Epilepsy and Intellectual and Developmental Disabilities

Epilepsy and Intellectual and DevelopmentalDisabilitiesHirokazu OguniDepartment of Pediatrics, Tokyo Women’s Medical University, Tokyo, Japan

Abstract The co-occurrence of epilepsy in people with intellectual disabilities (ID) and other developmental disabilities (DD) hasreceived attention because it has a significant negative impact on health, well-being, and quality of life. The current research inves-tigating the frequency and form of epilepsy in children with ID and DD is reviewed, with particular attention is paid to childrenpresenting with coexisting autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Complications inassessment and treatment arising from comorbidities are considered. The most recent and epidemiological survey of children withepilepsy demonstrates that approximately one-fourth of patients with childhood epilepsy had ID. The prevalence of DD (includingADHD and ASD) in children with epilepsy ranges from 7.1% to 32%, which exceeds that of the general population. Multiple studieshave suggested that ADHD in children with epilepsy is largely comorbid rather than cause and effect because it is already presentbefore the onset of epilepsy in 80% of these children. However, the co-occurrence of epilepsy and ASDs is frequent in people withknown organic brain disorders, in which several causal relationships have been speculated. Recent studies have shown that theseverity of ID is an important factor in determining the incidence of epilepsy complications in those with ASD, and also the inci-dence of ASD complications in those with epilepsy. The co-occurrence of epilepsy, ID, and DD appears common. ID might play akey role in increasing the burden of epilepsy, as well as DD comorbidity. The comorbidity of ID and DD in patients with epilepsymight reduce the seizure threshold, resulting in an increase in the frequency of seizures as well as epileptiform electroencephalo-graphic abnormalities, although evidence is limited and further investigations are warranted.

Keywords: comorbidity, developmental disability, epilepsy, intellectual disability, seizures

INTRODUCTION

The prognosis of childhood epilepsy is generally favorablebecause approximately 64% of patients enter remission inadulthood (Guerrini, 2006). However, children with epilepsy as agroup are at higher risk of poor academic functioning and nega-tive psychosocial outcomes (Baca, Vickrey, Caplan, Vassar, &Berg, 2011; Sillanpaa, 2004; Sillanpaa, Jalava, Kaleva, & Shinnar,1998). Although the co-occurrence of epilepsy and intellectual(ID) and developmental disability (DD) is well known, researchto explore the causal relationship of each condition has not beenperformed until recently. Epidemiologically, 5–10% of individu-als with epilepsy suffer from ID and DD. On the other hand, epi-lepsy is generally prevalent in 5–10% of people with ID, and10–50% of those with autism (Robinson, 2012). Although the

incidence of these co-occurrences is higher than the generalpopulation, the causal relationship has been speculated to beheterogeneous, similar to the etiology of these disorders.

Studies on children with epilepsy encountered many difficul-ties in obtaining precise neuropsychological informationbecause of the lack of appropriate methodology to explore cog-nitive functions. However, the number of studies investigatingthe cognitive and behavioral functions of children with epilepsy,to explore the causal relationship among the three conditionsin children, have increased because of methodological advances(Berg, Plioplys, & Tuchman, 2011; Berg, Zelko, Levy, & Testa,2012; Braakman et al., 2012; Clarke et al., 2005; Giannotti et al.,2008). In addition, several special types of epileptic syndromescarrying specific gene mutations were found to have both epi-lepsy and autism spectrum disorders (ASD), which providessome clue to understanding the biological mechanism of thecausal relationship (Han et al., 2012). In the present study, recentprogresses in research on the co-occurrence of epilepsy, and IDand DD were examined from the standpoint of epilepsy.

EPILEPSY AND ID

The co-occurrence of epilepsy and ID has been well studiedin the past. Most of the results obtained have been inconclusive;

Received April 8, 2013; accepted April 11, 2013Correspondence: Hirokazu Oguni, MD, Department of Pediatrics, TokyoWomen’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162,Japan. Tel: +81 3 3353 8111; Fax: +81 3 5269 7338; E-mail:hoguni@ped.twmu.ac.jpNote: This article is drawn from one of a series of invited addresses presentedat the Asia-Pacific IASIDD 3rd Regional Conference in Tokyo, Japan, July22–24, 2013. Dr. Oguni is a professor of paediatrics in the Department ofPaediatrics at the Tokyo Women’s Medical University in Tokyo, Japan and amember of the International League Against Epilepsy.

