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Summary: Purpose: ADHD is reported as a frequent comorbidity in pediatric epilepsy. We aimed to clarify the prevalence of ADHD, its neurological correlates and the role of ADHD in health-related quality of life (HRQOL) in children with severe epilepsy.
Method: Data from the ADHD Rating Scale-IV (ADHD-RS-IV) from 203 children (mean age = 11.8, SD = 3.8) from a tertiary center serving children with severe epilepsy were reviewed.
Results: Inattention was frequently elevated in the sample (40% vs. 18% for hyperactivity-impulsivity). Age of onset, epilepsy duration, and seizure frequency were not related to severity of inattention or hyperactivity-impulsivity. Over 60% of children met screening criteria for ADHD-Inattentive subtype (ADHD-I) or ADHD-Combined Inattentive/Hyperactive-Impulsive subtype (ADHD-C). Compared to ADHD-I, ADHD-C was associated with earlier onset of seizures, generalized epilepsy, lower adaptive level, and in normally developing children, a higher degree of intractability compared to ADHD-I. ADHD-I was more prevalent in localization-related epilepsy, and there was a trend for a higher use of AEDs with cognitive side effects in this group. ADHD was associated with poor HRQOL: children with ADHD-I and ADHD-C had a two- and four-fold likelihood of low HRQOL, respectively, compared to non-ADHD children.
Conclusions: Children seen at tertiary care centers for severe epilepsy are at high risk for attention problems and ADHD, and ADHD is a significant predictor of poor HRQOL in epilepsy, particularly in the case of ADHD-C. ADHD occurring in the context of severe epilepsy appears to be associated with specific neurological characteristics, which has implications for comorbidity models of ADHD and epilepsy.
The notion that many children with epilepsy present with symptoms of attention-deficit/hyperactivity disorder (ADHD) is not new. Over 50 years ago, Ounstead (1955) described a “hyperkinetic syndrome” in children with epilepsy that closely approximates our current definition of ADHD. Recent studies indicate that attention problems are frequently reported in children with severe variants of epilepsy such as intractable seizure disorders, cryptogenic epilepsy, and symptomatic epilepsy as well as in less severe conditions such as idiopathic epilepsy, well-controlled complex partial epilepsy, absence epilepsy and benign seizure disorders (Gaggero et al., 1992; Mitchell et al., 1992, Piccirilli et al., 1994; Struniolo and Galletti, 1994; Williams et al., 1996a, 1998; Slick et al., 2006). Although less studied, problems with impulsivity and behavioral dyscontrol in children with epilepsy have also been reported (Stores et al., 1978; Struniolo and Galletti, 1994; Slick et al., 2006).
There is compelling evidence that ADHD symptoms may in some cases predate the onset of epilepsy. A history of attention problems is twice as common in children seen after their first seizure versus controls (Austin et al., 2001), and community-based studies have indicated a 2.5-fold increase in preexisting ADHD, predominantly of the inattentive subtype, among children with new-onset seizures compared to control children (Hesdorffer et al., 2004). In tertiary care centers, ADHD is reported to be the most common disorder in children with epilepsy, affecting 31% of preschoolers and 63% of school-age children (Thome-Souza et al., 2004).
Increasingly, studies suggest that there is a difference between ADHD occurring in the general population (“Primary ADHD”) and ADHD occurring in the context of epilepsy. First, the rate of ADHD Combined subtype (ADHD-C), the ADHD subtype characterized by deficits in both impulse regulation and attention, far outstrips that of ADHD Predominantly Inattentive subtype (ADHD-I) in primary ADHD (Barkley, 2006). However, the pattern is reversed in epilepsy. Community-based studies indicate that ADHD-I is found more often than ADHD-C in children with new-onset seizures (Hesdorffer et al., 2004). Similarly, studies involving tertiary care samples indicate a prevalence of 24% of ADHD-I compared to 11% for ADHD-C in epilepsy (Dunn et al., 2003). Another difference is the gender ratio. In community-based studies involving primary ADHD, the prevalence of boys with ADHD is three to seven times greater than girls; the gender disparity is even greater in clinic-referred children, were five to nine boys are seen for every girl (Barkley, 2006). In contrast, most epilepsy samples are reported to have equal representation of boys and girls with ADHD (Dunn et al., 2003; Hesdorffer et al., 2004). There are nevertheless some similarities: ADHD symptoms tend to have an age-related expression, with fewer symptoms as children age, both in primary ADHD (Barkley, 2006) and in pediatric epilepsy (Thome-Souza et al., 2004). Barkley (2006) notes, however, that this may be a measurement artifact due to reduced sensitivity of clinical instruments to persisting symptoms over time.
