Wechsler
Intelligence Scale for Children

There is little doubt that epilepsy in childhood has an adverse
impact on a child’s life (Hermann, Jones, Jackson, & Seiden-
berg, 2012). Outcome is varied in terms of seizure control
(Geerts et al., 2010) and cognitive development (Berg et al.,
2008). Follow-up studies indicate that 50% to 60% of patients
with epilepsy have a favorable course and achieve seizure
freedom after use of antiepileptic drugs (AED; Geerts et al.,
2010; Schmidt & Sillanpää, 2012). Neuropsychological studies
on “uncomplicated epilepsies” have shown a close to normal
cognitive development over time in children with epilepsy
This article was published Online First November 4, 2013.
Loretta van Iterson, SEIN Epilepsy Institute in the Netherlands Foun-
dation, Department of Psychology, Heemstede, The Netherlands and De-
partment of Psychology, School De Waterlelie, Cruquius, The Netherlands;
Bonne J. H. Zijlstra, Research Institute of Child Development and Educa-
tion, University of Amsterdam, Amsterdam, The Netherlands; Paul B.
Augustijn, SEIN Epilepsy Institute in the Netherlands Foundation, Depart-
ment of Neurology; Aryan van der Leij and Peter F. de Jong, Research
Institute of Child Development and Education, University of Amsterdam.
Correspondence concerning this article should be addressed to Loretta
van Iterson, SEIN Epilepsy Institute in the Netherlands Foundation, P.O.
Box 540, 2130AM Hoofddorp, The Netherlands. E-mail: lviterson@sein.nl
212
(Hermann, Seidenberg, & Jones, 2008; Jones, Siddarth, Gur-
bani, Shields, & Caplan, 2010). These studies relate to children
with epilepsy who are not referred for psychological assess-
ment, who show seizure amelioration with or without medica-
tion, and who do not have co-occurring problems like brain
lesions or attention problems. Generally, children attend regular
classes, although school problems have been reported in about
half of the children with epilepsy (Reilly & Neville, 2011).
In a considerable proportion of children (⬃30%), however,
epilepsy is not uncomplicated, in terms of seizure control, cogni-
tive development, or both. After 15 years of follow-up, ⬃10% of
the children with epilepsy never had been seizure free longer than
3 months, and an additional ⬃13% showed a varying course of
remissions followed by relapses (Geerts et al., 2010). Cognitive
impairment has often been described in epilepsy in children (El-
lenberg, Hirtz, & Nelson, 1986; Nolan et al., 2003). In a commu-
nity based study it was shown that, 10 years after seizure onset,
⬃26% of children with epilepsy had an estimated IQ below 80
(Berg et al., 2008).
This raises a number of questions: What is the developmental
course of cognitive functioning over time? Can evidence be found
for cognitive decline? Is cognitive decline associated with age at
onset? Can epilepsy and demographic variables be identified
which affect cognitive development? Which area of cognitive
 DURATION OF EPILEPSY AND COGNITIVE DEVELOPMENT
development—verbal or nonverbal—is likely to be affected most?
Do the verbal and nonverbal domains follow similar trajectories?
There is a body of research regarding epilepsy factors that
contribute to the severity of cognitive impairment. Apart from
persistence of seizures (Bailet & Turk, 2000; Berg, Zelko, Levy, &
Testa, 2012), epilepsy syndrome is recognized as an important
factor. Generalized symptomatic epilepsies are associated with low
IQs (Berg et al., 2008; Bulteau et al., 2000; Nolan et al., 2003).
Localization related epilepsies and idiopathic epilepsies are asso-
ciated with relatively better outcome (Bulteau et al., 2000; Nolan
et al., 2003; Northcott et al., 2007).
Early age at onset of epilepsy (AOE) has been related to worse
outcome (Cormack et al., 2007), especially when the seizures
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
remain active (Berg, Zelko, Levy, & Testa, 2012). Also, greater
This document is copyrighted by the American Psychological Association or one of its allied publishers.
number of AEDs (Bulteau et al., 2000; Nolan et al., 2003; Smith,
Elliott, & Lach, 2002) have been associated with more cognitive
impairment. Demographic factors like parental educational level
have been acknowledged as being strongly associated with chil-
dren’s IQ in children without epilepsy (Lange, Froimowitz, Bigler,
& Lainhart, 2010), as well as in children with epilepsy (Mitchell,
Scheier, & Baker, 1994).
In cross-sectional studies, cognitive problems have been de-
scribed both for the verbal and nonverbal (performance) domains.
Studies on specific syndromes have reported lowered verbal IQ
(Overvliet et al., 2011); studies on mixed samples have reported
lowered nonverbal IQ (Høie et al., 2005; O’Leary, Burns, &
Borden, 2006; Smith et al., 2002). Longitudinal studies focusing
on the relation of the verbal and nonverbal (i.e., performance)
domains are scarce. Changes have been reported to be small and
similar for both the verbal and performance IQ (Aldenkamp,
Alpherts, De Bruine-Seeder, & Dekker, 1990; Bjørnæs, Stabell,
Henriksen, & Loyning, 2001; Skirrow et al., 2011). Studies on
children who underwent epilepsy surgery report increases on the
performance scale, regardless of hemispheric side of surgery (Skir-
row et al., 2011).
The pattern of cognitive impairment and cognitive change over
time in children with epilepsy is still insufficiently understood.
Models have been proposed describing cognitive decline as either
gradually progressive (“linear”) or, as a stepwise (“cascadic”)
decline. A cascadic decline is described as marked in the early
stages of epilepsy and plateauing thereafter (Devinsky & Tarulli,
2002; Meinardi, Aldenkamp, & Nunes, 1992; Seidenberg, Pulsi-
pher, & Hermann, 2007). There is still a dearth of studies to
substantiate these models on cognitive decline over time, and there
is still a need for a finer characterization of the course of devel-
opment in children with epilepsy (Hermann et al., 2012). This
study examined the developmental trajectory of cognitive decline
in children with epilepsy. More specifically, the course of epilepsy—
without intervening epilepsy surgery— over time was considered,
based on cognitive data on children at a Dutch tertiary epilepsy
center. The children were tested two or three successive times with
the Wechsler Intelligence Scales.
Various methodological problems need to be considered. These
problems stem from the heterogeneity of epilepsies in terms of
AOE, IQ, and course (Camfield, Camfield, Gordon, Smith, &
Dooley, 1993; Schmidt & Sillanpää, 2012). Inexorably, this means
a large variability in time elapsed between epilepsy onset and time
of first, second, or even third neuropsychological testing. As
children grow older, they are likely to make a transition from one
213
Wechsler test to another, implying variability in test versions used.
Multilevel modeling (Snijders & Bosker, 1999), a special statisti-
cal technique, was applied to account for these differences.
Method
Participants
From 452 Dutch children with epilepsy who had completed a
Wechsler test, 113 were selected as they met the criteria for
inclusion. Children were selected if they (1) were 4 to 15 years of
age at first testing (T1), (2) had been tested at least two times with
age-appropriate child Wechsler tests with an intertest interval of
one year or longer, and (3) had not had intervening epilepsy
surgery in between testing. The children presented either at a
Dutch tertiary epilepsy center or at a special school affiliated with
the center, which provided educational support for children with
epilepsy. Reasons for T1 were concerns about the cognitive de-
velopment of the child. Commonly results of the assessment were
also used in applications for special financial and educational
services to support the child within a regular or a special school.
Reasons for second and third testing (T2, T3) were requests for
follow-up as the epilepsy evolved and retesting was required for
continuation of the educational support. No exclusionary criteria
were set for type of epilepsy or initial IQ. Overall, there were 249
Wechsler test measurements: 113 at T1, 113 at T2, and 23 at T3.
The sample tested 3 times (n ⫽ 23) did not differ from the
sample tested 2 times (n ⫽ 90) on any IQ scale at T1 or T2, at any
epilepsy variable (AOE, duration up to T1 or T2, epilepsy type or
syndrome severity), or demographic variable (sex, handedness,
parental education).
