Is lower IQ in children with epilepsy due to lower parental IQ? A controlled comparison study

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1 DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY ORIGINAL ARTICLE Is lower IQ in children with epilepsy due to lower parental IQ? A controlled comparison study NATALIE M WALKER 1 DAREN C JACKSON 1 KEVIN DABBS 1 JANA E JONES 1 DAVID A HSU 1 CARL E STAFSTROM 1 RAJ D SHETH 2 MONICAAKOEHN 3 MICHAEL SEIDENBERG 4 BRUCE P HERMANN 1 1 Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI; 2 Department of Neurology, Nemours Clinic, Jacksonville, FL; 3 Epilepsy Center, Marshfield Clinic, Marshfield, WI; 4 Department of Psychology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA Correspondence to Daren C Jackson at Department of Neurology, University of Wisconsin School of Medicine and Public Health, UW Medical Foundation Building (7223), 1685 Highland Avenue, Madison, WI , USA. jackson@neurology.wisc.edu This article is commented on by Prentkowski and Dunn on page 204 of this issue. PUBLICATION DATA Accepted for publication 13th September Published online 6th December ABBREVIATIONS FSIQ Full-scale IQ WASI Wechsler Abbreviated Scale of Intelligence AIM The aim of this study was to determine the relationship between parent and child Full-scale IQ (FSIQ) in children with epilepsy and in typically developing comparison children and to examine parent child IQ differences by epilepsy characteristics. METHOD The study participants were 97 children (50 males, 47 females; age range 8 18y; mean age 12y 3mo, SD 3y1mo) with recent-onset epilepsy including idiopathic generalized (n=43) and idiopathic localization-related epilepsies (n=54); 69 healthy comparison children (38 females, 31 males; age range 8 18y; mean age 12y 8mo, SD 3y 2mo), and one biological parent per child. All participants were administered the Wechsler Abbreviated Scale of Intelligence (WASI). FSIQ was compared in children with epilepsy and typically developing children; FSIQ was compared in the parents of typically developing children and the parents of participants with epilepsy; parent child FSIQ differences were compared between the groups. RESULTS FSIQ was lower in children with epilepsy than in comparison children (p<0.001). FSIQ of parents of children with epilepsy did not differ from the FSIQ of the parents of typically developing children. Children with epilepsy had significantly lower FSIQ than their parents (p<0.001), whereas comparison children did not. The parent child IQ difference was significantly higher in the group with epilepsy than the comparison group (p=0.043). Epilepsy characteristics were not related to parent child IQ difference. INTERPRETATION Parent child IQ difference appears to be a marker of epilepsy impact independent of familial IQ, epilepsy syndrome, and clinical seizure features. This marker is evident early in the course of idiopathic epilepsies and can be tracked over time. Children with uncomplicated idiopathic epilepsies often have IQ scores within the average range, 1 but direct comparison of children with epilepsy with typically developing children frequently shows IQ to be significantly lower in the children with epilepsy. 2 This IQ difference is usually attributed to the effect of epilepsy on cognition. 3 The possibility that a lower IQ in children with idiopathic epilepsies may be related to genetic factors, socio-economic status, or other familial or environmental factors has not been examined to determine whether etiologies other than the epilepsy itself affect child IQ. It is important to consider cognitive scores in the context of the ability levels of other family members, given the growing evidence of familial aggregation of learning and cognitive anomalies in the siblings and even parents of children with epilepsy. 4 9 Further, when examining IQ, accounting for differences in parent IQ is an important consideration as the heritability of intelligence is well established, 10,11 with some studies revealing that genetics can account for 40 to 60% of variance in IQ scores in normative populations. 12,13 The difference in IQ between parent and child could conceivably distinguish groups of children with average IQ scores. For example, in one child an average or even low average IQ might be congruent with parental IQ, whereas in another case a solidly average IQ might be significantly lower than the IQ of the parent. Considering the IQ difference between a child and a parent may provide a novel way of characterizing the cognitive impact of epilepsy, rather than examining only the child s IQ in relation to a normative population. For this reason, a measure of child-to-parent cognitive scores could serve as a marker for the impact of a condition and its treatment, both at the time of diagnosis and over time. In the current study we examined parent child IQ difference in order to further refine our understanding of the effects of epilepsy on cognition. First, the traditional comparison of IQ difference between children with epilepsy and healthy children was examined: the typical contrast used to ascertain 278 DOI: /dmcn ª The Authors. Developmental Medicine & Child Neurology ª 2012 Mac Keith Press

