Journal of Clinical Neuroscience xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Behavioral comorbidity in children and adolescents with epilepsy Anita Choudhary a,c, Sheffali Gulati a,⇑, Rajesh Sagar b, Madhulika Kabra a, Savita Sapra a a
Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar East, Gautam Nagar, New Delhi 110029, India Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India c Department of Pediatrics, SMS Medical College, Jaipur, Rajasthan, India b
a r t i c l e
i n f o
Article history: Received 5 November 2012 Accepted 10 November 2013 Available online xxxx Keywords: Antiepileptic drugs Behavioral comorbidity Child behavior checklist Epilepsy
a b s t r a c t This cross sectional study assessed the prevalence of behavioral comorbidity and its association with epilepsy-related factors in children and adolescents with epilepsy. One hundred consecutive patients with active epilepsy, aged 6–16 years, were screened for behavioral comorbidity using the Child Behavior Checklist and those who qualified as having behavioral comorbidity were compared with those who did not have it. Behavioral comorbidity was found in 43 of 100 participants. Being treated with antiepileptic drug polytherapy (odds ratio 6.3, 95% confidence interval 1.4–17.3, p = 0.01) independently predicted behavioral comorbidity in the patients studied. The demonstrated high frequency of behavioral comorbidity in children with epilepsy suggests that pediatricians and pediatric neurologists should be sensitive to this fact in order to identify and manage behavioral comorbidity in children with epilepsy. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Epilepsy is one of the most prevalent chronic neurological disorders affecting children. The burden of epilepsy is greater in developing countries compared to developed countries [1]. The estimated prevalence of epilepsy in India is 5.59 cases per 1000 people [2]. It has been observed that children with epilepsy (CWE) are at an increased risk of behavioral and emotional problems. In the landmark pediatric psychiatric epidemiological Isle of Wight study, Rutter et al. observed that the prevalence of behavioral problems was 28.6% in children with uncomplicated epilepsy and 58.3% in children with seizures and structural brain abnormality, as compared to 6.6% in the general child population [3]. Prevalence of behavioral and emotional problems in CWE in developed countries is greater than in those with other chronic illnesses not involving the central nervous system, such as diabetes mellitus or bronchial asthma [4,5]. Reported prevalence of behavioral and emotional problems in CWE ranges from 24% to 66% [6–10]. Theoretical models of psychopathology propose that psychopathology in epilepsy can stem from a complex interplay of multiple etiological variables [11]. Risk factors may be biological (seizurerelated and treatment-related) or psychosocial. Some studies from developed countries have observed that behavioral and psychiatric problems are associated with frequent and severe seizures [12–14], early onset of seizures [12], antiepileptic drug (AED) polytherapy ⇑ Corresponding author. Tel.: +91 11 2659 4679; fax: +91 11 2658 8663. E-mail address: [email protected] (S. Gulati).
and symptomatic epilepsy [15], whereas other studies demonstrated no association of age at seizure onset, seizure frequency, seizure type, or lateralization of seizure focus with psychopathology in CWE [16,17]. There are limited data on the prevalence and association of epilepsy-related variables with behavioral comorbidity in children and adolescents with epilepsy from developing countries [9,10]. Therefore the present study’s primary objective was to determine the prevalence of behavioral comorbidity in children and adolescents aged 6 to 16 years with active epilepsy using the Child Behavior Checklist (CBCL) [18]. The secondary objective was to explore the potential epilepsy-related risk factors for behavioral comorbidity in the same study population.
