Original Article

When Is EEG Indicated in Attention-Deficit/ Hyperactivity Disorder?

Journal of Child Neurology 1-9 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073815580545 jcn.sagepub.com

Sennur Zaimoglu, ˘ MD1, Dils¸ ad Tu¨rkdogan, ˘ MD2, Betu¨l Mazlum, MD3, 4 Nural Bekiroglu, ˘ PhD , Aylin Tetik-Kabil, MA5, and Seda Eyilikeder, MSc6

Abstract The authors investigated the parameters for predicting epileptiform abnormalities in a group of children diagnosed with attention-deficit/hyperactivity disorder (ADHD). The sample consisted of 148 subjects aged between 6 and 13 (8.76 + 1.26; 25.7% female) years. Subtypes of ADHD and comorbid psychiatric disorders were defined according to DSM-IV criteria. The Wechsler Intelligence Scale for Children–Revised was applied to all patients. Most of the subjects (89.2%) had wakefulness and sleep electroencephalography examinations lasting about one hour. The authors found out that the coexistence of speech sound disorder (odds ratio [OR] 3.90, 95% confidence interval [CI]: 1.61-9.48) and higher Digit Span test performance (OR 1.24, 95% CI: 1.06-1.44) predicted the presence of accompanying epileptiform abnormalities. The prevalence of epileptiform abnormalities was 26.4%, and they were frequently localized in the frontal (41%) and centrotemporal (28.2%) regions. Higher percentage of speech sound disorder co-occurrence (64%) in subjects with rolandic spikes suggests that epileptiform abnormalities associated with ADHD can be determined genetically at least in some cases. Pathophysiology of epileptiform abnormalities in ADHD might have complex genetic and maturational background. Keywords attention-deficit/hyperactivity disorder, epileptiform abnormalities, speech-sound disorder, digit span, rolandic spikes Received March 13, 2014. Received revised December 21, 2014. Accepted for publication February 10, 2015.

ADHD (attention-deficit/hyperactivity disorder) is characterized by inattention, hyperactivity, and impulsivity. ADHD is an etiologically heterogeneous disorder and is highly associated with other psychopathologies such as oppositional defiant disorder, conduct disorder, learning disabilities, mood disorders, and anxiety disorders.1 Furthermore, ADHD is a common comorbidity accompanying pediatric epilepsy in up to onethird of the cases.2 Dunn et al3 reported that 38% of the epileptic children in their series had ADHD, and absence seizures and generalized tonic-clonic seizures were the most prevalent types. Hermann et al4 suggested that ADHD is significantly more prevalent in new onset epilepsy compared to healthy controls (31% versus 6%). They also stated that most of these children had ADHD, predominantly inattentive type, prior to the diagnosis of epilepsy. In addition, the history of inattentive type ADHD was more common among children with newly diagnosed unprovoked seizures in a population-based case-control study.5 It is suggested that ADHD that precedes new-onset epilepsy may represent an intrinsic pathological process common for both disorders.2,4,5 Besides the high prevalence of ADHD in epilepsy, epileptiform abnormalities were also found to be more common than expected in patients with ADHD who did not have any epileptic seizures compared to normal population. The percentage

of epileptiform abnormalities in ADHD have a wide range between 6% and 53%.6-9 This may be related to the differences between the selection criteria of the subjects and the study design. For instance, in a study in which the ictal and interictal epileptiform discharges and sleep disorders were examined in ADHD children, the percentage of sleep disorders was found to be 86% of the subjects.7 Among these 1

Child and Adolescent Psychiatry Istanbul, Institute of Neurological Sciences, Marmara University, Istanbul, Turkey 2 Department of Child Neurology, Medical School, Marmara University, Istanbul, Turkey 3 Department of Neuroscience, Institute of Experimental Medical Research, Istanbul University, Istanbul, Turkey 4 Department of Biostatistics and Bioinformatics, Medical School, Marmara University, Istanbul, Turkey 5 Foundation Development Year Psychological Counseling Center, School of Languages, Sabancı University, Istanbul, Turkey 6 Department of Speech and Language Therapy, Anadolu University, Eskisehir, Turkey Corresponding Author: Sennur Zaimo˘glu, MD, Child and Adolescent Psychiatry Institute of Neurological Sciences, Marmara Universitesi, Norolojik Bilimler Enstitusu, PK:53 Bas¸ ıbuyuk/Maltepe, Istanbul 34849, Turkey. Email: [email protected]; [email protected]