One of the major differences between children with primary ADHD and children with epilepsy is that children with epilepsy face several epilepsy-specific neurologically based risk factors for attentional disturbance. These include interictal, ictal, and postictal effects, medication effects, cognitive problems secondary to underlying brain abnormalities, and long-term effects of repeated seizures (Williams et al., 1996b; Espie et al., 1999; Meador, 2002; Laporte et al., 2002; Binnie et al. 2003; Helmsteadter et al., 2003; Aldenkamp and Arends, 2004; Elger et al., 2004; see also Schubert, 2005; Dunn and Kronenberger, 2006). Certain epilepsy syndromes may also predispose to ADHD-like behavior; for instance, frontal lobe epilepsy (FLE) shares behavioral features with ADHD, presenting in some patients with impulsivity, disinhibition, and excitement/irritability (Delgado-Escueta et al., 1991; Powell et al., 1997). Nevertheless, seizure type and focus of seizure discharges are not clear predictors of ADHD symptoms (Dunn et al., 2003), although frontal EEG discharges may be associated with ADHD symptoms (Sherman et al., 2000). Some researchers have posited that ADHD-I and epilepsy may share a common underlying deficit in the central norepinephrine system (Hesdorffer et al., 2004), but the exact mechanism remains elusive.
Given our access to a large tertiary care sample of children with epilepsy, we aimed to further delineate the nature of ADHD in severe epilepsy, with the goal of determining (1) the prevalence of ADHD symptoms, (2) which neurological and epilepsy-related factors are related to ADHD symptoms, and (3) whether ADHD symptoms are associated with poor health-related quality of life (HRQOL) and restrictions in daily activities.
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There is a high prevalence of ADHD symptoms in children with epilepsy; this is particularly true of children seen at tertiary care centers (Thome-Souza et al., 2004). In our tertiary-center epilepsy sample characterized by early age of onset (< age 3), significant duration of epilepsy (>7 years), polytherapy, intractability (failure of > 2 AEDs), high seizure frequency (three per month), and low adaptive level, this was quite evident. Over 40% of children were rated as having significant attention deficits, and the proportion of children meeting screening criteria for either ADHD-C or ADHD-I was over 60%. This is consistent with previous tertiary-care sample estimates (Thome-Souza et al., 2004), far exceeding the rate reported in children at first seizure (Hesdorffer et al., 2004). Further, ADHD was associated with a two- to four-fold increased likelihood of poor HRQOL, indicating that ADHD symptoms have significant, real-world adverse implications for children with epilepsy and their families. These findings mirror reports of poor HRQOL in primary ADHD without epilepsy (Graetz et al., 2001; Klassen et al., 2004; Matza et al., 2004; Topolski et al., 2004; Escobar et al., 2005).
We found specific subgroup differences when comparing ADHD-I versus ADHD-C. Age at seizure onset was later in children with ADHD-I than in ADHD-C, and there was a trend for more ADHD-I children to be taking medications with possible cognitive side effects (i.e., benzodiazepines, topiramate, and phenobarbital) than children with ADHD-C. ADHD-I children were more likely to have localization-related epilepsy than generalized epilepsy, which was more common in ADHD-C. Children with ADHD-C were younger than those with ADHD-I, and when low functioning children were excluded, had more failed medication trials. Overall, ADHD-C was characterized by earlier onset of seizures, generalized epilepsy, lower adaptive level, and in developmentally normal children, a higher degree of intractability compared to ADHD-I. These findings suggest that ADHD-C in epilepsy may be a marker for severe epilepsy and/or severe brain dysfunction.