2. Material and methods 2.1. Procedure This cross sectional, observational study was conducted between October 2008 and August 2009. All children and adolescents diagnosed with active epilepsy attending the outpatient services of the Division of Pediatric Neurology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi were screened for eligibility for this study. The International League Against Epilepsy (ILAE) definitions were used to define active epilepsy as two or more unprovoked seizures occurring 24 hours apart, with at least one epileptic seizure in the previous 5 years, regardless of AED treatment [19]. The inclusion criteria were (1) children aged from
http://dx.doi.org/10.1016/j.jocn.2013.11.023 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Choudhary A et al. Behavioral comorbidity in children and adolescents with epilepsy. J Clin Neurosci (2014), http:// dx.doi.org/10.1016/j.jocn.2013.11.023
2
A. Choudhary et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx
6–16 years and (2) duration of epilepsy for at least 6 months. Patients were excluded if they had an intellectual disability or comorbid chronic systemic disease. Intellectual disability was defined as a verbal intelligence quotient of 70 or less. Malin’s Intelligence Scale for Indian Children was used to screen children for intellectual disability [20]. Informed written consent was obtained from the primary caregivers of participants before inclusion into the study. The study design was approved by the Institutional Ethics Committee. All participants gave a detailed medical and neurological history and underwent clinical examination. Seizures were analysed by determining age at onset of epilepsy, predominant seizure type, seizure frequency, duration of epilepsy, etiology, and number of AED taken. Participants were placed into one of three categories of seizure frequency, being seizure free, having 1–10 seizures, or having >10 seizures, during the past 6 months. Epilepsy type was classified according to the recommendations of the ILAE [21]. Medical records were checked for confirmation of history. Caregivers were interviewed regarding educational problems of their child, and any repetition of a school grade was noted. If the child was not studying or had dropped out, the cause was evaluated. Socio-economic status was classified into six social classes as per the modified social classification (modification of Prasad’s classification) by Agrawal, based on per capita monthly income [22]. Digital electroencephalography (EEG) (Medelec profile; Oxford Instruments, Oxfordshire, UK) was performed using the international 10-20 system of electrode placement. Both awake and sleep recordings were taken. Hyperventilation, photic stimulation and sleep were used for the activation procedure. EEG was reported as normal or showing epileptiform abnormality. The latest available EEG was analysed by a pediatric neurologist if it had been recorded within 3 months of evaluation. In children without such a recent EEG one was recorded on the same day of completing the CBCL. 2.2. Evaluation tools Caregivers completed the CBCL while waiting in the hospital department. Questions were explained by an investigator if needed. The caregivers were asked to not report behavior which was present just before, during or after seizure. The questionnaire was scored as per manual specification. The CBCL consists of 118 behavior problem items on which caregivers rate their children using a three point scale, with higher scores reflecting more problems. The CBCL assesses broad band behavior problems (externalizing and internalizing behavior problems) and narrow band behavior problems (attention problems, aggressive behavior, delinquent behavior, withdrawnness, somatic complaints, anxiety/depression, thought problems and social problems). Previous research has shown that CBCL is useful for assessing psychopathology in CWE [23]. The CBCL has been standardized and cut-off scores for significant behavioral comorbidity have been previously established for the Indian population [24]. The score thresholds for having a behavioral problem in children aged 6– 11 years are 21 and 16 for males and females, respectively. For children aged 12–16 years the cut-off thresholds are 18 and 13 for males and females, respectively. This checklist has good psychometric properties. For this study, we used total scores only, as other scores have not been validated for Indian children. Children and adolescents were classified as having behavioral comorbidity if they scored above the relevant threshold for their age and sex on CBCL total scores. 2.3. Sample size estimation and statistical analysis The varied reported prevalence of behavioral comorbidity in CWE has been as high as 42%. We calculated that 97 patients would
be required for an expected 50% prevalence of behavioral comorbidity in our study population, with a 95% confidence level and ± 0.10 width of confidence interval (CI). Hence, the present study was planned as an observational study with a sample size of 97 patients. A Microsoft Excel spreadsheet was used for data entry (Microsoft, Redmond, WA, USA). Data were analysed using Stata software version 9 (StataCorp, College Station, TX, USA). Frequencies were calculated by descriptive analysis. Univariate analysis was done to detect differences between participants with and without behavioral comorbidity. The statistical significance of categorical data was determined using the chi-squared test. The statistical significance of continuous data was determined using Student’s t-test. The variables that differed significantly in the univariate analysis were used for multivariate analysis, using logistic regression. With the behavioral comorbidity as the dependant variable, odds ratios (OR) for epilepsy-related risk factors were calculated. A p value 0.05). Table 1 details the comparison of epilepsy-related variables between the two groups. Symptomatic epilepsy (p = 0.04), partial seizure (p = 0.03), epileptiform discharges on EEG (p = 0.04), being treated with AED polytherapy (p = 0.001) and duration of epilepsy more than 26 months (p = 0.01) were associated with behavioral comorbidity. Multivariate analysis was carried out using logistic regression. The medical epilepsy-related variables which were significant at the p < 0.1 level in univariate analysis were included in the equation as independent variables with behavioral comorbidity as the dependant variable. In the final equation, treatment with AED polytherapy independently predicted behavioral comorbidity in children and adolescents with epilepsy (OR 6.3, 95% CI 1.4–17.3, p = 0.01). Table 2 details epilepsy-related predictors of behavioral comorbidity. 3.5. Education profile Of the 43 patients with behavioral comorbidity, six children were not attending school as compared to three children in the Table 1 Association of epilepsy-related factors with behavioral comorbidity in children with epilepsy Behavioral comorbidity present (n = 43) n (%)
No behavioral comorbidity (n = 57) n (%)
v2
p value
Etiology Idiopathic Symptomatic
26 (36.6) 17 (58.6)
45 (63.4) 12 (41.4)
4.06
0.04
Seizure type Generalized Partial
18 (33.3) 25 (54.3)
36 (66.7) 21 (45.7)
4.47
0.03
EEG Normal Epileptiform
26 (36.6) 17 (58.6)
45 (63.4) 12 (41.4)
4.06
0.04
Seizure frequency (past 6 months) No seizure 12 (30.0) 1–10 seizures 22 (48.9) >10 seizures 9 (60.0)
28 (70.0) 23 (51.1) 6 (40.0)
5.16
0.07
Antiepileptic therapy No therapy 2 (33.3) Monotherapy 24 (33.3) Polytherapy 17 (77.3)
4 (66.7) 48 (66.7) 5 (22.7)
13.51
0.001
Epilepsy duration 626 months >26 months
11 (27.5) 32 (53.3)
29 (72.5) 28 (46.7)
6.53
0.01
Age at onset 674 months >74 months
25 (46.3) 18 (39.1)
29 (53.7) 28 (60.9)
0.52
0.47
Variable
EEG = electroencephalography.