2 epilepsy impact. Second, we made a series of novel comparisons including contrast between parents of the children with epilepsy and parents of the comparison children, followed by comparison of parent child dyads in the epilepsy and comparison groups, the outcomes of which speak to the presence or absence of unique effects of epilepsy on child IQ. Finally, we focused on parent child IQ differences in the epilepsy group only, in order to examine the effects of clinical seizure features (i.e. epilepsy syndrome, age at onset, antiepileptic medications). These comparisons were undertaken in children with new recent-onset epilepsies, thereby addressing cognitive effects in a cohort unencumbered by the effects of chronic and intractable epilepsies. METHOD Participants Research participants were 97 children (50 males, 47 females) with new and recent-onset epilepsy comprising children with idiopathic generalized (n=43) and idiopathic localizationrelated (n=54) epilepsies, 69 healthy first cousins of the children with epilepsy (38 females, 31 males), and one biological parent per child. Participants were recruited from the pediatric neurology clinics of two large regional medical centers in Wisconsin (University of Wisconsin-Madison, Marshfield Clinic). Patient inclusion criteria included diagnosis of epilepsy within the past 12 months, a chronological age between 8 years and 18 years, no other developmental disability, no other neurological disorder, and normal neuroimaging results. Children in the comparison group were age- and sex-equivalent first cousins of the children with epilepsy, with no history of an initial precipitating event (e.g. febrile seizures) or seizure or seizure-like episode, no diagnosed neurological disease, no history of loss of consciousness longer than 5 minutes, and no family history of a first-degree relative with epilepsy or febrile convulsions. All children were attending regular schools. Demographic information about the research participants is provided in Table I. Further details regarding participant selection processes are available elsewhere. 14 Procedures This study was approved by the institutional review boards at the University of Wisconsin-Madison and Marshfield Clinic, Wisconsin. Informed consent and assent were obtained from parents and children on the day of testing. Child and parent Table I: Participant and parent characteristics Variable Epilepsy group (n=97) Comparison group (n=69) Age, mo (37.72) (38.20) Sex, Male Female, n FSIQ a (11.53) (11.26) Parent relationship (% fathers) Parent FSIQ (14.45) (12.75) Parent education (% with some college education) Values are mean (SD). a p<0.05. FSIQ, Full-scale IQ. What this paper adds This is the first study to use parent IQ to examine familial differences among children with epilepsy and healthy participants. Lower IQ in children with epilepsy is not associated with lower parent IQ. participants Full-scale IQ (FSIQ) was obtained using the Wechsler Abbreviated Scale of Intelligence (WASI). 15 The WASI can be administered across a very broad age range (6 89y), which has the advantage that the same stimulus item pool can be administered across a wide age spectrum in both the child and the parent groups, thereby avoiding the methodological complications of administering different test versions with variable content within and across groups (adults vs children). Parents were administered the two-subtest version and children were administered the four-subtest version. Child four-subtest and two-subtest WASI IQ scores were strongly correlated in both children with (r=0.904, p<0.001) and without (r=0.898, p<0.001) epilepsy. The child four-subtest WASI was used for all analyses presented below. Statistical analysis Chi square and t-tests were used to examine demographic differences between groups. Pairwise comparisons (t-tests) were used to examine differences in FSIQ between children with epilepsy and healthy children, differences in FSIQ in the parents of these children, and differences within each group between parent and child. a To further explore the predictors of the relation between parent and child IQ, a difference score was created (subtracting child FSIQ from parent FSIQ) to represent parent versus child IQ difference. Using this metric, relationships