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Purpose: Evidence for a poor psychiatric, social, and vocational adult outcome in childhood absence epilepsy (CAE) suggests long-term unmet mental health, social, and vocational needs. This cross-sectional study examined behavioral/emotional, cognitive, and linguistic comorbidities as well as their correlates in children with CAE.
Methods: Sixty-nine CAE children aged 9.6 (SD = 2.49) years and 103 age- and gender-matched normal children had semistructured psychiatric interviews, as well as cognitive and linguistic testing. Parents provided demographic, seizure-related, and behavioral information on their children through a semi-structured psychiatric interview and the child behavior checklist (CBCL).
Results: Compared to the normal group, 25% of the CAE children had subtle cognitive deficits, 43% linguistic difficulties, 61% a psychiatric diagnosis, particularly attention deficit hyperactivity disorder (ADHD) and anxiety disorders, and 30% clinically relevant CBCL broad band scores. The most frequent CBCL narrow band factor scores in the clinical/borderline range were attention and somatic complaints, followed by social and thought problems. Duration of illness, seizure frequency, and antiepileptic drug (AED) treatment were related to the severity of the cognitive, linguistic, and psychiatric comorbidities. Only 23% of the CAE subjects had intervention for these problems.
Conclusions: The high rate of impaired behavior, emotions, cognition, and language and low intervention rate should alert clinicians to the need for early identification and treatment of children with CAE, particularly those with longer duration of illness, uncontrolled seizures, and AED treatment.
Children diagnosed with childhood absence epilepsy (CAE) represent approximately 8% of cases of epilepsy among school-aged children (Pavone et al., 2001). Based on earlier studies, CAE has been considered a benign disorder with relatively easily attained seizure control and minimal involvement of cognition and behavior (Dieterich et al., 1985; Covanis et al., 1992). However, more recent outcome studies report a varying rate of seizure control, associated generalized tonic–clonic seizures, progression to juvenile myoclonic epilepsy (Wirrell et al., 2001; Trinka et al., 2004; Grosso et al., 2005), as well as learning and cognitive difficulties (Pavone et al., 2001). In addition, young adults with a history of CAE have high rates of work and social difficulties, persistent difficulties in their relationships with family and friends, fewer regular social outings with friends or their partner, as well as psychiatric and emotional difficulties (Olsson & Campenhausen, 1993; Wirrell et al., 1997). These young adults are more likely to have required special educational help, had below average academic performance, and repeated a grade (Wirrell et al., 1997). The poor long-term vocational, educational, and social outcomes are found in subjects with and without adequate seizure control. However, the behavioral outcome is significantly worse in the patients with continued poor seizure control compared to those with good seizure control (Wirrell et al., 1997).
As CAE begins during childhood, there appears to be long-term unmet mental health, social, and vocational needs in patients with this “seemingly benign” epilepsy syndrome. Recent cross-sectional studies on small samples of CAE have, in fact, demonstrated that already during childhood and even at diagnosis these children have cognitive (Williams et al., 1996; Mandelbaum & Burack, 1997; Pavone & Niedermeyer, 2000; Henkin et al., 2005), linguistic (Caplan et al., 2001, 2002; Henkin et al., 2005), and behavioral/emotional problems (Williams et al., 1996; Mandelbaum & Burack, 1997; Caplan et al., 1998; Ott et al., 2001). The cognitive difficulties of these children involve visual sustained attention (Levav et al., 2002), visual spatial skills (Pavone et al., 2001), verbal and nonverbal attention (Henkin et al., 2005), as well as verbal (Nolan et al., 2004; Henkin et al., 2005; Hoie et al., 2006), and nonverbal memory (Pavone et al., 2001).
In terms of psychopathology, prior studies describe attentional deficits (Levav et al., 2002; Nolan et al., 2004; Henkin et al., 2005) and attention deficit hyperactivity disorder (ADHD), mainly inattentive type (Dunn et al., 2003), as well as affective/anxiety disorder diagnoses (Caplan et al., 2005b) in CAE. Using the child behavior checklist (CBCL), Williams et al. (1996) reported thought and attention problems, as well as withdrawn behavior in CAE children.
Of the few childhood studies that examined the relationship of seizure variables with cognition, language, and behavior in CAE, some show that the onset before age of 4 years is significantly associated with more global cognitive and nonverbal memory impairment (Pavone et al., 2001) as well as learning deficits (Lagae et al., 2001). Others find that poor seizure control is related to learning and behavioral difficulties (Williams et al., 1996) and to impaired use of language to organize and formulate thoughts (i.e., discourse deficits) in younger CAE children. However, duration of illness is associated with discourse deficits in older CAE patients (Caplan et al., 2006). The presence of a psychiatric diagnosis and the type of diagnosis in CAE are unrelated to seizures variables (Caplan et al., 1998; Ott et al., 2001).