Notably, both ADHD subgroups had lower adaptive levels than children without ADHD, an association that is also reported in children with primary ADHD (Barkley, 2006). It is possible that the lower adaptive levels of children with ADHD and epilepsy reflect the adverse effect of inattention and impulsivity on acquiring the skills of daily living, or that ADHD symptoms and lower adaptive levels are manifestations of a common underlying brain dysfunction.
We found several discrepancies between the characteristics of children meeting criteria for ADHD in our epilepsy sample and the known characteristics of children with primary ADHD, recently reviewed and compiled by Barkley (2006; see Table 7). Most striking was the prominence of inattention as a core symptom in our epilepsy sample compared to longstanding research indicating that impulsivity and dyscontrol are core symptoms of primary ADHD, found more frequently and consistently than inattention symptoms and prominent even in children with mental retardation (Barkley, 2006; Hastings et al., 2005). Other differences such as gender distribution and subtype prevalence are listed in Table 7, including results from the small number of stimulant response studies in epilepsy (e.g., Gross-Tur et al., 1997; Gucuyener et al., 2003, and reviews by Dunn and Kronenberger, 2006, and Schubert, 2005).
Table 7. Summary of core characteristics of primary ADHD and ADHD in severe epilepsy
| ||Primary ADHD||ADHD in epilepsy|
|Age at onset of ADHD||Prior to age 7; likely to manifest in preschool||Unknown, but likely prior to seizure onset|
|Gender distribution||Large preponderance of boys||Equal representation of boys and girls|
|Symptom characteristics||Impulsivity/Hyperactivity is core symptom||Inattention more severe and frequent than impulsivity/hyperactivity|
|Subtypes||Majority ADHD-C; ADHD-I less frequent||Equal representation of ADHD-C and ADHD-I or higher prevalence of ADHD-I|
|Cognition (IQ)||Slightly below average or average||Low (tertiary care centers)|
|Age-related changes||Symptoms become less severe as children agea||Hyperactivity-Impulsivity dimension decreases with agea|
|Stimulant medication response||Good in ADHD-C; moderate in ADHD-I||Moderate; not well studied|
|Underlying mechanisms||Unknown; likely genetic||Unknown; likely multifactorial|
The findings raise interesting questions about (1) the underlying mechanisms of ADHD in the context of epilepsy, and (2) the degree to which ADHD occurring in epilepsy is the same diagnostic entity as primary ADHD as defined by the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV; American Psychiatric Association, 1994). Comorbidity is defined as two or more diseases with distinct etiologies, pathogenesis, and pathophysiology occurring in the same individual for a defined time period (Wittchen, 1996; Vella et al., 2000). While the characteristics of a disorder occurring alone and in the presence of a second, unrelated disorder may differ due to influence of the second disorder on the expression of the first disorder, one would not expect a disorder's phenotype to be radically changed when occurring in the context of a comorbidity. Our findings suggest that the characteristics of ADHD occurring in the context of severe epilepsy deviate from those expected in primary ADHD (Table 7). This raises an important question: does ADHD occurring in the context of severe epilepsy arise from the comorbidity of two etiologically distinct disorders, or is there something about severe epilepsy that predisposes to ADHD? One possibility is that ADHD occurring in the context of severe epilepsy is a neurologically based disorder arising from epilepsy-related factors, and is diagnostically distinct from primary ADHD (epilepsy-specific model). Alternatively, epilepsy and ADHD may be comorbid, etiologically distinct conditions, but severe epilepsy might change the expression, severity or clinical characteristics of primary ADHD to yield some of the differences evident in Table 7. Finally, children seen at tertiary centers could include a mix of children presenting with primary ADHD (comorbid cases) and others presenting with an epilepsy-specific disorder characterized primarily by severe difficulties with attention. Others have posited that in epilepsy, ADHD-C represents a true comborbidity, while ADHD-I occurring in the context of epilepsy reflects a common nervous system dysfunction (Noeker and Haverkamp, 2003). This is a plausible scenario, but the fact that ADHD-C in epilepsy was associated with early onset, intractability and low cognitive functioning in this study indicates that the co-occurrence of ADHD-C and epilepsy is unlikely to be completely accounted for by chance association. Instead, ADHD-C also appears to relate in a fundamental way to the underlying epilepsy disorder. The question remains as to whether using the ADHD label (or even the more specific ADHD-I or ADHD-C label) accurately describes the clinical characteristics of children with severe epilepsy, given the prominence of attention symptoms and the differences between ADHD with and without epilepsy. Further research, including population-based studies of ADHD in epilepsy, will be key in clarifying these issues.
