|Year : 2015 | Volume
| Issue : 1 | Page : 13-19
Neurodevelopmental and neurobehavioral aspects of childhood epilepsy
Amir A Sarhan, Mostafa M Ayouty, Ashraf A Elsharkawy, Dina S Abd Elmagid MSc
Department of Pediatrics, Faculty of Medicine, Mansoura University, Mansoura, Egypt
|Date of Submission||06-May-2015|
|Date of Acceptance||24-May-2015|
|Date of Web Publication||26-Nov-2015|
Dina S Abd Elmagid
Department of Paediatrics, Faculty of Medicine, Mansoura University, Mansoura
Source of Support: None, Conflict of Interest: None
The aim of this study was to declare the frequency of neurodevelopmental, behavioral, and psychiatric comorbidities associated with epilepsy and the relation of these disorders with several variables, including age at onset of epilepsy, duration of epilepsy, type of epilepsy, antiepileptic medications (monotherapy or polytherapy), and seizure frequency.
Patients and methods
This cross-sectional study included 50 epileptic children selected from those regularly attending the Neurology Outpatient Clinic in Mansoura University Children Hospital and already diagnosed with primary epilepsy and maintained on antiepileptic medications. They were subjected to full general and neurological assessment, Wechsler Intelligence Scale (IQ), Child Behavior Checklist, and Developmental Profile-3. Data were analyzed using SPSS program, version 16.
Children with prolonged duration and earlier onset of epilepsy performed worse on Developmental Profile-3 assessment as they showed significantly delayed cognition, in addition to more attention problems and low IQ. Increased frequency associated with delayed cognitive, social, and communication development, low IQ, and attention problems were observed. Moreover, those with polytherapy were more significantly affected as regards cognition, communication, IQ, attention, social problems, thought problems, and anxiety depression. No significant differences were found between effects of sodium valproate and carbamazepine, but a high dose of valproate was associated with higher incidence of low IQ and cognitive and attention problems. Cognition, communication, and attention were more affected in patients with generalized epilepsy in comparison with those with partial epilepsy.
Childhood epilepsy is associated with cognitive deficits, intellectual decline, and behavioral problems, which are multifactorial, such as age of onset, frequency, type of seizure, prolonged seizures, antiepileptic drugs, and duration of epilepsy.
Keywords: attention, Child Behavior Checklist, children, cognition, Developmental Profile-3, epilepsy, IQ
|How to cite this article:|
Sarhan AA, Ayouty MM, Elsharkawy AA, Abd Elmagid DS. Neurodevelopmental and neurobehavioral aspects of childhood epilepsy. Benha Med J 2015;32:13-9
|How to cite this URL:|
Sarhan AA, Ayouty MM, Elsharkawy AA, Abd Elmagid DS. Neurodevelopmental and neurobehavioral aspects of childhood epilepsy. Benha Med J [serial online] 2015 [cited 2018 Jan 23];32:13-9. Available from: http://www.bmfj.eg.net/text.asp?2015/32/1/13/170553
| Introduction|| |
Epilepsy is one of the most common serious neurological disorders during childhood  . Epidemiological studies reveal that ~150 000 children sustain a first-time unprovoked seizure every year, of whom 30 000 develop epilepsy  . In a recent Egyptian study, the highest prevalence rate was recorded during the early and late childhood period (69.78/100 000 and 43.78/100 000, respectively)  .
Epilepsy can have a major impact on a child's development , . It is now generally known that a subset of children with epilepsy will manifest some degree of cognitive impairment; moreover, an association between childhood epilepsy and cognitive dysfunction has long been recognized , .
Most studies have provided proof that intellectual decline during childhood epilepsy is progressive and may be related to the duration of epilepsy, overall frequency of seizures, and age at epilepsy onset ,, . The correct treatment of epilepsy involves many issues beyond seizure control, including cognitive and social aspects  .
It has been shown that children with epilepsy are at increased risk of developing behavioral and emotional problems  . Children with seizures have 4.7 times higher risk for behavioral problems compared with those without seizures  . Risk factors for behavioral problems in epilepsy are multifactorial, involving both neurobiologic and psychosocial factors. The neurobiologic factors may include age at onset of epilepsy, duration of illness, frequency and severity of seizures, type of seizures, as well as the type and number of antiepileptic drugs (AEDs) taken  .
AEDs are often blamed for cognitive or behavioral problems in children treated for epilepsy, but the actual contribution to such problems in a particular child can be difficult to ascertain  . Epilepsy is usually controlled, but not cured, with medication. However, over 30% of people with epilepsy do not have seizure control even with the best available medications  . The question of monotherapy versus polytherapy has gained increasing importance with the availability of multiple AEDs  .
