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Progressive behavioral changes in children with epilepsy
T. Sutula and A. Pitk~inen (Eds.) Progress in Brain Research, Vol. 135 © 2002 Elsevier Science B.V. All rights reserved
CHAPTER 37
Progressive behavioral changes in children with epilepsy t Joan K. Austin 1,, and David W. D u n n 2 1 School of Nursing and 2 School of Medicine, Indiana University, 1111 Middle Drive, NU492, Indianapolis, IN 46202-5107, USA
Abstract: Children with epilepsy are known to have high rates of mental health problems. The role of seizures in the development of these problems is not known primarily because of difficulties in separating the effects of seizures from the three other potential causal factors: (a) poor child and family response to the condition, (b) side effects of antiepileptic medication, and (c) neurological dysfunction that causes both the seizures and the behavioral problems. Although cross-sectional studies focusing on children with chronic epilepsy show associations between behavior problems and each of these causal factors, it is not possible to isolate the effects of any one causal factor using this design. A stronger approach is to conduct prospective studies of children with new-onset seizures. Recent research on children with new-onset seizures suggests that side effects of antiepileptic medication and poor child and family response do not play major roles in the development of behavior problems. Results from a prospective study in children with new-onset seizures show an association between seizures and behavior problems. Separating effects of seizures from effects of neurological dysfunction on behavior problems, however, will be difficult even in prospective studies of children with new-onset seizures. Transient cognitive impairment (TCI) from interictal epileptiform discharges is proposed as an alternative explanation for behavior problems.
Introduction Children with epilepsy are known to have high rates of mental health problems such as anxiety, depression, attention problems, and behavioral disruptions (Hoare, 1984a; Ettinger et al., 1998; Dunn and Austin, 1999). They are almost 5 times more likely to have mental health problems than children from the general population (Rutter et al., 1970; McDermott et al., 1995). Moreover, children with epilepsy appear to differ even from other groups of chronically ill children in that they fare substantially worse psychologically. Although most research has *Correspondence to: J.K. Austin, Indiana University School of Nursing, 1111 Middle Drive, NU492, Indianapolis, IN 46202-5107, USA. Tel.: +1-317-274-8254; Fax: + 1-317-278-1811; E-mail: [email protected] Preparation of this paper was supported by grants PHS R01 NS22416 from the National Institute of Neurological Disorders and Stroke and PHS R01 NR04536 from the National Institute of Nursing Research to the first author.
been cross-sectional, there is evidence from studies in chronic childhood illness to suggest that children with epilepsy have both the risk associated with a chronic condition and the risk associated with a central nervous system disorder. The risk for psychiatric disorder appears to be about 2.5 times higher for children with epilepsy than for children with other physical disorders not involving the central nervous system. For example, in a major epidemiological study, Rutter et al. (1970) found the prevalence of behavior problems to be 6.6% in the general population, 11.6% in children with chronic conditions not involving the central nervous system, 28.6% in children with idiopathic epilepsy, 37.5% in children with neurological damage, and 58.3% in children with both neurological damage and seizures. These findings suggest that seizures somehow are related to the development of such problems. The role that seizures play in the development of behavioral problems is not known. A large number of cross-sectional studies have investigated the relationship between particular seizure variables and behav-
420 ioral problems. Seizure variables related to behavior problems include early age of onset, poor seizure control, long duration of epilepsy, high seizure frequency, and multiple seizure types (Hoare, 1984a; Austin, 1988; Hermann et al., 1989; Austin et al., 1994). The most consistent finding, however, has been a link between more frequent seizures and more mental health problems (Hartlage and Green, 1972; Hoare, 1984a; Austin, 1988; Hermann et al., 1989; Austin et al., 1992). The association between seizure frequency and mental health problems is unexpected because the relationship between frequency of symptoms and psychological functioning is generally weak in childhood chronic conditions (Drotar and Bush, 1985). However, studies by Austin and colleagues showed seizure frequency to be a significant predictor of behavior problems in children with epilepsy; in contrast, frequency of asthma attacks was unrelated to behavior problems in children with asthma (Austin et al., 1992, 1996). This association suggests that seizures might have an effect on behavior problems independent of disruptions from illness symptoms. It is difficult, however, to separate effects of seizures from other causal factors. In addition to seizures, three broad categories of variables have been identified as potential causes of these behavioral problems: (a) poor child and family response to the condition, (b) side effects of antiepileptic medications, and (c) neurological dysfunction that causes both the seizures and the behavioral problems. Moreover, there is substantial agreement that more than one factor contributes to the development of mental health problems and that these factors interact with each other, which further reduces the ability to isolate their respective effects. Empirical support for the association between each of these potential causal factors and behavior problems in children with epilepsy is briefly reviewed. In this paper there is a particular emphasis on the authors' work that is relevant to showing possible effects of seizures on behavior problems, including research in progress.
