Prevalence of epileptiform activity in healthy children during sleep

Sleep Medicine 9 (2008) 303–309 www.elsevier.com/locate/sleep

Original article

Prevalence of epileptiform activity in healthy children during sleep Oscar Sans Capdevila, Ehab Dayyat, Leila Kheirandish-Gozal, David Gozal

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Kosair Children’s Hospital Sleep Medicine and Apnea Center, Department of Pediatrics, University of Louisville, 570 South Preston Street, Suite 204, Louisville, KY 40202, USA Received 31 January 2007; received in revised form 9 March 2007; accepted 12 March 2007 Available online 16 July 2007

Abstract Background: The term epileptiform discharge typically refers to interictal paroxysmal activity that occurs more commonly during sleep. This type of paroxysmal activity does not include the electroencephalographic (EEG) activity observed during a seizure. The prevalence of epileptiform activity in the general pediatric population is unknown. Methods: Polysomnographic (PSG) studies were conducted in otherwise healthy children recruited from the general population and with no previous history of seizures or any other medical conditions. All sleep studies included an eight-lead EEG montage. Spike and sharp waves, either alone or accompanied by slow waves, occurring singly or in bursts lasting <5 s were considered as representing epileptiform activity. Results: Nine hundred seventy children underwent overnight PSG. In 14 children, evidence of epileptiform activity, in the absence of any additional abnormality in the PSG, occurred. Thus, the prevalence of epileptiform activity was 1.45%. Epileptiform patterns found were either spike or spike and wave and were more prominent during non-rapid eye movement (NREM) sleep, with 11 patients presenting spike and spike and wave patterns in the centro-temporal regions. Four of the six children who underwent neurocognitive tests exhibited abnormal findings in areas of behavior, attention, hyperactivity, and learning. Conclusion: Epileptiform activity in otherwise healthy children from the community is relatively frequent and, if confirmed by prospective studies, could be associated with suboptimal cognitive and behavioral functions. Increased awareness by sleep professionals and use of PSG montage that includes temporal leads and >2 standard EEG leads should facilitate the detection of epileptiform activity in children.  2007 Elsevier B.V. All rights reserved. Keywords: Seizures; Sleep; Children; Cognition

1. Introduction In their 1974 glossary of electroencephalographic (EEG) terms, Chatrian and colleagues described ‘‘epileptiform’’ as an interpretive term used in electroencephalography that applies to distinctive waves or complexes distinguishable from the background activity, and that resemble the waveforms recorded in a proportion of human subjects suffering from an epileptic disorder [1]. *

Corresponding author. Tel.: +1 502 852 2323; fax: +1 502 852 2215. E-mail address: [email protected] (D. Gozal). 1389-9457/$ - see front matter  2007 Elsevier B.V. All rights reserved. doi:10.1016/j.sleep.2007.03.024

Such epileptiform patterns included spike and sharp waves either alone or accompanied by slow waves, and also occurring either singly or in bursts lasting at most a few seconds. As it currently stands, the term epileptiform typically refers to interictal paroxysmal activity and not to the EEG activity seen during an actual seizure, which is called an electrographic seizure. Increasing evidence suggests that interictal EEG abnormalities can produce transient cognitive impairment [2–6]. Indeed, benign rolandic epilepsy (benign epilepsy of childhood with centrotemporal spikes) may not have such a favorable outcome after all, since the interictal discharges appear to impose a substantial deleteri-

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ous effect on cognitive function [7]. Additionally, the presence of abnormal discharges during sleep may cause disruption of hippocampal function and interfere with the consolidation of memory [8–10]. Based on such aforementioned considerations, we sought not only to increase awareness on the existence of epileptiform activity in children, but also to examine the prevalence of this condition in the general pediatric population. 2. Methods This study was approved by the University of Louisville Human Research Committee, and informed consent was obtained from the legal caretaker of each participant. 2.1. Subjects The study population included all otherwise healthy children between the ages of 5 and 8 years, who were recruited as control subjects from the community as part of several ongoing research projects, and who were evaluated by overnight polysomnography (PSG) from October 2001 to September 2006. 2.2. Overnight polysomnographic evaluation Children were studied for up to 12 h in a quiet, darkened room with an ambient temperature of 24C in the company of one of their parents. No drugs were used to induce sleep. The following parameters were measured: chest and abdominal wall movement by inductance plethysmography, heart rate by electrocardiogram (ECG), air flow was triply monitored with a sidestream end-tidal capnograph, which also provided breath-bybreath assessment of end-tidal carbon dioxide levels (PETCO2; BCI SC-300, Menomonee Falls, WI), a nasal pressure cannula, and an oronasal thermistor. Arterial oxygen saturation (SpO2) was assessed by pulse oximetry (Nellcor N 100; Nellcor Inc., Hayward, CA), with simultaneous recording of the pulse waveform. The bilateral electro-oculogram (EOG), eight EEG channels (2 frontal, 2 occipital, 2 temporal and 2 central leads), chin and anterior tibial electromyograms (EMGs), and analog output from a body position sensor were also monitored. All measures were digitized using a commercially available system (Rembrandt, MedCare Diagnostics, Amsterdam). Tracheal sound was monitored with a microphone sensor, and a digital time-synchronized video recording was performed. The sleep technician followed patient behavior and confirmed sleep position by the infrared camera inside the room. All studies were initially scored by a certified technician and then blindly reviewed by two physicians experienced in pediatric PSG, who had undergone training in an accredited fellowship program.