In our study, we aimed to declare the frequency of neurodevelopmental disorders, behavioral and psychiatric comorbidities associated with childhood epilepsy, and the relation of these disorders with several variables, including age at epilepsy onset, duration of epilepsy, type of epilepsy, antiepileptic medications (monotherapy or polytherapy), and seizure frequency.
| Patients and methods|| |
The study design was cross-sectional. From September 2012 until October 2014, 50 pediatric patients were selected, with ages ranging between 5 and 12 years, and regularly followed up at the Neurology Outpatient Clinic of Epilepsy at Mansoura University Children Hospital. All patients had a diagnosis of primary epilepsy and were already maintained on AEDs. Patients with severe neurological disabilities, severe visual or auditory deficits, severe mental deficiency, and cases of secondary epilepsy were excluded.
All patients underwent general and neurological assessment, including full history and examination, electroencephalogram, and the following data were collected: age, sex, age at epilepsy onset, duration of epilepsy, seizure type, seizure frequency, history of prolonged seizures, and drug therapy.
All of them were assessed with the Wechsler Intelligence Scale for Children  , translated into Arabic  . The scale consists of six verbal subtests (similarities, digit span, vocabulary, arithmetic, comprehension, and information) and five performance subtests (picture completion, picture arrangement, coding subtest, digit symbol, and block design).
In addition, they were assessed using Child Behavior Checklist (CBCL)  , which was translated into Arabic by Koura  to screen for child behavioral problems and emotional difficulties. Parents provided information for 20 competence items covering their child's activities, social relations, and school performance. The problem section contains 110 items on behavioral and emotional problems. The CBCL can be scored for the following syndromes: schizoid or anxious, depressed, uncommunicative, obsessive compulsive, somatic complaints, social withdrawal, hyperactive, aggressive, and delinquent behavior. These syndromes can be grouped into two broad scales: internalizing, which encompasses the first six, and externalizing, which encompasses the last three.
We used Developmental Profile-3 (DP-3)  as a measure of child development. The DP-3 utilizes input from parents or caregivers (as an interview or a checklist) to provide scores in five key areas of development: physical, adaptive behavior, social-emotional, cognitive, and communication. It provides five scales, each with 34-38 items, designed to assess the development and functioning of children from birth through age 12.
The collected data were computed and analyzed using the SPSS program, version 16. Parametric data were expressed as mean ± SD. Nonparametric data were expressed as median, minimum, and maximum. Normality of data was first tested with the one-sample K-S test. In addition, independent t-test was used to compare means for continuous parametric variables of two different groups. In addition, the Mann-Whitney U-test (Z) was used to compare nonparametric continuous variables between two different groups. In addition, the one-way analysis of variance test was used to compare means for continuous parametric variables between three different groups. Thereafter, two different groups were compared using the post-hoc test (least significant difference). Pearson's χ2 -test was used to compare the categorical variables between groups. A P value less than 0.05 was considered as statistically significant.
| Results|| |
Among the 50 epileptic patients, 30 patients had the onset of epilepsy before 5 years of age and 20 patients had onset of epilepsy after 5 years of age. The DP-3 scale results revealed significantly delayed cognitive (P < 0.001), communication (P = 0.04), social-emotional (P < 0.001), and general development (P = 0.001) in patients with early age of onset of epilepsy (<5 years) in comparison with patients with age of onset after 5 years ([Table 1]). No significant difference was found between the two groups as regards physical development and adaptive behavior development. Attention problem scale (88.8 ± 11.06), social problem scale (63.9 ± 9.09), thought problem scale (56.6 ± 4.7), and rule-breaking scale (63.9 ± 7.3) of CBCL and IQ (83.06 ± 4.9) ([Figure 1]) were significantly affected in patients with age of epilepsy onset before 5 years. We found that cognitive development (P = 0.004) was significantly delayed, and full-scale IQ (82.6 ± 3.90), attention problem (89.5 ± 7.8), and rule-breaking scores (65.3 ± 6.3) were significantly affected in patients with duration of epilepsy more than 5 years in comparison with patients with a duration of 2-5 years and in comparison with patients with duration less than 2 years.
