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Summary: Purpose: This study examined the role of cognition, language, seizure-related, and demographic variables in the psychopathology of children with complex partial seizure disorder (CPS) of average intelligence.
Methods: One-hundred one CPS and 102 normal children, aged 5.1 to 16.9 years, had a structured psychiatric interview and cognitive and language testing. Parents provided demographic, perinatal, and seizure-related information, as well as behavioral information through the Child Behavior Checklist (CBCL) and a structured psychiatric interview about the child.
Results: Significantly more CPS patients had psychopathology, cognitive deficits, and linguistic deficits than did those in the normal group. Among the patients, Verbal IQ predicted the presence of a psychiatric diagnosis, as well as CBCL scores in the borderline/clinical range. Seizure, linguistic, and demographic variables were unrelated to psychopathology. The cognitive and linguistic deficits of the CPS group, however, were predicted by seizure factors (e.g., prolonged seizures/febrile convulsions; seizure frequency/number of antiepileptic drugs) and demographic factors (e.g., minority status).
Conclusions: Because subtle verbal cognitive deficits predict behavioral disturbances in pediatric CPSs, the study's findings highlight the importance of assessing behavior, cognition, and language in these children. They also underscore the negative impact of prolonged seizures, febrile convulsions, seizure frequency, and antiepileptic drug polytherapy on cognition and language in pediatric CPSs.
Hermann et al. (1) proposed a multifactorial model to delineate the mechanisms underlying behavioral disturbances in children with epilepsy. Relevant factors included seizure-related variables, such as type of seizure disorder, age at onset, duration of illness, EEG pattern, and neuropsychological status; antiepileptic drug (AED) variables, such as number of drugs and types of drugs; psychosocial variables, such as parents' marital status; and demographic variables, such as gender and median family income. They found that seizure control was the most powerful predictor of behavioral disturbances by using parent-based Child Behavior Checklist (CBCL) in 183 children with epilepsy, 53% with partial and 40% with primarily generalized epilepsy.
Since then, several studies have shown that seizure-related variables, particularly seizure control (2–10), type of seizure disorder (6,11–15), severity of seizure disorder (10,16–18), age at onset (4,19), duration of illness (4,20), AEDs (4,11,21–24), and focal EEG findings (6) are associated with psychopathology in children with epilepsy. When controlling for the effects of IQ, however, presence of a psychiatric diagnosis (7) and behavioral outcome (23) are unrelated to seizure variables in children with epilepsy.
As in psychopathology, different aspects of cognition are associated with seizure-related variables both in children with epilepsy who have mental retardation (25) [see review in (26)] and in children with normal intelligence (4,9,10,27–34). Nevertheless, only few studies examined the relation among psychopathology, IQ, and seizure-related variables in children with epilepsy. Sturniolo and Galletti (33) showed that emotional maladjustment in children with idiopathic epilepsy is associated with poor school performance, and Schoenfeld et al. (9) found a significant correlation between total CBCL scores and overall neuropsychological status in children with CPS. These studies did not determine how seizure-related variables interacted with both psychopathology and cognition.
Psychopathology in childhood is related to language difficulties (35–38). Children seen in psychiatric clinics for both externalizing and internalizing behavioral difficulties have high rates of undiagnosed language disorders (36,38). Linguistic deficits also are found in children with attention deficit hyperactivity disorder (ADHD) (35,37).
Only one study examined language in children with epilepsy with average intellectual skills. Schoenfeld et al. (9) reported significantly lower language scores in word knowledge, category fluency, and response to commands of increasing length and complexity in children with CPSs with average intelligence compared with their siblings, even after controlling for between-group differences in overall intelligence. Age at onset correlated significantly with the overall language score of the CPS group. No studies to date, however, considered the interaction among linguistic deficits, seizure variables, and psychopathology in medically treated children with epilepsy of normal intelligence.
Finally, demographic variables (e.g., age, gender, socioeconomic status) have been variably related to psychopathology in children with epilepsy. Earlier studies indicate that boys, particularly those with CPSs, have more behavioral problems (1,11,15,39). More-recent studies suggest that girls with epilepsy are more behaviorally impaired (40,41), and others found no gender effect (17,18,23,42). Age (17,18,40,43), socioeconomic status (1,44,45), and social acculturation (23) also have been related inconsistently to psychopathology in children with epilepsy.