Poor child and family response Most past research focusing on child and family response has been based on the assumption that mental health problems in the child with epilepsy result
from difficulties inherent in living with a chronic condition. Some authors propose that a maladaprive family environment contributes to problems. For example, negative family responses to the epilepsy such as parental over-control and perceptions of stigma associated with the epilepsy are proposed to lead to behavior problems in children with epilepsy (Carlton-Ford et al., 1997). The few empirical studies exploring the relationship between family environment variables and behavior problems in children with epilepsy do show a relationship. For example, Hoare and Kerley (1991) found family stress and lower socioeconomic status to be associated with child behavior problems. Dunn et al. (1999) found child satisfaction with family relationships to be associated with depression in adolescents. The few studies on parenting support its relationships to mental health outcomes in children with epilepsy. Lothman et al. (1990) observed mother-child interactions and found parental praise to be related to child competence and child positive affect. In contrast, intrusive and over-controlling parenting behaviors were related to decreased autonomy and confidence in these children with epilepsy. Other studies showed that both family and seizure variables were significantly associated with child mental health problems. For example, Austin et al. (1992) found family variables (family stress and fewer family resources) and seizure variables (high seizure frequency) to be significant predictors of behavior problems. The cross-sectional nature of this past research, however, makes it difficult to determine if families are reacting to problems in the child, if the child is influenced by the parent's maladaptive response to the child's epilepsy, or if both the child and the family are coping poorly with the child's seizures. Recent studies suggest that both children with newonset seizures and their parents have many concerns and fears related to seizures. For example, Brown (1994) found that about one half of the children with seizures felt helpless, scared, and different from others. In another study parents were found to have many concerns and fears related to their child's seizures including death, brain damage, loss of intelligence, and the possible presence of a brain tumor (Shore et al., 1998). Recent studies of psychosocial care needs of children with new-onset seizures and
421 their parents showed that approximately one third to one half of parents were not satisfied with explanations about epilepsy given to them and desired more information (Shore et al., 1998; Webb et al., 1998). These findings suggest that new-onset seizures in children can be very stressful for both children and parents and that this stress could lead to maladaptive coping responses in both the child and the family. Moreover, it is logical to propose that more frequent seizures would lead to increased stress.
Side effects of antiepileptic medication The case that antiepileptic medications can lead to emotional and behavioral disorders in people with epilepsy has some empirical support (Reynolds, 1991), although it is likely that such effects are limited. Behavioral problems were associated with polypharmacy in a study by Hermann et al. (1989). In contrast, Austin et al. (1992) did not find polypharmacy to be significantly associated with behavior problems in a study of children with chronic epilepsy. Children treated with phenobarbital were described by Brent et al. (1990) to have depression and suicidal ideation. It is difficult to separate effects of seizures from side effects of antiepileptic medication in children with chronic epilepsy because children who have more seizures are more likely to be on either more medications or on higher doses of medications. Two approaches have been used to explore the role of side effects of medications in relation to behavior problems: measuring behavior before and after initiation of medications in children with newonset seizures and measuring behavior before and after withdrawal of medication in children whose seizures are well controlled. Both types of prospective studies have suggested that antiepileptic medications may have minimal effect on cognitive and behavioral functioning. For example, in a prospective study of children with recent onset seizures Mandelbaum and Burack (1997) found no significant deterioration over a 12-month period in cognitive and behavioral performance related to the initiation of antiepileptic medication. In a similar study Williams et al. (1998) also did not find significant differences in behavioral disruptions between children with newonset epilepsy and controls during the first 6 months
following initiation of antiepileptic medication. Similar results on cognition and behavior were found in two recent withdrawal studies. For example, out of eight areas studied for differences after drug withdrawal, children reported improvements only in the area of tiredness (Aldenkamp et al., 1998). In this same study parents reported improvements in areas of activation (e.g., alertness, drowsiness, and concentration disorders) but not in behavioral problems (e.g., depression and aggressiveness). In the second study focusing on six cognitive functioning areas only improvements in psychomotor speed could be attributed to antiepileptic drug withdrawal (Aldenkamp et al., 1993). In general, findings using either approach are consistent with the hypothesis that underlying neurological dysfunction might play a more important role in the development of behavior problems than do side effects from antiepileptic medications (Corbett et al., 1985; Mandelbaum and Burack, 1997).
Neurological dysfunction Some researchers have proposed that underlying neurological dysfunction causes both seizures and behavior problems. Support for this hypothesis comes from cross-sectional studies indicating that children with chronic neurological conditions have higher rates of behavior problems than children with chronic conditions that do not involve the brain (Breslau, 1985; Howe et al., 1993). For example, Austin et al. (1994)found children with epilepsy to have higher scores for both internalizing and externalizing behavior problems as measured by parents' ratings on the Child Behavior Checklist (CBCL, Achenbach, 1991a) than those with chronic asthma. Behavioral ratings in this study by teachers on the Teacher's Report Form of the CBCL (TRF, Achenbach, 1991b) also showed children with epilepsy to have higher rates of internalizing behavior problems than children with asthma. In addition, empirical studies show that children with epilepsy who have accompanying deficits in neurological functioning are at increased risk for poor mental health outcomes (Hermann, 1981, 1982; Rutter, 1981). The few available cross-sectional studies of children with new-onset seizures also indirectly suggest that underlying neurological dysfunction might play