were examined in regard to clinical seizure characteristics (epilepsy syndrome, age at onset, antiepileptic medications) and demographic characteristics (age, sex, parent education). Given the number of children with attentiondeficit hyperactivity disorder (ADHD) and academic problems in the epilepsy group (26.8% and 51.5% respectively), we also examined parent child IQ difference scores as a function of the presence or absence of a diagnosis of ADHD or academic problems to rule out the possibility that these comorbidities were responsible for any possible overall group differences. RESULTS FSIQ based on the four-subtest WASI was significantly lower in children with epilepsy (mean 99.5, SD 11.5) than in the comparison children (mean 107.8, SD 11.3; t(164)=4.7, p<0.001; Fig. 1). In contrast, FSIQ did not differ between the parents of children with epilepsy (mean 107.1, SD 14.4) and parents of comparison children (mean 110.2, SD 12.8; t(157)=1.4, p=0.16). Children with epilepsy had significantly a In the families of the healthy children, some had more than one child who met the inclusion criteria and participated in the study. In the families of the children with epilepsy, there was no instance of more than one child with epilepsy per family. We examined IQ scores for parents and children from the comparison families where more than one child met entry criteria compared with singleton families and the findings were identical (parent mean scores and , child mean scores and respectively). No IQ bias was introduced. Parent Child IQ Difference in Epilepsy Natalie M Walker et al. 279

3 IQ score Child Parent * Epilepsy * Control *p<0.001 Figure 1: Parent and child IQ of epilepsy and comparison groups. lower IQ than their parents (Fig. 1; p<0.001), while no such difference was found in the comparison group (p=0.126). FSIQ difference (parent FSIQ minus child FSIQ) also differed between epilepsy and comparison groups (Fig. 2). Difference scores were greater in the epilepsy group child parent dyads (mean 6.6, SD 13.4) than in comparison group child parent dyads (mean 2.4, SD 12.7; t(157)=2.04, p=0.043). We also compared those participants with epilepsy with and without ADHD, and found no differences in parent child IQ difference (t(88)=0.785, p=0.435). Additionally, we examined those children with epilepsy who had received any type of educational support service, the frequency of which is shown in Table II: Characteristics of participants with epilepsy by syndrome Variable ILRE a (n=54) IGE a (n=43) Age at seizure onset, y b (2.39) (3.39) Epilepsy duration, mo 7.72 (3.58) 8.49 (3.33) Antiepileptic drugs (0 1 2+) b,c FSIQ (11.35) (11.89) ADHD (%) 17 (31.5) 9 (20.9) Educational services (%) 31 (59.6) 19 (44.2) Values are mean (SD) except where otherwise stated. a ILRE subsyndromes: benign epilepsy with centrotemporal spikes, n=22; temporal lobe epilepsy, n=9; frontal lobe epilepsy, n=6; focal epilepsy not otherwise specified, n=17. IGE subsyndromes: childhood absence epilepsy, n=6; juvenile absence epilepsy, n=6; juvenile myoclonic epilepsy, n=25; generalized epilepsy not otherwise specified, n=6. b p<0.05. c Missing data for one participant. Treatment medications were as follows: valproic acid (26 participants), oxcarbazepine (17), carbamazepine (15), lamotrigine (13), ethosuximide (6), levetiracetam (6), gabapentin (2), topiramate (2), zonisamide (1). Note that the total does not equal the epilepsy group sample size, as some participants were taking multiple medications. ILRE, idiopathic localization-related epilepsy; IGE, idiopathic generalized epilepsy; FSIQ, Full-scale IQ; ADHD, attention-deficit hyperactivity disorder. Table II. There was no difference in parent child IQ difference between children who had or had not received education support (t(86)=1.560, p=0.122); thus, these comorbidities were not responsible for the overall epilepsy versus comparison group differences. In both the comparison and epilepsy groups, parent child IQ difference was uncorrelated with child age or sex. In the epilepsy group, parent child IQ difference was also unassociated with epilepsy variables (age at epilepsy onset, syndrome Comparison GROUP Epilepsy IQ difference IQ difference Frequency Figure 2: IQ difference score distributions for epilepsy and comparison groups. 280 Developmental Medicine & Child Neurology 2013, 55:

4 type, and number of current antiepileptic medications). Although there was no difference in the sex (mother vs father) or education level of participating parents between the epilepsy and comparison groups, participating parents education level was associated with greater parent child IQ difference. In both the epilepsy and comparison groups, parent child IQ difference scores were greater in dyads consisting of parents with at least some college education (epilepsy group: mean 11.3, SD 12.0; comparison group: mean 8.4, SD 10.3) than in dyads consisting of parents with no post-high school or equivalent education (epilepsy group: mean 1.5, SD 13.3, t(87)=3.70, p=0.001; comparison group: mean 2.7, SD 13.7, t(58)=3.56, p=0.001). In other words, in both epilepsy and comparison groups, parent child IQ difference was significantly greater in dyads in which the participating parent had at least some college education than in dyads in which the parent had a lower level education. Furthermore, there was no difference between mothers (108.93) and fathers (106.18) IQ (p=0.306) in the groups. DISCUSSION This study produced four major conclusions. First, consistent with the general epilepsy literature, this sample of children with idiopathic epilepsies had a mean IQ (99.5, SD 11.5) within the average range. Second, despite average normative IQ, the IQ of children with epilepsy was significantly lower than that of comparison children. Third, there was no difference in IQ between the parents of children with epilepsy and the parents of healthy children. Finally, children with epilepsy showed significantly lower IQ than their parents whereas typically developing children did not, indicating a direct effect of epilepsy. A consistent finding in the neuropsychology of childhood epilepsy is that IQ is significantly lower in children with epilepsy than in comparison populations (for reviews, see references 16 and 3). This is not surprising in children with symptomatic or difficult-to-control seizures, but is more surprising in children with uncomplicated idiopathic epilepsies children who are typically viewed as having broadly average IQ. Furthermore, the children investigated here are best conceptualized as epilepsy-only in the fashion described by Oostrom et al.: 17 children of average intelligence, attending regular schools, with normal neurological examinations, and normal imaging results. Further, the children examined in this study had new recent-onset epilepsy and therefore did not have years of seizures and treatment. The mean IQ of these children was average, but significantly below that of comparison parents and first cousins. The etiology underlying this IQ difference is of interest. There are known genetic and environmental contributions to intelligence, 10,11 and one possibility not examined previously is that overall intellectual level may be mildly lower in the families of children with epilepsy. This does not appear to be the case, as not only was there no IQ difference between parents of children with epilepsy and the parents of healthy children, but levels of educational attainment were similar as well. By quantifyingtheiqdifferenceinchild parentdyads,wehave shown a direct effect associated with the presence of epilepsy. Children with epilepsy exhibited a significantly lower IQ than their parents relative to healthy children (the first cousins of the children with epilepsy examined here). Although there is an effect of epilepsy, we attempted to determine whether the difference in parent child IQ was associated with epilepsy syndrome or other features of the disorder. We found that the parent child IQ difference in epilepsy dyads was not associated with demographic characteristics (e.g. age, sex) or clinical epilepsy characteristics (e.g. age at epilepsy onset, presence or absence of antiepileptic medications). Furthermore, we found no difference in parent child IQ difference when comparing broad-band epilepsy syndromes (idiopathic generalized epilepsy and idiopathic localization-related epilepsy). Although Nolan et al. 18 reported differences in FSIQ across epilepsy syndromes, it is important to recognize that they found no difference across children with focal epilepsies (central epilepsy, temporal lobe epilepsy, frontal lobe epilepsy) and idiopathic generalized epilepsy. Conversely, children with generalized symptomatic epilepsy had significantly lower FSIQ than children in the syndrome groupings listed above. Given that the current study did not include children with generalized symptomatic epilepsy, and focused only on children with idiopathic epilepsies, the absence of significant differences in parent child IQ difference across broad idiopathic generalized epilepsy and idiopathic localization-related epilepsy syndromes is not inconsistent with Nolan et al. s findings; parent child IQ difference appears to be affected regardless of clinical seizure characteristics or treatment status. Several additional points are noteworthy. First, although the IQ of the children with idiopathic epilepsies was significantly lower than that of the typically developing comparison children, it is