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children with ADHD, 53.1% of them had interictal epileptiform discharges while electroencephalography (EEG) seizures were recorded in 3 patients during polysomnography. On the other hand Socanski et al10 determined the percentage of epileptiform abnormalities during wakefulness as 5.4% in children diagnosed with ADHD which is not different compared to healthy children (5%).10,11 In another study using both hyperventilation and photic stimulation the prevalence of epileptiform abnormalities during wakefulness was found to be 6.1% in children with ADHD.8 EEG examination is not a part of routine clinical assessments in patients with ADHD. Although the prevalence of ADHD in pediatric care centers varies if different inclusion criteria are used, it was found to be not more than 11.2%, a rate similar to the results in general population studies.12 If scholars assume that studies that find a high rate of epileptiform abnormalities in ADHD are correct, then it would be reasonable to perform EEG studies in psychiatry clinics where the diagnosis of ADHD reaches up to 50%. Considering the frequent comorbidity of epilepsy with ADHD, clinical parameters are needed to catch the patients with ADHD at high risk for epilepsy in child psychiatry practices. Otherwise underdiagnosis of comorbid epilepsy may delay the appropriate treatment of the patient. EEG is suggested to be indicated in cases where there is strong evidence of at risk conditions in the medical history such as an encephalopathy that might masquerade as ADHD according to the American Academy of Child and Adolescent Psychiatry practice parameters.13 Absence epilepsy is another condition for which EEG examination is indicated since the differential diagnosis with ADHD might be difficult clinically.14 However, some investigators advise broadening the indication of EEG examination in ADHD since nonepileptic children with rolandic spikes may have associated neuropsychiatric problems mimicking symptoms typically of ADHD.15,16 However Duane17 recommends electrographic examination in developmental disorders if there is a history of clinical events suggestive of a potential seizure (either nocturnal or febrile), a family history of epilepsy, a history of perinatal stress, a history of head trauma, or fluctuating behavioral manifestations. Furthermore, it is also controversial whether the use of antiepileptic medication in nonepileptic ADHD patients who have epileptiform discharges on the EEG is indicated.18,19 Thus, the proper definition of epileptiform abnormalities in ADHD would result in considerable changes on clinical assessments and prognostic expectations in addition to treatment procedures in the future. The authors controlled the predictive value of several clinical and developmental parameters for epileptiform abnormalities in a sample of children diagnosed with ADHD in this study. The authors’ aim was to determine whether any clinical, behavioral, neurodevelopmental, or neuropsychological parameter might be related to epileptiform discharges in ADHD. While including the parameters suggested in the current literature, the authors also examined new possible parameters.

Methods Participants The study was designed to be cross-sectional and descriptive. Children who were referred to the outpatient unit of the Child and Adolescent Psychiatry Clinic at the Institute for Neurological Sciences of Marmara University with complaints of attention deficiency or hyperactivity were invited to participate in the study. One hundred eighty-eight children aged between 6 and 13 and free of any obvious neurological problems were recruited. Eighteen children did not meet the full criteria of ADHD according to DSM-IV.20 Thirteen children were also excluded due to full-scale intelligence quotient (IQ) scores below 80 (3 subjects), comorbidity with pervasive developmental disorder (4 subjects), suspicion of epilepsy (2 subjects), genetic syndromes (1 subject with Kleinfelter syndrome), or history of a hearing deficit proved by audiometric testing (3 subjects). Four children did not complete the EEG procedure, and 5 children were also excluded who had only focal slowing on EEG examination. Finally, 87% of subjects who fulfilled DSM-IV criteria for ADHD, 148 subjects aged between 6 and 13 (mean ¼ 8.76 + 1.26; 25.7% female) were included in the study. All subjects were evaluated while they were drug-naive or had been drug free for at least 1 month. The study was approved by the ethics council of Marmara University, and all parents gave written informed consent.