422 an important role in the development of behavior problems. Hoare (1984a,b) investigated psychiatric disturbance across several groups of children, including those with new-onset epilepsy, new-onset diabetes, and controls. He found 45% of children with new-onset epilepsy to already have mental health problems. In contrast, only 17% of the children with new-onset diabetes and only 10% of controls were found to have mental health problems. Authors investigating the effects of initiating antiepileptic medications in children with new-onset epilepsy also have noted higher than expected rates of behavior problems in children. Stores et al. (1992) noted that children had behavior problems prior to medication treatment and hypothesized that these problems were due to the epileptic process. Williams et al. (1998) rated children's behavior problems on the day they were diagnosed with epilepsy, prior to initiation of antiepileptic medication, and found internalizing behavior problems to be substantially higher than norms. Only a few prospective studies of children with new-onset epilepsy have been conducted. Dunn et al. (1997) investigated behavior problems in 42 children with new-onset seizures. Children were recruited into the study within 6 weeks of their initial seizure and parents were asked at the first interview (baseline) to rate their child's behavior in the 6-month period prior to the child's first recognized seizure. The children's behavior was rated a second time 4 months later (follow-up) by the same parent. Seizure severity at baseline was rated as high, moderate, or low based on type of seizure, duration of the initial seizure, additional number of seizures, and placement on medication. Mean scores were the highest at baseline for those children in the high seizure severity group. All three groups tended to improve from baseline to follow-up, and scores for those in the low and moderate seizure severity groups were near the population average. In contrast, even at follow-up the mean score for those in the high seizure severity group was approximately one-half standard deviation above the population mean. Although children with higher seizure severity had more behavior problems, it was not possible to separate out effects of seizures (either the length of the initial seizure or the number of repeated seizures) from other factors such as side effects of medication because the calculation
of the seizure severity score included seizure type and treatment with antiepileptic medication. As part of a larger prospective study Austin et al. (2001) continued to study behavior problems in children with first-recognized seizures. Recruitment of participants was within 6 weeks of the first recognized seizure. Data on behavior problems were collected four times: baseline, 6 months, 12 months, and 24 months. At each data collection point the major caregiving parent rated the child's behavior during the prior 6 months. Importantly, this included the baseline collection, when the parent rated the child's behavior during the 6 months prior to the child's first-recognized seizure. To control for family factors parents also rated the behavior of the sibling who was nearest in age to the child with the seizure. In this study parents also were systematically interviewed to determine if the child had had any prior seizure-like episodes that had not been recognized as such before the seizure that led to their being enrolled into the study. Parents of approximately one third of the children responded that their child had prior episodes that were most likely seizures. Parents' ratings showed higher than expected rates of behavior problems in the 6 months prior to the first-recognized seizure in the total seizure sample, with approximately one third being in the clinical or at-risk range (Austin et al., 2001). However, rates of behavior problems were highest in the group of children who had had prior seizures, with almost 40% being in the clinical or at-risk range. Children with no prior seizures had fewer behavior problems than children with prior unrecognized seizures. Comparisons with siblings showed the children with seizures to have more internalizing, attention, thought, and somatic complaint problems than their nearest-in-age healthy siblings (Austin et al., 2001). Interactions of previously unrecognized seizures with gender (boys were doing the worst) and seizure type (children with partial seizures were doing the worst) were also found. Because a limitation of most past research of behavior problems in this population is the reliance on parents' ratings of the children's behavior, ratings of the child in this study also were obtained from the child's teacher using the teacher's form of the CBCL (Teacher's Report Form, TRF, Achenbach, 1991b). Results were similar for teachers' ratings
423 of the children's behavior. The mean total behavior problem score was higher for children with prior seizures than for children without prior seizures. In comparison to children with no prior seizures, the children with prior seizures also had more problems in the area of internalizing, somatic complaints, anxious/depressed, thought problems, and attention problems (Dunn et al., 2002). A limitation of this study is that little information was obtained about the prior seizures. It is possible that some children had prior seizures that went unrecognized or that children who were thought to have prior seizures based on parents' descriptions did not have them. Differences in behavior problems between the prior and no-prior seizure groups also might be a result of children with prior unrecognized seizures having less involved parents than children whose seizures were recognized by their parents. The fact that baseline ratings of behavior were made for the period prior to the child being placed on medication substantially reduces the possibility that side effects of medication accounted for the behavior problems. In addition, the higher rates of problems in children who had prior unrecognized seizures also reduces the possibility that poor child and family adjustment to seizures accounted for the behavior problems. The higher rates of behavior problems in children with prior unrecognized seizures, however, might reflect that these children worried because they were aware that something was happening to them and no one was noticing it. Finally, a recent study of children having epilepsy surgery supports the link between removal of epileptic focus, seizure reduction, and changes in behavior problems. Lendt et al. (2000) found significant reductions in behavior problems within three months following epilepsy surgery in a study of children aged 4 to 16 years. Behavior problems were measured before and after surgery in 28 children who had pharmacoresistant focal epilepsy. The control group was a sample of 28 children with focal epilepsy who were conservatively treated with antiepileptic medication. The two groups did not differ on demographic variables (age, sex, or IQ), seizure characteristics (type or frequency), or on number of medications at baseline. Behavior problems were measured using parents' ratings on the Child Behavior Checklist (CBCL, Achenbach, 1991a). Baseline
CBCL scores did not significantly differ between the two groups. At the 3-month follow-up the surgical group had significantly lower internalizing problems, externalizing problems, thought problems, and attention problems than the control group. Within-group analyses showed that behavior problems improved in the surgery group and tended to become worse in the control group. Within the surgery group, greater improvements in the total behavior problem score from before to after surgery were strongly associated with greater reduction in seizures. These authors propose that the epileptic focus directly causes behavior problems. Limitations of the study include the lack of random assignment to surgery and control groups and the failure to consider any other psychosocial factors that might have been related to behavioral improvement. Although these authors did not address the possible effects of repeated seizures, findings suggest that behavior problems in epilepsy are linked to abnormal brain tissue and to electrical discharge. It is difficult to separate effects of seizures on behavior from the other causal factors in samples of children with chronic epilepsy. A stronger approach is to study children with new-onset seizures. Measuring the child's behavior prior to the firstrecognized seizure helps to control for the variables of poor parent response to the seizures and side effects of medication. Prospective studies of children with new-onset seizures are needed to identify if there are changes in behavior problems in children who have additional seizures.