The 339 children not selected for the study had been tested only
once (n ⫽ 303); had been tested with an age-inappropriate test
(n ⫽ 3); had been retested within a year (n ⫽ 22); had been
retested with another Wechsler Scale (WAIS/WAIS-IIINL n ⫽ 5,
other n ⫽ 1); had undergone surgery (n ⫽ 2) or had missing values
on an IQ scale (n ⫽ 2); other reasons (n ⫽ 1). Comparison of
selected and nonselected children (after Bonferroni adjustment)
showed similarities in terms of IQ at T1, seizure type and syn-
drome severity or AOE. However, duration up to T1 and age at T1
was higher in the nonselected sample (n ⫽ 19 had been tested with
the WAIS/WAIS-IIINL).
Approval for the study was obtained from the tertiary epilepsy
institution and epilepsy school (SEIN/De Waterlelie). Parents gave
written informed consent for the use of observational test material
and retrieval of available testing done elsewhere.
Wechsler Test Versions
The study concerns the scaled scores of the Wechsler Intelli-
gence Scales in The Netherlands, here designated as WPPSI-RNL
(Vander Steene & Bos, 1997), WISC-RNL (van Haasen et al.,
1986), and WISC-IIINL (Wechsler, 2005) allowing test changes
between T1 and T2 or T3.
Other Measures
Epilepsy variables. The epilepsy variables were available
from neurological or neuropsychological reports and relate to
 214 VAN ITERSON ET AL.
information as documented at last testing. AOE, seizure type, onset
side and topographical localization, presence of MRI lesion, and
number of AEDs tried in the course of the epilepsy were included.
Seizure status was scored as active or inactive (seizure freedom of
at least one year), uncertain or unknown. The Syndrome Severity
Scale for Children with Epilepsy (ESSS-C; Dunn, Buelow, Austin,
Shinnar, & Perkins, 2004) was used to measure epilepsy syndrome
severity. This 10-point scale encompasses various epilepsy vari-
ables such as seizure type, etiology and AOE within a single scale.
The present sample included syndrome severity scores ranging
from 2 to 9: idiopathic localization related epilepsy (benign epi-
lepsy with centrotemporal spikes [BECTS], n ⫽ 4, 3.5%, score 2);
localization related symptomatic epilepsy (by virtue of etiology,
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
n ⫽ 19, 16.8%, score 7; by virtue of localization n ⫽ 36, 31.9%,
This document is copyrighted by the American Psychological Association or one of its allied publishers.
score 5; cryptogenic n ⫽ 5, 4.4%, score 6.55); idiopathic gener-
alized epilepsies (childhood absence epilepsy [CAE], n ⫽ 2, 1.8%,
score 3; other n ⫽ 10, 8.8%, score 5); symptomatic generalized
epilepsies (n ⫽ 6, 5.3%, score 8 –9); epilepsy syndromes (epilepsy
with continuous spikes and waves during slow sleep [CSWS] and
atypical BECTS, n ⫽ 14, 12.4%, score 8; other (n ⫽ 10, 8.8%,
scores 2– 6); unknown (n ⫽ 7, 6.2%).
Demographic variables. The educational status of the child
was dichotomized as regular education (with special facilities) or
special school placement. For parental education, the highest ed-
ucational level completed (CBS, 2007) was averaged across par-
ents. Sex and handedness were also included.
Analyses
The trajectories over time of Verbal, Performance, and Full
Scale IQs and VIQ – PIQ discrepancy were estimated with a
multilevel model for longitudinal data with variable measurements
occasions (Snijders & Bosker, 1999). An advantage of this model
is that it allows any number of repeated observations for each
subject, without restrictions on the temporal spacing between the
measurements. Time was taken to be the duration since the first
epileptic seizure. Test versions were modeled with separate
dummy variables for the WPPSI-RNL and the WISC-IIINL, taking
the WISC-RNL as reference. The predictors time and test version
could change over repeated observations, whereas the demo-
graphic and epilepsy variables were constant for each child. For
these variables the effect on individual differences in IQ level
(regardless of time), as well as the effect on individual differences
in the rate of change in IQ over time were estimated. Individual
differences unaccounted for by the predictors were modeled with
a random intercept. The standard deviation of the random intercept
indicates the amount of residual differences in IQ level. A random
slope for residual differences in the rate of change in IQ over time
was not included because these models could not be estimated (the
models were not identified).
The selection of an appropriate model to fit the trajectories of
the IQ scores over time was done in three steps, applying a
statistical significance level of .01. Results of the first step led to
the Base Model, results of the last step to the Final Model. In the
first step, an adequate model for the change over time was sought,
entering duration of epilepsy as well as Wechsler test version.
Curvilinear functions (quadratic, logarithmic and square root) of
duration of epilepsy in months (and months plus one for the
logarithmic transformation) were added to the linear model to
check for a significant increase in model fit. To find the most
parsimonious model, a reverse strategy was also applied by drop-
ping the linear component whenever this did not significantly
decrease the model fit. Models with the same number of parame-
ters were compared on Bayes factors (Kass & Raftery, 1995),
approximated from the Schwarz criterion, to assess the evidence in
favor of the best fitting model. This model was called the Base
Model.
In the second step, time and Wechsler test version were main-
tained and AOE (in months) and the demographic variables were
included in the model: special education, parental education, and
the dummy variables handedness (left-handedness was coded 1),
and sex (boy was coded 1). For these predictors, the effect on the
individual differences in IQ level were always included in the
model. The effect on individual differences in the rate of change in
IQ over time were only included whenever they reached statistical
significance. For AOE and parental education, the overall means
were set to zero.
In the third step, the predictors from the first two steps were
maintained and the epilepsy variables were included in the
model. The predictors entered were focal seizures, generalized
seizures, left hemisphere seizures, right hemisphere seizures,
frontal seizures, ESSS-C score of epilepsy syndrome severity,
seizure freedom, number of AEDs tried, MRI lesion (and its
interaction with handedness). In this step, the effects of the
predictors on individual differences in IQ level and on individ-
ual differences in the rate of change in IQ over time were
included in the model only whenever they reached statistical
significance. However, for the latter effect (change over time)
statistical significance had to be established taking into account
the (possibly nonsignificant) effect of the predictor on individ-
ual differences in IQ level.
Results
Table 1 shows the characteristics of the sample and Table 2 the
unadjusted mean IQs. Results for the longitudinal multilevel mod-
els are presented in Table 3 (for the Verbal Scale, Performance
Scale, and Full Scale) and Table 4 (VIQ – PIQ discrepancy) and
include the Base and Final Model. None of the epilepsy predictors
could be added to the final models in the third stage of model
selection. Therefore, the Final Model comprises the results of the
second stage.
Figure 1 shows the approximated predicted outcomes according
to the Base Model for the Verbal, Performance, and Full Scale IQs
for the middle 95% of the observed durations of epilepsy (i.e.,
ranging from 8 to 146 months). The figure shows a strong decline
initially, leveling off with increasing duration of the epilepsy.
Bayes factors for the Performance Scale and Full Scale indicated
positive to very strong evidence (Kass & Raftery, 1995) for a
logarithmic decline compared with the square, linear, and square
root decline. For the Verbal Scale there was nearly as much
evidence for square root decline, indicating that the decline leveled
off to a slightly lesser degree, but there was strong evidence
against linear and square decline.
In the Final Model, results were overall similar for the Verbal
and Full Scales. The magnitude of estimates of the effect of time
was comparable between the models for VIQ and FS-IQ. The
positive effect for parental education in Table 3 suggested that
 DURATION OF EPILEPSY AND COGNITIVE DEVELOPMENT 215