Sleep architecture was assessed by standard techniques [11]. The proportion of time spent in each sleep stage was expressed as percentage of total sleep time (%TST). Central, obstructive and mixed apneic events were counted. Obstructive apnea was defined as the absence of airflow with continued chest wall and abdominal movement for duration of at least two breaths [12,13]. Hypopneas were defined as a decrease in oronasal flow of >50%, with a corresponding decrease in SpO2 of >4% and/or arousal [12]. The obstructive apnea/hypopnea index (AHI) was defined as the number of apneas and hypopneas per hour of TST. Arousals were defined as recommended by the American Sleep Disorders Association Task Force report [14] and included respiratory-related (occurring immediately following an apnea, hypopnea or snore), technicianinduced, and spontaneous arousals. Arousals were expressed as the total number of arousals per hour of sleep time. Periodic leg movements during sleep (PLMS) were scored if there were at least four movements of 0.5–5 s duration, and between 5 and 90 s apart [15]. A PLMS index of >5 per hour of sleep is generally considered as exceeding the normal range in children [15]. Criteria used to define the presence of epileptiform activity (sharp wave, spike, spike-and-slow-wave and multiple spike-and-slow-wave complex) were based on definitions of the International Federation of Societies for Clinical Neurophysiology [16] and were classified as follows: • Sharp wave: Transient, clearly distinguishable from background activity, with pointed peak at conventional paper speeds and a duration of 70–200 ms. • Spike: Same as sharp wave, but with duration of 20 to less than 70 ms. • Spike-and-slow-wave complex: Pattern consisting of a spike followed by a slow wave (classically the slow wave being of higher amplitude than the spike). • Multiple spike-and-slow-wave complex: Same as spike-and-slow-wave complex, but with two or more spikes associated with one or more slow waves.

2.3. Neurobehavioral assessments A battery of neurocognitive and behavioral tests was administered to six of the participating children in the morning following PSG assessment, as well as to 813 children. The parent completed the long form of the Conners’ Rating Scales-Revised [18], while the child was undergoing neurocognitive assessment. The Conners’ is used to identify behavioral problems in children. The long version yields seven factors: Oppositional, Cognitive Problems/Inattention, Hyperactivity, Anxious-Shy, Perfectionism, Social Problems, and Psycho-

