Ictal and Interictal EEG Abnormalities in ADHD Children Recorded Over Night by Video-Polysomnography

Epilepsy Research (2007) 75, 130—137

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Ictal and interictal EEG abnormalities in ADHD children recorded over night by video-polysomnography

Rosalia Silvestri a,∗, Antonella Gagliano b, Tiziana Calarese b, Irene Aric`o a, Clemente Cedro a, Rosaria Condurso a, Eva German`o b, Giuseppe Vita c, Gaetano Tortorella b a Sleep Medicine Centre, Department of Neurosciences, Psychiatric and Anaesthesiological Sciences, University of Messina, Italy b Division of Child Neurology and Psychiatry, University of Messina, Italy c Department of Pathology and Experimental Microbiology, University of Messina, Italy

Received 24 January 2007; received in revised form 7 April 2007; accepted 4 May 2007 Available online 27 June 2007

KEYWORDS Summary In this paper we explore the prevalence of ictal and interictal epileptiform dis- ADHD; charges (IEDs) and sleep disorders in ADHD children referred to a sleep clinic for all night Children; video-PSG. Forty-two ADHD outpatients (35 males and 7 females) underwent video-PSG and Interictal EEG a behavioural/neuropsychological assessment. Spearman correlation coefficients (p < 0.05 cri- discharges; terion level) were used to assess the association between cognitive, behavioural, clinical Sleep disorders (co-morbidity), sleep (sleep efficiency) and EEG (seizures, IEDs, localization of IEDs foci) variables. Sleep disorders were found in 86% of ADHD children; among these, 26% had RLS. 53.1% of ADHD children had IEDs (28.2% centro-temporal spikes, 12.5% frontal spikes, 9.3% temporal—occipital spikes and 2.3% generalized S—W). Nocturnal seizures were recorded in three patients: two with atypical interictal rolandic spikes and one with left frontal slow abnormalities. A significant relationship (p < 0.05) emerges between nocturnal seizures and WISC-R IQ score and visual—spatial memory test and between some cognitive variables and interictal rolandic spikes. High levels of inattention, impulsivity/hyperactivity and oppositional behaviours were related (p < 0.01 or 0.05) with Restless Leg Syndrome diagnosis. In conclusion, ADHD is a condition often associated with EEG epileptiform abnormalities. Seizures/IEDs presence seems to play a role on cognitive abilities, conversely sleep disorders have a stronger impact on behavioural rather than cognitive indicators. © 2007 Published by Elsevier B.V.

∗ Corresponding author at: Centro di Medicina del Sonno, Dipartimento di Neuroscienze, Scienze Psichiatriche e Anestesiologiche, Policlinico Universitario di Messina, Italy. Tel.: +39 0902212289; fax: +39 0902923847. E-mail address: [email protected] (R. Silvestri).