|Figure 1 IQ is borderline in 30%, low average in 60%, and average in 10% of cases with early epilepsy onset (>5 years).|
Click here to view
|Table 1 Developmental Profile-3 scale among patients with age of onset of epilepsy before 5 years versus patients with age of onset after 5 years using the c2 -test|
Click here to view
As regards the effect of seizure frequency on DP-3 scale, cognitive development (P < 0.001), communication development (P < 0.001), social-emotional development (P < 0.001), adaptive behavior development (P < 0.001), and general development (P < 0.001) were significantly delayed in patients with seizure frequency more than three seizures/month in comparison with patients with seizure frequency less than three seizures/month. There was no significant difference between the two groups as regards physical development. Attention problem scale (93.2 ± 3.5), aggression problem scale (63.3 ± 7.1), thought problem scale (57.3 ± 4.9), and behavioral somatic scale (60.1 ± 6.6) were significantly affected in patients with seizures frequency more than three seizures/month ([Table 2]).
|Table 2 Child Behavior Checklist among patients with seizure frequency less than three seizures/month versus patients with seizure frequency more than three seizures/month using the t-test|
Click here to view
We also found that cognitive, communication, social-emotional, and general development were significantly delayed in patients maintained on polytherapy in comparison with those on duotherapy and on monotherapy, with no significant difference between them as regards physical development ([Table 3]).
|Table 3 Developmental Profile-3 scale among patients maintained on monotherapy versus patients on duotherapy versus patients on polytherapy using the c2 -test|
Click here to view
It was found that attention problem scale (94.4 ± 2.5), social problem scale (65.6 ± 8.7), thought problem scale (57.5 ± 4.9), and anxiety depression scale (63.18 ± 8.3) of CBCL were significantly affected in patients on polytherapy ([Table 4]).
|Table 4 Child Behavior Checklist among patients maintained on monotherapy versus patients on duotherapy versus patients on polytherapy using the one-way analysis of variance test|
Click here to view
No significant differences were found as regards DP-3, IQ, and CBCL results between patients maintained only on valproic acid and those maintained only on carbamazepine, with a duration of therapy of 1-1.5 years in both groups ([Table 5]).
|Table 5 Cognition, social development, and IQ among patients maintained only on valproic acid versus patients maintained only on carbamazepine with duration of therapy of 1– 1.5 years using the c2 test|
Click here to view
In patients maintained only on valproate, we found that cognitive development (P = 0.006) was significantly delayed and IQ (86.3 ± 4.04) was significantly lower in patients maintained on high dose (>20 mg/kg) in comparison with those on low dose (<20 mg/kg). A highly significant P value (< 0.001) was found as regards the results of attention problem scale (87.6 ± 1.15) of CBCL of patients maintained on high valproic acid dose ([Table 6]).
|Table 6 Child Behavior Checklist, IQ among patients on low-dose valproic acid (<20 mg/kg) versus those on high-dose valproic acid (< 20 mg/kg) using the t-test|
Click here to view
We found that 35 patients had generalized epilepsy and 15 had partial epilepsy. This study revealed that cognitive, communication, and general development were significantly delayed in patients with generalized epilepsy in comparison with those with partial epilepsy. In contrast, no statistically significant differences were found between the two groups as regards physical development and social-emotional development. Those with generalized epilepsy showed more attention problems (84.6 ± 13.7), and patients with partial epilepsy showed more behavioral somatic complains (62.3 ± 7.6) (P < 0.05) ([Table 7]).
|Table 7 Developmental Profile-3 scale among patients with generalized epilepsy versus patients with partial epilepsy using the c2 -test|
Click here to view
| Discussion|| |
Among the 50 patients, 32 patients were male (64%) and 18 patients were female (36%), with their ages ranging between 5 and 12 years (8.7 ± 2.5). Children with earlier epilepsy onset (>5 years) performed worse on DP-3 assessment, which revealed delayed cognitive, communication, social-emotional, and general development. In addition, they had lower IQ and higher attention, social, thought, and rule-breaking problems of CBCL in comparison with children with later epilepsy onset (>5 years).
Several studies have observed that young age of onset of seizure disorder is associated with more severe cognitive impairment, with significant impairment of attention, concentration, and memory ,,, . Similarly, Freilinger et al.  found that children with earlier onset of epilepsy might be at higher risk of developing social problems. These results might be due to early age of epilepsy onset, which means that epilepsy occurred during the critical period of learning and development, as well as greater plasticity. Moreover, seizures might interfere with the mechanisms of learning and memory and, in a developing brain, actually impede acquisition of mature function during critical periods of development.
It was also found that increased duration of epilepsy is associated with delayed cognition, lower IQ, and higher attention problems. Correspondingly, Kent et al.  and Neyens et al.  found that the longer the duration of epilepsy the higher the likelihood of cognitive deterioration and smaller gains in IQ scores.