3
group without behavioral comorbidity (p = 0.13). Eight children had dropped out of school on account of epilepsy. Of the 91 children who were attending regular school, repetition of a grade was significantly higher in children with behavioral comorbidity than in children without (16 versus four, respectively; p < 0.001). 4. Discussion In this study we estimated the prevalence of behavioral comorbidity in children and adolescents with epilepsy who were not intellectually disabled. We also tried to understand the association of medical epilepsy-related factors with behavioral comorbidity in children and adolescents with epilepsy in a developing country. In accordance with previous studies, this tertiary care center cross sectional study demonstrated a high prevalence (43%) of behavioral comorbidity in this sample of children with active epilepsy. A previous tertiary care center based study from south India reported a 53.8% prevalence of psychopathology in CWE on the CBCL [9]. 4.1. Association of epilepsy-related variables with behavioral problems In the sample studied, AED polytherapy independently predicted behavioral comorbidity in CWE (OR 6.3, 95% CI 1.4–17.3, p = 0.01). This association of AED polytherapy with behavioral comorbidity in CWE has also been reported in other studies in the pediatric population [9,15,25]. In a hospital based study, Datta et al. observed that AED polytherapy (OR 3.08, 95% CI 1.09–8.72, p = 0.03), belonging to a higher income group and living in an urban area (OR 7.61, 95% CI 2.78–20.8, p = 0.0001) and having epilepsy for longer than 3 years (OR 2.39, 95% CI 2.18–5.67, p = 0.03) independently predicted psychopathology [9]. Freilinger et al. reported that children suffering from epilepsy for more than 1 year treated with AED polytherapy scored significantly higher on social problems (r = 0.278, p = 0.004), attention problems (r = 0.214, p = 0.03), and aggressive behavior (r = 0.275, p = 0.005) [15]. In a sample of 106 children with idiopathic epilepsy, Dafoulis et al. found that later age of onset of epilepsy, AED polytherapy, and male sex predicted behavioral problems [25]. This association must be viewed with caution as association does not mean causality, as children with difficult to control seizures may require the addition of more AED. But this possibility of behavioral comorbidity caused by AED polytherapy should not be discarded completely, particularly when there may be a biological explanation. At present AED are the mainstay of epilepsy treatment. All AED have the potential to cause behavioral side effects [26]. AED suppress epileptic seizures by regulating neuronal excitability. The various mechanisms of action include inhibitory GABAergic and excitatory glutamatergic neurotransmission, as well as ion (sodium and calcium) conductance through voltage-gated channels. These mechanisms are also implicated in the regulation of behavior, which may explain the adverse behavioral effects of AED [27]. Various patient related factors such as age, epilepsy type, and premorbid behavioral problems may be implicated in the adverse behavioral effects of AED. AED-related factors can also be linked to the occurrence of adverse behavioral effects, including dosage, rapid dose titration, seizure control, and concurrent AED [26]. Many observations on the adverse behavioral effects of specific AED come from case reports or uncontrolled studies, thus, there are considerable limitations in drawing firm conclusions about the possible links between specific adverse behavioral effects and AED [26].
Please cite this article in press as: Choudhary A et al. Behavioral comorbidity in children and adolescents with epilepsy. J Clin Neurosci (2014), http:// dx.doi.org/10.1016/j.jocn.2013.11.023
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A. Choudhary et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx
Table 2 Epilepsy-related risk factors for behavioral comorbidity in children with epilepsy Variable
Unadjusted OR
95% CI
Adjusted OR
95% CI
p value
Symptomatic epilepsy Partial seizure Epileptiform EEG Antiepileptic drug polytherapy 1–10 seizures in past 6 months >10 seizures in past 6 months Epilepsy duration >74 months
2.5 2.3 2.5 6.3 2.2 3.5 2.8
1.01–5.9 1.06–5.2 1.01–5.9 2.3–20.4 0.9–5.5 1.01–12 1.3–6.3
1.1 1.7 2.0 4.95 1.1 1.6 1.7
0.4–3.5 0.6–4.4 0.7–5.7 1.4–17.3 0.4–3.0 0.3–7.4 0.6–4.6
0.7 0.28 0.22 0.01 0.9 0.6 0.27
CI = confidence interval, EEG = electroencephalography, OR = odds ratio.