Psychiatric Evaluation and Scales Psychiatric assessments were made by a child and adolescent psychiatrist (SZ) to determine comorbid psychiatric conditions such as anxiety disorders, mood disorders, oppositional defiant disorder, tic disorder, developmental speech and language disorders, and enuresis nocturna according to DSM-IV criteria. Both parents and teachers filled out ADHD Rating Scale–IV, which is derived from the 18 DSM-IV category A symptoms of ADHD diagnostic criteria to evaluate whether the behavior characterized as ADHD is present in multiple settings.20 Both parent and teacher forms of the ADHD Rating Scale–IV have been shown to have adequate criterion-related validity and good reliability in different cultures.21,22 The psychometric properties of the Turkish version of this scale was studied by Ercan et al as a subscale of the Turgay DSMIV-based child and adolescent behavior disorders screening and rating scale (T-DSM-IV-S).23 Discrimination analysis revealed significant discriminant functions for both inattention (89.4%) and hyperactivity/impulsivity (84%) domains and item analysis revealed high internal reliability. The Cronbach’s alpha values for inattention and hyperactivity/impulsivity were .88 and .95, respectively.24 This scale was based on responses with 4 Likert levels. To convert these responses to a 2-level ‘‘yes’’ or ‘‘no’’ format, ‘‘does not apply’’ and ‘‘applies just a little’’ were scored as ‘‘no,’’ and ‘‘applies quite a bit’’ and ‘‘applies most of the time’’ were scored as ‘‘yes.’’ Children who had 6 or more chronic symptoms out of 9 DSM-IV criteria related to inattention were classified as inattentive subtype (ADHD-I), while children who had 6 or more chronic symptoms out of 9 DSM-IV criteria for hyperactive-impulsive behavior were classified as hyperactive-impulsive subtype (ADHD-HI). Finally, children were diagnosed with the combined type (ADHD-C) when they met at least 6 or more criteria for both subtypes. The authors used the Conners Rating Scales to screen psychopathology generally and to compare the EEG-N and EEG-A groups according to the severity level of ADHD and related externalizing disorders (conduct disorder, oppositional defiant disorder).32 The

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Conners Parent Rating Scale is a parent-report questionnaire that has been used to survey inattention, hyperactivity, oppositional behavior, anxiety, and psychosomatic behavior problems in children.25 The Conners Parent Rating Scale was adapted to a Turkish population by Dereboy et al.26,27 The Conners Teacher Rating Scale, which screens inattention, hyperactivity/impulsivity, and behavior problems, was developed by Goyette et al.25 A validity and reliability study of the scale for Turkish children was published by S¸ ener et al.28 Subjects were also examined for any associated reading disorder. Reading disorder was evaluated by reading tests and taking information from teachers of the children. The performances of the subjects in reading tests were evaluated according to the number of words correctly read in 1 minute (reading speed), comprehension of the text (reading comprehension), and number of errors. Since the standardization studies of these tests hadn’t been completed yet, the data were evaluated by using the means and standard deviations for each class level.24,29-31 In addition to reading assessment, the authors reviewed the errors of grammar, spelling, letter omission, reversing letters, and punctuation in a sentence completion task to identify writing difficulties.

Neurological Evaluation and EEG All subjects’ neurological evaluations were made by a child neurologist (DT). The neurological examination was normal in all patients. Wakefulness and sleep EEG examinations lasting about 1 hour were done by an 18-channel EEG. Most of the patients were sedated with doxylamine or chloral hydrate for the EEG examination. 89.2% of the sample (148 children) had a sleep (minimum 30 minutes) EEG following wakefulness, and 6.1% had only wakefulness EEGs, while 4.7% had only sleep EEGs. Epileptiform abnormalities were classified based on the following features: frequency (rare or frequent), location, relation with vigilance (sleep or wakefulness), and relation with activation procedures (hyperventilation and photic stimulation). Numbers of spikes greater than 1 per minute were described as frequent. Generalized epileptiform abnormalities were defined as discharges of a single spike or multiplespikes and slow-wave complexes with phase reversals in a minimum of 3 channels recording from both hemispheres and midline contacts.

Intelligence Assessment IQ scores of all subjects’ were measured with WISC-R (Wechsler Intelligence Scale for Children–Revised).33 Six (information, similarities, arithmetic, vocabulary, comprehension, digit span) subtests were applied in the verbal section, whereas 5 subtests (picture completion, picture arrangement, block design, object assembly, coding) were provided for the performance section .