Table 1 seen. For the VIQ, an effect was seen for AOE, also in inter-
Characteristics of the Sample action with time. The (negative) values on time and AOE
indicated that a longer duration and a later onset were associ-
n Mean SD Range
ated with a lower VIQ. The (positive) value for the interaction
Full sample 113 of AOE and time showed that the decline of the VIQ over time
Age at onset of epilepsy (AOE) 113 4.8 3.0 0.1 to 13.2 was somewhat less pronounced for children with a higher AOE.
Age at T1 113 8.4 2.3 4.7 to 15.0 No other epilepsy variable made a significant contribution to
Age at T2 113 11.2 2.7 5.8 to 16.9
Age at T3 23 12.9 2.7 6.9 to 16.8 the models.
Duration epilepsy to T1 113 3.5 2.6 0.2 to 12.2 For the Performance Scale, a similar albeit nonsignificant effect
Duration epilepsy to T2 113 6.3 3.1 1.6 to 15.8 of time could be found in the Final Model, compared with the Base
Duration epilepsy to T3 23 8.6 3.5 3.3 to 16.2
Model. A positive effect could be observed for AOE (see Table 3),
AEDs tried 102 2.5 1,7 0 to 12
Epilepsy syndrome severity 106 5.9 1.6 2 to 9 meaning that children with later AOE (above the mean of the
Parental education 105 4.4 0.9 2.7 to 6.0 sample) were likely to have a slightly higher PIQ score. A positive
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effect was seen for parental education also.

This document is copyrighted by the American Psychological Association or one of its allied publishers.

N n %
The intercept for VIQ – PIQ differed from zero (see Table 4);
Seizure type 113 the positive value indicated that the difference favored the Verbal
Generalized seizures 15 13.3
Focal (all focal) 75 66.4 Scale (VIQ ⬎ PIQ). Change over time presented as a square root
Focal: LH/RH 33/17 29.2/15.0 curve, although Bayes factors for the Base Model suggested that
Bilateral of mutifocal 25 22.1 there was almost as much evidence for a linear or logarithmic
Uncertain 16 14.2 downward slope. The negative value for time suggested that the
Unknown 7 6.2
MRI ⫺/MRI ⫹ 113 82/31 72.6/27.4 VIQ – PIQ discrepancies decreased over time. The negative value
Boys/girls 113 61/52 54/46 for age of onset implied that a younger AOE was associated with
Education: regular/special 112 61/51 54.5/45.5 larger VIQ ⬎ PIQ discrepancies.
Test versions For all models, the standard deviations of the random intercepts
Test version at T1 113
WPPSI-RNL 20 17.7 were larger than the residual standard deviations, implying that the
WISC-RNL 63 55.8 differences not accounted for by the predictors in the models
WISC-IIINL 30 26.5 between the children were larger than the residuals around the
Test version at T2 113
predicted individual trajectories. Therefore, the model estimates
WPPSI-RNL 3 2.7
WISC-RNL 46 40.7 indicated there was less uncertainty about the individual trajecto-
WISC-IIINL 64 56.6 ries (and their shape) than about the IQ levels of children (regard-
Test version at T3 23 20.4 less of time). No significant effect of Wechsler test version was
WPPSI-RNL 1 0.9
WISC-RNL 5 4.4
seen on any Scale. Large differences between individual trajecto-
WISC-IIINL 17 15.0 ries can be found.
Note. T1 ⫽ test 1, T2 ⫽ test 2, T3 ⫽ test 3, AEDs tried ⫽ number of
anti-epileptic drugs tried, LH ⫽ left hemisphere; RH ⫽ right hemisphere;
MRI ⫹ ⫽ lesion found on neuroimaging; MRI ⫺ ⫽ no lesion found on
Discussion
neuroimaging or no neuroimaging available.
This study provided evidence for progressive cognitive decline
over time in clinically referred children with epilepsy. Decline was
higher parental education was associated with higher VIQ and largest in the early stages of epilepsy; thereafter, decline continued
FS-IQ. No effect of parental education on individual differences in at an increasingly slower pace. Also, a differential trajectory for
change over time was found, suggesting that lower parental edu- VIQ and PIQ was seen, which was not described earlier. The curve
cation did not imply an increased risk of decline over time. described was logarithmic—not linear. On an individual bases,
Similarly, special education was associated with lower VIQ and cascadic decline cannot be excluded. Large individual variation
FS-IQ, although no significant effect for change over time was was found.

Table 2
Wechsler Intelligence Scale Data at Different Measurement Points

Full sample Subsample

T1 T2 T1 T2 T3
Scale Mean SD Mean SD Mean SD Mean SD Mean SD

VIQ 89.3 15.4 81.5 15.9 85.7 11.8 73.1 13.0 71.4 11.9
PIQ 84.3 17.0 82.1 18.0 80.3 15.4 76.5 15.9 72.3 16.2
FS-IQ 85.5 16.0 79.8 16.9 81.5 12.8 73.7 11.7 69.3 13.0
VIQ ⫺ PIQ 5.0 14.1 ⫺0.6 14.1 5.7 14.8 ⫺0.3 18.4 ⫺0.9 14.0
Note. The full sample was based on n ⫽ 113. The subsample included the 23 children who had been administered the Wechsler three times.
 216 VAN ITERSON ET AL.

Table 3
Results of Multilevel Analysis for Model 1 and The Final Model

Verbal Scale Performance Scale Full Scale

Estimate SE p value 95% CI Estimate SE p value 95% CI Estimate SE p value 95% CI

Base model
Fixed effects
Intercept 115.57 3.86 ⬍.001 (108.0, 123.2) 103.16 4.50 ⬍.001 (94.3, 112.0) 109.35 3.98 ⬍.001 (101.5, 117.2)
Time: logarithmic ⫺7.56 0.97 ⬍.001 (⫺9.5, ⫺5.6) ⫺4.97 1.14 ⬍.001 (⫺7.2, ⫺2.7) ⫺6.66 1.00 ⬍.001 (⫺8.6, ⫺4.7)
WISC-IIINL ⫺3.04 1.72 .078 (⫺6.4, 0.3) ⫺1.93 2.01 .337 (⫺5.8, 2.0) ⫺2.90 1.77 .104 (⫺6.4, 0.6)
WPPSI-RNL ⫺1.17 2.51 .641 (⫺6.1, 3.7) ⫺2.99 2.98 .317 (⫺8.9, 2.9) ⫺1.75 2.60 .502 (⫺6.9, 3.4)
Random effects
Intercept SD 13.29 13.85 13.54
Residual SD 7.53 9.19 7.82
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Deviance 1944.00 2012.79 1958.96

This document is copyrighted by the American Psychological Association or one of its allied publishers.