Introduction Methods

Attention deficit hyperactivity disorder (ADHD) is a com- Patients mon childhood problem estimated to affect 3—5% of school-aged children. It is characterized by a persis- Forty-two consecutive ADHD outpatients (35 males and 7 tent pattern of inattention (ADHD-I) and/or hyperactive females; mean age 8.9 years, S 2.8) were included in impulsive behaviour (ADHD-H). Diagnosis requires onset this study. They were referred by Pediatric Neurology and before age 7 and impaired function (DSM IV). The core Psychiatry to our Sleep Clinic from October 2004 to May behavioural symptoms of ADHD are inappropriate pat- 2006, within a sleep disorders screening project in ADHD terns of inattentiveness, impulsivity and hyperactivity children. All children were referred independently from any although other common childhood disorders may be co- reported symptoms regarding possible nocturnal seizures or morbid with ADHD, such as Oppositional Defiant Disorder, any sleep disorder. Each referred subject had previously met learning difficulties, dyspraxia, Tic Disorder. Recent lit- DSMIV criteria for ADHD of any subtype (APA, 1994): 32 chil- erature draws attention to the role and prevalence of dren presented the hyperactive or combined type (76.1) EEG abnormalities in ADHD children (Hughes et al., and 10 the inattentive type (23.8). Oppositional-defiant dis- 2000). order (ODD) was present in 27/42 children (64.2%). Both The relationship between ADHD and epilepsy has been children and parents were assessed by means of a semi- explored by many authors who considered the preva- structured psychiatric interview (Kiddie—Sads). All children lence of ADHD in samples of children with epilepsy underwent neurological examination in order to exclude (Shubert, 2005). Describing a higher risk of ADHD in chil- neurological disease. Subjects with known seizures or intel- dren with generalized or frontal epilepsy. The prevalence lectual disability were preventively excluded from the study. for interictal epileptiform discharges (IEDs) data range Neuroimaging by magnetic resonance imaging (MRI), was from 4.9% (Richer et al., 2002) to 60% (Abdeldayem negative in all patients. Co-morbidity between ADHD and and Salim, 2005) in ADHD children without clinical other developmental disorders (reading disability, language, seizures, whereas the background incidence of epilep- Tic, sleep and eating disorders, dyspraxia) was screened in tiform abnormalities in normal school-aged children is all subjects. All patients were recruited at the moment of estimated around 2—3%. IEDs are predominantly focal, their first diagnosis, and none received any medications until mostly bilateral or right sided and, especially in the they all underwent overnight polysomnographic evaluation. predominantly hyperactive type ADHD, distributed over Written informed consent was obtained from the parents of rolandic areas (Holtmann et al., 2003). The effects of all participants. subclinical electroencephalographic epileptiform activity during sleep on cognition and behaviour have been studied mostly in children with rolandic epilepsy (Nicolai et al., Measures 2006). As for seizures occurrence in ADHD some authors Neuropsychological and behavioural measures (Williams et al., 2001; Ishii et al., 2003) found that All children underwent neuropsychological assessment no risk of unprovoked seizures was associated with including cognitive, memory, visual- perception and atten- ADHD while others (Hesdorffer et al., 2004) report a tion ability. Also behaviour rating scales were collected form OR of 3.7 for de novo seizures in ADHD-inattentive parents and teachers for all patients. type. Aldenkamp et al. (2004) underlined the impact of both seizures and paroxysmal activity on cognitive development, especially on ‘‘state dependent processes’’ Intellectual ability such as attention, information processing and behavi- Each child was tested on the complete form of the Revised our. Wechsler Intelligence Scale for Children (WISC-R). All sub- Conversely, well-established data exist about sleep dis- scales scores were used to estimate the cognitive profile of orders in ADHD children (O’Brien and Gozal, 2004; Frolich the subjects. All verbal subtests (information, similarities, et al., 2005). Among all, especially Sleep Related Move- vocabulary, arithmetic, comprehension, digit span) and per- ment Disorders (SRMD) such as Periodic Limb Movement formance subtests (picture completion, block design, object Disorders (PLMD) and Restless Leg Syndrome (RLS) have assembly, coding, mazes) were evaluated. been reported with a high prevalence. Their co-occurrence is hypothesized to be related to a common genetic sub- Memory strate relying on dopaminergic deficit (Wagner et al., Three TOMAL (Test of Memory and Learning, Reynolds and 2004). Bigler, 1995) subtests were administered: word selective Few previous reports explored the yielding power of reminding (WSR TOMAL), paired recall (PR TOMAL), memory- sleep to record IEDs in ADHD children (Larsson and for-location (MFL TOMAL). These subtests evaluate verbal Wilson, 2005). Due to all these previous reports we and visual—spatial short term memory. decided to look at the prevalence of IEDs and seizures in ADHD children referred to a sleep clinic for all night video-PSG, exploring the possibility of co-diagnosing Visual perception sleep disorders and IEDs in order to study the influence The Visual-Motor Integration Test (VMI, Beery and Buktenica, of these variables on behavioural and cognitive perfor- 2000) measures visual-motor integration ability by means a mances. copying task of geometric figures. 132 R. Silvestri et al.