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somatic and several summary indices, all with a mean Tscore of 50 and a standard deviation (SD) of 10 [18]. The Child Behavior Check List (CBCL) is the most welldeveloped, empirically derived behavior rating scale available for assessing psychopathology and social competence in children [19,20]. The parent-report version of the questionnaire yields eight factors: Withdrawn, Somatic Complaints, Anxious/Depressed, Social Problems, Thought Problems, Attention Problems, Delinquent Behavior, and Aggressive Behavior and three summary indices, all with a mean T-score of 50 and SD of 10 [19]. The neurocognitive assessment included the Preschool Form of the Differential Ability Scales (DAS) [21] and the NEPSY (NeuroPsychological Assessment) [22]. The DAS is a battery of cognitive tests designed to measure verbal, reasoning, and spatial ability. Individual DAS subtests are designed to measure separate and distinct areas of cognitive functioning and thus have high specificity. The ability score for a subtest is expressed as a T-score with a mean of 50 and SD of 10 [20]. The sum of the core subtest T-scores is converted to a total standard score, with a mean of 100 and SD of 15. In addition to the six core subtests, two diagnostic subtests were administered (Matching Letterlike Forms and Recall of Digits). The NEPSY is a relatively new neurobehavioral test battery designed to assess neurocognitive development in five functional domains: attention/executive functions, language, sensorimotor functions, visuospatial processing, and memory and learning [22]. Domain and subtest standard scores have a mean of 100 and SD of 15. The sensorimotor domain was not assessed. In addition to the core subtests, two supplemental subtests were administered: Design Fluency and Sentence Repetition. 3. Results Nine hundred seventy otherwise healthy children underwent an overnight PSG and, of these, 819 children were tested for neurocognitive and behavioral functioning. Fourteen of the 970 children presented evidence of epileptiform activity in the absence of any additional abnormalities in the PSG, indicating a prevalence of 1.45%. Table 1 shows the demographic and PSG characteristics of these 14 children. It should be mentioned that none of the first-degree relatives of the 14 children with epileptiform activity had a history of seizure disorder. No electrographic seizures occurred in any of the children. The epileptiform patterns found were either spike or spike and wave (Figs. 1 and 2). The epileptiform activity was more prominent during non-rapid eye movement (NREM) sleep, although two subjects had spike and wave activity during rapid eye movement (REM) sleep. The distribution of the epileptiform activ-

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ity included central, temporal, occipital, and frontal regions, with 11 patients presenting spike and spike and wave patterns in centro-temporal regions, one patient in fronto-central regions, and two patients in temporo-occipital regions. None of these 14 children had a history of febrile seizures, attention-deficit/hyperactivity disorder (ADHD), or any other neurological disorder, and none were receiving any medication. Neurocognitive testing results were available in 6 out of the 14 children with epileptiform activity, and showed abnormal findings in the areas of behavior, attention, hyperactivity, and learning in three of these children, while one of these children was a posteriori diagnosed with mild mental retardation. None of the 813 children without epileptiform activity presented any cognitive deficits (p < 0.00001). 4. Discussion This study represents, to the best of our knowledge, the first attempt to report the prevalence of epileptiform activity as encountered during PSG in a pediatric population recruited from the community. We found that the prevalence of epileptiform activity in otherwise normal children was 1.45%, a rather high prevalence that clearly merits awareness to this possibility and justifies the use

Table 1 Polysomnographic characteristics in 14 children with epileptiform activity Age (years) Gender Sleep latency (min) REM latency (min) Total sleep time (min) Sleep efficiency (%) Stage 1 (%) Stage 2 (%) Stage 3 (%) Stage 4 (%) Slow wave sleep (%) REM sleep (%) Spontaneous arousal index (/h TST) Respiratory arousal index (/h TST) Total arousal index (/h TST) PLM index with arousal (/h TST) PLM index in sleep (/h TST) PLM index total (/h TST) AHI (/h TST) AI (/h TST) Mean SpO2 SpO2 nadir % TST SpO2 < 90% Mean PETCO2 %TST PETCO2 > 50 mmHg

6.1 ± 0.9 11 M: 3 F 25.6 ± 11.1 106.5 ± 35.7 466.4 ± 44.8 91.1 ± 5.7 4.3 ± 2.6 47.5 ± 7.8 8.13 ± 3.9 20.2 ± 5.1 28.2 ± 8.9 22.5 ± 6.7 5.7 ± 3.1 0.52 ± 0.77 6.3 ± 2.8 0±0 2.5 ± 6.1 0.3 ± 0.7 0.7 ± 0.6 0.44 ± 0.33 97.5 ± 0.5 93.5 ± 2.8 0±0 40 ± 5.5 0%

Mean ± SD; PETCO2, end tidal carbon dioxide; SpO2, oxyhemoglobin saturation by pulse oximetry; REM, rapid eye movement; TST, total sleep time; AI, apnea index; AHI, apnea and hypopnea index; PLM, periodic leg movement.