Final Model
Fixed effects
Intercept 124.71 5.58 ⬍.001 (113.7, 135.7) 98.24 5.77 ⬍.001 (86.9, 109.6) 106.75 4.77 ⬍.001 (97.3, 116.1)
Time: logarithmic ⫺9.34 1.30 ⬍.001 (⫺11.9, ⫺6.8) ⫺3.28 1.37 .018 (⫺6.0, ⫺0.6) ⫺5.62 1.12 ⬍.001 (⫺7.8, ⫺3.4)
WISC-IIINL ⫺2.13 1.66 .200 (⫺5.4, 1.1) ⫺2.20 2.16 .311 (⫺6.4, 2.1) ⫺2.49 1.80 .170 (⫺6.0, 1.1)
WPPSI-R NL
⫺5.09 2.65 .056 (⫺10.3, 0.1) ⫺1.38 3.28 .674 (⫺7.8, 5.1) ⫺1.68 2.69 .534 (⫺7.0, 3.6)
Age at onset ⫺0.33 0.12 .007 (⫺0.6, ⫺0.1) 0.15 0.05 .001 (0.1, 0.2) 0.08 0.04 .059 (⫺0.003, 0.2)
Parental education 6.54 1.36 ⬍.001 (3.8, 9.2) 4.25 1.63 .011 (1.0, 7.5) 5.79 1.42 ⬍.001 (3.0, 8.6)
Lefthandedness ⫺3.58 2.95 .228 (⫺9.4, 2.3) ⫺4.79 3.52 .178 (⫺11.8, 2.2) ⫺4.24 3.07 .170 (⫺10.3, 1.9)
Sex (boy) 5.96 2.34 .012 (1.3, 10.6) 2.56 2.80 .362 (⫺3.0, 8.1) 4.46 2.44 .070 (⫺0.4, 9.3)
Special education ⫺9.18 2.49 ⬍.001 (⫺14.1, ⫺4.2) ⫺6.08 2.98 .044 (⫺12.0, ⫺0.2) ⫺8.56 2.60 .001 (⫺13.7, ⫺3.4)
Time: logarithmic by AOE 0.08 0.03 .005 (0.02, 0.1)
Random effects
Intercept SD 9.66 11.27 10.04
Residual SD 6.87 9.52 7.70
Deviance 1520.60 1627.54 1554.47
Note. SE ⫽ standard error; SD ⫽ standard deviation.

Different Trajectories for the Verbal
and Performance IQ
Previous studies have described lower IQ for very early AOE
(Bulteau et al., 2000; Cormack et al., 2007). The present study
points toward differential impact on the various scales: earlier
AOE was associated with a better (initial) VIQ and a more pro-
nounced decline—therefore a worse trajectory. Earlier AOE was
associated with particularly lowered PIQ and larger VIQ ⬎ PIQ
discrepancies.
The VIQ ⬎ PIQ gap was seen early in the course of the epilepsy,
and closed over time. The results suggested that Verbal IQ was
“spared” initially and declined over time, while Performance IQ
possibly showed its vulnerability early in the course of the epilepsy
and showed an attenuated decline later on. Future research includ-
ing children tested before epilepsy onset (e.g., children with an
increased genetic risk for developing epilepsy), could be directed
at elucidating whether the VIQ ⬎ PIQ discrepancy exists already
prior to the onset of epilepsy, or emerges together with the seizure
condition.
As in the present study, some evidence for less decline (or more
gains) at retesting for PIQ rather than VIQ has been given in
samples without intervening surgery (Aldenkamp, Alpherts, De
Bruine-Seeder, & Dekker, 1990), after epilepsy surgery (Skirrow
et al., 2011; Westerveld et al., 2000), and in the light of amelio-
ration of seizures (Van Mil et al., 2010). Part of these effects may
be interpreted in the light of studies of children without epilepsy,
where the Performance Scale has been shown to be more prone to
profit from practice effects or test familiarity (Canivez & Watkins,
1998). The impact of test familiarity in the present study should be
limited, given the interval of a year or longer between testings.
Variables Contributing to Cognitive Level and
Cognitive Change: Epilepsy Variables
Similar to earlier studies on heterogeneous samples (Reijs et al.,
2007; Strauss et al., 1995), no epilepsy variable other than age of
epilepsy onset and duration of epilepsy, could be singled out as
contributing significantly to cognitive level or to cognitive change
over time. This is particularly puzzling concerning variables like
epilepsy syndrome severity and underlying symptomatology. Sev-
eral issues should be pointed out regarding the variables studied.
First, the results may challenge the utility of the syndrome severity
scale as used in this study. In fact, various authors have indicated
that the best way to determine epilepsy syndrome severity is still
under debate and that syndrome severity should be studied in
combination with cognitive outcome (Dunn et al., 2004; Reijs et
al., 2006; Wirrell, Grossardt, So, & Nickels, 2011). Second, as
Elger, Helmsteadter and Kurthen (2004) pointed out, etiology and
AOE are difficult to disentangle, because specific disorders peak at
certain age groups (Wirrell, Grossardt, Wong-Kisiel, & Nickels,
2011). This means that the findings related to early AOE may be
seen as valid for early onset etiologies. Third, some cases with
MRI-negative findings are reclassified as positive cases after MRI
 DURATION OF EPILEPSY AND COGNITIVE DEVELOPMENT 217

Table 4 of particular relevance in long-term evaluations of children and

Results of Multilevel Analysis for the VIQ – PIQ Discrepancy may aid in explaining why none of these variables had a statisti-
cally significant contribution to the models.
VIQ – PIQ Newer types of seizure classification and conceptualization are
Estimate SE p value 95% CI being proposed (Berg et al., 2010). These classifications may
potentially prove to be differentially associated with cognitive
Base model
Fixed effects
outcome in epilepsy. Literature suggests that an underlying cause
Intercept 9.06 2.63 .001 (3.9, 14.2) leading to seizures— be it hereditary, structural, metabolic, or
Time: square root ⫺0.93 0.33 .005 (⫺1.6, ⫺0.3) unknown (Berg et al., 2010)—may affect the cognitive develop-
WISC-IIINL ⫺0.63 1.80 .726 (⫺4.2, 2.9) ment of the child even before the epilepsy surfaces (Schouten,
WPPSI-RNL 1.49 2.61 .570 (⫺3.7, 6.6) Oostrom, Jennekens-Schinkel, & Peters, 2001), and may continue
Random effects
Intercept SD 11.84 to influence cognitive development for a prolonged period of time.
Residual SD 8.11 The present study proposes that the impact of the seizure con-
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Deviance 1944.38 dition on an already affected brain (Hermann et al., 2006) is

This document is copyrighted by the American Psychological Association or one of its allied publishers.

synergistic, leading to progressive decline in cognitive function.

