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Introduction
Children
with epilepsy often experience psychiatric and
behavioral issues, such as ADHD, conduct disorder,
autism spectrum disorder, and affective and
aggressive disorders. These can negatively impact
their quality of life if not properly addressed.
[1-3] Compared to children with other chronic
diseases like arthritis, diabetes, asthma, and
cardiac conditions, those with epilepsy tend to
perform worse.[4-5]
Recent studies in
developed countries show that many children with
epilepsy have behavioral problems, and one third
of them have mental illness. [6-8] However, these
studies are not globally representative;
developing countries have a much higher number of
children with epilepsy.
The use of
antiepileptic drug monotherapy or polytherapy has
been reported to have a higher prevalence of
behavioral problems in epileptic children. [9-10]
The causes of
behavioural problems in children with epilepsy are
unclear. Studies suggest various psychosocial and
biomedical factors, such as the type, severity,
and duration of epilepsy, family dynamics,
parenting, and individual cognitive performance
levels, but results remain inconsistent. [11-13]
These risk factors in developing countries require
more investigation.
This study examined
behavioral problems in children with epilepsy aged
6 to 15 years. The goal was to compare behavioral
issues in children with epilepsy to those in
healthy controls matched by age and gender. The
study also investigated whether factors such as
age of onset, duration of epilepsy, frequency of
seizures, type of epilepsy, and anti-epileptic
drug therapy could predict the likelihood of
behavioral problems.
Material and Methods
Study setting
A controlled study
was conducted in the departments of paediatrics,
psychiatry and pharmacology at a tertiary care
teaching hospital from Jan 2022 to December 2023.
The center provides free anti-seizure medications
to patients below the poverty line. Approval was
obtained from the institutional ethics committee.
Written informed consent was collected from the
parents or guardians of the children in accordance
with the tenets of the Declaration of Helsinki.
Study
participants
Inclusion
criteria: Children with epilepsy older
than 6 years were selected by non-probability
sampling. Behavioral problems in these children
with epilepsy are reported in this study. It is
assumed that older children (over 6 years) may
provide a more comprehensive picture of the
long-term behavioral consequences of epilepsy
compared to younger children. Age and
gender-matched children visiting the pediatric
outpatient department for minor ailments served as
controls.
Exclusion
criteria: Patients diagnosed with
symptomatic epilepsy, epileptic encephalopathy,
febrile seizures, cerebral palsy, developmental
delay, intellectual disability, neurodegenerative
and metabolic disorders, cerebral tuberculosis, or
neurocysticercosis were excluded from the study.
Behaviour
The primary outcome
measure was behavioral disorders, assessed by a
clinical psychologist. The Child Behaviour
Checklist (CBCL) is a parent-completed
questionnaire for children aged 4-16 years, with
113 questions scored on a three-point Likert scale
(0=absent, 1=sometimes, 2=often). The CBCL is
validated for assessing behavioral disorders and
is widely used in various settings including
mental health services, schools, and medical
facilities.
A language expert
translated the CBCL questions from English, and
each parent/guardian was asked the same questions.
The scale includes standardised scores for age and
gender, covering behaviours like emotional
reactivity, anxiety/depression, somatic
complaints, withdrawal, sleep issues, attention
problems, and aggression in children aged 2-5. For
ages 6-14, it covers anxiety/depression,
withdrawal/depression, somatic complaints, social
problems, thought issues, attention problems,
rule-breaking, and aggression. It also provided a
total behavior problem score and two second-order
factor scores for internalizing problems
(emotional reactivity, anxiety/depression, somatic
complaints, withdrawal, and sleep issues) and
externalizing behavior (attention issues and
aggressive behavior in younger age groups, and
rule-breaking and aggressive behavior in older
children). [14]
The study evaluated
external variables such as age, gender,
socioeconomic status, age at epilepsy onset,
duration of epilepsy, type of seizures (partial
vs. GTCS), and the number of anti-seizure
medications.
Definitions
The number of
anti-seizure medications (ASM) was defined as the
number of different ASM types currently taken by
the patient and categorized as either monotherapy
or polytherapy.
Age at onset was
defined as the child's age in years when epilepsy
was diagnosed.
