David W. Dunn and William G. Kronenberger
Children with epilepsy have substantially more problems with behavior and difficulties with school performance than siblings or normal population controls. Problems with attention and attention deficit hyperactivity disorder (ADHD) are found consistently in the evaluation of both emotional troubles and academic delays. In this chapter there are two primary questions. Is ADHD in epilepsy the expression of a neurological disorder? Is ADHD in epilepsy different from ADHD in children without epilepsy? In this chapter we will review studies of the prevalence of problems of attention in children with epilepsy and will explore possible reasons for difficulties with attention in this population. We also will address the controversy about the most appropriate treatment for the child with ADHD and epilepsy.
ADHD is one of the most extensively studied disorders in child and adolescent psychiatry. ADHD affects 4—12% of children and 3—5% of adults. The prevalence is higher in males with a range of ratios of 3:1 to 10:1, although the male-to-female ratio is smaller for ADHD, predominantly inattentive type. ADHD is classified as predominantly inattentive type if there are at least six symptoms of inattention but less than six symptoms of hyperactivity—impulsivity, predominantly hyperactive-impulsive type if there are six or more symptoms of hyperactivity and impulsivity and less than six symptoms of inattention, and combined type if there are six or more symptoms in each category. In clinical samples, ADHD, combined type is
Psychiatric Controversies in Epilepsy
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most common. ADHD is often comorbid with other conditions. In at least half of the children with ADHD, additional diagnoses of oppositional defiant disorder, conduct disorder, anxiety disorders, mood disorders, Tourette 's disorder, and/or learning disorder may be found.
ADHD is a familial disorder with an estimated heritability of 0.76 (Biederman and Faraone, 2005) . The genetic studies of ADHD suggest multiple genes conferring vulnerability for ADHD. Studies have particularly implicated dopamine receptor and dopamine transporter genes. Biological factors associated with ADHD are maternal smoking and alcohol use, prematurity, and fetal hypoxia. Neurological causes of ADHD include lead poisoning and traumatic brain injury. Psychosocial adversity may contribute to the severity of ADHD but does not seem to be a sole etiological factor.
Both the dopaminergic and the noradrenergic systems are involved in attention. Dopamine and norepinephrine influence working memory, and norepinephrine is important in orienting and vigilance. Vigilance and orienting are centered in the posterior cerebral cortex where the parietal lobe functions in disengagement and the superior colliculi in directing attention to a new stimulus. The anterior cingulate cortex, orbitofrontal cortex, and prefrontal cortex play a critical role in executive function. The cerebellar vermis may also influence attention.
Imaging studies in ADHD have shown abnormalities in multiple areas of the central nervous system (CNS). The most consistent findings are reduction in the volume of the dorsolateral prefrontal cortex, caudate, and cerebellum (Castellanos, 2001). One longitudinal study found enlargement of the lateral ventricles, decreased volume of the cerebral and cerebellar volumes, and smaller caudate volumes early but not later in adolescence (Castellanos et al., 2002). Functional magnetic imaging and proton magnetic imaging have demonstrated reduced metabolism in the prefrontal cortex, more in the nondominant side.
Recent treatment algorithms of ADHD suggest starting with stimulant medication (Biederman and Faraone, 2005' Pliszka et al., 2006) . This is based on the impressive effect size (0.91—0.095) for stimulant medication. Atomoxetine is also effective with an effect size of 0.6—0.7. Other agents that may be effective are bupropion, modafinil, tricyclic antidepressants, risperidone, the alpha-2 agonists and monoamine oxidase (MAO) inhibitors.
If ADHD in children with epilepsy is the same as ADHD in children without epilepsy, there should be a higher rate of ADHD in boys with epilepsy compared to girls with epilepsy. Here the data are not consistent. Two older studies found more inattention and hyperkinetic behavior in boys with epilepsy than in girls (Ounsted, 1955 ' Stores et al., 1978). In one, the sample seemed to fit ADHD plus oppositional disorder or conduct disorder or possibly early onset juvenile bipolar disorder. In contrast, three recent studies found no gender difference (Dunn et al, 2003 ; Hesdorffer et al, 2004; Gonzalez-Heydrich et al, 2007). These three recent studies used standardized testing and DSM criteria for the diagnosis of ADHD. The evidence from these studies suggests that ADHD in children with epilepsy differs from that seen in the typical psychiatric clinic sample.
