Epilepsia, 49(11):1838–1846, 2008 doi: 10.1111/j.1528-1167.2008.01680.x
FULL-LENGTH ORIGINAL RESEARCH
Childhood absence epilepsy: Behavioral, cognitive, and linguistic comorbidities ∗
Rochelle Caplan, ∗ Prabha Siddarth, ∗ Lesley Stahl, ∗ Erin Lanphier, ∗ Pamela Vona, ySuresh Gurbani, zSusan Koh, zRaman Sankar, and zW. Donald Shields
Department of ∗ Psychiatry, University of California at Los Angeles (UCLA), Los Angeles, California, U.S.A.; yDepartment of Pediatrics, University of California at Irvine, U.S.A.; and zDepartment of Pediatrics, University of California at Los Angeles (UCLA), Los Angeles, California, U.S.A.
SUMMARY 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 ¼ 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,
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 diffiAccepted April 22, 2008; Early View publication June 28, 2008. Address correspondence to Rochelle Caplan, M.D., Semel Institute for Neuroscience and Human Behavior, 760 Westwood Plaza, Los Angeles, CA 90024, U.S.A. E-mail:
[email protected] Wiley Periodicals, Inc. ª 2008 International League Against Epilepsy
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. KEY WORDS: Childhood absence epilepsy, Psychopathology, Cognition, Language, Risk factors, Development.
culties (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
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1839 Risk for Comorbidities 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
Table 1. Demographic features of study groups n Age (years) Gender Male Female Socioeconomic status High (i, ii) Low (iii–v) Ethnicity Caucasian Non-Caucasian
CAE
Normal
69 9.64 (2.49)
103 9.9 (2.33)
38% 62%
49% 51%
19% 81%
25% 75%
46% 54%
48% 52%
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.
Methods Subjects The study included 69 CAE children, aged 6.7–11.2 years with IQ scores of 70 and higher and 103 normal children. Table 1 presents demographic features of the sample. We determined socioeconomic status (SES) using the Hollingshead 2 factor index (Hollingshead, 1973), based on parental occupational and educational status. There were no significant differences in the demographic variables of the CAE and normal groups. Sixty-six subjects were recruited during 1994–1998 and 73 during 1999–2005. We recruited 35% of the CAE subjects from tertiary centers (i.e., UCLA and USC based clinics) and 65% from community services (i.e., Los Angeles and Anaheim Kaiser Permanente, the Los Angeles and San Diego Chapters of the Epilepsy Foundation of America, private practices). There were no significant differences in the recruitment source of the new (tertiary 30%, community 70%) and old cohorts (tertiary 38%, community 62%). The primary study inclusion criterion for each subject was that he/she had a diagnosis of CAE and at least one seizure in the year prior to participation in the study. A pediatric neurologist at each recruitment site made a diagnosis of CAE according to the International Classification of Epilepsy (Commission, 1989). As described in this classification, all CAE patients had EEG evidence of 3 Hz spike and wave in addition to absence seizures induced by hyperventilation. We excluded patients with a mixed seizure disorder, previous epilepsy surgery, atypical spike and wave complexes, juvenile myoclonic epilepsy, generalized tonic clonic seizures, a neurological illness other than epilepsy, chronic medical illness, imaging evidence for structural brain abnormalities, a metabolic disorder, a hearing Epilepsia, 49(11):1838–1846, 2008 doi: 10.1111/j.1528-1167.2008.01680.x
1840 R. Caplan et al. disorder, mental retardation based on school/classroom placement, and bilingual speakers of American English who did not attend English speaking schools or speak English at home. UCLA IRB approved recruitment flyers were available for parents of CAE children at each recruitment site. Parents who decided to enter their children into the study contacted the study coordinator who provided information about the study and used a UCLA IRB approved telephone script to determine if the children met the study’s inclusionary but none of the exclusionary criteria. The study coordinator also contacted the child’s pediatric neurologist to confirm the child’s diagnosis and to rule out exclusionary criteria. One UCLA pediatric neurology investigator (WDS.) reviewed the history, EEG records, and diagnosis of each CAE subject from the different recruitment sites. If he did