The duration of
epilepsy in years was defined as the period
between the diagnosis confirmation and the
completion of the questionnaire.
Sample size
calculation
The sample size was
calculated using the University of British
Columbia's web-based calculator, accessible at
https://www.stat.ubc.ca/~rollin/stats/ssize/n2.html.
The calculation followed the principle of
'Inference for Means: Comparing a mean to a known
value'.
A pilot study on 10
subjects calculated the sample size needed to
compare mean CBCL T-scores between children with
epilepsy and controls. The mean total behaviour
problem score was 57.4 for children with epilepsy
and 52.2 for controls, with a standard deviation
of 17.4. With 80% power (alpha = 0.05) and a 5%
precision error to detect a 20% difference, the
estimated sample size was 88.
Statistics
We used IBM SPSS
version 29 for statistical analysis. Data
normality was checked with the Shapiro-Wilk test,
and outliers were identified via boxplots. Means
and standard deviations were calculated for
continuous variables, while frequencies and
percentages were determined for categorical
variables. The independent-samples t-test assessed
differences between two groups on a continuous
variable. Chi-square tests evaluated associations
between categorical variables. The independent
variable was epilepsy; the dependent variable was
behavioral disorders based on CBCL scores.
Linear regression
was employed to identify determinants influencing
total behavioral scores in children with epilepsy.
Subsequently, a logistic regression model was
developed to ascertain the factors associated with
the likelihood of developing behavioral problems
in children with epilepsy, after adjusting for
confounding variables such as age, gender, and
socioeconomic status. Variables with a univariate
P value ≤0.05 were included in the logistic
regression model to identify independent risk
factors. A P value <0.05 was deemed
statistically significant.
Age Matching
The age matching was
performed using MATLAB software Version 1, which
is available at
https://in.mathworks.com/matlabcentral/fileexchange/66984-age_gender_match-year_gap-group1-group2-.
This function randomly matches the ages of two
groups within the specified year gap.
Results
This study enrolled
100 children with epilepsy (Group 1) and 100
healthy age-matched controls (Group 2). The mean
age was 9.5±2.2 years for Group 1 and 9±1.8 years
for Group 2 (paired t-test, P=0.192). The average
disease onset age was 5.2±2.2 years. Group 1 had
32 males (male: female ratio 1.7:1), and Group 2
had 23 males (male: female ratio 0.8:1) (Fisher’s
exact test, P=0.559).
Sixty-six percent
(66%) of the children experienced generalized
tonic-clonic seizures (GTCS), while 34% had
partial seizures. Among the patients with GTCS, 30
exhibited normal behavior and 36 exhibited
abnormal behavior. In the group of 34 patients
with partial seizures, 24 demonstrated normal
behavior and 10 demonstrated abnormal behavior.
The Chi-square test result was P=0.236.
Behavioral problems
were identified in 44 (44%) children with epilepsy
and 20% of controls, as determined by Chi-square
tests (P=0.001). Table 1 presents a comparison of
the mean scores for CBCL domains between the two
groups. The mean behavioral scores in patients
with epilepsy were significantly elevated across
all CBCL domains compared to controls
(P<0.001).
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Table 1: CBCL scores for domains
between epilepsy and controls
|
|
CBCL domain
|
Group 1 (Epilepsy)
|
Group 2 (controls)
|
P value
|
|
Anxious /depressed
|
57.02
|
8.15
|
50.4
|
1.6
|
<0.001
|
|
Withdrawn/depressed
|
61.26
|
12.47
|
53.3
|
6.7
|
<0.001
|
|
Somatic complaints
|
57.36
|
9.1
|
52.56
|
6.30
|
<0.028
|
|
Social problems
|
59.26
|
10.54
|
50.88
|
3.2
|
<0.001
|
|
Thought problems
|
55.52
|
7.616
|
52.14
|
4.6
|
<0.084
|
|
Attention problems
|
59.48
|
11.259
|
51.24
|
4.9
|
<0.001
|
|
Rule breaking behaviour
|
57.78
|
8.89
|
51.3
|
5.24
|
<0.001
|
|
Aggressive behaviour
|
61.02
|
11.29
|
54.8
|
8.65
|
<0.001
|
|
Internalizing problems
|
58.67
|
10.11
|
52.12
|
5.51
|
<0.001
|
|
Externalizing Problems
|
60.66
|
10.62
|
53.05
|
7.33
|
<0.001
|
|
Total Behavioural problems
|
58.63
|
10.10
|
52.0
|
3.61
|
<0.001
|
|
CBCL: Child behaviour checklist
|
Patients undergoing
monotherapy were administered sodium valproate,
while children receiving polytherapy were treated
with either phenytoin (64%) or levetiracetam
(36%).