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one study showed that the mean intelligence quotient (IQ) levelwas not significantly different between people with and withoutepilepsy, while another study either showed the mean IQ levelwas lower or higher in people with epilepsy than in thosewithout. The reasons for these different results were attributed tothe different methodologies used in the study design. Bourgeois,Prensky, Palkes, Talent, and Busch (1983) longitudinally fol-lowed the IQ scores of children with epilepsy as well as theirsiblings without epilepsy from the onset of epilepsy, and demon-strated that IQ scores were not significantly different betweenprobands and their siblings. Only 11.1% of these patientsshowed deterioration in IQ of more than 10 points. Thesepatients had an earlier onset age of epilepsy, more resistantseizure problems, and toxic levels of antiepileptic drugs thanthose without a deterioration in IQ. In summary, they concludedthat the cognitive deteriorations observed in children with epi-lepsy were associated with these risk factors.

The most recent and epidemiological survey on childrenwith epilepsy demonstrated that approximately one-fourth ofpatients with childhood epilepsy had ID, while ID and DDwere prevalent in 5% of the general pediatric population (Berget al., 2004). If children with epilepsy and underlying organicdisorders were excluded, the prevalence of ID increased up to15.2% (Berg et al., 2011). In addition, ID was shown to bemore prevalent in children with epilepsy who first developedseizures younger than the school-age-period because they weremore likely to have pharmaco-resistant seizures than those whodeveloped seizures at a later age. Thus, children with epilepsyare at increased risk of developing ID when they have underly-ing organic disorders or pharmaco-resistant seizures from thepreschool-age-period (Berg et al., 2012). Patients with intrac-table epilepsy during infancy and early childhood largely sufferfrom epileptic encephalopathy defined as “epileptic activityitself may contribute to severe cognitive and behavioral impair-ments above and beyond that expected from the underlyingpathology alone” (Berg et al., 2010). West syndrome is the mostrepresentative example, causing not only severe cognitiveimpairment, but also prominent autistic features. Therefore, theearlier the onset of intractable epilepsy, the more significant theadverse effects are on cognitive and behavioral functionsbecause epileptic activity has a more significant effect on thedeveloping brain during infancy and early childhood.

EPILEPSY AND DEVELOPMENTAL(BEHAVIORAL) DISABILITY

ADHD and ASD are the most common DD in children.There is global concern that the incidence of DD may increase inthe general population, although this may be an operational esti-mate because of changes in widening diagnostic criteria andincreased recognition or awareness of ASD. The causes of theco-occurrence of epilepsy and DD have been speculated to beeither due to (1) cerebral dysfunction related to the epilepticfocus (i.e., frontal lobe and temporal lobe dysfunctions inpatients with frontal lobe and temporal lobe epilepsies,respectively) (Braakman et al., 2012), (2) secondary cerebraldysfunctions due to epileptic seizures or epileptic electroence-

phalographic (EEG) discharges (Seegmuller et al., 2012), or (3)cognitive impairment due to the adverse effects of antiepilepticdrugs (Bourgeois et al., 1983). However, recent studies have sug-gested the importance of the neurodevelopmental aspects of DDsharing an underlying mechanism with epilepsy.

EPILEPSY AND ADHD

Multiple studies have reported that the prevalence of ADHDis significantly high in children with epilepsy, ranging from 30 to40% (Hermann et al., 2007; Reilly, 2011; Schubert, 2005). Anincreased risk of seizures and epileptiform EEG abnormalitieshas also been shown in children with ADHD. Children withADHD more frequently have a rolandic epileptiform EEGabnormality than those without ADHD, which may furtheraggravate their behavior (Holtmann, Becker, Kentner-Figura, &Schmidt, 2003). However, many factors must be consideredwhen evaluating children with epilepsy and behavioral problemsbecause the effect of frequent subclinical seizures, undiagnosedlearning difficulties, or the adverse effects of antiepileptic drugscannot be excluded (Schubert, 2005). Idiopathic focal epilepsy inchildren is characterized by its onset during the school-age-period, its occurrence in previously normal children, the absenceof organic cerebral dysfunction, and favorable seizure andintellectual prognoses, which permit these children to undergoprecise neuropsychological evaluations.