Based on the findings of the previously reviewed studies, the study presented here examined how seizure factors, cognition, language, and demographic variables play a role in the behavioral disturbances of a large group of 101 children with CPSs. In adults, an association of temporal lobe epilepsy with hippocampal sclerosis, history of febrile seizures, and status epilepticus is found (46,47), which might reflect underlying perinatal abnormalities involving the hippocampus rather than the consequence of seizures. In animal models, early febrile seizures alter hippocampal connectivity even in the absence of cell loss or neurogenesis (48), and prolonged seizures produce hippocampal and extrahippocampal injury (49–52). Therefore in addition to the previously reviewed seizure-related variables, we also investigated the association of psychopathology measures with a history of prolonged seizures, febrile seizures, and perinatal abnormalities (e.g., pregnancy, delivery).
We first compared IQ, language, and psychopathology measures in the CPS group with those of children without epilepsy, controlling for demographic (e.g., age, gender, ethnicity, socioeconomic status) and perinatal differences between the groups. We hypothesized that, compared with the normal children, significantly more patients would have a psychiatric diagnosis, CBCL scores in the clinical range, higher mean CBCL scores, cognitive deficits, and linguistic deficits.
Because of the interrelation of seizure variables, such as age at onset, duration, seizure frequency, number of AEDs, history of prolonged seizures, history of febrile convulsions, and EEG patterns, we included these variables in a principal components analysis to determine independent seizure components. We then developed a model to examine the role played by seizure, cognitive, linguistic, demographic, and perinatal variables in the psychopathology of the CPS group. We hypothesized that IQ, language, demographic, and perinatal variables but not seizure variables would predict psychopathology in the CPS group. In contrast, we posited that seizure, demographic, and perinatal variables would predict both IQ and language measures in these children.
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This is the first study to examine the role of independent seizure factors, cognition, and language in the behavioral disturbances of a large sample of children with CPS by using both child- and parent-based measures of psychopathology, as well as a control group of normal subjects. Compared with the normal group, significantly more CPS patients had a psychiatric diagnosis and CBCL scores (e.g., total, internalizing) in the clinical range. The patients also had significantly higher mean total and internalizing CBCL scores but lower mean IQ and SLQ scores than did the normal subjects.
Within the CPS group, Verbal IQ predicted the presence of a psychiatric diagnosis and CBCL scores in the borderline/clinical range. Seizure factors were unrelated to measures of psychopathology. They were, however, associated with IQ and SLQ scores. The prolonged seizure/febrile convulsions and the seizure frequency/AEDs components were significantly related to IQ, and the seizure frequency/AEDs component, to SLQ. Although demographic factors accounted for 11 to 18% of the variance of Full-Scale, Verbal IQ, and SLQ scores, they were unrelated to psychopathology. Perinatal factors were not associated with the study's psychopathology, IQ, or SLQ measures.
In contrast to studies that found that seizure variables predict behavioral problems in children with epilepsy (1,4,9,10,16–18), when independent seizure factors, cognition, language, and demographic factors are in the model, Verbal IQ is the most robust predictor of psychopathology in pediatric CPS. Similarly, Mitchell et al. (23) found that seizure variables were unrelated to the 18-month behavioral outcome of children with epilepsy by using structural equation modeling that included seizure, cognition, and demographic variables.
In our study, because seizure components accounted for only 8% of the variance of the Verbal IQ scores, the association between psychopathology measures and Verbal IQ does not simply represent the effect of seizure-related variables. The large number of children with one type of seizure disorder and the exclusion of children with mental retardation could account for the difference in our findings compared with those of others.
Furthermore, as demonstrated in this study, parent-based internalizing CBCL scores in the clinical range were a consistent finding in prior studies of children with epilepsy (12,64–68), unlike externalizing CBCL scores (9). Oostrom et al. (13) found no relation of parent-based CBCL internalizing scores with child-based IQ and seizure-related variables. They suggested that parental concerns, misinterpretation of seizure-related behaviors, or other psychosocial factors might underlie this finding (13,67). By demonstrating that seizure, demographic, perinatal, and linguistic variables were unrelated to the internalizing CBCL scores, our findings highlight the importance of determining how psychosocial factors, such as parental depression, coping difficulties, overinterpretation of behaviors as seizure-related phenomena, lack of community support, marital strife, and sociocultural factors (2,3,23,67,69) might be related to psychopathology in children with CPS.