The mean total
behavioral problems (T-score) did not
significantly differ between monotherapy (58±8)
and polytherapy (59.4±8.4) (independent t-test,
P=0.646). Table 2 shows that the mean CBCL domain
scores were similar for children on both
therapies, except for the anxious/depressed
domain, where a significant difference was found
(P=0.025).
|
Table 2: CBCL T
scores for domains between mono and
polytherapy
|
|
CBCL domain
|
Monotherapy
|
Polytherapy
|
P value
|
|
Anxious /depressed
|
54.48
|
6.0
|
59.56
|
9.28
|
0.025
|
|
Withdrawn/depressed
|
60.2
|
12.6
|
62.32
|
12.42
|
0.550
|
|
Somatic complaints
|
57.88
|
8.9
|
56.84
|
9.511
|
0.690
|
|
Social problems
|
57.12
|
9.1
|
61.4
|
11.62
|
0.150
|
|
Thought problems
|
55.04
|
6.9
|
56
|
8.38
|
0.720
|
|
Attention problems
|
58.04
|
10.7
|
60.92
|
11.85
|
0.370
|
|
Rule breaking behaviour
|
60.08
|
10.6
|
56.24
|
7.24
|
0.489
|
|
Aggressive behaviour
|
61.76
|
11.76
|
60.36
|
11.80
|
0.670
|
|
Internalizing problems
|
57.52
|
9.7
|
59.57
|
10.6
|
0.480
|
|
Externalizing Problems
|
60.92
|
10.74
|
58.3
|
9.9
|
0.370
|
|
Total Behavioural problems
|
58.08
|
8.152
|
59.205
|
8.514
|
0.630
|
The age of seizure
onset demonstrated significant inverse
correlations with total behavioral problems
(Pearson’s correlation coefficient, r = -0.496, P
< 0.001), the internalizing problems domain
(Pearson’s correlation coefficient, r = -0.428, P
< 0.001), and the externalizing problems domain
(Pearson’s correlation coefficient, r = -0.446, P
< 0.001).
Seizure frequency
showed positive and significant correlations with
total behavioral problems (Pearson’s correlation
coefficient, r = 0.364, P < 0.001) and the
externalizing problems domain (Pearson’s
correlation coefficient, r = 0.468, P < 0.001).
Additionally, the
duration of drug intake exhibited positive and
significant correlations with total behavioral
problems (Pearson’s correlation coefficient, r =
0.361, P < 0.010).
Univariate analysis
found that seizure frequency (P=0.020), active
epilepsy (P=0.010), and clinical neurological
deficits (P=0.008) were significantly linked to
worse behavioral scores.
A multivariate
analysis examined how factors like age of seizure
onset, duration, frequency, type, antiepileptic
drug use (mono vs. polytherapy), and therapy
duration affect the likelihood of children having
behavioral problems, adjusting for confounders
such as age, gender, and socioeconomic status. The
Box-Tidwell procedure confirmed that all
continuous variables were linearly related to the
logit of the dependent variable. One standardized
residual with a value of 3.349 standard deviations
was included in the analysis.
The logistic
regression model was statistically significant,
χ2(11) = 134.063, P < .0001,
explaining 78.0% (Nagelkerke R2) of the
variance in behavioral problems and correctly
classifying 90.0% of cases. The model had a
sensitivity of 90% and specificity of 86%. Out of
five predictors, three were significant: duration
of seizures (OR=2.4), seizure frequency (OR=2.1),
and polytherapy. Table 3 provides detailed
coefficients, statistical significance, and odds
ratios with confidence intervals.