4.2. Impact of behavioral problems Behavioral disorders have a major impact on the child and their family in terms of quality of life, education and leisure activities. CWE living in rural areas of developing countries face the added burden of myths and misconception about the disease [28]. Academic underachievement has been demonstrated to be associated with disordered behavior in CWE [29]. In the present study, repetition of a grade was significantly higher in children with behavioral comorbidity. This study is one of the few exploring behavioral comorbidity in CWE in India. We also investigated the medical epilepsy-related predictors for behavioral comorbidity. However the study is limited as the study population was made up of a tertiary care center population, making it difficult to generalize results to the general population. Information on behavioral comorbidity was obtained from the primary caregivers; school teacher and adolescent reports were not obtained and due to the small sample size behavioral comorbidity could not be correlated with specific AED. The study design did not include assessment of all family-related factors (all family stress factors, parent/child relationship and family dynamics) and personality traits that could have contributed to the degree of psychosocial disturbances in CWE. The cross-sectional design did not allow us to make causal conclusions. Larger prospective studies are needed to assess the causal relationship of epilepsy-related variables with behavioral comorbidity. 5. Conclusion This tertiary care center based study demonstrated significant behavioral comorbidity in CWE. Therefore, periodic psychosocial assessment should be a standard part of multidisciplinary care of CWE, with early counselling and appropriate management to prevent the additional disability that behavioural problems confer. Further studies are required to evaluate the efficacy of various treatment modalities, including behavioral therapy and drug therapy for behavioral comorbidities and their effect on improving quality of life. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Carpio A, Hauser WA. Epilepsy in developing world. Curr Neurol Neurosci Rep 2009;9:319–26. [2] Sridharan R, Murthy BN. Prevalence and pattern of epilepsy in India. Epilepsia 1999;40:631–6. [3] Rutter M, Graham P, Yule W. A neuropsychiatric study in childhood. Philadelphia: Lippincott; 1970.
[4] Austin JK, Smith SM, Risinger MW, et al. Childhood epilepsy and asthma: comparison of quality of life. Epilepsia 1994;35:608–15. [5] Davies S, Heyman I, Goodman R. A population survey of mental health problems in children with epilepsy. Dev Med Child Neurol 2003;45:292–5. [6] Dunn DW, Austin JK, Huster GA. Behaviour problems in children with newonset epilepsy. Seizure 1997;6:283–7. [7] Austin JK, Perkins SM, Johnson CS, et al. Behavior problems in children at time of first recognized seizure and changes over the following 3 years. Epilepsy Behav 2011;21:373–81. [8] Rodenburg R, Marie Meijer A, Dekovic M, et al. Family predictors of psychopathology in children with epilepsy. Epilepsia 2006;47:601–14. [9] Datta SS, Premkumar TS, Chandy S, et al. Behaviour problem in children and adolescents with seizure disorder: associations and risk factors. Seizure 2005;14:190–7. [10] Burton K, Rogathe J, Hunter E, et al. Behavioural comorbidity in Tanzanian children with epilepsy: a community-based case-control study. Dev Med Child Neurol 2011;53:1135–42. [11] Kraemer HC, Stice E, Kazdin A, et al. How do risk factors work together? Mediators, moderators, and independent, overlapping, and proxy risk factors. Am J Psychiatry 2001;158:848–56. [12] Hoie B, Sommerfelt K, Waaler PE, et al. Psychosocial problems and seizurerelated factors in children with epilepsy. Dev Med Child Neurol 2006;48:213–9. [13] Berg AT, Smith SN, Frobish D, et al. Longitudinal assessment of adaptive behavior in infants and young children with newly diagnosed epilepsy: Influences of etiology, syndrome, and seizure control. Pediatrics 2004;114:645–50. [14] Besag FM. Behavioral aspects of pediatric epilepsy syndromes. Epilepsy Behav 2004;5:S3–S13. [15] Freilinger M, Reisel B, Reiter E, et al. Behavioral and emotional problems in children with epilepsy. J Child Neurol 2006;21:939–45. [16] Austin JK, Huster GA, Dunn DW, et al. Adolescents with active or inactive epilepsy or asthma: a comparison of quality of life. Epilepsia 1996;37:1228–38. [17] Caplan R, Siddarth P, Gurbani S, et al. Psychopathology and pediatric complex partial seizures: seizure-related, cognitive, and linguistic variables. Epilepsia 2004;45:1273–81. [18] Achenbach T. Manual for the child behavior checklist/4-16 and 1983 profile. Burlington: Department of Psychiatry, Univ of Vermont; 1983. [19] Sander JW. ILAE commission report. The epidemiology of the epilepsies: future directions. International league against epilepsy. Epilepsia 1997;38:614–8. [20] Malins