Final model The impact of selected epilepsy variables on this decline could not
Fixed effects
easily be singled out. Evidence of this synergistic effect is also
Intercept 12.87 3.61 ⬍.001 (5.7, 20.0)
Time: square root ⫺1.53 0.40 ⬍.001 (⫺2.3, ⫺0.7) provided by studies on unilateral brain lesions, showing that the
WISC-IIINL 0.64 1.95 .745 (⫺3.2, 4.5) added presence of seizures alters the course of cognitive develop-
WPPSI-RNL ⫺1.64 2.82 .562 (⫺7.2, 3.9) ment, turning growth into decline (Ballantyne, Spilkin, Hesselink,
Age at onset ⫺0.17 0.04 ⬍.001 (⫺0.3, ⫺0.1) & Trauner, 2008). Further support comes from recent studies
Parental education 1.85 1.52 .227 (⫺1.2, 4.9)
Lefthandedness 1.64 3.30 .620 (⫺4.9, 8.1) showing changes in brain networks of children with focal epilepsy,
Sex (boy) 2.99 2.61 .255 (⫺2.2, 8.2) which extend beyond the epileptic region and was most prominent
Special education ⫺3.55 2.79 .206 (⫺9.1, 2.0) in children with lower IQ (Braakman et al., 2013). A study on
Random effects adults showed that changes in brain networks could be associated
Intercept SD 10.85
with cognitive decline (Vaessen et al., 2012). The decisive factor
Residual SD 8.01
Deviance 1576.42 leading to cognitive decline may not be the presence or absence of
seizures or a brain lesion alone, but their co-occurrence and pos-
sible interaction.
reevaluation (Funke, Moore, Orrison, & Lewine, 2011). Changes
in MRI-interpretation have implications for the reliability of the
Demographic Variables, Special Education
distinction between symptomatic and nonsymptomatic etiologies
and consequent syndrome classification. Fourth, seizure freedom School problems are frequently seen in children with epilepsy
may be temporary and may be followed by relapse (Schmidt & (Fastenau, Shen, Dunn, & Austin, 2008; Reilly & Neville, 2011).
Sillanpää, 2012). Fifth, AEDs can both impair and enhance cog- In the present study, special education was associated with lower
nitive functioning (Kwan & Brodie, 2001). All these issues may be VIQ. No interaction with the duration of epilepsy was seen,