We previously reported psychopathology findings and treatment rate of a relatively small CAE sample (Caplan et al., 1998; Ott et al., 2003). The goal of the observational study presented in this paper was to describe the cognitive, linguistic, and behavioral comorbidities and their correlates in a large sample of children with CAE. We hypothesized that significantly more children with CAE would have cognitive deficits, impaired language, and psychopathology compared to normal age and gender matched children. In addition, they would have significantly more problems with attention, thinking, and withdrawn behavior compared to normal age and gender matched subjects. Within the CAE group, we posited that significantly more children would meet diagnostic criteria for ADHD than for psychiatric diagnoses, such as depression and anxiety disorders. In terms of the correlates of the comorbidities in the CAE group, we hypothesized that seizure-related variables would be associated with IQ and linguistic deficits, and explored the role played by seizure, cognitive, linguistic, and demographic variables in the predicted psychopathology findings.
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Supporting the findings of prior studies on smaller CAE samples (Caplan et al., 1998; Dunn & Austin, 1999; Lagae et al., 2001; Ott et al., 2001; Pavone et al., 2001; Henkin et al., 2003, 2005), we found a broad range of untreated cognitive, linguistic, and behavioral/emotional comorbidities in CAE. Thus, despite mean average IQ and SLQ scores, one fourth of the CAE children had subtle cognitive difficulties, just under a half had linguistic deficits, almost two-thirds had psychiatric diagnoses, particularly ADHD and anxiety disorder diagnoses, and about one third had CBCL broad band and narrow band scores (i.e., somatic complaints, social problems, thinking, attention) in the clinical/borderline range.
The association of seizure variables (i.e., duration of illness, AED treatment, seizure frequency) with IQ and SLQ scores, the presence and type of psychiatric diagnosis, as well as CBCL scores emphasize that CAE is not a “benign” disorder. Treatment of these comorbidities in only 23% of the children together with the reported poor functional outcome (Olsson & Campenhausen, 1993; Wirrell et al., 1997) of CAE further emphasize the importance of timely detection and treatment of these problems.
In terms of the study’s psychopathology findings, the role seizure control played predicting the presence of a psychiatric diagnosis is similar to Wirrell et al’s follow-up findings (Wirrell et al., 1997) of a higher rate of psychiatric diagnoses in the CAE subjects with poor seizure control compared to those with good seizure control. The increased frequency of ADHD, problems with attention, thinking, and social problems, and association of ADHD with problems in attention and thinking are also comparable to findings in other children with epilepsy (Dunn & Austin, 1999; Hesdorffer et al., 2004; Rodenburg et al., 2005; Hermann et al., 2007; Jones et al., 2007). However, we had not predicted the high rate of anxiety disorder diagnoses and somatic complaints found in our CAE sample.
Examination of variables associated with anxiety disorder diagnoses revealed that, as reported in children without epilepsy with anxiety disorders, girls with CAE were more likely to have anxiety disorder diagnoses than boys (Lewinsohn et al., 1998). The association of anxiety disorders with both increased seizure frequency and duration of illness in the CAE subjects implies that repeated episodes of loss of consciousness over a prolonged period might be associated with a feeling of a lack of control and increased anxiety. In fact, Dunn et al. (1999) have shown that external locus of control, perceiving others as socially powerful, was associated with the anxiety/depression factor score of the Youth Self Report (Achenbach, 1991) in adolescents with epilepsy.
In addition, the significant relationship of increased somatic complaints with later age of onset might also imply that the uncertainty of unpredicted repeated episodes of brief loss of consciousness could be more anxiety provoking in older children. Children with anxiety disorders without epilepsy, particularly older rather than younger children, have frequent somatic complaints (Ginsburg et al., 2006). Alternatively, parents might confuse the manifestations of CAE with behavior problems (Oostrom et al., 2001). The high parent based CBCL somatic complaint scores might, therefore, reflect parental misinterpretation of brief absence episodes as the child or adolescent “not feeling well” (i.e., a somatic complaint).
From the biological perspective, the frontal lobe, thalamus, and impaired 5HT metabolism are implicated in both absence seizures (Holmes et al., 2004; Meeren et al., 2005; Betting et al., 2006a, 2006b; Midzyanovskaya et al., 2006) and anxiety disorders (Jakus et al., 2004; Bercovici et al., 2006; Monk et al., 2006). More specifically, EEG recordings demonstrate that absence seizures begin with discrete spikes that are often unilateral in the dorsolateral frontal and orbital frontal regions and then evolve to engage orbital frontal and mesial frontal regions during the repeating spike and wave cycles (Holmes et al., 2004). MRI studies reveal increased gray matter concentration in the superior mesiofrontal region (Betting et al., 2006b) and larger anterior thalamus volumes (Betting et al., 2006a) in young adults with absence seizures. Rats show an association between their response to stress and the propensity to have absence seizures, reduced 5HT metabolism in the thalamus, and increased metabolism in the prefrontal cortex in contrast to those without absence seizures (Midzyanovskaya et al., 2006).