Table 1. Questions for Speech and Speech-Sound Development. Questions related to speech development: 1. 2. 3. 4. 5.

When were the first words spoken? What were the first words? How many words were acquired up to the second birthday? When were two or more words put together as meaningful sentences? Could long sentences be used between ages 3-4? Were gestures used instead of sentences to mention requests after the second birthday? Were there problems of communication with peers and classmates during the preschool years?

Questions related to speech-sound development: 1. 2. 3. 4. 5. 6.

Was the speech intelligible to other people? (Or was it intelligible only to parents?) If the speech was unintelligible to others, how long did this problem survive? Were the places of the sounds in words being switched? Were some (first, middle, or last) sounds in words being omitted? Was one sound being used for another? Were there any sounds that could not be produced until the sixth birthday?

examples . The patients with speech sound problems that were unresolved at 6 years of age were diagnosed as speech sound disorder (Table 1).

Parameters Examined for Epileptiform Abnormalities The authors determined certain parameters to test whether these predict epileptiform abnormalities. These parameters were the history of febrile convulsions of the patient or first degree relatives, seizure history in first degree relatives, speech sound problems, receptive and expressive vocabulary problems, speech delay, perinatal distress, low birth weight (less than 2500 gr), complicated head trauma history, and low verbal or performance IQ scores (discrepancy  15 points). The authors’ criteria for complicated head trauma included mild traumatic brain injury with loss of consciousness for a short duration (for a few seconds or minutes), nausea, vomiting and dizziness. Perinatal events such as delay in onset of spontaneous respiration, meconium aspiration, need for resuscitation and/or ventilation, fetal distress were accepted as perinatal distress. The subjects were grouped as EEG-normal (EEG-N) and EEGabnormal (EEG-A) according to the presence or absence of epileptiform activity.

Speech and Language Assessment and History

Statistical Analyses

Since the studies to adapt the standard tests for comprehensive language evaluation to a Turkish population has not been completed yet, the authors evaluated the receptive and expressive vocabulary in subjects. The authors used the Peabody Picture Vocabulary Test for receptive vocabulary. The vocabulary subtest of WISC-R was preferred for expressive vocabulary and a standard score 7 was accepted as positive. The Boston Naming Test was applied to evaluate naming difficulties. The Peabody Picture Vocabulary test was developed by Dunn and adapted to Turkish by Katz et al.34 The authors also asked questions of parents about speech development and the intelligibility of the speech by demonstrating with

For univariate analysis, Student’s t test, the chi-square test, and Fisher’s exact test were used. For multivariate analysis, stepwise logistic regression analysis was performed. Data were analyzed with SPSS 16.0 for Windows. P < .05 was considered as significant.

Results Demographic Data Demographic data are shown in Table 2. Full-scale, verbal, and performance IQ levels were not different between the EEG-N

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Table 2. Demographic Data Are Defined Below for EEG-N and EEG-A Groups Separately. EEG-N (n ¼ 109) Mean (SD) Female/male (n, % female) Mean age (year) Mean age (month) Grade Educational years of mother Educational years of father Conners teacher score Conners family score Hand dominance (R/L/A) Verbal IQ Performance IQ Full-scale IQ Borderline IQ (80-90) (n, %)

30/79 (27.5) 8.78 (1.97) 110.79 (23.83) 3.59 (1.96) 10.55 (3.55)

EEG-A (n ¼ 39) Mean (SD) 8/31 (20.5) 8.69 110.15 3.56 11.28

(2.08) (24.92) (2.12) (3.74)

Table 3. Parameters Tested for Prediction of EEG Abnormalities in ADHD and P Values for Each Parameter.