|
Table 3: Multiple Logistic
Regression Coefficients
|
|
Variable
|
B (constant)
|
SE
|
df
|
P value
|
OR
|
95%CI
|
|
Seizure duration
|
0.214
|
7.344
|
1
|
0.001
|
2.1
|
1.61
|
2.80
|
|
Seizure frequency
|
0.812
|
114.5
|
1
|
0.049
|
2.4
|
2.12
|
3.42
|
|
Duration of antiepileptic therapy
|
1.119
|
25.5
|
1
|
0.005
|
1.8
|
0.9
|
2.2
|
|
Polytherapy
|
1.887
|
9.3
|
1
|
0.112
|
1.01
|
0.64.6
|
1.4
|
|
Seizure type
|
1.614
|
8.4
|
1
|
0.2132
|
0.8
|
0.72
|
0.94
|
|
Constant
|
-401.4
|
346.93
|
1
|
0.881
|
0.000
|
-
|
-
|
|
SE: standard error, df: degree of
freedom, OR: odds ratio, CI: confidence
interval
|
Discussion
This study examined
behavioral issues in children with epilepsy at a
tertiary care teaching institute in southeast
Asia. Consistent with findings from other
research, we observed that behavioral problems
were more prevalent among children with epilepsy
compared to age-matched controls without epilepsy.
Frequency of
behaviour problems
The frequency of
behaviour problems in children with epilepsy
varies by region. Higher rates are seen in
developing countries and resource-poor areas
despite the fact that many epilepsy patients seek
help from quacks and religious healers or conceal
their illness due to social stigma.[15-16] A study
in rural Kenya reported that 49% of children with
epilepsy had behavioural problems.[17] Our
findings are consistent with a similar study in
Thailand, which also reported behavioural problems
in 49% of children with epilepsy. [18]
A study conducted in
Norway reported that 56.3% of subjects had
disorders within the category of total behavioral
scores. [19] A study conducted by Datta et al.
found that 53.8% of behavioral disorders were
observed among 132 children with epilepsy, as
measured by the Child Behaviour Checklist (CBCL).
[20] Various socio-demographic factors, including
the target population, as well as the inclusion
and exclusion criteria and the evaluation
instruments employed, may contribute to variations
in the frequency of behavioural problems.
Factors
affecting behaviour problems
Previous studies
have indicated that the age at which seizures
begin, the frequency of seizures, and the number
of anti-seizure medications may significantly
influence behavioral problems in children. [21-23]
Our study identified that an earlier age of onset
and frequent seizures were significantly linked to
behavioral issues. Conversely, an Indonesian study
found no significant relationship between
behavioral disorders in children with epilepsy and
factors like gender, child’s age, duration of
epilepsy, age at onset, maternal education, or the
number of anti-seizure medications. [24]
Multivariate
analysis showed that seizure frequency and
duration were more likely to be associated with
the development of behavior problems after
accounting for gender, age, and socioeconomic
status. These findings align with other studies
that have identified a significant link between
increased seizure frequency and various behavioral
scales. [25]
Anti-seizure
medication and behaviour problems
In our study, the
duration of disease and anti-epileptic medications
specifically impacted the internalizing domain.
Conversely, no significant differences in
behavioral issues were found between monotherapy
and polytherapy, except in the anxious/depressed
domain. Freilinger et al found that children on
anticonvulsive polytherapy show more aggressive
behaviour and face social and attention problems
compared to those on monotherapy or no therapy.
Mishra et al. found no significant differences in
total behavioural problems between children on
monotherapy and polytherapy. [27]
Limitations
and strength
The study's strength
was the use of a standardized validated
measurement tool to observe behavioral patterns.
However, the sample size was small (n=100),
limiting the power to detect subgroup differences
in behavioral problems. Recall bias cannot be
ruled out, and the study lacked sufficient power
to establish a causal link between epilepsy and
behavioral disorders.
Conclusion
The study indicates that not all children with
epilepsy experience behavioral problems. Compared
to age-matched controls, behavioral problems were
noted in 44% of children. In developing countries,
epilepsy in children is linked to considerable
psychopathology, potentially due to the interplay
of seizures, socio-demographic variables,
treatment-related factors, and family-related
factors. Multivariate analysis identified higher
seizure frequency and longer duration of epilepsy
as independent predictors of behavioral problems
in children with epilepsy.
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