Figure 1. Approximated effect of time according to the Base Model for Verbal IQ, Performance IQ, and Full
Scale IQ.
 218 VAN ITERSON ET AL.
suggesting that special education per se is not associated with
lowering of IQ over time. In line with research showing that
parental education is a predictor of cognitive functioning (Mitchell
et al., 1994), a significant effect was seen for parental educational
level. Again, no interaction was seen between parental education
and change over time, suggesting that lower parental education
was no risk factor for decline. Conversely, higher parental educa-
tion was not “protective” against decline.
Test Versions
Epilepsies emerge at different ages and progress with remissions
and relapses (Camfield et al.,1993; Schmidt & Sillanpää, 2012). A
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first step to approaching a wide spectrum of epilepsies longitudi-
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nally is the inclusion of children at various ages—and therefore the
inclusion of various test versions, and changes of test versions over
time. However, studies with more than one test version carry the
risk of contaminating results with nonequivalence of test versions
and Flynn effects (Bourgeois, Prensky, Palkes, Talent, & Busch,
1983; Flynn, 2007; Kaufman, 2010; Neyens & Aldenkamp, 1997;
Wechsler, 2005). A major advantage of the present study is that it
modeled different test versions explicitly, adjusting for their po-
tential differential contributions. Similarly, the present model al-
lowed entering children regardless of the number of times they
were tested.
Mechanisms Related to the Initial Drop in IQ and the
Posterior Slowing of Decline
The mechanisms leading to an initial drop— differential for the
two IQ scales and more pronounced in the younger child—and
posterior stabilization of cognitive functions are not completely
understood. The large individual variability among individuals
suggests different mechanisms between individuals and between
etiological groups. An approach to understanding the mechanisms
may be undertaken from the perspective of the interaction between
brain, epilepsy and cognitive function, and psychometrics.
Before the onset of epilepsy, learning problems may already be
seen (Hermann et al., 2012; Schouten et al., 2001) pointing toward
ongoing latent changes in the brain (Hermann et al., 2010). The
period of epileptogenesis culminates in the disruption of the bal-
ance between excitation and inhibition of the brain network (Jen-
sen, 2011) and in the emergence of seizures proper. Generalized,
nonspecific cognitive problems become evident, affecting mainly
attention, executive functions, and visual-motor speed (Bhise, Bu-
rack, & Mandelbaum, 2010; Fastenau et al., 2009; Hermann,
Jones, Jackson, & Seidenberg, 2012; Hermann et al., 2006). These
difficulties may give rise to the lowered PIQ and to the concom-
itant VIQ ⬎ PIQ gap described in the present study. Soon after the
seizures become apparent, abnormalities in brain organization are
seen. Of particular interest in relation to the low PIQ are the white
matter abnormalities and a disturbed pattern of white matter
growth observed in several studies (Hermann et al., 2010; Hutchin-
son et al., 2010), which may hamper speed of information pro-
cessing.
The more preserved VIQ at first testing may be giving a closer
estimate of the child’s original cognitive level. PIQ, with its lower
initial score and more gradual decline, may be giving a better
indication of the vulnerable reaction of the brain already during
this process of epileptogenesis and emergence of the seizure con-
dition. The younger child, with its more immature brain, has a
reduced seizure threshold and is particularly vulnerable to disrup-
tion (Rakhade & Jensen, 2009) and more prone to show impaired
cognitive development (Cormack et al., 2007), a lowered PIQ and
a worse trajectory of VIQ.
With the emergence of seizures, the already ongoing process of
abnormal development exacerbates, leading to a cascade of
changes, both in the brain and in cognition (Jensen, 2011; Rakhade
& Jensen, 2009). Cognitive decline becomes more generalized and
affects also the initially spared verbal IQ. Information that was
already acquired and consolidated (“wired”) may be preserved and
account for the initial higher level of VIQ. To maintain the original
IQ, children must earn higher raw scores when they grow older
(Wechsler, 2005). An adverse impact of the epilepsy on novel
problem solving abilities and on the ability to acquire new infor-
mation, may account for the reduced rate of cognitive growth.
Reduced cognitive growth is detected by the IQ test as lower
scores at retesting. Decline in verbal IQ shows a steeper downward
curve and becomes more evident over months or years. The present data
suggest that this decline in verbal IQ can possibly be understood as
being largely nonspecific (associated to the failure of the brain to
develop and to acquire new information in the same pace as
before) rather than specific (associated with the brain areas respon-
sible for language and verbal abilities). A nonspecific effect is
suggested by the lack of association between side of seizure onset
(right vs. left hemisphere) with VIQ – PIQ difference or with the
VIQ – PIQ pattern (the closing of the VIQ – PIQ gap) over time.
Also, the association between low verbal IQ and the presence of
epileptic activity during the night described in the literature (Over-
vliet et al., 2011) may be interpreted as largely nonspecific.
Over time, the brain itself may activate (inhibitory) mechanisms
to deal with the heightened excitation of the brain, possibly be-
cause of brain maturation (Rakhade & Jensen, 2009), leading to
self-containment of the seizure condition. In addition, antiepileptic
medications aid in seizure suppression and affect cognitive func-
tion (Geerts et al., 2010; Kwan & Brodie, 2001). Many of the
childhood epilepsies ameliorate after several years (Geerts et al.,
2010). These factors may all contribute to slowing down cognitive
decline, giving way to renewed development, although often at a
lower level than the original level. The role of reorganization of
brain networks and its implications for cognitive development
remain unclear. Alterations in brain networks in children with
frontal lobe epilepsy were seen more clearly in those with low
intellectual ability but were not associated with duration of epi-
lepsy (Braakman et al., 2013). The timing of the initial epileptic
seizure, the effects of AEDs, and changes in brain development
may depend on etiology and may be positive in some children and
negative in others, explaining the difference between those who
continue to decline and those who resume development. Further
research is needed to determine the factors. In some children with
low IQs already at baseline, reaching the floor of the test may
occur; thereafter, decline can no longer be quantified by the test.
Limitations and Utility of the Study
An important consideration is that this study used a clinical
sample from a tertiary epilepsy setting to study the cognitive
course over time. The children had been referred and repeatedly
 DURATION OF EPILEPSY AND COGNITIVE DEVELOPMENT
assessed because concerns about the neuropsychological function-
ing had risen. The sample consisted of children who were more
likely to have refractory epilepsy, epilepsy with an unstable course
(Geerts et al., 2010; Schmidt & Sillanpää, 2012), epilepsy that
changed into a more atypical and severe forms (Fejerman, Cara-
ballo, & Tenembaum, 2000), and relatively higher rates of children
with moderate and high epilepsy severity. Therefore, the results
cannot be generalized to “uncomplicated” epilepsy without devel-
opmental concerns. However, it should be borne in mind that
cognitive problems are not restricted to children with more severe
epilepsies or epileptic encephalopathies.
Just as uncomplicated cases may not be referred for testing, it
would be expected that children tested more often (one vs. two,
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two vs. three times) may be “worse” cases. Preliminary analyses
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showed that— up to second testing—these differences were not
statistically significant.
Given the differential impact of duration of epilepsy on the VIQ
and PIQ, (cross-sectional) studies should always include data on
duration of epilepsy.
Clinical Implications
Vulnerability at group level implies that clinically significant
decline is likely to be found for a proportion of the children with
epilepsy. An earlier study on reliable cognitive change suggested
that this proportion is indeed elevated (van Iterson, Augustijn, de
Jong, & van der Leij, 2012).
Lowering of IQ is associated with the failure of schoolchildren
to progress in school. Repeating grades, being set down to a lower