.52 .81 .88 .93 .28

10.90 (3.44)

12.16 (3.59)

.06

35.27 (13.35)

36.26 (11.40)

.69

43.85 (15.75)

39.72 (16.12)

.20

97/9/3

32/7/0

.15

102.49 (12.34) 109.58 (14.79) 106.51 (12.32) 10/99 (9.2)

102.13 109.92 106.56 5/34

(15.10) (16.78) (15.12) (12.8)

EEG-N (n ¼ 109) EEG-A (n ¼ 39) (n, %) (n, %)

P

.88 .90 .98 .54

Abbreviations: A, ambidextrous; EEG-A, EEG-abnormal; EEG-N, EEG-normal; IQ, intelligence quotient; L, left; R, right.

and EEG-A groups. Subtests scores of WISC-R were not different except Digit Span, which was significantly (P ¼ .02) higher in the EEG-A (mean + SD ¼ 9.69 + 2.64) group compared to the EEG-N (mean + SD ¼ 8.65 + 2.42) group.

Psychiatric Evaluation The subjects with ADHD included 34% inattentive type, 12% hyperactive/impulsive type, and 54% combined type. The EEG-N and EEG-A groups were not statistically different according to the accompanying ADHD subtype. Of the subjects, 62% had 1 or more comorbid diagnoses according to DSM-IV criteria: oppositional defiant disorder 26.1%, anxiety 30.1%, mood disorder 13.7%, tic disorder 11.8%, obsessive compulsive disorder 2.6%, stuttering 1.3%, enuresis nocturna 15.7%. The authors found that 34% had a reading disorder, and 35.3% had writing difficulties associated with ADHD. When the EEG-N and EEG-A groups were compared by the chi-square test according to comorbid psychiatric diagnosis and learning disorders, there was no statistical difference between groups.

History of FC (þ/-) FC in family Seizure in family Head trauma Low birth weight Perinatal distress Low verbal IQ Low performance IQ Speech sound disorder Receptive vocabulary Expressive vocabulary Delay in speech

a

8/100 (7.3%) 9/98 (8.3%)a 2/105 (1.8%)a 4/104 (3.7%)a 5/103 (4.6%)a 11/96 (10.1%)a 36/73 (33%) 7/102 (6.4%) 17/92 (15.6%) 9/109 (7.6%) 13/93 (12.3%)b 20/88 (18.5%)a

4/35 (10.3%) 4/34 (10.3%)a 0/38a 3/36 (7.7%) 2/36 (5.1%)a 4/34 (10.3%)a 16/23 (41.0%) 3/36 (7.7%) 14/25 (35.9%) 6/33 (15.4%) 4/35 (10.3%) 12/27 (30.8%)

P .73 .74 1.00 .38 1.00 1.00 .44 .72 .009 .22 1.00 .12

Abbreviations: EEG-A, EEG-abnormal; EEG-N, EEG-normal; FC, febrile convulsion; IQ, intelligence quotient. a Missing information of the 2 adopted cases. b Missing information of 3 cases (vocabulary subtest is missing).

and 12%, respectively. The EEG-A and EEG-N groups did not differ according to the vocabulary impairments (Table 3). All but 1 of the subjects’ early speech sound problems as reported by the parents persisted after 6 years of age. The percentage of persistent speech sound problems in the whole group was 21% and this percentage was significantly higher in EEG-A group (Table 3). When the authors analyzed the nature of speech sound problems, similar problems were observed in the EEGN and the EEG-A groups. Articulatory errors (especially related to /r/ sound, lipsing, and vowel distortions) and phonological errors (gliding of liquids, fronting, voicing, consonant harmony, and substitutions of vowels) were observed.

Predictive Parameters for Epileptiform Abnormalities Of all the parameters the authors tested to predict the presence of epileptiform abnormalities, only the presence of speech sound disorder was found to be statistically significant (Table 3). Digit Span, a subtest of WISC-R, was another significantly different variable between the groups. Speech sound disorder and Digit Span were conducted in the stepwise logistic regression model. The presence of speech sound disorder highly predicts the presence of epileptiform abnormalities (OR 3.90, 95% CI: 1.61-9.48). Higher Digit Span performance was associated with epileptiform abnormalities (OR 1.24, 95% CI: 1.06-1.44).