PREVALENCE OF ATTENTION PROBLEMS AND ADHD IN EPILEPSY SAMPLES
The prevalence figures for ADHD or problems with attention in children with epilepsy can be used to compare children with epilepsy to those with ADHD without epilepsy. These prevalence rates also may help determine etiological factors for ADHD in children with epilepsy. If ADHD is found more often in subgroups of children with epilepsy, this may suggest possible causes for problems with attention.
Prevalence rates for ADHD in children with epilepsy vary widely from 0% to 77%. Variations in prevalence may be partially the results of differences in measures of ADHD or may be the result of assessing different samples of children with epilepsy. Several studies reported symptoms of inattention, hyperactivity, or impul-sivity without using Diagnostic and Statistical Manual (DSM) criteria. In a population-based survey, 28.1% of children with epilepsy were described as hyperactive and 39% as impulsive compared to 4.9% and 11% of normal population controls (Carlton-Ford et al, 1995 ; McDermott et al, 1995) . Teachers reported inattention in 42% of children with epilepsy in the report by Holdsworth and Whitmore (1974) and inattention or hyperactivity in 58% of the children described by Sturniolo and Galletti (1994).
In general, those studies that utilized standard measures found slightly lower rates. Reviewing 15 studies of ADHD in children or adolescents with epilepsy, we found prevalence rates from 0% to 50%. In three studies, prevalence rates were less than 20% (Ounsted, 1955 ) Davies et al, 2003) Freilinger et al, 2006), two were 20-30% (Thome-Souza et al.) 2004; Keene et al.) 2005), five were 30-40% (Hoare and Mann, 1994) Hempel et al, 1995 ; Semrud-Clikeman and Wical, 1999 ) McCusker et al, 2002) Dunn et al., 2003), and two were higher than 40% (Salpekar et al, 2005) Hanssen and Bauer et al, 2007). Two studies described change over time. Williams e t al. (2002a) noted rates dropping from 31% to 21-24% and Borgatti et al. (2004) found rates increasing 21-42%. Though not all studies used impairment criteria, the more common prevalence figures of 30-40% are 3-4 times higher than rates found in the general population, again suggesting a difference in the ADHD found in children with epilepsy compared to that found in the general population.
Children with ADHD without epilepsy are more likely to have ADHD, combined type. ADHD, predominantly hyperactive-impulsive type is least common. ADHD, predominantly inattentive type, is seen more in population studies than clinical samples and may be more prevalent in girls with ADHD (Biederman and
Faraone, 2005) . Separation of ADHD in subtypes occurs infrequently in studies of children with epilepsy. Dunn et al. (2003) found a prevalence of 37.7% for ADHD in a clinical sample of children with epilepsy. They reported ADHD, combined type in 11.4%, ADHD, predominantly inattentive type in 24%, and ADHD, predominantly hyperactive—impulsive type in 2.4%. Williams et al. (2002a) noted inattention in 31% and hyperactivity—impulsivity in 31% of children with epilepsy at baseline. At follow up, a mean of 7 months later, 27% had inattention and 24% hyperactivity—impulsivity. Gonzalez-Heydrich et al. (2007) found more ADHD, combined type (58%) than ADHD, predominantly inattentive type (42%) in their clinical sample of children with epilepsy. They noted that the sample was drawn from a medication trial for ADHD in children with epilepsy and may have been biased toward patients with the more disruptive symptoms of hyperactivity and impulsivity. The reports by Dunn et al. (2003) and Williams et al. (2002a) suggest that the inattentive form of ADHD is more common in children with epilepsy than seen in children without seizures, but the report by Gonzalez-Heydrich et al. (2007) finds similar distributions of subtypes of ADHD. More research is needed before definite conclusions can be made.
Comorbidity in children with ADHD without epilepsy is common. However, only two groups have specifically commented on additional disorders in children with epilepsy and ADHD. Caplan et al. (2004) reported ADHD plus other disruptive behavior disorders in 17% of children with complex partial seizures compared to 6% of controls. In addition, they found ADHD with comorbid anxiety or depressive disorders in another 23% of children with epilepsy compared to 3% of controls. Gonzalez-Heydrich et al. (2007) found a comorbid condition in 67% of children with epilepsy and ADHD. They noted an anxiety disorder in 36% and oppositional defiant disorder in 31%. Though the data are limited, the rate of comorbid psychiatric conditions in children with epilepsy and ADHD is similar to the rate seen in children with ADHD without epilepsy.