type of education than they enrolled at the start of secondary
school, or both, were seen in a substantial 70% of a sample of 32
youngsters referred to a tertiary center. A correlation of .41 was
found between failure to maintain school level and reliable cog-
nitive decline (van Iterson, 2010). Even after IQs cease to drop, the
result is a significantly reduced school career—with its implica-
tions for emotional adjustment and future perspectives.
Clinicians, parents and educators should stay alert to signs
suggesting that a child is deviating from its developmental curve,
particularly early in the course of the epilepsy, but also beyond the
first years. This deviation may be observed as failure to grow in the
pace expected for the age, or worse, as loss of acquired cognitive
abilities. The risk of decline should also be considered in epilepsies
deemed of lower severity.
The study advocates for the inclusion of cognitive outcome in
measures of severity. That is, a child with epilepsy who shows
concomitant slowing or stagnation of development or loss of
cognitive functions, should be reclassified adding a constituent on
cognitive function in the descriptive diagnosis, regardless of
whether the initial epilepsy diagnosis per se is of low or moderate
severity and whether diagnosis has changed after reevaluation.
This would be in agreement with the revised guidelines of the
ILAE stating that “encephalopathic effects [that is, severe cogni-
tive impairment] of epilepsy may occur in association with any
form of epilepsy” (Berg et al., 2010, p.682). This addition on
cognitive course should have implications for the educational
needs of the child.
In like manner, the study advocates an early start of long-term
remediation interventions for all children who develop epilepsy.
This educational remediation should be an individually tailored
219
process, if necessary lasting beyond seizure remission. Also, the
results of the present study urge researchers to intensify the search
for underlying etiologies and optimalization of medical treatment.
References
Aldenkamp, A. P., Alpherts, W. C. J., De Bruine-Seeder, D., & Dekker,
M. J. A. (1990). Test-retest variability in children with epilepsy - a
comparison of WISC-R profiles. Epilepsy Research, 7, 165–172. doi:
10.1016/0920-1211(90)90102-2
Bailet, L. L., & Turk, W. R. (2000). The impact of childhood epilepsy on
neurocognitive and behvioral performance: A prospective longitudinal
study. Epilepsia, 41, 426 – 431. doi:10.1111/j.1528-1157.2000
.tb00184.x
Ballantyne, A. O., Spilkin, A. M., Hesselink, J., & Trauner, D. A. (2008).
Plasticity in the developing brain: Intellectual, language and academic
functions in children with ischaemic perinatal stroke. Brain, 131, 2975–
2985. doi:10.1093/brain/awn176
Berg, A. T., Berkovic, S. F., Brodie, M. J., Buchhalter, J., Cross, J. H., van
Emde Boas, W., . . . Scheffer, I. E. (2010). Revised terminology and
concepts for organization of seizures and epilepsies: Report of the ILAE
Commission on Classification and Terminology, 2005–2009. Epilepsia,
51, 676 – 685. doi:10.1111/j.1528-1167.2010.02522.x
Berg, A. T., Langfitt, J. T., Testa, F. M., Levy, S. R., DiMario, F.,
Westerveld, M., & Kulas, J. (2008). Global cognitive function in chil-
dren with epilepsy: A community-based study. Epilepsia, 49, 608 – 614.
doi:10.1111/j.1528-1167.2007.01461.x
Berg, A. T., Zelko, F. A., Levy, S. R., & Testa, F. M. (2012). Age at onset
of epilepsy, pharmacoresistence, and cognitive outcomes. Neurology,
79, 1384 –1391. doi:10.1212/WNL.0b013e31826c1b55
Bhise, V. V., Burack, G. D., & Mandelbaum, D. E. (2010). Baseline
cognition, behavior and motor skills in children with new-onset, idio-
pathic epilepsy. Developmental Medicine & Child Neurology, 52, 22–
26. doi:10.1111/j.1469-8749.2009.03404.x
Bjørnæs, H., Stabell, K., Henriksen, O., & Loyning, Y. (2001). The effects
of refractory epilepsy on intellectual functioning in children and adults.
A longitudinal study. Seizure, 10, 250 –259. doi:10.1053/seiz.2000.0503
Bourgeois, B. F., Prensky, A. L., Palkes, M. A., Talent, B. K., & Busch,
S. G. (1983). Intelligence in epilepsy: A prospective study in children.
Annals of Neurology, 14, 438 – 444. doi:10.1002/ana.410140407
Braakman, H. M., Vaessen, M. J., Jansen, J. F., Debeij-van Hall, M. H., de
Louw, A., Hofman, P. A., . . . Backes, W. H. (2013). Frontal lobe
connectivity and cognitive impairment in pediatric frontal lobe epilepsy.
Epilepsia, 54, 446 – 454. doi:10.1111/epi.12044
Bulteau, C., Jambaqué, I., Viguier, V., Kieffer, V., Dellatolas, G., & Dulac,
O. (2000). Epileptic syndromes, cognitive assessment and school place-
ment: A study of 251 children. Developmental Medicine & Child Neu-
rology, 42, 319 –327. doi:10.1017/S0012162200000566
Camfield, C., Camfield, P., Gordon, K., Smith, B., & Dooley, J. (1993).
Outcome of childhood epilepsy: A population-based study with a simple
predictive scoring system for those treated with medication. The Journal
of Pediatrics, 122, 861– 868. doi:10.1016/S0022-3476(09)90008-7
Canivez, G. L., & Watkins, M. W. (1998). Long-term stability of the
Wechsler Intelligence Scale for Children - third ed. Psychological As-
sessment, 10, 285–291.
CBS. (2007). Centraal Bureau voor de Statistiek (Central Statistics Bu-
reau). Standaard Onderwijs Indeling, Onderwijsniveaus van de SOI
2006. (Standard classification of education). Retrived from http://www
.cbs.nl/NR/rdonlyres/6091E080-373F-4A5E-B08C-706D544835FA/0/
2006soiniveauindeling201112.pdf. Retrieved May 28 2012.
Cormack, F., Cross, J. H., Isaacs, E., Harkness, W., Wright, I., Vargha-
Khadem, F., & Baldewag, T. (2007). The development of intellectual
abilities in pediatric temporal lobe epilepsy. Epilepsia, 48, 201–204.
doi:10.1111/j.1528-1167.2006.00904.x
 220 VAN ITERSON ET AL.
Devinsky, O., & Tarulli, A. (2002). Progressive cognitive and behavioral
changes in epilepsy. In O. Devinsky & L. E. Westbrook (Eds.), Epilepsy
and developmental disabilities (pp. 133–149). Woburn, MA: Butter-
worth-Heinemann.
Dunn, D. W., Buelow, J. M., Austin, J. K., Shinnar, S., & Perkins, S. M.
(2004). Development of syndrome severity scores for pediatric epilepsy.
Epilepsia, 45, 661– 666. doi:10.1111/j.0013-9580.2004.53903.x
Elger, C. E., Helmstaedter, C., & Kurthen, M. (2004). Chronic epilepsy and
cognition. Lancet Neurology, 3, 663– 672. doi:10.1016/S1474-
4422(04)00906-8
Ellenberg, J. H., Hirtz, D. G., & Nelson, K. B. (1986). Do seizures in
children cause intellectual deterioration? The New England Journal of
Medicine, 314, 1085–1088. doi:10.1056/NEJM198604243141705
Fastenau, P. S., Johnson, C. S., Perkins, S. M., Byars, A. W., deGrauw,
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
T. J., Austin, J. K., & Dunn, D. W. (2009). Neuropsychological status at
This document is copyrighted by the American Psychological Association or one of its allied publishers.
seizure onset in children: Risk factors for early cognitive deficits. Neu-
rology, 73, 526 –534. doi:10.1212/WNL.0b013e3181b23551
Fastenau, P. S., Shen, J., Dunn, D. W., & Austin, J. K. (2008). Academic
underachievement among children with epilepsy: Proportion exceeding
psychometric criteria for learning disability and associated risk factors.
Journal of Learning Disabilities, 41, 195–207. doi:10.1177/
0022219408317548
Fejerman, N., Caraballo, R., & Tenembaum, S. N. (2000). Atypical evo-
lutions of benign localization-related epilepsies in children: Are they
predictable? Epilepsia, 41, 380 –390. doi:10.1111/j.1528-1157.2000
.tb00177.x
Flynn, J. R. (2007). What is intelligence? Cambridge, UK: Cambridge
University Press.
Funke, M. E., Moore, K., Orrison, W. W., Jr., & Lewine, J. D. (2011). The
role of magnetoencephalography in “nonlesional” epilepsy. Epilepsia,
52, 10 –14. doi:10.1111/j.1528-1167.2011.03144.x
Geerts, A., Arts, W. F., Stroink, H., Peeters, E., Brouwer, O., Peters, B.,
. . . Van Donselaar, C. (2010). Course and outcome of childhood
epilepsy: A 15-year follow-up of the Dutch Study of Epilepsy in Child-
hood. Epilepsia, 51, 1189 –1197. doi:10.1111/j.1528-1167.2010.02546.x
Hermann, B. P., Dabbs, K., Becker, T., Jones, J. E., Myers y Gutierrez, A.,
Wendt, G., . . . Sidenberg, M. (2010). Brain development in children
with new onset epilepsy: A prospective controlled cohort investigation.
Epilepsia, 51, 2038 –2046. doi:10.1111/j.1528-1167.2010.02563.x
Hermann, B., Jones, J., Jackson, D. C., & Seidenberg, M. (2012). Starting
at the beginning: The neuropsychological status of children with new-
onset epilepsies. Epileptic Disorders, 14, 12–21.
Hermann, B., Jones, J., Sheth, R., Dow, C., Koehn, M., & Seidenberg, M.
(2006). Children with new-onset epilepsy: Neuropsychological status
and brain structure. Brain, 129, 2609 –2619. doi:10.1093/brain/awl196
Hermann, B., Seidenberg, M., & Jones, J. (2008). The neurobehavioural
comorbidities of epilepsy: Can a natural history be developed? Lancet