AJ. Malins intelligence scale for children-manual. Lucknow: Indian Psychological Corporation; 1969. [21] Proposal for revised classification of epilepsies and epileptic syndromes. Commission on classification and terminology of the international league against epilepsy. Epilepsia 1989;30: 389–99. [22] Agrawal AK. Social classification: the need to update in the present scenario. Indian J Community Med 2008;33:50. [23] Dorenbaum D, Cappeli M, Hons BA, et al. Use of child behavior checklist in the psychological assessment of children with epilepsy. Clin Pediatr (Phil) 1985;24:634–7. [24] Srinath S. Indian Council of Medical Research Task Force on Child Psychiatry, Epidemiological study on child and adolescent psychiatric disorders in urban and rural areas. 2001. [25] Dafoulis V, Kalyva E. Factors associated with behavioral problems in children with idiopathic epilepsy. Epilepsy Res 2012;100:104–12. [26] Eddy CM, Rickards HE, Cavanna AE. Behavioral adverse effects of antiepileptic drugs in epilepsy. J Clin Psychopharmacol 2012;32:362–75. [27] Perucca P, Mula M. Antiepileptic drug effects on mood and behavior: molecular targets. Epilepsy Behav 2013;26:440–9. [28] Osungbade KO, Siyanbade SL. Myths, misconceptions and misunderstandings about epilepsy in a Nigerian rural community: implications for community health interventions. Epilepsy Behav 2011;21:425–9. [29] Singh H, Aneja S, Unni KE, et al. A study of educational underachievement in Indian children with epilepsy. Brain Dev 2012;34:504–10.
Please cite this article in press as: Choudhary A et al. Behavioral comorbidity in children and adolescents with epilepsy. J Clin Neurosci (2014), http:// dx.doi.org/10.1016/j.jocn.2013.11.023
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Behavioral comorbidity in children and adolescents with epilepsy Anita Choudhary a,c, Sheffali Gulati a,⇑, Rajesh Sagar b, Madhulika Kabra a, Savita Sapra a a
Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar East, Gautam Nagar, New Delhi 110029, India Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India c Department of Pediatrics, SMS Medical College, Jaipur, Rajasthan, India b
a r t i c l e
i n f o
Article history: Received 5 November 2012 Accepted 10 November 2013 Available online xxxx Keywords: Antiepileptic drugs Behavioral comorbidity Child behavior checklist Epilepsy
a b s t r a c t This cross sectional study assessed the prevalence of behavioral comorbidity and its association with epilepsy-related factors in children and adolescents with epilepsy. One hundred consecutive patients with active epilepsy, aged 6–16 years, were screened for behavioral comorbidity using the Child Behavior Checklist and those who qualified as having behavioral comorbidity were compared with those who did not have it. Behavioral comorbidity was found in 43 of 100 participants. Being treated with antiepileptic drug polytherapy (odds ratio 6.3, 95% confidence interval 1.4–17.3, p = 0.01) independently predicted behavioral comorbidity in the patients studied. The demonstrated high frequency of behavioral comorbidity in children with epilepsy suggests that pediatricians and pediatric neurologists should be sensitive to this fact in order to identify and manage behavioral comorbidity in children with epilepsy. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Epilepsy is one of the most prevalent chronic neurological disorders affecting children. The burden of epilepsy is greater in developing countries compared to developed countries [1]. The estimated prevalence of epilepsy in India is 5.59 cases per 1000 people [2]. It has been observed that children with epilepsy (CWE) are at an increased risk of behavioral and emotional problems. In the landmark pediatric psychiatric epidemiological Isle of Wight study, Rutter et al. observed that the prevalence of behavioral problems was 28.6% in children with uncomplicated epilepsy and 58.3% in children with seizures and structural brain abnormality, as compared to 6.6% in the general child population [3]. Prevalence of behavioral and emotional problems in CWE in developed countries is greater than in those with other chronic illnesses not involving the central nervous system, such as diabetes mellitus or bronchial asthma [4,5]. Reported prevalence of behavioral and emotional problems in CWE ranges from 24% to 66% [6–10]. Theoretical models of psychopathology propose that psychopathology in epilepsy can stem from a complex interplay of multiple etiological variables [11]. Risk factors may be biological (seizurerelated and treatment-related) or psychosocial. Some studies from developed countries have observed that behavioral and psychiatric problems are associated with frequent and severe seizures [12–14], early onset of seizures [12], antiepileptic drug (AED) polytherapy ⇑ Corresponding author. Tel.: +91 11 2659 4679; fax: +91 11 2658 8663. E-mail address: [email protected] (S. Gulati).