EEG Findings Speech Language and Speech Sound Characteristics Of the sample, 31% had a history of delay at least 1-2 years in saying their first words and multiword sentences according to the reports of the parents. Although this percentage was higher in EEG-A group, this was not found to be statistically significant (Table 3). The percentages of receptive and expressive vocabulary impairments in the sample were found to be 10%

Epileptiform abnormalities were found in 26.4% (n ¼ 39) of subjects (n ¼ 148). Details of EEG findings are shown in Table 4. The frequency for epileptiform abnormalities was high at frontal (41.%) and centrotemporal (28.2%) regions, and they were high either bilaterally or in the left hemisphere. The overall percentage of temporal, occipital, and parietal epileptiform abnormalities was 15.4%. Frontal and generalized

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Table 4. The Characteristics of the EEG Abnormalities. States when EEG abnormalities appeared Awakea Sleep Awake þ sleep Hyperventilation

% 12.8 64.1 20.5 2.6

Type of EEG abnormalities Epileptogenic potentials Epileptogenic potentials þ focal slowing

94.9 5.2

Frequency of epileptogenic potentials Infrequentb Frequentb

69.2 30.8

Lateralization of EEG abnormalities Left hemisphere Right hemisphere Bilateral

28.2 20.5 35.9

Localization of EEG abnormalities Frontal Temporal Centrotemporal/rolandic Parietal Occipital Generalized

41 7.7 28.2 2.6 5.1 15.4

Abbreviation: EEG, electroencephalography. a This group did not have sleep recordings. b Spikes >1/minute were described as frequent.

epileptiform abnormalities were infrequent. More than half of the epileptiform abnormalities were detected only during sleep.

Rolandic Spikes Of the whole group, 7.4% (n ¼ 148) and 28.2% of the EEG-A group had rolandic spikes. Of the 11 cases who had rolandic spikes, 8 had epileptiform abnormalities during both wakefulness and sleep. Two subjects had spikes only during sleep whereas 1 subject had spikes when awake (this subject did not have a sleep recording). In addition, 5 patients had spikes on the left, 2 on the right, and 4 bilaterally. Ten of 12 subjects with frequent activity had rolandic spikes. This means that most of the frequent spike activity seen in ADHD was mainly rolandic spikes (83%).

Speech Sound Disorder Coexistence With ADHD and Epileptiform Abnormalities Fourteen patients out of 39 with epileptiform abnormalities had speech sound disorder. In 3 of these patients, epileptiform abnormalities were localized in the frontal and the others were in posterior regions. The percentage of speech sound disorder in patients with rolandic spikes was 64% (P ¼ .03). Of the

patients with frequent spikes, 75% had speech sound disorder comorbidity (P ¼ .001).

Discussion To predict the presence of epileptiform abnormalities in ADHD, the authors evaluated the significance of clinical, neuropsychological and developmental parameters. The authors determined that the coexistence of speech sound disorder and higher performance in the Digit Span subtest of WISC-R have a significant relationship with epileptiform abnormalities. Speech sound disorder is a developmental disorder characterized by speech output that does not include developmentally expected speech sounds appropriate for age and in which the intelligibility of the speech is significantly affected.35,36 ADHD is a neurodevelopmental disorder defined by basic symptoms including inattention, hyperactivity and impulsivity. Developmental speech problems are not components of the core syndrome. The significance of speech sound disorder coexistence as a predictor of epileptiform abnormalities in ADHD, which was unexpected can be considered under 3 main topics: coexistence of ADHD with speech sound disorder, epileptic syndromes associated with speech-language problems, and last epileptiform abnormalities accompanying speech-language disorders. First of all the coexistence of ADHD with speech-language disorders have previously been investigated both in population and clinical based studies.37-39 The literature about the coexistence of speech sound disorder with ADHD is limited compared to the data on the co-occurrence of language impairment with ADHD.40 The percentage of speech sound problems reported by parents persisting after 6 years of age 21% in the cohort. It has been suggested that preschool children with speech and language problems are more prone to develop ADHD at school.41 McGrath et al42 reported that children who have developmental speech-sound problems associated with specific language impairment are at higher risk for having inattentive ADHD symptoms when compared to a speech sound disorder–only group.42 Speech sound disorder, specific language impairment, and ADHD are common developmental disorders with both genetic and environmental factors contributing to the etiology. Elucidation of the exact nature of coexistence of these disorders may help to explain the predictive value of speech sound disorder for epileptiform abnormalities. Second, it has been suggested that speech-language disorders are a part of a clinical presentation of childhood epileptic syndromes.43 Speech sound disorder, specific language impairment, reading disorder, and ADHD coexist frequently with rolandic epilepsy, one of the most frequent childhood epileptic syndromes. In a case-control study, reading disorder and speech sound disorder were found to be inherited traits in families with rolandic epilepsy.44 These authors found the association between rolandic epilepsy and speech sound disorder in relatives independent of the proband’s speech sound disorder status and suggested that possible risk factors were shared between speech sound disorder and centrotemporal spikes to