Neurology, 7, 151–160. doi:10.1016/S1474-4422(08)70018-8
Høie, B., Mykletun, A., Sommerfelt, K., Bjornaes, H., Skeidsvoll, H., &
Waaler, P. E. (2005). Seizure-related factors and non-verbal intelligence
in children with epilepsy. A population-based study from Western Nor-
way. Seizure, 14, 223–231. doi:10.1016/j.seizure.2004.10.006
Hutchinson, E., Pulsipher, D., Dabbs, K., Myers y Gutierrez, A., Sheth, R.,
Jones, J., . . . Hermann, B. (2010). Children with new-onset epilepsy
exhibit diffusion abnormalities in cerebral white matter in the absence of
volumetric differences. Epilepsy Research, 88, 208 –214. doi:10.1016/j
.eplepsyres.2009.11.011
Jensen, F. E. (2011). Epilepsy as a spectrum disorder: Implications from
novel clinical and basic neuroscience. Epilepsia, 52, 1– 6. doi:10.1111/
j.1528-1167.2010.02904.x
Jones, J. E., Siddarth, P., Gurbani, S., Shields, W. D., & Caplan, R. (2010).
Cognition, academic achievement, language, and psychopathology in
pediatric chronic epilepsy: Short-term outcomes. Epilepsy & Behavior,
18, 211–217. doi:10.1016/j.yebeh.2010.03.015
Kass, R. E., & Raftery, A. E. (1995). Bayes factors. Journal of the
American Statistical Association, 90, 773–795. doi:10.1080/01621459
.1995.10476572
Kaufman, A. S. (2010). In what way are apples and oranges alike? A
critique of Flynn’s interpretation of the Flynn Effect. Journal of Psy-
choeducational Assessment, 28, 382–398. doi:10.1177/
0734282910373346
Kwan, P., & Brodie, M. J. (2001). Neuropsychological effects of epilepsy
and antiepileptic drugs. Lancet, 357, 216 –222. doi:10.1016/S0140-
6736(00)03600-X
Lange, N., Froimowitz, M. P., Bigler, E. D., & Lainhart, J. E. (2010).
Associations between IQ, total and regional brain volumes, and demog-
raphy in a large normative sample of healthy children and adolescents.
Developmental Neuropsychology, 35, 296 –317. doi:10.1080/
87565641003696833
Meinardi, H., Aldenkamp, A. P., & Nunes, B. (1992). Mental deterioration
at epilepsy onset: A hypothesis. Acta Neurochirugica, 55, 68 –71.
Mitchell, W. G., Scheier, L. M., & Baker, S. A. (1994). Psychosocial,
behavioral and medical outcome in children with epilepsy: A develop-
mental risk factor model using longitudinal data. Pediatrics, 94, 471–
477.
Neyens, L. G. J., & Aldenkamp, A. P. (1997). Stability of cognitive
measures in children of average ability. Child Neuropsychology, 3,
161–170.
Nolan, M. A., Redoblado, M. A., Lah, S., Sabaz, M., Lawson, J. A.,
Cunningham, A. M., . . . Bye, A. M. E. (2003). Intelligence in childhood
epilepsy syndromes. Epilepsy Research, 53, 139 –150. doi:10.1016/
S0920-1211(02)00261-9
Northcott, E., Connolly, A. M., Berroya, A., McIntyre, J., Christie, J.,
Taylor, A., . . . Bye, A. M. E. (2007). Memory and phonological
awareness in children with Benign Rolandic Epilepsy compared to a
matched control group. Epilepsy Research, 75, 57– 62. doi:10.1016/j
.eplepsyres.2007.04.004
O’Leary, S. D., Burns, T. G., & Borden, K. A. (2006). Performance of
children with epilepsy and normal age-matched controls on the WISC-
III. Child Neuropsychology, 12, 173–180. doi:10.1080/
09297040500276844
Overvliet, G. M., Besseling, R. M. H., Vles, J. S. H., Hofman, P. A. M., van
Hall, M. H. J. A., Backes, W., & Aldenkamp, A. P. (2011). Association
between frequency of nocturnal epilepsy and language disturbances in
children. Pediatric Neurology, 44, 333–339. doi:10.1016/j.pediatrneurol
.2010.10.014
Rakhade, S. N., & Jensen, F. E. (2009). Epileptogenesis in the immature
brain: Emerging mechanisms. Nature Reviews Neurology, 5, 380 –391.
doi:10.1038/nrneurol.2009.80
Reijs, R. P., van Mil, S. G., Arends, J., Van Hall, M. H., Weber, J. W.,
Renier, W. O., & Aldenkamp, A. P. (2007). Cryptogenic localization
related epilepsy in children from a tertiary outpatient clinic: Is neuro-
psychological outcome predictable? Clinical Neurology and Neurosur-
gery, 109, 422– 430. doi:10.1016/j.clineuro.2007.03.004
Reijs, R. P., van Mil, S. G. M., van Hall, M. H. J. A., Arends, J. B. A. M.,
Weber, J. W., Renier, W. O., & Aldenkamp, A. P. (2006). Cryptogenic
localization-related epilepsy with childhood onset: The problem of def-
inition and prognosis. Epilepsy & Behavior, 8, 693–702. doi:10.1016/j
.yebeh.2006.03.004
Reilly, C., & Neville, B. G. (2011). Academic achievement in children with
epilepsy: A review. Epilepsy Research, 97, 112–123. doi:10.1016/j
.eplepsyres.2011.07.017
Schmidt, D., & Sillanpää, M. (2012). Evidence-based review on the natural
history of the epilepsies. Current Opinion Neurology, 25, 159 –163.
doi:10.1097/WCO.0b013e3283507e73
Schouten, A., Oostrom, K. J., Jennekens-Schinkel, A., & Peters, A. C. B.
(2001). School career of children at risk before diagnosis of epilepsy
 DURATION OF EPILEPSY AND COGNITIVE DEVELOPMENT
only. Developmental Medicine & Child Neurology, 43, 574 –576. doi:
10.1017/S0012162201241048
Seidenberg, M., Pulsipher, D. T., & Hermann, B. (2007). Cognitive pro-
gression in epilepsy. Neuropsychology Review, 17, 445– 454. doi:
10.1007/s11065-007-9042-x
Skirrow, C., Cross, J. H., Cormack, F., Harkness, W., Vargha-Khadem, F.,
& Baldeweg, T. (2011). Long-term intellectual outcome after temporal
lobe surgery in childhood. Neurology, 76, 1330 –1337. doi:10.1212/
WNL.0b013e31821527f0
Smith, M. L., Elliott, I. M., & Lach, L. (2002). Cognitive skills in children
with intractable epilepsy: Comparison of surgical and nonsurgical can-
didates. Epilepsia, 43, 631– 637. doi:10.1046/j.1528-1157.2002.26101.x
Snijders, T. A. B., & Bosker, R. J. (1999). Multilevel Analysis: An intro-
duction to Basic and Advanced Multilevel Modeling. London, UK:
This article is intended solely for the personal use of the individual user and is not to be disseminated broadly.
SAGE Publications Inc.
Strauss, E., Loring, D. W., Chelune, G. J., Hunter, M., Hermann, B.,
This document is copyrighted by the American Psychological Association or one of its allied publishers.
Perrine, K., . . . Barr, W. (1995). Predicting cognitive impairment in
epilepsy: Findings from the Bozeman epilepsy consortium. Journal of
Clinical and Experimental Neuropsychology, 17, 909 –917. doi:10.1080/
01688639508402439
Vaessen, M. J., Jansen, J. F., Vlooswijk, M. C. G., Hofman, P. A., Majoie,
H. J. M., Aldenkamp, A. P., & Backes, W. H. (2012). White matter
network abnormalities are associated with cognitive decline in chronic
epilepsy. Cerebral Cortex, 22, 2139 –2147. doi:10.1093/cercor/bhr298
Vander Steene, G., & Bos, A. (1997). WPPSI-R Wechsler Preschool and
Primary Scale of Intelligence. Vlaams-Nederlandse Aanpassing. Han-
dleiding. Test Manual, Lisse, The Netherlands.
van Haasen, P., de Bruyn, E., Pijl, Y., Poortinga, Y. H., lutje Spelberg,
H. C., Vandersteene, G., . . . Stinissen, J. (1986). WISC-R. Wechsler
Intelligence Scale for Children Revised. Nederlandstalige uitgave. Lisse,
The Netherlands: Swets Test Services.
van Iterson, L. (2010). Failing to progress in secondary school and reliable
Changes in cognitive functioning in adolescents with epilepsy (Falta de
progreso escolar en enseñanza secundaria y Cambios Confiables (RC) de
View publication stats
221
nivel cognitivo en adolescentes con epilepsia). Poster presented at the
6th Latin American Congress on Epilepsy, Cartagena, Colombia, Aug
1– 4, 2010.
van Iterson, L., Augustijn, P. B., de Jong, P. F., & van der Leij, A. (2012).
Establishing reliable cognitive change in children with epilepsy: The
procedures and results for a sample with epilepsy. Journal of Psychoe-
ducational Assessment, 31, 448 – 458. doi:10.1177/0734282912465716.
Van Mil, S. G. M., Reijs, R. P., Van Hall, M. H. J. A., Snoeijen, S. M., de
la Parra, N. M., & Aldenkamp, A. P. (2010). Behavior in children with
cryptogenic localisation related epilepsy: A follow-up study. Pediatric
Neurology, 42, 107–110. doi:10.1016/j.pediatrneurol.2009.08.008
Wechsler, D. (2005). WISC-IIINL. Wechsler Intelligence Scale for Chil-
dren. Derde editie NL. Handleiding en Verantwoording. London/
Amsterdam: The Psychological Corporation/Nederlands Dienstencen-
trum NIP.
Westerveld, M., Sass, K. J., Chelune, G. J., Hermann, B. P., Barr, W. B.,
Loring, D. W., . . . Spencer, D. D. (2000). Temporal lobectomy in
children: Cognitive outcome. Journal of Neurosurgery, 92, 24 –30. doi:
10.3171/jns.2000.92.1.0024
Wirrell, E. C., Grossardt, B. R., So, E. L., & Nickels, K. C. (2011). A
population-based study of long-term outcomes of cryptogenic focal
epilepsy in childhood: Cryptogenic epilepsy is probably not symptom-
atic epilepsy. Epilepsia, 52, 738 –745. doi:10.1111/j.1528-1167.2010
.02969.x
Wirrell, E. C., Grossardt, B. R., Wong-Kisiel, L. C., & Nickels, K. C.
(2011). Incidence and classification of new-onset epilepsy and epilepsy
syndromes in children in Olmsted County, MN from 1980 to 2004: A
population-based study. Epilepsy Research, 95, 110 –118. doi:10.1016/
j.eplepsyres.2011.03.009
Received May 1, 2013
Revision received August 30, 2013
Accepted September 2, 2013 䡲