and symptomatic epilepsy [15], whereas other studies demonstrated no association of age at seizure onset, seizure frequency, seizure type, or lateralization of seizure focus with psychopathology in CWE [16,17]. There are limited data on the prevalence and association of epilepsy-related variables with behavioral comorbidity in children and adolescents with epilepsy from developing countries [9,10]. Therefore the present study’s primary objective was to determine the prevalence of behavioral comorbidity in children and adolescents aged 6 to 16 years with active epilepsy using the Child Behavior Checklist (CBCL) [18]. The secondary objective was to explore the potential epilepsy-related risk factors for behavioral comorbidity in the same study population.
2. Material and methods 2.1. Procedure This cross sectional, observational study was conducted between October 2008 and August 2009. All children and adolescents diagnosed with active epilepsy attending the outpatient services of the Division of Pediatric Neurology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi were screened for eligibility for this study. The International League Against Epilepsy (ILAE) definitions were used to define active epilepsy as two or more unprovoked seizures occurring 24 hours apart, with at least one epileptic seizure in the previous 5 years, regardless of AED treatment [19]. The inclusion criteria were (1) children aged from
http://dx.doi.org/10.1016/j.jocn.2013.11.023 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Choudhary A et al. Behavioral comorbidity in children and adolescents with epilepsy. J Clin Neurosci (2014), http:// dx.doi.org/10.1016/j.jocn.2013.11.023
2
A. Choudhary et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx
6–16 years and (2) duration of epilepsy for at least 6 months. Patients were excluded if they had an intellectual disability or comorbid chronic systemic disease. Intellectual disability was defined as a verbal intelligence quotient of 70 or less. Malin’s Intelligence Scale for Indian Children was used to screen children for intellectual disability [20]. Informed written consent was obtained from the primary caregivers of participants before inclusion into the study. The study design was approved by the Institutional Ethics Committee. All participants gave a detailed medical and neurological history and underwent clinical examination. Seizures were analysed by determining age at onset of epilepsy, predominant seizure type, seizure frequency, duration of epilepsy, etiology, and number of AED taken. Participants were placed into one of three categories of seizure frequency, being seizure free, having 1–10 seizures, or having >10 seizures, during the past 6 months. Epilepsy type was classified according to the recommendations of the ILAE [21]. Medical records were checked for confirmation of history. Caregivers were interviewed regarding educational problems of their child, and any repetition of a school grade was noted. If the child was not studying or had dropped out, the cause was evaluated. Socio-economic status was classified into six social classes as per the modified social classification (modification of Prasad’s classification) by Agrawal, based on per capita monthly income [22]. Digital electroencephalography (EEG) (Medelec profile; Oxford Instruments, Oxfordshire, UK) was performed using the international 10-20 system of electrode placement. Both awake and sleep recordings were taken. Hyperventilation, photic stimulation and sleep were used for the activation procedure. EEG was reported as normal or showing epileptiform abnormality. The latest available EEG was analysed by a pediatric neurologist if it had been recorded within 3 months of evaluation. In children without such a recent EEG one was recorded on the same day of completing the CBCL. 2.2. Evaluation tools Caregivers completed the CBCL while waiting in the hospital department. Questions were explained by an investigator if needed. The caregivers were asked to not report behavior which was present just before, during or after seizure. The questionnaire was scored as per manual specification. The CBCL consists of 118 behavior problem items on which caregivers rate their children using a three point scale, with higher scores reflecting more problems. The CBCL assesses broad band behavior problems (externalizing and internalizing behavior problems) and narrow band behavior problems (attention problems, aggressive behavior, delinquent behavior, withdrawnness, somatic complaints, anxiety/depression, thought problems and social problems). Previous research has shown that CBCL is useful for assessing psychopathology in CWE [23]. The CBCL has been standardized and cut-off scores for significant behavioral comorbidity have been previously established for the Indian population [24]. The score thresholds for having a behavioral problem in children aged 6– 11 years are 21 and 16 for males and females, respectively. For children aged 12–16 years the cut-off thresholds are 18 and 13 for males and females, respectively. This checklist has good psychometric properties. For this study, we used total scores only, as other scores have not been validated for Indian children. Children and adolescents were classified as having behavioral comorbidity if they scored above the relevant threshold for their age and sex on CBCL total scores. 2.3. Sample size estimation and statistical analysis The varied reported prevalence of behavioral comorbidity in CWE has been as high as 42%. We calculated that 97 patients would