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explain this result. In addition Pal et al45 identified a pleiotropic role of the 11p13 locus in the development of speech sound disorder and centrotemporal spikes. While the centrotemporal spikes is the hallmark of rolandic epilepsy, speech sound disorder is a well-known comorbid disorder in subjects with rolandic epilepsy. In this study, the speech sound disorder percentage was significantly higher in subjects with rolandic/centrotemporal spike activity in the EEG-A group (P ¼ .03). This relationship can be explained in 2 different ways: First, there might be a subgroup of ADHD, highly determined genetically, associated with centrotemporal spikes and speech sound disorder. Second, the authors’ finding about high percentage of speech sound disorder in centrotemporal spikes might be a sign of a relationship between speech sound disorder and centrotemporal spikes rather than a clinical relationship with ADHD. Further studies, which should include a speech sound disorder group without ADHD or a group diagnosed with a different psychiatric illness, might give additional information to understand the strength of this relationship. Last, the association of epileptiform abnormalities with specific language impairment is much better documented than that of epileptiform abnormalities accompanying speech sound disorder.46 The relationship between specific language impairment and epileptiform abnormalities is not always found to be significant according to the literature and EEG evaluation is recommended if there is regression in language acquisition.47,48 Since the adaptation of standard language tests to Turkish population had not been completed yet, the authors were not able to evaluate specific language impairment in the subjects. There was no significant difference between EEG-A and EEG-N groups in terms of expressive and receptive vocabulary and a 1-2 years of speech delay reported by parents. Although restricted vocabulary and speech delay are common presenting features of specific language impairment, they are not enough for a diagnosis of specific language impairment.49 Since some of the children with specific language impairment have difficulty in sentence level morphology and syntax, evaluations restricted to receptive and expressive vocabulary may lead to an underestimation of the diagnosis in these children. In addition there was no language regression in any of the subjects. Speech sound disorder is a heterogeneous construct and has several components, including oral motor skills, phonological memory, phonological awareness, vocabulary and speeded naming.50 Phonological memory, one of these subtypes, is found to be significantly low in speech sound disorder patients particularly when it is evaluated with pseudowords. Intuitively, it would be logical to expect low Digit Span performance in the subgroup with epileptiform abnormalities because of 2 reasons: First, the accompanying epileptiform abnormalities would render this group’s cognitive performance worse and lead to low Digit Span performance. Second, the higher percentage of speech sound disorder subjects in the epileptiform abnormalities group would lower the Digit Span performance in relation to a possible speech sound disorder subgroup with low performance for verbal working memories. However, the authors