Prospective study To explore further the effects of seizures on the development of behavior problems we conducted a prospective study of behavior problems in 212 children (ages 4-14 years) with new-onset seizures (Austin et al., 2002). Behavior problems were measured using the caregiving parent's ratings on the Child Behavior Checklist (CBCL, Achenbach, 1991a). The CBCL has 118 behavioral items on which parents rate how well the behavior describes their child's behavior on 3-point scales: 0 (not true), 1 (somewhat or sometimes true), and 2 (very true or often true). The scale yields a total behavior problem score as well as subscale scores that are normed
424 based on child age and gender; results for the total behavior problem scores will be discussed here. To reduce the possibility that parents might rate seizure activity as a behavior, parents were cautioned to not include any behaviors that might be seizures or related to seizures in their ratings. Data on behavior problems were collected four times: baseline, 6 months, 12 months, and 24 months. To help control for family environment factors parents also rated the behavior of the sibling (n = 135) who was nearest in age to the child with the seizure on the CBCL. Siblings were similar in age and gender to the child with the seizure. In an effort to reduce bias in parent ratings because they knew the child had had a seizure, the child's teacher also was asked to rate the child's behavior using the teacher's form of the CBCL (Teacher's Report Form, TRF, Achenbach, 1991b) three times: baseline, 12 months, and 24 months. Data were analyzed using descriptive statistics and two-sample t-tests. At the 24-month data collection period 117 children (55%) had no additional seizures and 95 (45%) had at least one additional seizure. At baseline, on average both groups of children had similar total behavior problems scores that were approximately onehalf standard deviation above the population mean. At the 24-month visit, the group without further seizures had decreased about 2 points on average, while children with at least one additional seizure over the 24-month period had stable mean behavior problem scores. Results were similar for teachers' ratings of the children's behavior. The consistency of findings between parents' and teachers' ratings of the children supports the validity of the parents' ratings. Score differences in behavioral problems between children with a first-recognized seizure and their healthy siblings were explored for the two seizure groups: those with additional seizures during the 24-month period and those who had no additional seizures. We hypothesized that, if seizures were affecting behavior, those who had additional seizures would show increasingly worse behavior problems compared to their siblings. Likewise, we hypothesized that those children who had no further seizures would show fewer differences from their siblings over the 24-month period. Although children with no additional seizures had more behavioral prob-
lems than their siblings throughout the whole study period, there was a tendency for the difference to decrease over time. In contrast, the group with at least one additional seizure had higher behavior problems scores than their healthy siblings throughout the 24month period and there was a tendency for this difference to increase. These results supported our hypotheses. In this prospective study of behavior problems in children with new-onset seizures there are two major findings that bear on our understanding of the possible effects of seizures on behavioral disruptions: (a) children who had additional seizures were found to have higher total behavior problem scores on average than children who did not have additional seizures, and (b) children who had additional seizures showed increasingly more behavior problems compared to their siblings than children who did not have additional seizures. Taken as a whole these findings show a positive association between the seizure occurrence and behavior problems. Even in this prospective study, however, it was not possible to isolate effects of the seizures from the other presumed causes. It is highly likely that children who have more severe neurological dysfunction also would be more likely to have additional seizures during the 2-year period than those with a less severe neurological dysfunction. Children who had additional seizures also might be more likely to have side effects of antiepileptic medication because they would more likely be on higher doses of medications compared to children who had no additional seizures. Compared to children who had no additional seizures those with additional seizures would have been more likely to be given the diagnosis of epilepsy. As a result, during this period these children and their families would be experiencing the ramifications of living with a chronic condition that has an associated stigma.
Transient cognitive impairment Aicardi (1996) suggests that epilepsy is more pervasive in some children and that both seizures and behavior problems are a manifestation of epilepsy. An explanation for the pattern of findings related to behavior problems in this prospective study is that of transient cognitive impairment (TCI) caused by sub-
425 clinical seizures. Interictal epileptiform discharges are proposed to lead to transient cognitive impairment, which in turn leads to changes in behavior (Aicardi, 1996). It is logical to propose that children who had additional seizures would be more likely to have interictal epileptiform discharges than children who did not have additional seizures. It might be that TCI is one mechanism through which subclinical interictal epileptiform discharges both influence behavior and lead to seizures. Because different causes will presumably have different treatments, it would be important to investigate if TCI leads to behavior problems. There is limited empirical support that episodes of TCI can influence behavior. Binnie (1993, 2001) proposes that episodes of TCI can adversely affect interpersonal interactions by causing the child to miss important cues during interactions with his or her peers. For example, if a child experiences interruptions in the flow of conversations because of TCIs, it could lead to the child failing to respond appropriately. There is some support for these hypotheses. During recording of abnormal discharges, impaired cognitive performance has been observed for neuropsychological skills such as abstract reasoning (Siebelink et al., 1988). Future research should investigate if TCI adversely affects behavior in children with seizures. If behavioral disruptions are found to be associated with TCI, then the effect of treating subclinical interictal epileptiform discharges with antiepileptic medication (Binnie, 2001) should be explored in future research. If future research supports this hypothesis, then treatment of seizures with antiepileptic medication or removal of epileptiform tissue might be considered. In one small study pharmaceutical treatment of children with subclinical seizures was shown to reduce electroencephalographic epileptiform abnormalities, which in turn resulted in improved cognitive and emotional-behavioral functioning (Marston et al., 1993).
Summary and conclusion There are four potential causal factors for the high rate of behavior problems found in children with epilepsy: (a) effect of seizures, (b) poor child and family response to the condition, (c) side effects of
antiepileptic medication, and (d) neurological dysfunction that causes both the seizures and the behavioral problems. Although cross-sectional studies of children with chronic epilepsy consistently show a link between seizure frequency and behavior problems, it is not possible to isolate effects of seizures from the other possible causes. Recent studies of children with new-onset seizures suggest that neither poor child and family response nor side effects of antiepileptic medication plays a major role in the development of behavior problems. Results from a prospective study in children with new-onset seizures show that children who had additional seizures over a 24-month period exhibit an increase in behavior problems. Separating effects of seizures from effects of neurological dysfunction on behavior problems, however, is not possible even in prospective studies of children with new-onset seizures. Transient cognitive impairment (TCI) from interictal epileptiform discharges is offered as one possible mechanism through which interictal epileptiform discharges can directly disrupt behavior. If behavior problems are caused by TCI in some children, then treatments that reduce these subclinical seizures should be investigated.