Furthermore, involvement of ventrolateral prefrontal cortex (Monk et al., 2006) and impaired 5HT metabolism (Jakus et al., 2004; Bercovici et al., 2006) are also found in anxiety disorders unrelated to epilepsy. Our clinical findings of high rates of anxiety disorder diagnoses and the association with increased seizure variables in CAE, therefore, highlight the importance of examining the possible biological basis of anxiety in pediatric CAE.
Similarly, the role of the frontal lobe in CAE (Holmes et al., 2004; Betting et al., 2006a, 2006b) might also underlie the high rate of ADHD in this epilepsy syndrome. Studies in children with ADHD without epilepsy show decreased cortical thickness (Shaw et al., 2006), volume reductions (Sowell et al., 2003; Durston et al., 2004), and reduced activation in the rostral mesial prefrontal region during tasks related to decision making/response selection aspects of the inhibitory processes (Smith et al., 2006). A recent study in children with new onset epilepsy which included both generalized and localization related epilepsy demonstrated increased rather than decreased gray matter volume in the frontal lobes of the children with ADHD compared to those without ADHD (Hermann et al., 2007).
In terms of linguistic comorbidities, smaller sample size and use of different instruments might underlie discrepant linguistic findings of impaired language skills in our study compared to (Pavone et al., 2001; Henkin et al., 2003). Auditory evoked potential findings of longer P3 latency during semantic processing and a lack of difference in P3 amplitudes over the left and right scalp during phonetic and semantic processing suggested semantic deficit and different patterns of language organization in CAE compared to normal children (Henkin et al., 2003). These findings, evidence for the role of the frontal lobe and thalamus in cognition, attention, and language (Posner & DiGirolamo, 1998; Radanovic et al., 2003; Szaflarski et al., 2006; Stringaris et al., 2007), and the association of seizure variables with impaired cognition and language in CAE highlight the need to focus future studies on involvement of these brain regions in the cognitive and linguistic comorbidities of CAE.
Several limitations restrict generalizability of the study’s findings to other CAE populations. First, regarding seizure control, as each CAE subject had to have had at least one seizure in the year prior to participation in the study, 71% of our CAE sample had 10 or more absence seizures during that period. Thus, the association of a psychiatric diagnosis with seizure frequency could reflect the study’s inclusionary criterion. Second, Grosso et al. (2005) suggest that the wide range of seizure control in CAE outcome studies, 33–79%, reflects differences across studies in the inclusion of patients with generalized tonic–clonic seizures during the active stage of CAE, myoclonic seizures, eyelid myoclonia, and EEG features of atypical CAE. Although we excluded children who had generalized tonic–clonic seizures from the data analysis, we had no information on the presence or absence of eyelid and perioral myoclonia which, like generalized tonic–clonic seizures, predict an unfavorable prognosis (Grosso et al., 2005) or different course (Incorpora et al., 2002). Our secondary analyses, however, suggest that the presence of slowing on EEG and onset at or prior to age 4 years did not drive the study's findings.
Third, the modeling findings indicating a significant association between the number of AEDs and mean SLQ scores might reflect a cohort effect given the higher seizure frequency in the new CAE cohort and lower mean SLQ scores in the old cohort. Of note, as described in the Methods section, there were no significant differences in the recruitment sources (tertiary vs. community) of the new and old cohorts.
Fourth, SLQ scores based on three age related forms of the language instrument, the TOLD-P, TOLD-I, and TOAL do not rule out the possible role of undiagnosed linguistic deficits as an associated factor. Fifth, although we used different IQ instruments (i.e., WISC-R, WISC-III), we found no significant differences in the mean IQ scores of the children tested with the WISC-R and the WISC-III. Sixth, the normal group had significantly higher mean IQ score than the CAE subjects. However, we controlled for these differences in the between group analyses of language and psychopathology. In addition, these between group IQ differences played no role in the modeling analyses conducted within the CAE group. Seventh, while we computed multiple statistical tests, they were hypothesis driven, and we reported findings with a p-level below 0.05.
In conclusion, our findings alert clinicians to the importance of identifying and treating the broad spectrum of comorbidities in CAE, particularly in children with longer duration of illness, ongoing seizures, and AED treatment. They also point to the need to elucidate the role of the underlying pathology and psychosocial variables in the comorbid anxiety and ADHD diagnoses, impaired cognition, and linguistic deficits of pediatric CAE.