Hermann et al. (2007) compared the complications ofADHD between 75 children with new-onset idiopathic epilepsyand 62 age-matched controls. ADHD was significantly moreprevalent in the former than in the latter groups (31% vs. 6%;p < 0.01). In addition, 52.1% of children with ADHD in theformer group were recognized as being the inattentive type. Thediagnosis of ADHD was made prior to the onset of epilepsy in80% of those in the epilepsy group. A volumetric study of thebrain demonstrated that those with epilepsy and ADHD had asignificantly larger gray matter volume in the frontal lobe andsmaller volume in the brain stem than those in the controls.Thus, ADHD in most patients with epilepsy appears to be acomorbidity rather than the cause and effect of seizures or epi-leptiform EEG abnormalities.

EPILEPSY AND ASD

The prevalence of ASD in children with epilepsy rangesfrom 7.1% to 32%, and exceeds that in the general population,which ranges from 0.6% to 1% (Clarke et al., 2005; Saemundsen,Ludvigsson, Hilmarsdottir, & Rafnsson, 2007). A prospectivefollow-up study of 542 children with epilepsy in the regionalcohorts showed that 28 cases or 5% were complicated with ASD(general control: 0.5–0.9%) (Berg et al., 2011). However, theprevalence of ASDs was reduced to 2.2% among those who hadnormal cognitive levels and was increased up to 13.8% amongthose who had impaired cognitive levels. They also found thatID (prevalence ratio: 4.46) and being male (prevalence ratio:3.71) were risk factors for ASD.

In contrast, several studies have investigated the prevalenceof epilepsy among patients with ASD. One study showed that

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33 of 130 patients (25%) with autism developed epilepsy ina 10-year follow-up cohort study (Hara, 2007). In these 33patients, epilepsy was characterized by the onset age, rangingfrom 8 to 26 years (average: 14 years), focal seizures were seenin 20 patients or 61%, and no sex differences were observed.Patients who developed epilepsy had significantly lower IQs aswell as social maturational levels and more frequent epileptiformEEG abnormalities than those who did not. Another studycompared 104 patients with autism (nondeterioration type: 70patients, deterioration-type: 34 patients) and 162 age-matchednormal controls (Giannotti et al., 2008). This study demon-strated that patients with the deterioration-type developedepilepsy more frequently and also displayed more active epilepti-form EEG abnormalities than those with the nondeteriorationtype (p < 0.05).

Thus, the co-occurrence of epilepsy and DD appears to becommon, and the severity of ID may play a key role in increasingthe burden of the co-occurrence of epilepsy (Amiet et al., 2008;Tuchman, Cuccaro, & Alessandri, 2010). Berg concluded in herreview article that the level of ID has a great impact on the inci-dence of epilepsy among people with ASD (Berg, 2011; Berg &Plioplys, 2012). She proposed the hypothesis of “essentialco-morbidity” in which the relationship between epilepsy, ID,and DD is not simply caused by recurrent seizures or active epi-leptic EEG abnormalities, but by the presence of preexisting(hereditary) predispositions to the development of ID or DD inchildren with epilepsy; in other words, a common mechanismexists between epilepsy, ID, and DD (Berg & Plioplys, 2012; Berget al., 2011; Hesdorffer, Caplan, & Berg, 2012).

HOW DO ID AND DD MAKE EPILEPTIC SEIZURESREFRACTORY?

Few studies have investigated the adverse effects of ID andDD on seizure control in children with known epilepsy. Frag-mentary evidence showed that their comorbidity could aggra-vate epilepsy. The comorbidity of ADHD in children wasreported to increase the frequency of epileptic EEG abnormali-ties above that of normal controls (Holtmann et al., 2003). Inchildhood absence epilepsy, ID was considered to be one signifi-cant risk factor for poor seizure prognosis (Sato, Dreifuss, Penry,Kirby, & Palesch, 1983). We also reported that children withPanayiotopoulos syndrome co-occurring with ID and DD hadmore frequent and pharmaco-resistant seizures in spite ofultimate remission (Hirano, Oguni, Funatsuka, Imai, & Osawa,2009). Although evidence is limited, the comorbidity of ID andDD in patients with epilepsy may reduce seizure thresholds,resulting in an increase in the frequency of seizures. Furtherstudies investigating the effect of the combination of ID and DDon epileptic seizures is warranted to consider better treatmentpolicies for those with epilepsy, ID, and DD.

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