Our study revealed significantly delayed cognitive, social, and communication development, lower IQ, and higher attention problems in children with increased frequency of epilepsy (>3/month). This is in agreement with other studies, which found that the more frequent the attacks of seizures the greater is the likelihood of impaired cognition , . Similarly, Barza  found that poorly controlled seizures correlated with lower reading scores, withdrawn behavior, and attention problems. These findings might be due to a direct relationship between the number of seizure attacks and cell loss in the hippocampus, an essential structure in some memory processes  , and also due to uncontrolled seizures mostly associated with longer duration of epilepsy and need for polytherapy of AEDs of high dose.
As one of the main aim of this study was to evaluate the impact of the number of AEDs that the patients received on our results, we assessed development, IQ, and behavioral disorders in patients maintained on monotherapy, duotherapy, and polytherapy. We found delayed cognition, communication, social, and general development and higher attention, social, thought, and anxiety depression problems in patients maintained on polytherapy in comparison with those on duotherapy and those on monotherapy. It has been reported that polypharmacy of AEDs are associated with adverse cognitive effects  and behavioral problems  . This can be explained by the effect of AEDs that decrease neuronal excitability, interfere with normal neuronal networks, and induce cognitive deficits. Moreover, polytherapy may lead to problems of chronic toxicity, drug interactions, failure to evaluate chronic toxicity, drug interactions with failure to evaluate individual drugs, and sometimes exacerbation of seizures. Moreover, it might be due to polytherapy mostly associated with history of uncontrolled seizures, prolonged duration of epilepsy, and high dosage of AEDs.
We also found that there were no significant differences between patients maintained only on valproate and those maintained on carbamazepine, with the duration of therapy in both groups being 1-1.5 years. This is in agreement with that reported by Stores, who found that both drugs were equally effective in producing seizure control without common serious adverse physical complications, and that they were also equivalent in being associated with no reduction in intelligence and school attainments with inferior scores on various tests of specific cognitive ability, mainly those involving aspects of attention over the first 12 months of treatment  .
Highly significant P value (<0.001) in the results of attention problem scale with delayed cognitive development and significantly low IQ were reported in patients maintained on high dose valproate (<20 mg/kg) in comparison with those on low dose (>20 mg/kg). This is in agreement with the results of Trimble  and Mitchell et al.  , who reported impairment of cognitive functions in association with higher doses of AEDs.
This study also revealed that cognitive, communication, and general development were significantly delayed with more attention problems in patients with generalized epilepsy in comparison with those with partial epilepsy. In contrast, no statistically significant differences were found between the two groups as regards physical and social-emotional development. Patients with partial epilepsy showed more behavioral Somatic complains. Correspondingly, Huang et al.  and Reynolds et al.  found that cognitive deterioration is worse among patients with generalized seizures than among those with partial seizures.
| Conclusion|| |
Children with epilepsy are at increased risk of cognitive deficits, intellectual decline, and behavioral and emotional problems, which are multifactorial, including early age of onset, increased duration of epilepsy, high frequency of seizures, polytherapy of AEDs, and high dose of AEDs.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Pavlou E, Gkampeta A. Learning disorders in children with epilepsy. Childs Nerv Syst 2011; 27
Mcabee GN, Wark JE. A practical approach to uncomplicated seizures in children. Am Fam Physician 2000; 62
Khedr EM, Shawky OA, Ahmed MA, Elfetoh NA, Al Attar G, Ali AM, et al.
A community based epidemiological study of epilepsy in Assiut Governorate/Egypt. Epilepsy Res 2013; 103
Holdsworth J, Whitmore K. A study of children with epilepsy attending normal schools. Dev Med Child Neurol 1974; 196
Stores G. School children with epilepsy at risk for learning and behavioral problems. Dev Med Child Neurol 1978; 20
MacAllister WS, Schaffer SG. Neuropsychological deficits in childhood epilepsy syndromes. Neuropsychol Rev 2007; 17
Bhise VV, Burack GD, Mandelbaum DE. Baseline cognition, behavior, and motor skills in children with new-onset, idiopathic epilepsy. Dev Med Child Neurol 2010; 52
Bourgeois BF, Prensky AL, Palkes HS, Talent BK, Busch SG. Intelligence in epilepsy: a prospective study in children. Ann Neurol 1983; 14:438-444.