be required for an expected 50% prevalence of behavioral comorbidity in our study population, with a 95% confidence level and ± 0.10 width of confidence interval (CI). Hence, the present study was planned as an observational study with a sample size of 97 patients. A Microsoft Excel spreadsheet was used for data entry (Microsoft, Redmond, WA, USA). Data were analysed using Stata software version 9 (StataCorp, College Station, TX, USA). Frequencies were calculated by descriptive analysis. Univariate analysis was done to detect differences between participants with and without behavioral comorbidity. The statistical significance of categorical data was determined using the chi-squared test. The statistical significance of continuous data was determined using Student’s t-test. The variables that differed significantly in the univariate analysis were used for multivariate analysis, using logistic regression. With the behavioral comorbidity as the dependant variable, odds ratios (OR) for epilepsy-related risk factors were calculated. A p value 0.05). Table 1 details the comparison of epilepsy-related variables between the two groups. Symptomatic epilepsy (p = 0.04), partial seizure (p = 0.03), epileptiform discharges on EEG (p = 0.04), being treated with AED polytherapy (p = 0.001) and duration of epilepsy more than 26 months (p = 0.01) were associated with behavioral comorbidity. Multivariate analysis was carried out using logistic regression. The medical epilepsy-related variables which were significant at the p < 0.1 level in univariate analysis were included in the equation as independent variables with behavioral comorbidity as the dependant variable. In the final equation, treatment with AED polytherapy independently predicted behavioral comorbidity in children and adolescents with epilepsy (OR 6.3, 95% CI 1.4–17.3, p = 0.01). Table 2 details epilepsy-related predictors of behavioral comorbidity. 3.5. Education profile Of the 43 patients with behavioral comorbidity, six children were not attending school as compared to three children in the Table 1 Association of epilepsy-related factors with behavioral comorbidity in children with epilepsy Behavioral comorbidity present (n = 43) n (%)
No behavioral comorbidity (n = 57) n (%)
v2
p value
Etiology Idiopathic Symptomatic
26 (36.6) 17 (58.6)
45 (63.4) 12 (41.4)
4.06
0.04
Seizure type Generalized Partial
18 (33.3) 25 (54.3)
36 (66.7) 21 (45.7)
4.47
0.03
EEG Normal Epileptiform
26 (36.6) 17 (58.6)
45 (63.4) 12 (41.4)
4.06
0.04
Seizure frequency (past 6 months) No seizure 12 (30.0) 1–10 seizures 22 (48.9) >10 seizures 9 (60.0)
28 (70.0) 23 (51.1) 6 (40.0)
5.16
0.07
Antiepileptic therapy No therapy 2 (33.3) Monotherapy 24 (33.3) Polytherapy 17 (77.3)
4 (66.7) 48 (66.7) 5 (22.7)
13.51
0.001
Epilepsy duration 626 months >26 months
11 (27.5) 32 (53.3)
29 (72.5) 28 (46.7)
6.53
0.01
Age at onset 674 months >74 months
25 (46.3) 18 (39.1)
29 (53.7) 28 (60.9)
0.52
0.47
Variable
EEG = electroencephalography.
3
group without behavioral comorbidity (p = 0.13). Eight children had dropped out of school on account of epilepsy. Of the 91 children who were attending regular school, repetition of a grade was significantly higher in children with behavioral comorbidity than in children without (16 versus four, respectively; p < 0.001). 4. Discussion In this study we estimated the prevalence of behavioral comorbidity in children and adolescents with epilepsy who were not intellectually disabled. We also tried to understand the association of medical epilepsy-related factors with behavioral comorbidity in children and adolescents with epilepsy in a developing country. In accordance with previous studies, this tertiary care center cross sectional study demonstrated a high prevalence (43%) of behavioral comorbidity in this sample of children with active epilepsy. A previous tertiary care center based study from south India reported a 53.8% prevalence of psychopathology in CWE on the CBCL [9]. 4.1. Association of epilepsy-related variables with behavioral problems In the sample studied, AED polytherapy independently predicted behavioral comorbidity in CWE (OR 6.3, 95% CI 1.4–17.3, p = 0.01). This association of AED polytherapy with behavioral comorbidity in CWE has also been reported in other studies in the pediatric population [9,15,25]. In a hospital based study, Datta et al. observed that AED polytherapy (OR 3.08, 95% CI 1.09–8.72, p = 0.03), belonging to a higher income group and living in an urban area (OR 7.61, 95% CI 2.78–20.8, p = 0.0001) and having epilepsy for longer than 3 years (OR 2.39, 95% CI 2.18–5.67, p = 0.03) independently predicted psychopathology [9]. Freilinger et al. reported that children suffering from epilepsy for more than 1 year treated with AED