Attention Results Small bells test (Biancardi and Stoppa, 1997) measures selective-visual attention ability. It is a figure cancellation Demographic and clinical characteristics of the children par- task consisting of groups of objects’ pictures randomly inter- ticipating in the survey are presented in Table 1. spersed with a designated target object (small bell). The Most children/parents (86%) reported sleep disorders child is instructed to cross out all target objects. The test during the administration of the structured sleep interview, considers two scores: the first one is the total number of of which 26% would fit the diagnosis of RLS by the IRLS- objects detected during the trial (accuracy); the second one SG Criteria for a pediatric population (Allen et al., 2003). is the number of bells detected in the first 30 s (speed). The video-PSG confirmed these reports: sleep related movement disorders in 73.8% of children, disorders of arousal Behaviour rating scales in 47.6% and sleep related breathing disorders in 21.4% of ADHD-RS (Du Paul et al., 1998) were completed as the first children. stage of the initial assessment by a trained clinician with None of the subjects affected by ADHD showed intellec- experience in ADHD. On the basis of the informant’s descrip- tual deficit (mean IQ in 94.7, S 15.2). 6% had co-morbid Tic tions of the child behaviours, the interviewer rates the disorder; 12.8% language disorders, 33.3% specific learning frequency and severity of the child’s behaviours on 4-point disorders, 12.8% dyspraxia, 7.6% eating disorder. No seizure scales (0—3). At the second stage, parents and teachers were history was reported during the interview but 18.7% had an asked to rate child behaviour, using the Conners’ Teachers abnormal routine EEG. On video-PSG, 53.1% children had Rating Scale (CTRS), Conners’ Parents Rating Scales (CPRS) IEDs (28.2% centro-temporal spikes (Fig. 1), 12.5% frontal (Conners, 1989) and SNAP IV Rating Scales (short form) spikes (Fig. 2), 9.3% temporal—occipital spikes and 2.3% gen- (Swanson, 1992). eralized S—W). As for the SNAP-IV the interview provides measures on Nocturnal seizures were recorded in three patients: two three separate subscales: (1) Inattention (time spent on a with atypical interictal rolandic spikes and one with left single activity), (2) Activity Level (rating of restlessness, fid- frontal slow abnormalities. Children had two, eight (of getiness, and activity level, in structured situations such as which six paroxysmal arousals) and one nocturnal ictal meals and car trips) and (3) defiance/antisocial behaviour (items concerning temper tantrums, lying, stealing, defiance, disobedience, truancy, and destructiveness). Table 1 Demographic and clinical characteristics of 42 children with ADHD

Mean (age) 8.9 years, S 2.8 Sleep and neurophysiological assessment Sex (M/F) 35 males/7females Intelligence quotient 94.7, S 15.2 Sleep questionnaire All children filled out a validated pediatric sleep question- ADHD subtype (%) naire and went through a structured sleep interview with Hyperactive and combined 76.1 their parents before all night video-PSG. Inattentive 23.8 ODD 64.2 Co-morbidity (%) Nocturnal video-polysomnography (video-PSG) Dyslexia 33.3 Sleep EEG recording included 18 leads (21 electrodes, 10—20 Language disorder 12.8 system), EOG, submental, bilateral anterior tibialis and Tic disorder 6 masseter EMGs, oronasal flow, thoracic and abdominal pneu- Eating disorder 7.6 mograms, ECG and oxymetry. In order to assess sleep quality Sleep disorders 86 with a simple global evaluation, we did take into considera- Dyspraxia 12.8 tion sleep efficiency (total sleep time/total time in bed %), of all variables referring to sleep structure and continuity. EEG variables (%) Abnormal routine EEG 18.7 Nocturnal seizures 7.1 EEG Variables IEDs (video-PSG) 53.1 We considered: presence or absence of seizures; pres- Frontal 12.5 ence or absence of epileptiform generalized or focal Centro-temporal 28.2 EEG discharges occurring without apparent clinical events Temporal—occipital 9.3 (IEDs); localization of IEDs foci (centro-temporal, frontal, Generalized S—W 2.3 temporal—occipital). Sleep disorders by structured sleep interview (%) Total disorders 86 Statistical analysis Restless Leg Syndrome (RLS) 26 Sleep disorders by video-PSG (%) Spearman correlation coefficients (p < 0.05 criterion level) Sleep related movement disorders 73.8 were used to examine the association between cognitive and Disorders of arousal 47.6 behavioural variables and clinical (co-morbidity) and EEG Sleep related breathing disorders 21.4 variables. EEG abnormalities and ADHD 133

Figure 1 Sleep stage 2. Atypical interictal rolandic spikes and spike and wave complexes in a child who subsequently showed hypermotor seizures during sleep. episodes respectively. Seizures semeiology was typical of Neuropsychological and behavioural variables frontal or insular hypermotor seizures; their origin being correlation (Spearman coefficient) right frontal, right central or not clearly identifiable, respectively. No children presented with spikes during their No statistical correlation was found between behavioural seizures. indicators and seizures/IEDs presence, while a significant

Figure 2 Sleep stage 2. Interictal spike and waves and sharp waves on bifrontal leads with right predominance. 134 R. Silvestri et al.