important to re-emphasize that their mean IQ level falls within the average range. Therefore, this is a mild, but detectable, effect. Second, this effect was observed in children with new recent-onset epilepsy. Therefore, the impact on IQ is present early in the course of the disorder and does not result from years of recurrent seizures and chronic medication. Third, because these are new recent-onset epilepsy cases, the question of how IQ changes may occur over time remains to be determined. Fourth, only FSIQ was examined here. Other aspects of cognition, such as executive and psychomotor function, are also important in determining a child s overall cognitive ability. These aspects of cognition could not be examined because of limited data from the parents. Finally, the nature of the IQ test used here allowed administration of the same subtests and even stimulus items to the children and their parents. Thus, this is a direct comparison of overall intellectual ability that is not confounded by use of different tests and stimulus materials. Re-administration of this test in the future will provide a precise characterization of the developmental trajectory of epilepsy and its treatment on intellectual status. Limitations This investigation has several limitations. Only intelligence was examined and inclusion of other cognitive domains in Parent Child IQ Difference in Epilepsy Natalie M Walker et al. 281

5 parent child comparisons might be informative. We could not evaluate parent child IQ differences across specific epilepsy subsyndromes (e.g. childhood absence, juvenile absence, frontal lobe epilepsy) because of the limited sample size. Both mothers and fathers were represented, as opposed to only one parent grouping (e.g. mothers), but the distribution of tested mothers and fathers did not differ across groups, with the IQ scores being virtually identical. Being limited to cases of new/ recent-onset epilepsy, we could not assess the longitudinal effects of seizures on IQ; this analysis is planned for future studies. Finally, remaining limitations of the current study include the relatively limited battery administered to children and parents and the lack of inclusion of siblings of either the children with epilepsy or healthy children. The recently reported link by Hesdorffer et al. 19 between behavioral disorders in probands with epilepsy and presence of seizures in family members could not be assessed in this sample for these reasons. In conclusion, the combination of findings reported here suggests that the lower IQ in children with epilepsy is not a result of a low familial IQ and is rather a direct effect associated with the disorder. This is further suggested by the fact that parent-child IQ differences are significant in the epilepsy group but not different in the healthy comparison group. ACKNOWLEDGEMENTS This study was supported by the National Institutes of Health (NINDS ROI 44351), which provided funding for study design, data collection, and data analysis. The funder was not involved in manuscript preparation or publication decisions. BPH, JEJ, DAH, RDS, MAK, and MS receive research support from the National Institutes of Health (NIH; NINDS RO [co-investigators]). This project was supported by the Clinical and Translational Science Award (CTSA) program, previously through the National Center for Research Resources (NCRR) grant 1UL1RR025011, and now by the National Center for Advancing Translational Sciences (NCATS), grant 9U54TR The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. DISCLOSURES DAH receives research support from Citizens United for Research on Epilepsy. RDS serves on the editorial board of Epilepsy and Behavior and the Journal of Child Neurology. CES has received compensation as a consultant for Questcor Pharmaceuticals (2011), serves on the Scientific Board of The Charlie Foundation, serves as an Associate Editor of Epilepsia and Co-Editor-in-Chief for Basic Science of Epilepsy Currents, has received royalties from publication of the books Epilepsy and the Ketogenic Diet and Epilepsy: Mechanisms, Models and Translational Perspectives, and received support from the NIH (NINDS RO [co-investigator]). BPH serves as an Associate Editor for Epilepsia and receives research support from the NIH (NINDS 2RO1 NS44351 [PI], RO1 AG [co-investigator], P50AG3314 [coinvestigator], 1RO1NS [co-investigator], and RO1AG [co-investigator]). REFERENCES 1. Berg AT, Smith SN, Frobish D, et al. Special education needs of children with newly diagnosed epilepsy. Dev Med Child Neurol 2005; 47: Fastenau PS, Johnson CS, Perkins SM, et al. Neuropsychological status at seizure onset in children: risk factors for early cognitive deficits. 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