Seidenberg M, O′Leary DS, Giordani B, Berent S, Boll TJ Test-retest IQ. Changes of epilepsy patients: assessing the influence of practice effects. J Clin Neuropsychol 1981; 3
Meinardi H, Aldenkamp AP, Nunes B. Mental deterioration at epilepsy onset: a hypothesis. Acta Neurochir Suppl 1992; 55
Vinayan KP. Epilepsy, antiepileptic drugs and educational problems. Indian Pediatr 2006; 43
Rutter M, Graham P, Yule W A neuropsychiatric study in childhood. Philadelphia: JB Lippincott. Clin Dev Med 1970; 35
McDermott S, Mani S, Krishnaswami S. A population-based analysis of specific behavior problems associated with childhood seizure disorders. J Epilepsy 1995; 8
Pellock JM. Defining the problem: psychiatric and behavioral comorbidity in children and adolescents with epilepsy. Epilepsy Behav 2004; 5:3-9.
Pellock JM. The challenge of neuropsychiatric issues in pediatric epilepsy. J Child Neurol 2004; 19
Cascino GD. Epilepsy: contemporary perspectives on evaluation and treatment. Mayo Clinic Proc 1994; 69
Kwan P, Brodie MJ. Early identification of refractory epilepsy. Neurol Engl J Med 2000; 342
Wechsler DI. Examiner′s Manual: Wechsler Intelligence Scale for Children,Third Edition. Psychological Corporation: New York, NY, 1991.
Ismael M, Maleka L. The Wechsler Intelligence Scale for Children (WISC): the Arabic version. Egypt Anglo Library 1993.
Achenbach TM. Child behavior checklist and 1991 profiles for children and adolescents
. USA: Department of Psychiatry, Vermont University; 1997.
Koura MR. Study of the role of Alexandria primary health care program in assessment of behavioral disorder in primary school children [thesis], Alexandria, Egypt. Alexandria University High Institute of Public Health; 1998
Alpern G. Developmental Profile 3: manual
. Los Angles: Western Psychological Services; 2007.
Zelnic N, Sa′adi L, Silman-Stolar Z, Goikhman I. Seizure control and educational outcome in childhood-onset epilepsy. J Child Neurol 2001; 16
Nolan MA, Redoblado MA, Lah S, Sabaz M, fLawson JA, Cunningham AM, Bye AM. Intelligence in childhood epilepsy syndrome. Epilepsy Res 2003; 35
El Sabbagh S, Soria C, Escolona S, Bulteau C, Dellatolas G. Impact of epilepsy characteristics and behavioral problems on school placement in children. Epilepsy Behav 2006; 9
Berg AT. Epilepsy, cognition, and behavior: the clinical picture. Epilepsia 2011; 52
Freilinger M, Reisel B, Reiter E, Zelenko M, Hauser E, Seidl R. Behavioral and emotional problems in children with epilepsy. J Child Neurol 2006; 21
Kent GP, Schefft BK, Howe SR, Szaflarski JP, Yeh HS, Privitera MD. The effects of duration of intractable epilepsy on memory function. Epilepsy Behav 2006; 9
Neyens LG, Aldenkamp AP, Meinardi HM. Prospective follow-up of intellectual development in children with a recent onset of epilepsy. Epilepsy Res 1999; 34
Alphert WC, Aldenkamp AP. Neuropsychological assessment of cognitive functioning in children with epilepsy. Epilepsia 1990; 31
Thompson PJ, Hupper F, Trimble M. Anti-convulsant drugs, cognitive function and memory. Acta Neurol Scand 1980; 80
Barza L. Cognition and achievement in children with seizure disorders. Eur Scient J 2014; 10
Mouritzen A. Epilepsy and neuron in the hippocampus. Epilepsia 1980; 20
Sankar R, Holmes GL. Mechanisms of action for the commonly used antiepileptic drugs: relevance to antiepileptic drug-associated neurobehavioral adverse effect. J Child Neurol 2004; 19
Hermann BP, Whitman S, Dell J. Correlates of behavior problems and social competence in children with epilepsy, ages 6-11. In: Herrman BP, Seidenberg M. Childhood epilepsies: neuropsychological, psychosocial and intervention aspects
. New York: Wiley; 1989. 143-157.
Stores G. Electroencephalographic parameters in assessing the cognitive function of children with epilepsy. Epilepsia 1990; 31
Trimble M. Antiepileptic drugs, cognitive functions and behavior in children: evidence from recent advances. Epilepsia 1990; 31
Mitchell WG, Zhou Y, Charez JM, Guzman BL. Effects of anti-epileptic drugs on reaction time, attention and impulsivity in children. Pediatrics 1993; 91
Huang CW, Hsieh YJ, Tsai JJ, Pai MC. Cognitive performance in cryptogenic epilepsy. Acta Neurol Scand 2005; 112
Reynolds EH, Elwes RD, Shorvon SP. Why does epilepsy become intractable? Prevention of chronic epilepsy. Lancet 1983; 11
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]