Table 2 Neuropsychological and behavioural variables correlation (Spearman coefﬁcient) in the ADHD children

IEDs (video-PSG) Nocturnal Sleep variables (Restless Sleep efﬁciency seizures Leg Syndrome) (SE%) Rolandic Frontal Temporal—occipital

TIQ −0.414* −0.360* VIQ −0.367* PIQ −0.358* Similarities −0.411* Vocabol −0.392* Arithmetics 0.383* Coding 0.518** TOMAL WSR 0.566* TOMAL MFL −0.548* Language disorder 0.382* Tic disorder 0.372* Dyspraxia 0.384* −0.389* Conners-PRS 0.447** Conners-TRS 0.400* SNAP-I 0.315* SNAP-H 0.424** SNAP-O 0.329*

* p < 0.05. ** p < 0.01. relationship emerges between some cognitive abilities and children. For instance data collected through the use of a epileptic variables. Conversely, a sleep disorder such as structured telephone interview found a prevalence rate of RLS, seem to have a stronger impact on behavioural rather 37% for ADHD-I and 29% for ADHD-H in children with newly than cognitive indicators. In fact there was a signifi- diagnosed unprovoked seizures compared to healthy con- cant correlation between RLS diagnosis and inattention, trols (Hesdorffer et al., 2004). Conversely no or slightly impulsivity/hyperactivity, oppositional behaviours scoring, (2% versus 1% in the pediatric population) increased risk of as emerged by CPRS (p < 0.01), CTRS (p < 0.05), SNAP-I seizures associated with ADHD was reported by Williams et (p < 0.01), SNAP-H (p < 0.05) and SNAP-O (p < 0.05). al. (2001) and Ishii et al. (2003). In our newly diagnosed As for the cognitive abilities, we describe a negative rela- ADHD children seizure prevalence accounted for 7.1%. This tion (p < 0.05) between the presence of nocturnal seizures apparently discrepant prevalence may depend on a data and WISC-R IQ total and verbal score, similarities WISC- collection bias since in our sample, seizures presence was R subtest score and TOMAL-MFL score (see Table 2). It never reported by parents and was a fortuitous finding on means that our ADHD children with nocturnal seizures per- nocturnal video-EEG. Conversely the few data reported by formed worse in some WISC-R verbal cognitive tasks, and in literature refer to telephone interviews. Given the known particular in analogical reasoning, and in a short term spa- prevalence of sleep disorders in the ADHD population, it is tial memory task. A significant relationship emerged also possible that some of the reported hypermotor behaviours between some cognitive variables and interictal rolandic during the night could be diagnosed as nocturnal seizures spikes, the latter being negatively related with TIQ, PIQ when properly recorded by an extended EEG montage. For and Vocabular subtest score of WISC-R scale (see Table 2). this reason our data could reflect a more objective preva- Language disorder and Dyspraxia co-morbidity was posi- lence of paroxysmal events than previous reports. Many data tively related to the presence of frontal interictal spikes exist about IEDs prevalence in ADHD children. The positive (p < 0.05), while Tic co-morbid disorder with the presence predictive value of IEDs presence for developing subsequent of a temporal—occipital focus (see Table 2). seizures in ADHD children was 14% in a recent literature Sleep efficiency (SE%) showed a positive correlation with review (Richer et al., 2002). The authors run to the conclu- two WISC-R subtest scores: arithmetics (p < 0,05) and cod- sion that the routine use of EEG in the evaluation of ADHD is ing (p < 0,01). It was also significantly related to a short currently unwarranted. However it is well known that even term verbal memory task (TOMAL Word Selective Remanding subclinical epileptic discharges alone could cause transient score). Dyspraxia and SE were inversely related: a lower SE% cognitive impairment (TCI). Binnie demonstrated that TCI being associated with a higher presence of dyspraxia. actually occurs during approximately 1/3 of discharges in 2/3 of patients (Binnie, 1993). Some epileptic syndromes such as Electrical Status Epilepticus During Sleep (ESES) and Discussion Landau—Kleffner Syndrome (LK) provide good example of a cause-effect correlation between severe epileptiform EEG ADHD and epilepsy co-occurrence have been studied by sev- discharges and specific cognitive deterioration (Metz-Lutz eral authors in samples of ADHD as well as in epileptic and Filippini, 2006; Scholtes et al., 2005). EEG abnormalities and ADHD 135