Neuropsychological deficits are common in both groups of children. Sánchez-Carpintero and Neville (2003) ) in a review of attention in children with epilepsy, found consistent abnormalities in sustained attention and some evidence of deficits in divided attention. Selective attention was less often impaired. Widespread deficits in executive function have been found by H0ie et al. (2006) in children with epilepsy. Impairment was found in children with all epilepsy syndromes except benign childhood epilepsy with centrotemporal spikes. No differences have been reported in the neuropsychological assessments of children with epilepsy and ADHD compared to children with ADHD alone.
The risk factors for psychopathology in children with epilepsy can be divided into three major categories-neurological problems, seizure-related problems, and psychosocial problems. CNS problems in addition to epilepsy significantly increase the risk of behavioral problems. This has been shown by epidemiological studies that find children with complicated epilepsy to have twice the rate of behavioral problems seen in children with uncomplicated seizures. Seizure-related variables are age of onset, duration of epilepsy, recurrent seizures, and antiepileptic drugs (AEDs). Psychosocial variables are family functioning and child attitude toward illness. These same risk factors may be important in ADHD in children with epilepsy.
The association of neurological factors with ADHD in children with epilepsy has been shown by the increased risk of ADHD in children with complicated epilepsy compared to those with uncomplicated seizures. Davies et al. (2003) found a prevalence of ADHD of 12% in children with complicated epilepsy compared to none in children with uncomplicated seizures. The study with the highest reported rate of hyperactivity (77%) was completed in children with intractable epileptic encephalopathies (Ferrie et al., 1997) . In contrast, the prevalence of ADHD in children with epilepsy and intellectual disability (mental retardation) is not higher than found in children with normal intelligence. Steffenburg et al. (1996) noted ADHD in 7% of children with epilepsy and intellectual disability and Thome-Souza et al. (2004) found ADHD in 44% of children with epilepsy and IQ <70 compared to 56% in children with IQ >70. The lower rate of ADHD in the population of children with epilepsy and intellectual disability may be due to the presence of more autistic disorders that normally preclude the diagnosis of ADHD. There are few data on the association of an abnormal neurological examination or abnormalities on neuroimaging with ADHD in children with epilepsy. Williams et al. (2002a) did find that normal magnetic resonance imaging (MRI) was associated with fewer symptoms of ADHD on follow up examination.
Another way of assessing the role of neurological factors is to evaluate children with new-onset seizures. Problems present at the time of a first seizure could not be attributed to recurrent seizures, AEDs, or the psychosocial stresses of epilepsy. Instead, they are more likely secondary to a common underlying neurological dysfunction that causes both seizures and attention deficits. Three studies have in part shown increased rates of ADHD in children with new-onset seizures. In a population-based study, Hesdorffer et al. (2004) found an association of the inattentive form of ADHD with new-onset seizures. The history of ADHD, predominantly inattentive type was 2.5-fold more common in children with seizures than in controls. In contrast, the increased risk of seizures was not seen in those with ADHD, combined type. Similarly, Austin et al. (2001), in a study of children with first recognized seizures, used the CBCL to assess behavior in the 6 months prior to the first recognized seizures. They divided the seizure group into those with prior unrecognized seizures and those with no prior seizures. They found more elevated attention problems scores in children with new-onset seizures than seen in sibling controls. The prevalence of children in the clinical range for attention problems was 15.8% in the children with prior unrecognized seizures, 8.1% in those with apparently true new-onset seizures, and 2.2—3.4% in siblings. In contrast, Oostrom et al. (2002) found only partial differences between children with new-onset seizures and controls. When compared to controls, the children with new-onset epilepsy had more errors on a reaction time measure and more errors of omission on a sustained attention task, but execution time and motor speeds were not different.
Seizure-related factors also may be important. Imaging studies in children with ADHD without epilepsy would suggest that children with an epileptic focus in the frontal cortex are at greater risk. However, seizure type and seizure focus have not been consistently associated with ADHD in children with epilepsy. Small case series of children with frontal lobe epilepsy have noted frequent symptoms of ADHD but in another case series, children with generalized seizures were more likely to have symptoms of ADHD than those with focal seizures (Hempel et al, 1995 ) Sherman et al, 2000) Hernandez et al, 2003). There were no significant differences by seizure type or focus in the children reported by Bennett-Levy and Stores (1984) ) Carlton-Ford et al. (1995) ) Williams et al. (2002a)) or Dunn et al. (2003). Studies of children with benign focal epilepsy with centrotemporal spikes have found more attention problems in the children with bilateral or right-sided temporal spikes (Piccirilli et al, 1994).