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An audit of pediatric epilepsy care. Arch. Dis. Child., 79: 145-148. Williams, J., Bates, S., Griebel, M.L., Lange, B., Mancias, P., Pihoker, C.M. and Dykkman, R. (1998) Does short-term antiepileptic drug treatment in children result in cognitive or behavioral changes?. Epilepsia, 39: 1064-1069.
CHAPTER 37
Progressive behavioral changes in children with epilepsy t Joan K. Austin 1,, and David W. D u n n 2 1 School of Nursing and 2 School of Medicine, Indiana University, 1111 Middle Drive, NU492, Indianapolis, IN 46202-5107, USA
Abstract: Children with epilepsy are known to have high rates of mental health problems. The role of seizures in the development of these problems is not known primarily because of difficulties in separating the effects of seizures from the three other potential causal factors: (a) poor child and family response to the condition, (b) side effects of antiepileptic medication, and (c) neurological dysfunction that causes both the seizures and the behavioral problems. Although cross-sectional studies focusing on children with chronic epilepsy show associations between behavior problems and each of these causal factors, it is not possible to isolate the effects of any one causal factor using this design. A stronger approach is to conduct prospective studies of children with new-onset seizures. Recent research on children with new-onset seizures suggests that side effects of antiepileptic medication and poor child and family response do not play major roles in the development of behavior problems. Results from a prospective study in children with new-onset seizures show an association between seizures and behavior problems. Separating effects of seizures from effects of neurological dysfunction on behavior problems, however, will be difficult even in prospective studies of children with new-onset seizures. Transient cognitive impairment (TCI) from interictal epileptiform discharges is proposed as an alternative explanation for behavior problems.
Introduction Children with epilepsy are known to have high rates of mental health problems such as anxiety, depression, attention problems, and behavioral disruptions (Hoare, 1984a; Ettinger et al., 1998; Dunn and Austin, 1999). They are almost 5 times more likely to have mental health problems than children from the general population (Rutter et al., 1970; McDermott et al., 1995). Moreover, children with epilepsy appear to differ even from other groups of chronically ill children in that they fare substantially worse psychologically. Although most research has *Correspondence to: J.K. Austin, Indiana University School of Nursing, 1111 Middle Drive, NU492, Indianapolis, IN 46202-5107, USA. Tel.: +1-317-274-8254; Fax: + 1-317-278-1811; E-mail: [email protected] Preparation of this paper was supported by grants PHS R01 NS22416 from the National Institute of Neurological Disorders and Stroke and PHS R01 NR04536 from the National Institute of Nursing Research to the first author.
been cross-sectional, there is evidence from studies in chronic childhood illness to suggest that children with epilepsy have both the risk associated with a chronic condition and the risk associated with a central nervous system disorder. The risk for psychiatric disorder appears to be about 2.5 times higher for children with epilepsy than for children with other physical disorders not involving the central nervous system. For example, in a major epidemiological study, Rutter et al. (1970) found the prevalence of behavior problems to be 6.6% in the general population, 11.6% in children with chronic conditions not involving the central nervous system, 28.6% in children with idiopathic epilepsy, 37.5% in children with neurological damage, and 58.3% in children with both neurological damage and seizures. These findings suggest that seizures somehow are related to the development of such problems. The role that seizures play in the development of behavioral problems is not known. A large number of cross-sectional studies have investigated the relationship between particular seizure variables and behav-
420 ioral problems. Seizure variables related to behavior problems include early age of onset, poor seizure control, long duration of epilepsy, high seizure frequency, and multiple seizure types (Hoare, 1984a; Austin, 1988; Hermann et al., 1989; Austin et al., 1994). The most consistent finding, however, has been a link between more frequent seizures and more mental health problems (Hartlage and Green, 1972; Hoare, 1984a; Austin, 1988; Hermann et al., 1989; Austin et al., 1992). The association between seizure frequency and mental health problems is unexpected because the relationship between frequency of symptoms and psychological functioning is generally weak in childhood chronic conditions (Drotar and Bush, 1985). However, studies by Austin and colleagues showed seizure frequency to be a significant predictor of behavior problems in children with epilepsy; in contrast, frequency of asthma attacks was unrelated to behavior problems in children with asthma (Austin et al., 1992, 1996). This association suggests that seizures might have an effect on behavior problems independent of disruptions from illness symptoms. It is difficult, however, to separate effects of seizures from other causal factors. In addition to seizures, three broad categories of variables have been identified as potential causes of these behavioral problems: (a) poor child and family response to the condition, (b) side effects of antiepileptic medications, and (c) neurological dysfunction that causes both the seizures and the behavioral problems. Moreover, there is substantial agreement that more than one factor contributes to the development of mental health problems and that these factors interact with each other, which further reduces the ability to isolate their respective effects. Empirical support for the association between each of these potential causal factors and behavior problems in children with epilepsy is briefly reviewed. In this paper there is a particular emphasis on the authors' work that is relevant to showing possible effects of seizures on behavior problems, including research in progress.