In our ADHD children, seizure presence seems to affect We hypothesize that the co-occurrence of frontal IEDs with total and verbal WISC-R IQ score with specific falls in ana- two of the most frequent ADHD co-morbid disorders (lan- logical reasoning and a short term spatial memory task. As guage and dyspraxia) might constitute a further element in for a specific subtests deficient performance, Metz-Lutz and favor of plural circuits involvement and represent a salient Filippini (2006) found a decrease in two verbal subtests: diagnostic finding for the definition of ADHD co-morbid digit and vocabulary, as well as two from the performance prophile. score: block design and coding, in rolandic epilepsy, suggest- In the literature there are several indications of a similar ing that these deficits resulted from a long standing effect neurobiological basis for ADHD, Tic Disorder and Tourette’s of reported SW during sleep. Conversely the involvement of Syndrome that are all characterized by an impairment of frontal regions could account for the highly variable impair- executive functioning and often co-occur. Children with ment of ‘‘executive functions’’ (Risse, 2006; Ryvlin et al., Tourette’s syndrome plus ADHD have more additional co- 2006). morbid disorders overall and lower psychosocial function In our sample, the involvement of orbito frontal or mesial than children with ADHD alone (Spencer et al., 1998). Neu- frontal regions, as suggested by the hypermotor aspects roimaging studies show the involvement of orbito-frontal, of our recorded nocturnal seizures, are more linked to midtemporal, and parieto-occipital regions and suggest that disrupted sleep and daytime sleepiness and related with a broadly distributed cortical systems may be impaired in the behavioural rather than cognitive disturbance. Lateraliza- TS (Moriarty et al., 1995; Peterson et al., 2001; Vloet et al., tion of focus in the absence of a structural lesion does 2006). Impairment of executive functions (EF), in particular not seem to specifically affect cognitive impairment. It is inhibitory deficits, may be directly linked to brain abnor- interesting to notice that at least in two of our children malities (Roessner et al., 2006). IEDs presence in the ADHD with clearcut interictal bilateral rolandic and occipital foci, plus Tic disorder phenotype might have a further disturbing seizures appeared to originate, EEG wise, from the right impact on cerebral circuits involved in executive and motor frontal and central leads. control. As for the presence of IEDs without clinical seizures, in As for sleep variables and co-morbid sleep disorders, we our population we found an overall presence (53%), by all found RLS scores to be significantly related to all behavioural night EEG recording, mainly distributed over rolandic areas ratings while sleep efficiency, reflecting continuity against (28.2%), against Holtmann et al., 2003 (5.6%) in daytime major disruption, positively and significantly affected verbal routine EEGs, well beyond the usual range in school aged and non verbal intellectual abilities and verbal memory, in children, thus underlining the exquisite yielding power of agreement with findings typical of adult chronic insomnia. all night EEG recording. The correlations between the neuropsychologi- Several literature reports have just underlined the role cal/behavioural and epileptic variables in our sample of Rolandic focus in cognitive dysfunction in subjects with of ADHD children, suggest that sleep disorders have a Rolandic spikes (Piccirilli et al., 1994). Problems in attention stronger impact on behavioural rather than cognitive or language processing in children with rolandic epilepsy indicators, as already described by others papers (Chervin are considered a result of a mild epileptic encephalopa- et al., 2002; Silvestri et al., 2005). Conversely seizures/IEDs thy due to frequent discharges in sleep (Sanchez-Carpintero´ presence seem to play a stronger role on cognitive abilities and Neville, 2003; Pinton et al., 2006) or to a poor day- rather than behavioural patterns in our sample of ADHD time alertness related to sleep fragmentation (Kohrman and children. Carney, 2000). More recent works reported subtle neurocog- We recognize several limitations to our study mainly due nitive deficits in the domain of phonological awareness, to a relatively small sample size from a single site which visual—spatial memory and drawing with lower academic might not be representative of the entire ADHD population. abilities (Northcott et al., 2005; Pinton et al., 2006) related In particular the fortuitous finding of nocturnal seizures in to rolandic focus. In our sample both TIQ and PIQ scores only three patients makes it difficult to draw any defini- were inversely related to the presence of centro-temporal tive statement about the additive effect of seizures over IEDs, suggesting a negative impact on cognition for rolandic cognition. foci in ADHD children. Moreover, our remarks support the In conclusion, we suggest that more attention should be hypothesis that rolandic discharges may play a significant given to the yielding power of EEG in ADHD. 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