In addition to psychosocial factors, the underlying neuropathology also might contribute to the psychopathology of children with CPSs. A complex relation exists between the underlying neuropathology, the impact of seizures on the developing brain, the development of cognition, and the severity of epilepsy in children (70). The association between verbal IQ and psychopathology might, therefore, reflect the fact that both Verbal IQ and psychopathology are determined by the underlying pathology.
Evidence from recent animal studies suggests that prolonged seizures/febrile convulsions and their impact on cognition might represent the effects of the underlying pathology. In an animal model of febrile seizures in very immature animals (postnatal day 10, P10), Bender et al. (48) demonstrated hippocampal circuit rearrangement even in the absence of cell loss or neurogenesis. Weanling rat pups (P21) subjected to the lithium–pilocarpine model of status epilepticus demonstrated hippocampal and extrahippocampal cell loss, reactive neurogenesis, and mossy fiber sprouting accompanying epilepsy (49–51). Roch et al (52) confirmed lesions by MRI and found an almost identical incidence of epilepsy in P21 rats subjected to lithium–pilocarpine seizures. Cilio et al. (71) found that such injury and reorganization resulting from seizures in immature animals had a cognitive consequence when tested in the Morris water maze.
The findings of two recent clinical studies also point to a possible role for the underlying pathology. In children with new-onset epilepsy, Austin et al. (60) found behavioral disturbances before the onset of their seizures. In an MRI study of adults with CPS, Hermann et al. (72) demonstrated an association between reduced white matter volume in the frontal, temporal, and parietal lobes and the severity of neuropsychological deficits, and between increased amygdala volume and depression (73). In an ongoing MRI study we are investigating how the underlying neuropathology is related to psychopathology, Verbal IQ, and the independent seizure components in children with CPS.
Our current findings have five important clinical implications. First, the robust association of Verbal IQ with psychopathology, together with the reported relation between total CBCL scores and overall intelligence in CPS (9), and between emotional maladaptation and school performance in children with epilepsy (33) underscore the importance of ruling out subtle learning disorders in CPS children who have behavioral disturbances. Second, in light of evidence for a high rate of unmet mental health need in children with CPS and childhood absence epilepsy (74), this finding also implies the need for behavioral assessments in CPS children with subtle verbal IQ deficits.
Third, unlike the general population of children (36,37), psychopathology in pediatric CPS is unrelated to language deficits. However, the association of linguistic deficits with seizure frequency/number of AEDs and ethnicity further emphasizes the need for language assessment in CPS children with normal intelligence whose seizures are poorly controlled, who receive AED polytherapy, and who are minorities.
Fourth, similar to CPS in adults (72), childhood CPS affects broad areas of cognitive function. Seizure frequency, number of AEDs, prolonged seizures, and febrile convulsions contribute to the variance of IQ in pediatric CPS. These findings emphasize the need for prevention of prolonged seizures and febrile convulsions, as well as prompt intervention for ongoing seizures with fewer rather than more AEDs.
In terms of the study's limitations, the seizure-related information collected primarily from the parents might be subject to memory bias and subjectivity. Although we used different IQ instruments (i.e., WISC-R, WISC-III) on the children in the study, we found no significant differences in the mean IQ scores of the children tested with the WISC-R and the WISC-III, respectively.
In addition, computing SLQ scores from three different age-related forms of the language instrument—the TOLD primary, the TOAL Intermediate, and the TOAL—does not rule out undiagnosed linguistic deficits in the CPS and normal groups. Although missing language data in 15 patients did not affect the study's psychopathology findings, they might have affected the SLQ modeling findings. Significantly lower IQ scores and a higher rate of a history of prolonged seizures/febrile convulsions in this subgroup of CPS patients suggest that prolonged seizures/febrile convulsions rather than only seizure frequency and number of AEDs, as demonstrated in the study, might affect both cognitive and linguistic competence in children with CPS. Similarly, missing EEG data in 14 subjects does not rule out possible EEG effects on the study's measures.
With these limitations in mind, from the methodologic perspective, the study's findings underscore the need to control for the effects of cognitive, linguistic, and demographic variables when comparing psychopathology in children with CPS to that in normal children. From the clinical perspective, they demonstrate that subtle Verbal IQ deficits increase the vulnerability of these patients for behavioral disturbances and that multiple aspects of CPS adversely affect cognition and language in children. The study's findings highlight the importance of evaluating behavior, cognition, and language, as well as the negative impact of prolonged seizures, febrile seizures, seizure frequency, and AED polytherapy on cognition and language in pediatric CPS.