Poor child and family response Most past research focusing on child and family response has been based on the assumption that mental health problems in the child with epilepsy result
from difficulties inherent in living with a chronic condition. Some authors propose that a maladaprive family environment contributes to problems. For example, negative family responses to the epilepsy such as parental over-control and perceptions of stigma associated with the epilepsy are proposed to lead to behavior problems in children with epilepsy (Carlton-Ford et al., 1997). The few empirical studies exploring the relationship between family environment variables and behavior problems in children with epilepsy do show a relationship. For example, Hoare and Kerley (1991) found family stress and lower socioeconomic status to be associated with child behavior problems. Dunn et al. (1999) found child satisfaction with family relationships to be associated with depression in adolescents. The few studies on parenting support its relationships to mental health outcomes in children with epilepsy. Lothman et al. (1990) observed mother-child interactions and found parental praise to be related to child competence and child positive affect. In contrast, intrusive and over-controlling parenting behaviors were related to decreased autonomy and confidence in these children with epilepsy. Other studies showed that both family and seizure variables were significantly associated with child mental health problems. For example, Austin et al. (1992) found family variables (family stress and fewer family resources) and seizure variables (high seizure frequency) to be significant predictors of behavior problems. The cross-sectional nature of this past research, however, makes it difficult to determine if families are reacting to problems in the child, if the child is influenced by the parent's maladaptive response to the child's epilepsy, or if both the child and the family are coping poorly with the child's seizures. Recent studies suggest that both children with newonset seizures and their parents have many concerns and fears related to seizures. For example, Brown (1994) found that about one half of the children with seizures felt helpless, scared, and different from others. In another study parents were found to have many concerns and fears related to their child's seizures including death, brain damage, loss of intelligence, and the possible presence of a brain tumor (Shore et al., 1998). Recent studies of psychosocial care needs of children with new-onset seizures and
421 their parents showed that approximately one third to one half of parents were not satisfied with explanations about epilepsy given to them and desired more information (Shore et al., 1998; Webb et al., 1998). These findings suggest that new-onset seizures in children can be very stressful for both children and parents and that this stress could lead to maladaptive coping responses in both the child and the family. Moreover, it is logical to propose that more frequent seizures would lead to increased stress.
Side effects of antiepileptic medication The case that antiepileptic medications can lead to emotional and behavioral disorders in people with epilepsy has some empirical support (Reynolds, 1991), although it is likely that such effects are limited. Behavioral problems were associated with polypharmacy in a study by Hermann et al. (1989). In contrast, Austin et al. (1992) did not find polypharmacy to be significantly associated with behavior problems in a study of children with chronic epilepsy. Children treated with phenobarbital were described by Brent et al. (1990) to have depression and suicidal ideation. It is difficult to separate effects of seizures from side effects of antiepileptic medication in children with chronic epilepsy because children who have more seizures are more likely to be on either more medications or on higher doses of medications. Two approaches have been used to explore the role of side effects of medications in relation to behavior problems: measuring behavior before and after initiation of medications in children with newonset seizures and measuring behavior before and after withdrawal of medication in children whose seizures are well controlled. Both types of prospective studies have suggested that antiepileptic medications may have minimal effect on cognitive and behavioral functioning. For example, in a prospective study of children with recent onset seizures Mandelbaum and Burack (1997) found no significant deterioration over a 12-month period in cognitive and behavioral performance related to the initiation of antiepileptic medication. In a similar study Williams et al. (1998) also did not find significant differences in behavioral disruptions between children with newonset epilepsy and controls during the first 6 months
following initiation of antiepileptic medication. Similar results on cognition and behavior were found in two recent withdrawal studies. For example, out of eight areas studied for differences after drug withdrawal, children reported improvements only in the area of tiredness (Aldenkamp et al., 1998). In this same study parents reported improvements in areas of activation (e.g., alertness, drowsiness, and concentration disorders) but not in behavioral problems (e.g., depression and aggressiveness). In the second study focusing on six cognitive functioning areas only improvements in psychomotor speed could be attributed to antiepileptic drug withdrawal (Aldenkamp et al., 1993). In general, findings using either approach are consistent with the hypothesis that underlying neurological dysfunction might play a more important role in the development of behavior problems than do side effects from antiepileptic medications (Corbett et al., 1985; Mandelbaum and Burack, 1997).
Neurological dysfunction Some researchers have proposed that underlying neurological dysfunction causes both seizures and behavior problems. Support for this hypothesis comes from cross-sectional studies indicating that children with chronic neurological conditions have higher rates of behavior problems than children with chronic conditions that do not involve the brain (Breslau, 1985; Howe et al., 1993). For example, Austin et al. (1994)found children with epilepsy to have higher scores for both internalizing and externalizing behavior problems as measured by parents' ratings on the Child Behavior Checklist (CBCL, Achenbach, 1991a) than those with chronic asthma. Behavioral ratings in this study by teachers on the Teacher's Report Form of the CBCL (TRF, Achenbach, 1991b) also showed children with epilepsy to have higher rates of internalizing behavior problems than children with asthma. In addition, empirical studies show that children with epilepsy who have accompanying deficits in neurological functioning are at increased risk for poor mental health outcomes (Hermann, 1981, 1982; Rutter, 1981). The few available cross-sectional studies of children with new-onset seizures also indirectly suggest that underlying neurological dysfunction might play