found high Digit Span test performances in the subgroup with epileptiform abnormalities. Rommelse et al51 reported the relationship of low Digit Span performance with locus 13q12.11 in a study that looked for neuropsychological endophenotypes in ADHD. ADHD subjects without epileptiform abnormalities may represent a genetically different ADHD subgroup with low Digit Span performance. It may be reasonable to exclude EEG-A cases in studies searching genes for ADHD. The percentage of epileptiform abnormalities (26.4%) in the cohort was comparable with results of studies with similar methodologies, namely Hughes et al6 reporting 25.7% and Millichap et al9 reporting 30.1%. The authors suggest that it is critical to assess sleep EEG examinations since 59.1% of epileptiform abnormalities were identified only in sleep EEGs in this study. One of the studies that reported the highest percentage of epileptiform abnormalities (53%) in ADHD had a sample bias since only the subjects with sleep disorders were referred for EEG examination.7 In this study the cohort was composed of consecutive child psychiatry referrals and most of the subjects in this study had sleep recordings (93.9%). There is not any firm conclusion in the literature about the scalp distribution and frequency of epileptiform abnormalities in ADHD. In contrast to other studies, the frontal regions (41%) were the most frequent location in this sample. This result is compatible with the executive dysfunction hypothesis about ADHD. Since the authors strictly used DSM-IV criteria on ADHD for the selection of subjects and the age interval was between 6 and 13, this might have had an effect on the high percentage of epileptiform abnormalities at frontal regions. Other studies include younger subjects for example 3 years old children.6 Compared to other studies, a significant percentage (28.2%) of epileptiform abnormalities was composed of rolandic spikes in this EEG-A sample. The authors observed the percentage of rolandic spikes as 7.4% in the whole sample and this is higher than the ratio (5.6%) reported by Holtmann et al.15 Their subjects were aged between 2 and 16 and they evaluated only awake EEGs.15 It is well-known that school-age is a peak time for occurrence of rolandic spikes even in normal children and with benign rolandic epilepsy. Rolandic spikes are most frequently seen in sleep recordings. The possible effects and pathogenesis of the association of epileptiform abnormalities to ADHD remains largely unknown. Although antiepileptic agents decrease the frequency of spikes and improve the behavioral and cognitive problems accompanying to epileptiform abnormalities in some studies, there are also studies showing deterioration in cognitive functions.19,52-54 Besides, methylphenidate has been frequently used for the cognitive problems of epileptic subjects and neuropsychiatric disorders associated with epileptiform abnormalities and it is suggested to be safe and effective.55 In addition, researchers claimed that the possible seizure risk can not be attributed to methlyphenidate in ADHD subjects with epileptiform EEG.56 As a result, associated epileptiform abnormalities to ADHD without any clinical seizure do not change the individual clinical management of patients. On

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the other hand, the data about the role of epileptiform abnormalities in ADHD on clinical features, etiology, pathogenesis and prognosis are even more limited.57 The results of future studies which will focus on these unresolved issues might reshape the clinical management of ADHD. The lack of the formal evaluation of the subjects for specific language impairment diagnosis and the dependence of the speech sound disorder diagnosis on informal clinical processes are the limitations of this study. However, there are studies which used history based assessment to diagnose speech sound disorder.45,58 Moreover, if it is considered that the speech sound disorders in the preschool period mostly resolve after 6 years of age, the evaluations based on history become important. Speech sound disorder defines a group of disorders which are phenotypically and etiologically heterogeneous and there are still on-going effort to reach consensus on the development of a classifying system for speech sound disorder.59 This is the first study which reports a possible relationship between epileptiform abnormalities and speech sound disorder seen in ADHD patients. This finding gains in importance when the authors consider current studies that emphasize the clinical importance of speech-language problems in childhood epileptic syndromes. The future EEG studies in ADHD may be promising if they include formal language tests and discriminate the articulatory and cognitive properties (or endophenotypes) of speech sound disorder.

Conclusions The authors investigated several parameters for indications of an EEG evaluation in ADHD patients. These parameters are the history of febrile convulsions of patients or first degree relatives, seizure history of first degree relatives, speech sound problems, receptive and expressive vocabulary problems, speech delay, perinatal distress, low birth weight, complicated head trauma history and low verbal or performance IQ scores. Speech sound disorder coexistence seems meaningful in EEG evaluations in ADHD although the exact nature of this coexistence is unknown. It is still questionable whether a routine EEG examination in ADHD should be made. It seems reasonable to evaluate EEG in selected cases instead of taking routine EEGs. More studies are needed to determine predictive parameters for epileptiform abnormalities such as speech sound disorder subtypes, sleep disturbances, motor coordination problems, and so on. These studies may also be helpful to determine different subgroups and/or endophenotypes for ADHD. Acknowledgments We acknowledge professor R. W. Guillery for English editing.

Author Contributions SZ conceived the article, collected the data, and drafted the manuscript. DT did the neurological evaluation of the patients, interpreted the EEG recordings, contributed to the drafting, and reviewed the manuscript. BM made significant contributions to the process of drafting and revision of the manuscript. NB did the statistics and

interpreted the data. ATK contributed to data collection and evaluation of the subjects. SE contributed to interpretation of the data. All authors approved the final manuscript for publication.

Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: DT was supported as a travel bursary by the Marmara University Scientific Research Committee to present the study at the 8th European Pediatric Neurology Congress held in Harrogate GB.

Ethical Approval The study was approved by the ethics council of Marmara University. (MAR-YC¸-2009-0202).

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