polytherapy scored significantly higher on social problems (r = 0.278, p = 0.004), attention problems (r = 0.214, p = 0.03), and aggressive behavior (r = 0.275, p = 0.005) [15]. In a sample of 106 children with idiopathic epilepsy, Dafoulis et al. found that later age of onset of epilepsy, AED polytherapy, and male sex predicted behavioral problems [25]. This association must be viewed with caution as association does not mean causality, as children with difficult to control seizures may require the addition of more AED. But this possibility of behavioral comorbidity caused by AED polytherapy should not be discarded completely, particularly when there may be a biological explanation. At present AED are the mainstay of epilepsy treatment. All AED have the potential to cause behavioral side effects [26]. AED suppress epileptic seizures by regulating neuronal excitability. The various mechanisms of action include inhibitory GABAergic and excitatory glutamatergic neurotransmission, as well as ion (sodium and calcium) conductance through voltage-gated channels. These mechanisms are also implicated in the regulation of behavior, which may explain the adverse behavioral effects of AED [27]. Various patient related factors such as age, epilepsy type, and premorbid behavioral problems may be implicated in the adverse behavioral effects of AED. AED-related factors can also be linked to the occurrence of adverse behavioral effects, including dosage, rapid dose titration, seizure control, and concurrent AED [26]. Many observations on the adverse behavioral effects of specific AED come from case reports or uncontrolled studies, thus, there are considerable limitations in drawing firm conclusions about the possible links between specific adverse behavioral effects and AED [26].
Please cite this article in press as: Choudhary A et al. Behavioral comorbidity in children and adolescents with epilepsy. J Clin Neurosci (2014), http:// dx.doi.org/10.1016/j.jocn.2013.11.023
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A. Choudhary et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx
Table 2 Epilepsy-related risk factors for behavioral comorbidity in children with epilepsy Variable
Unadjusted OR
95% CI
Adjusted OR
95% CI
p value
Symptomatic epilepsy Partial seizure Epileptiform EEG Antiepileptic drug polytherapy 1–10 seizures in past 6 months >10 seizures in past 6 months Epilepsy duration >74 months
2.5 2.3 2.5 6.3 2.2 3.5 2.8
1.01–5.9 1.06–5.2 1.01–5.9 2.3–20.4 0.9–5.5 1.01–12 1.3–6.3
1.1 1.7 2.0 4.95 1.1 1.6 1.7
0.4–3.5 0.6–4.4 0.7–5.7 1.4–17.3 0.4–3.0 0.3–7.4 0.6–4.6
0.7 0.28 0.22 0.01 0.9 0.6 0.27
CI = confidence interval, EEG = electroencephalography, OR = odds ratio.
4.2. Impact of behavioral problems Behavioral disorders have a major impact on the child and their family in terms of quality of life, education and leisure activities. CWE living in rural areas of developing countries face the added burden of myths and misconception about the disease [28]. Academic underachievement has been demonstrated to be associated with disordered behavior in CWE [29]. In the present study, repetition of a grade was significantly higher in children with behavioral comorbidity. This study is one of the few exploring behavioral comorbidity in CWE in India. We also investigated the medical epilepsy-related predictors for behavioral comorbidity. However the study is limited as the study population was made up of a tertiary care center population, making it difficult to generalize results to the general population. Information on behavioral comorbidity was obtained from the primary caregivers; school teacher and adolescent reports were not obtained and due to the small sample size behavioral comorbidity could not be correlated with specific AED. The study design did not include assessment of all family-related factors (all family stress factors, parent/child relationship and family dynamics) and personality traits that could have contributed to the degree of psychosocial disturbances in CWE. The cross-sectional design did not allow us to make causal conclusions. Larger prospective studies are needed to assess the causal relationship of epilepsy-related variables with behavioral comorbidity. 5. Conclusion This tertiary care center based study demonstrated significant behavioral comorbidity in CWE. Therefore, periodic psychosocial assessment should be a standard part of multidisciplinary care of CWE, with early counselling and appropriate management to prevent the additional disability that behavioural problems confer. Further studies are required to evaluate the efficacy of various treatment modalities, including behavioral therapy and drug therapy for behavioral comorbidities and their effect on improving quality of life. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Carpio A, Hauser WA. Epilepsy in developing world. Curr Neurol Neurosci Rep 2009;9:319–26. [2] Sridharan R, Murthy BN. Prevalence and pattern of epilepsy in India. Epilepsia 1999;40:631–6. [3] Rutter M, Graham P, Yule W. A neuropsychiatric study in childhood. Philadelphia: Lippincott; 1970.
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