422 an important role in the development of behavior problems. Hoare (1984a,b) investigated psychiatric disturbance across several groups of children, including those with new-onset epilepsy, new-onset diabetes, and controls. He found 45% of children with new-onset epilepsy to already have mental health problems. In contrast, only 17% of the children with new-onset diabetes and only 10% of controls were found to have mental health problems. Authors investigating the effects of initiating antiepileptic medications in children with new-onset epilepsy also have noted higher than expected rates of behavior problems in children. Stores et al. (1992) noted that children had behavior problems prior to medication treatment and hypothesized that these problems were due to the epileptic process. Williams et al. (1998) rated children's behavior problems on the day they were diagnosed with epilepsy, prior to initiation of antiepileptic medication, and found internalizing behavior problems to be substantially higher than norms. Only a few prospective studies of children with new-onset epilepsy have been conducted. Dunn et al. (1997) investigated behavior problems in 42 children with new-onset seizures. Children were recruited into the study within 6 weeks of their initial seizure and parents were asked at the first interview (baseline) to rate their child's behavior in the 6-month period prior to the child's first recognized seizure. The children's behavior was rated a second time 4 months later (follow-up) by the same parent. Seizure severity at baseline was rated as high, moderate, or low based on type of seizure, duration of the initial seizure, additional number of seizures, and placement on medication. Mean scores were the highest at baseline for those children in the high seizure severity group. All three groups tended to improve from baseline to follow-up, and scores for those in the low and moderate seizure severity groups were near the population average. In contrast, even at follow-up the mean score for those in the high seizure severity group was approximately one-half standard deviation above the population mean. Although children with higher seizure severity had more behavior problems, it was not possible to separate out effects of seizures (either the length of the initial seizure or the number of repeated seizures) from other factors such as side effects of medication because the calculation
of the seizure severity score included seizure type and treatment with antiepileptic medication. As part of a larger prospective study Austin et al. (2001) continued to study behavior problems in children with first-recognized seizures. Recruitment of participants was within 6 weeks of the first recognized seizure. Data on behavior problems were collected four times: baseline, 6 months, 12 months, and 24 months. At each data collection point the major caregiving parent rated the child's behavior during the prior 6 months. Importantly, this included the baseline collection, when the parent rated the child's behavior during the 6 months prior to the child's first-recognized seizure. To control for family factors parents also rated the behavior of the sibling who was nearest in age to the child with the seizure. In this study parents also were systematically interviewed to determine if the child had had any prior seizure-like episodes that had not been recognized as such before the seizure that led to their being enrolled into the study. Parents of approximately one third of the children responded that their child had prior episodes that were most likely seizures. Parents' ratings showed higher than expected rates of behavior problems in the 6 months prior to the first-recognized seizure in the total seizure sample, with approximately one third being in the clinical or at-risk range (Austin et al., 2001). However, rates of behavior problems were highest in the group of children who had had prior seizures, with almost 40% being in the clinical or at-risk range. Children with no prior seizures had fewer behavior problems than children with prior unrecognized seizures. Comparisons with siblings showed the children with seizures to have more internalizing, attention, thought, and somatic complaint problems than their nearest-in-age healthy siblings (Austin et al., 2001). Interactions of previously unrecognized seizures with gender (boys were doing the worst) and seizure type (children with partial seizures were doing the worst) were also found. Because a limitation of most past research of behavior problems in this population is the reliance on parents' ratings of the children's behavior, ratings of the child in this study also were obtained from the child's teacher using the teacher's form of the CBCL (Teacher's Report Form, TRF, Achenbach, 1991b). Results were similar for teachers' ratings
423 of the children's behavior. The mean total behavior problem score was higher for children with prior seizures than for children without prior seizures. In comparison to children with no prior seizures, the children with prior seizures also had more problems in the area of internalizing, somatic complaints, anxious/depressed, thought problems, and attention problems (Dunn et al., 2002). A limitation of this study is that little information was obtained about the prior seizures. It is possible that some children had prior seizures that went unrecognized or that children who were thought to have prior seizures based on parents' descriptions did not have them. Differences in behavior problems between the prior and no-prior seizure groups also might be a result of children with prior unrecognized seizures having less involved parents than children whose seizures were recognized by their parents. The fact that baseline ratings of behavior were made for the period prior to the child being placed on medication substantially reduces the possibility that side effects of medication accounted for the behavior problems. In addition, the higher rates of problems in children who had prior unrecognized seizures also reduces the possibility that poor child and family adjustment to seizures accounted for the behavior problems. The higher rates of behavior problems in children with prior unrecognized seizures, however, might reflect that these children worried because they were aware that something was happening to them and no one was noticing it. Finally, a recent study of children having epilepsy surgery supports the link between removal of epileptic focus, seizure reduction, and changes in behavior problems. Lendt et al. (2000) found significant reductions in behavior problems within three months following epilepsy surgery in a study of children aged 4 to 16 years. Behavior problems were measured before and after surgery in 28 children who had pharmacoresistant focal epilepsy. The control group was a sample of 28 children with focal epilepsy who were conservatively treated with antiepileptic medication. The two groups did not differ on demographic variables (age, sex, or IQ), seizure characteristics (type or frequency), or on number of medications at baseline. Behavior problems were measured using parents' ratings on the Child Behavior Checklist (CBCL, Achenbach, 1991a). Baseline
CBCL scores did not significantly differ between the two groups. At the 3-month follow-up the surgical group had significantly lower internalizing problems, externalizing problems, thought problems, and attention problems than the control group. Within-group analyses showed that behavior problems improved in the surgery group and tended to become worse in the control group. Within the surgery group, greater improvements in the total behavior problem score from before to after surgery were strongly associated with greater reduction in seizures. These authors propose that the epileptic focus directly causes behavior problems. Limitations of the study include the lack of random assignment to surgery and control groups and the failure to consider any other psychosocial factors that might have been related to behavioral improvement. Although these authors did not address the possible effects of repeated seizures, findings suggest that behavior problems in epilepsy are linked to abnormal brain tissue and to electrical discharge. It is difficult to separate effects of seizures on behavior from the other causal factors in samples of children with chronic epilepsy. A stronger approach is to study children with new-onset seizures. Measuring the child's behavior prior to the firstrecognized seizure helps to control for the variables of poor parent response to the seizures and side effects of medication. Prospective studies of children with new-onset seizures are needed to identify if there are changes in behavior problems in children who have additional seizures.