Important caveats of this study methodology and sample must be addressed. First, a comprehensive assessment including psychiatric interview is necessary for making reliable ADHD diagnoses. Rating scales are one component of such an assessment, and when used for screening for ADHD yield overestimates of the true prevalence of the syndrome of primary ADHD; they are therefore useful for determining the upper bounds of ADHD prevalence rather than its true prevalence (Barkley, 2006). Determining the lower boundaries of ADHD prevalence requires targeted evaluation of symptom duration, age of onset, and degree of impairment secondary to ADHD symptoms to supplement the information provided by rating scales. Of note is the fact that diagnostic cutoff based on categorical boundaries do not inform on the proportion of children with milder but still impairing disturbances (e.g., subclinical or borderline cases).
The second limitation involves the use of a tertiary center study sample; a related point is that the sample originated from Neuropsychology referrals rather than from random cases. As noted in Participants, the majority of referrals were made on a routine basis for surgical work-up or follow-up, with only a minority of the group referred because of specific learning or behavioral issues. Because of the potential for ascertainment bias towards more severe ADHD symptoms in this minority (the assumption being that children with cognitive or behavioral symptoms would be more likely to be referred to Neuropsychology than those without), we compared this group's ADHD-RS-IV scores to the other referral groups, where referrals occurred on a routine basis (presurgical vs. postsurgical vs. general referrals); the group means were not significantly different. Thus, while the sample was not selectively biased towards cases with behavioral impairments because of selective referral to Neuropsychology, there is no doubt that it contained a higher number of children with severe cognitive and behavioral issues than would be expected in other settings, by virtue of being a sample of refractory epilepsy cases—the majority of which had been referred for additional surgical treatment because of repeated medication trial failures. A lower prevalence of attention problems would be expected in community samples or general clinic samples, as previous studies have found. While our results cannot be extended to other settings, the results provide important information for those working in tertiary care settings such as ours, and most specifically, to those working with children who have refractory epilepsy. Ideally, future studies would include the entire spectrum of children with epilepsy, including nonreferred children.
A third limitation is the use of parent ratings rather than teacher ratings or combined parent–teacher ratings. Barkley (2006) discusses the pros and cons of using different raters in screening for ADHD, and concludes that parent ratings are sufficient, in most cases, for diagnosing ADHD. Nevertheless, it will be important to replicate our results using teacher ratings, and determine whether parent–teacher agreement on ADHD symptoms in children with epilepsy mirrors that reported in general samples.
This study has significant clinical implications. Because ADHD is a treatable behavioral syndrome with effective pharmacological and behavioral therapies, a large number of children with epilepsy might potentially benefit from screening and medical intervention. To our knowledge, systematic screening of children for ADHD is rarely employed at epilepsy centers. This practice may need to be reconsidered in light of our findings and those of others (e.g., Thome-Souza et al., 2004). Screening and treatment of ADHD in pediatric epilepsy is particularly relevant given the association between ADHD symptoms and poor HRQOL.
Several avenues for future research remain, including whether there is a specific neuropsychological profile for children with ADHD in epilepsy, whether ADHD symptoms correlate with objective measures of attention and impulsivity in children with epilepsy, and delineation of other cognitive, neuropsychological, behavioral and psychosocial correlates of ADHD in epilepsy. Most importantly, research identifying specific antecedents of ADHD occurring in epilepsy is needed, given that ADHD symptoms in children with epilepsy are multifactorial and likely influenced by factors such as ictal effects, interictal disturbances, medications, and underlying brain abnormalities. Research on etiological subtypes in children presenting with ADHD symptoms and epilepsy, and on the relative importance of different etiological factors in ADHD subtypes are avenues of future research.