Some authors have suggested that transient cognitive impairment may occur in children with epileptiform discharges not associated with seizures. However, Pressler et al. (2005) were only able to demonstrate general improvement in behavior after reduction of spike number, not specific improvement in attention. In a very well-controlled study, Aldenkamp and Arends (2004) used video-EEG monitoring during neuropsychological testing to evaluate the effect of seizure discharges and seizures on attention and processing speed. They found that non-convulsive seizures were associated with impaired attention and slow processing speed and frequent epileptiform discharges with slow processing speed. Additional support for the importance of seizure-related factors comes from the new-onset study of Austin et al. (2001). They found that, at the time of initial diagnosis, the children with prior unrecognized seizures had almost twice the rate of problems with attention as the children with true first seizures.
Children with recurrent seizures may be at increased risk for ADHD compared to those with controlled seizures. Hermann et al. (1989) found that in girls, intractable epilepsy was associated with hyperactivity. McCusker et al. (2002) found an association between ADHD and seizure frequency.
Treatment of seizures can contribute to symptoms of ADHD (Kwan and Brodie, 2001) Bourgeois, 2004. Loring and Meador, 2004) . Problems with attention and hyperactivity have occurred most commonly with the barbiturates and, to a lesser extent, with phenytoin, carbamazepine, and valproic acid. Of the newer AEDs, topiramate has been associated with impaired attention as well as language difficulties. Hyperactivity was reported as a side effect of gabapentin in children with developmental delay and epilepsy. Hyperactivity has been seen with vigabatrin.
Psychosocial factors have not been implicated in the etiology of ADHD, but may contribute to the severity of symptoms. In children with epilepsy, psychosocial factors have been associated with symptoms of ADHD. McDermott et al. (1995) found that hyperactivity was associated with poverty and urban residence. Carlton-Ford et al. (1995) noted that the association between impulsivity and epilepsy was eliminated after controlling for learning disability and family processes. McCusker et al. (2002) reported an association between both family cohesion and family conflict and ADHD in children with intractable epilepsy. Oostrom et al. (2002) described a stronger association of attention problems with family factors than seizure variables.
Problems with attention in children with epilepsy do not appear to be a nonspecific reaction to a chronic illness. Rodenburg et al. (2005) in a recent meta-analysis of 46 studies of behavioral problems in children with epilepsy found that attention problems, thought problems, and social problems were more specific to epilepsy, whereas depression, withdrawn behavior, somatic complaints, and aggressive behavior were a more generic response to chronic illness. They found smaller effect sizes when comparing children with epilepsy to siblings. They suggested that family factors may be more related to behavior problems in general than specifically to attention, thought, or social problems in children with epilepsy.
Treatment of problems of attention in children with epilepsy
Is treatment of ADHD in children with epilepsy different from treatment in children without epilepsy? Pharmacological treatment of ADHD in children without epilepsy starts with stimulant medication. If stimulants are not effective or cause side effects, next choices are atomoxetine, antidepressants such as bupropion or tricyclic antidepressants, and adrenergic agents such as clonidine and guanfacine.
In children with epilepsy, stimulants may be more problematic. In the product information from the pharmaceutical companies there are warnings against the use of stimulants in patients with seizures. Presumably there may be lowering of the seizure threshold with the use of stimulant medication. The data to support this concern are limited. Feldman et al. (1989) treated children with ADHD and well-controlled epilepsy with methylphenidate 0.3 mg/kg/dose and found improvement in attention without adverse effect on seizure control. Gross-Tsur et al. (1997) found that children with ADHD and controlled seizures had no breakthrough seizures when treated with methylphenidate 0.3 mg/kg/day for 2 months. In the small group with active seizures, 2 improved and 3 experienced worsening seizure control. Gucuyener et al. (2003) noted no new seizures in 62 children with ADHD and an abnormal EEG that were treated with methylphenidate for 12 months and no increase in mean seizure frequency in the 57 children with ADHD and epilepsy that received methylphenidate 0.3—1 mg/kg/day. In this second group, 5 of 57 had an increase in seizure frequency. The data seem to suggest that stimulants are safe and effective in children with controlled seizures and probably though less definitely safe in those with active seizures.