not concur with the diagnosis or EEG findings, the child was not included in the study. The parents and child’s medical records provided information on seizure variables. The mean age of onset and duration of illness in the CAE group were 6.15 (SD 2.52) and 3.54 (SD 2.82) years, respectively. Twenty-five percent of the CAE group had at least one seizure, 4% had 2–10, and 71% had 10 or more seizures during the year prior to participation in the study. Twelve percent of the CAE group received no antiepileptic drugs (AEDs), 76% were on AED monotherapy (51% on valproic acid, 35% on ethosuximide, 14% other), and 13% on AED polytherapy. Ten percent of the children had experienced febrile convulsions and 4% prolonged febrile seizures (i.e., >5 min). Six CAE subjects had slowing on EEG. Comparison of the new and old CAE cohorts on seizure variables revealed significantly higher mean seizure frequency in the new cohort [t (66) ¼ 2.47, p < 0.02] but no other significant differences between groups. To include children from a wide range of ethnic and SES backgrounds similar to that of the CAE group, we recruited the normal control subjects from four public and two private schools in the Los Angeles community. The study coordinator screened potential participants for neurological, psychiatric, language, and hearing disorders through a telephone conversation with a parent. We excluded children with diagnoses of these disorders in the past from the study. Procedures Written informed consent and assent were obtained from the parents and children, respectively, in accordance with policies of the Human Subject Protection Committees of the UCLA after the procedures were fully explained. Cognition IQ The Wechsler Intelligence Scale for Children-Revised (WISC-R), (Wechsler, 1974) given to children tested from Epilepsia, 49(11):1838–1846, 2008 doi: 10.1111/j.1528-1167.2008.01680.x
1994 to 1998, and the Wechsler Intelligence Scale for Children-3rd edition (WISC-III), (Wechsler, 1991) administered to children tested from 1999 to 2005, generated full scale, verbal, and performance IQ scores (see detailed description in Caplan et al., 2005b). Language The Test of Language Development [TOLD (Newcomer & Hammil, 1988)] As presented in (Caplan et al., 2006), the spoken language quotient (SLQ) was derived from the three forms of this test, the TOLD-2 primary, the TOLD-2 intermediate, and the Test of Adolescent Language (TOAL), administered to 38%, 50%, and 12%, respectively, of the CAE and normal subjects. Psychopathology The Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) The Schedule for Affective Disorders and Schizophrenia for School-Age Children, Epidemiologic Version (KSADS-E) (Orvaschel & Puig-Antich, 1987) during 1994– 1998 and the Present and Lifetime Version (K-SADS-PL) (Kaufman et al., 1997) during 1998–2005, were administered separately to each child and parent by RC or a research assistant trained in the administration of the interview, as detailed in (Caplan et al., 2005b). The Child Behavior Checklist Parents completed the 118 behavior problem items (Achenbach, 1991), as elaborated in Caplan et al. (2005b). The cutoff point for borderline/clinically significant pathology in this study was based on the age and gender normed T score of 60 for the broad band and 67 for the narrow band scales (Achenbach, 1991). Treatment Parents provided information on whether the child was undergoing or had received any type of treatment for cognitive, linguistic, or behavioral difficulties. Data analysis Prior to statistical analyses, all data were inspected for outliers, skewness, kurtosis, and homogeneity of variance to ensure their appropriateness for parametric statistical tests. ANCOVAs, controlling for demographic variables (namely, age, gender, SES, and ethnicity), were used to compare the CAE and normal groups on cognition and SLQ, and logistic regressions were used to compare the two groups on the presence of a psychiatric diagnosis and CBCL scores in the clinical/borderline range. In addition to demographic variables, IQ was included as a covariate in the logistic regressions. To compare the two groups on their mean CBCL scores, ANCOVAs with demographic and IQ variables in the model were estimated. Given the
1841 Risk for Comorbidities Table 2. Mean IQ and SLQ scores and distribution of scores in the CAE and normal groups Distribution of scores Means (SD) CAE
Normal
CAE F(df)
p
FSIQ 101 (15.61) 111 (13.22) 19.71 (1,166)