Prospective study To explore further the effects of seizures on the development of behavior problems we conducted a prospective study of behavior problems in 212 children (ages 4-14 years) with new-onset seizures (Austin et al., 2002). Behavior problems were measured using the caregiving parent's ratings on the Child Behavior Checklist (CBCL, Achenbach, 1991a). The CBCL has 118 behavioral items on which parents rate how well the behavior describes their child's behavior on 3-point scales: 0 (not true), 1 (somewhat or sometimes true), and 2 (very true or often true). The scale yields a total behavior problem score as well as subscale scores that are normed
424 based on child age and gender; results for the total behavior problem scores will be discussed here. To reduce the possibility that parents might rate seizure activity as a behavior, parents were cautioned to not include any behaviors that might be seizures or related to seizures in their ratings. Data on behavior problems were collected four times: baseline, 6 months, 12 months, and 24 months. To help control for family environment factors parents also rated the behavior of the sibling (n = 135) who was nearest in age to the child with the seizure on the CBCL. Siblings were similar in age and gender to the child with the seizure. In an effort to reduce bias in parent ratings because they knew the child had had a seizure, the child's teacher also was asked to rate the child's behavior using the teacher's form of the CBCL (Teacher's Report Form, TRF, Achenbach, 1991b) three times: baseline, 12 months, and 24 months. Data were analyzed using descriptive statistics and two-sample t-tests. At the 24-month data collection period 117 children (55%) had no additional seizures and 95 (45%) had at least one additional seizure. At baseline, on average both groups of children had similar total behavior problems scores that were approximately onehalf standard deviation above the population mean. At the 24-month visit, the group without further seizures had decreased about 2 points on average, while children with at least one additional seizure over the 24-month period had stable mean behavior problem scores. Results were similar for teachers' ratings of the children's behavior. The consistency of findings between parents' and teachers' ratings of the children supports the validity of the parents' ratings. Score differences in behavioral problems between children with a first-recognized seizure and their healthy siblings were explored for the two seizure groups: those with additional seizures during the 24-month period and those who had no additional seizures. We hypothesized that, if seizures were affecting behavior, those who had additional seizures would show increasingly worse behavior problems compared to their siblings. Likewise, we hypothesized that those children who had no further seizures would show fewer differences from their siblings over the 24-month period. Although children with no additional seizures had more behavioral prob-
lems than their siblings throughout the whole study period, there was a tendency for the difference to decrease over time. In contrast, the group with at least one additional seizure had higher behavior problems scores than their healthy siblings throughout the 24month period and there was a tendency for this difference to increase. These results supported our hypotheses. In this prospective study of behavior problems in children with new-onset seizures there are two major findings that bear on our understanding of the possible effects of seizures on behavioral disruptions: (a) children who had additional seizures were found to have higher total behavior problem scores on average than children who did not have additional seizures, and (b) children who had additional seizures showed increasingly more behavior problems compared to their siblings than children who did not have additional seizures. Taken as a whole these findings show a positive association between the seizure occurrence and behavior problems. Even in this prospective study, however, it was not possible to isolate effects of the seizures from the other presumed causes. It is highly likely that children who have more severe neurological dysfunction also would be more likely to have additional seizures during the 2-year period than those with a less severe neurological dysfunction. Children who had additional seizures also might be more likely to have side effects of antiepileptic medication because they would more likely be on higher doses of medications compared to children who had no additional seizures. Compared to children who had no additional seizures those with additional seizures would have been more likely to be given the diagnosis of epilepsy. As a result, during this period these children and their families would be experiencing the ramifications of living with a chronic condition that has an associated stigma.
Transient cognitive impairment Aicardi (1996) suggests that epilepsy is more pervasive in some children and that both seizures and behavior problems are a manifestation of epilepsy. An explanation for the pattern of findings related to behavior problems in this prospective study is that of transient cognitive impairment (TCI) caused by sub-
425 clinical seizures. Interictal epileptiform discharges are proposed to lead to transient cognitive impairment, which in turn leads to changes in behavior (Aicardi, 1996). It is logical to propose that children who had additional seizures would be more likely to have interictal epileptiform discharges than children who did not have additional seizures. It might be that TCI is one mechanism through which subclinical interictal epileptiform discharges both influence behavior and lead to seizures. Because different causes will presumably have different treatments, it would be important to investigate if TCI leads to behavior problems. There is limited empirical support that episodes of TCI can influence behavior. Binnie (1993, 2001) proposes that episodes of TCI can adversely affect interpersonal interactions by causing the child to miss important cues during interactions with his or her peers. For example, if a child experiences interruptions in the flow of conversations because of TCIs, it could lead to the child failing to respond appropriately. There is some support for these hypotheses. During recording of abnormal discharges, impaired cognitive performance has been observed for neuropsychological skills such as abstract reasoning (Siebelink et al., 1988). Future research should investigate if TCI adversely affects behavior in children with seizures. If behavioral disruptions are found to be associated with TCI, then the effect of treating subclinical interictal epileptiform discharges with antiepileptic medication (Binnie, 2001) should be explored in future research. If future research supports this hypothesis, then treatment of seizures with antiepileptic medication or removal of epileptiform tissue might be considered. In one small study pharmaceutical treatment of children with subclinical seizures was shown to reduce electroencephalographic epileptiform abnormalities, which in turn resulted in improved cognitive and emotional-behavioral functioning (Marston et al., 1993).
Summary and conclusion There are four potential causal factors for the high rate of behavior problems found in children with epilepsy: (a) effect of seizures, (b) poor child and family response to the condition, (c) side effects of
antiepileptic medication, and (d) neurological dysfunction that causes both the seizures and the behavioral problems. Although cross-sectional studies of children with chronic epilepsy consistently show a link between seizure frequency and behavior problems, it is not possible to isolate effects of seizures from the other possible causes. Recent studies of children with new-onset seizures suggest that neither poor child and family response nor side effects of antiepileptic medication plays a major role in the development of behavior problems. Results from a prospective study in children with new-onset seizures show that children who had additional seizures over a 24-month period exhibit an increase in behavior problems. Separating effects of seizures from effects of neurological dysfunction on behavior problems, however, is not possible even in prospective studies of children with new-onset seizures. Transient cognitive impairment (TCI) from interictal epileptiform discharges is offered as one possible mechanism through which interictal epileptiform discharges can directly disrupt behavior. If behavior problems are caused by TCI in some children, then treatments that reduce these subclinical seizures should be investigated.
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