The response of children with epilepsy and ADHD may be different from that seen in children with ADHD alone. Though children with epilepsy and ADHD respond to stimulant medication, stimulants seem to be less efficacious in these children. Semrud-Clikeman and Wical (1999) treated children with complex partial seizures and ADHD and children with ADHD alone with methylphenidate. On a computer performance task, the children with ADHD alone normalized after methylphenidate whereas the children with epilepsy and ADHD improved from 3.5 standard deviations below normal to 1.5 standard deviations below normal. Gonzalez-Heydrich et al. (2004) found that 63% of children with epilepsy responded to methylphenidate and 24% to amphetamine preparations.
Atomoxetine is often employed if stimulants are not effective or cause unacceptable side effects. Atomoxetine is a norepinephrine reuptake inhibitor that is effective in the treatment of ADHD. It has not been extensively studied in children with epilepsy. Hernández and Barragán (2005) used atomoxetine in 17 children with epilepsy and ADHD and found an improvement in symptoms of ADHD without an increase in seizure frequency. In a review of the clinical trials of atomoxetine, Wernicke et al. (2006) found that new-onset seizures occurred at a rate of 2/1,000/year. Assessing the reports for new seizures after the introduction of atomoxetine on the market, they found a rate of new seizures of 8.2/100,000, which is below expected incidence rates.
In children with ADHD without epilepsy, bupropion and tricyclic antidepressants are used as alternative agents. However, both bupropion and the tricyclic antidepressants may be problematic in children with epilepsy. Bupropion carries a high relative risk for seizures at high does and an intermediate risk at moderate or low doses. The tricyclic antidepressants have an intermediate risk at moderate to high dose (Alldredge, 1999) . Drug interactions between valproic acid and tri-cyclics may lead to elevated serum levels of tricyclic antidepressants and interaction between barbiturates, phenytoin, and carbamazepine and tricyclics may cause decreased serum levels of tricyclics.
Is there sufficient evidence to conclude that the co-occurrence of ADHD and epilepsy exceeds that expected by chance and that the co-occurrence of these disorders is not an artifact of measurement? Many studies of ADHD and epilepsy are based on clinical samples from comprehensive epilepsy centers. There could be a referral bias with those children having both epilepsy and psychiatric problems seen in these clinics. Though the lack of ADHD in the epidemiological study of Davies et al. (2003) might suggest this is the case, the population-based surveys reported by Carlton-Ford et al. (1995) and McDermott et al. (1995) and the community series by Austin et al. (2001) show the increased prevalence of ADHD in children with epilepsy is not the result of a referral bias.
Could the comorbidity be an artifact of measurement? If problems with attention are an ictal manifestation of seizures or occur only as a side effect of medication there would be no reason to consider epilepsy and ADHD comorbid conditions. Here the evidence for true comorbidity seems strong. Problems with attention have been documented at the onset of epilepsy prior to adverse effects of recurrent seizures and before the introduction of AEDs. In addition, Williams et al. (2002b) have demonstrated differences in symptoms when comparing ADHD ratings in children with absence seizures to those in children with ADHD.
A final question is more difficult to answer. Is the co-occurrence of ADHD and epilepsy an example of a common syndrome complex with both disorders sharing a genetic or biologic cause or does one disorder predispose or provoke the other? Hesdorffer et al. (2004) hypothesized a common underlying etiology suggesting a possible common dysfunction in the central norepinephrine system. The increased risk of ADHD in children with additional neurological disturbance would favor a common underlying cause for both disorders. The increased rate of epileptiform abnormalities on EEGs in children with ADHD also is evidence for a common underlying condition. In contrast, the prominence of inattentive symptoms might suggest that seizures and AEDs adversely affect neuropsychologi-cal functioning resulting in symptoms of ADHD (Noeker and Haverkamp, 2003). It may be that just as epilepsy is a heterogeneous condition, ADHD and epilepsy may be the results of multiple causes that vary by the individual patient.
ADHD in children with epilepsy is more common than ADHD in the general population. There do seem to be significant differences between ADHD and epilepsy and ADHD alone. Comparing ADHD with epilepsy to ADHD alone, there does not seem to be gender differences, symptoms of inattention appear to be more common, and the response to stimulant medication is less robust. The presence of symptoms of ADHD prior to or at the onset of epilepsy and the increased prevalence in children with epilepsy and additional CNS dysfunction suggests a common underlying etiology. However, the association of ADHD with prior unrecognized seizures, more frequent seizures, and AED adverse effects suggest that seizure-related factors contribute to the presence or severity of symptoms of ADHD. Appropriate treatment should begin with assessment of seizure control and AEDs followed by pharmacotherapy with stimulants or atomoxetine.
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