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Fig. 1. Polysomnographic examples illustrating the presence of spike and wave activity in 2 healthy children. Panels (a) and (c) show 30-s epochs while panels (b) and (d) show 10-s epochs.

of more extended montages incorporating 8-16 EEG leads for detection of epileptiform activity during routine PSG in children. Furthermore, although only a limited number of subjects underwent cognitive evaluation, we raise the possibility that the occurrence of epileptiform activity in children may be associated with suboptimal cognitive and behavioral functions, and that such possibility should be further evaluated in future prospective studies. As other authors have previously suggested, interictal spikes, particularly if frequent and widespread, can impair cognitive abilities, through interference with waking, learning and memory and memory consolidation during sleep [5–7]. Indeed, as described by Binnie, [5–7] patients with interictal epileptiform activity may display brief episodes of impaired cognitive function during such discharges. This phenomenon of transitory cognitive impairment (TCI) is found in approximately 50% of patients who manifest interictal epileptiform discharges during testing, indicating that TCI is not simple inattention but rather that the cognitive effects of epileptiform activity are tangible and site-specific. More spe-

cifically, lateralized epileptiform discharges as encountered during routine EEG are associated with deficits of functions mediated by the hemisphere in which the discharges occur [5–7]. Conversely, specific tasks can activate or suppress focal discharges over the brain regions that mediate the cognitive activity in question, such that TCI clearly reflects cognitive problems in some patients with epilepsy. Furthermore, TCI is demonstrable in many cases of benign partial epilepsy of childhood, a disorder previously considered void of any adverse psychological effects, and can contribute to abnormalities of psychological test profiles, possibly interfering with daily tasks such as reading and driving [5–7]. In children, epileptiform activity may be associated with behavioral disorders [17]. An important issue that is worthy of mentioning is that we did not monitor EEG activity during neurobehavioral testing and, as such, cannot comment on the possibility that TCI may have interfered with performance in those children in whom neurocognitive deficits were identified. We are currently unaware of any similar work conducted in a setting of community-based children under-

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Fig. 2. Polysomnographic example epileptiform activity in a 6-year-old otherwise healthy boy. Panels (a) and (b) show 30-s and 10-s epochs, respectively.

going PSG. Evidence suggesting that frequent sleeprelated conditions such as sleep-disordered breathing (SDB) are associated with worsening of epilepsy has emerged, such that it is currently accepted that gas exchange abnormalities as seen in SDB may unmask underlying seizure disorders [23–25]. Similarly, children with conditions such as ADHD may be at higher risk for the presence of epileptiform activity [26,27]. In a longitudinal study of 3,726 children aged from 6 to 13 years, who were neurologically normal and had no history of epileptic seizures, Cavazzuti and colleagues reported on the presence of spike activity in 3.5% of their cohort during waking EEG recordings obtained at rest and during hyperventilation [28]. This prevalence

is somewhat higher than the one reported herein, as well as that reported by others [29], and while the reasons for such discrepant findings are unclear, they may be due to the different EEG montage techniques and to the use of activation procedures to elicit the emergence of paroxysmal EEG patterns. We should also emphasize that the EEG patterns described in the current study differ from continuous spikes and waves during slow wave sleep, a well-recognized EEG pattern that can be associated with cognitive and behavioral deficits [30,31]. The EEG montage employed in our routine PSG recordings included eight leads distributed over the scalp, aiming to maximize seizure detection within the constraints of routine nocturnal PSG. In the latter,

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fewer than four EEG leads are normally used and, as illustrated by some of our cases, such approach may not allow for proper detection of epileptiform activity. Although the seizure detection performance characteristics of our EEG montage match those of more extended EEG montages, we should also point out that our abbreviated EEG montage may not be ideal for focal frontal epilepsy [32,33]. Sleep-related modulation of epileptic activity is a now well established feature of different epilepsy syndromes. NREM sleep has been shown by most authors to activate interictal epileptic activity in both partial [34] and primary generalized epilepsy syndromes [35], whereas REM and waking has a contrary effect. Furthermore, spike counts and other quantitative measures of spikes can provide potential estimates of hippocampal dysfunction in temporal epilepsy [36], and certain spike amplitude and frequency characteristics can further elaborate on the source of the epileptic focus and its potential consequences in childhood epilepsies [37–40]. Based on these considerations, we acknowledge the absence of spike counts in our patients, such that it will be interesting to further characterize the temporal and amplitude characteristics of sporadic epileptiform activity discovered during routine PSG and determine whether such measures may differentiate between those children with and without cognitive deficits. In summary, we have identified a measurable prevalence of epileptiform activity during sleep in otherwise normal children, which appears to carry an increased risk for neurobehavioral and cognitive deficits. Increased awareness by sleep professionals to this entity and the use of extended EEG montages that include temporal and frontal leads should facilitate the detection of epileptiform activity in children.

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Acknowledgments We thank the many sleep technicians for performing the nocturnal polysomnographic recordings. This study was supported by NIH Grant HL-65270, The Children’s Foundation Endowment for Sleep Research, and by the Commonwealth of Kentucky Challenge for Excellence Trust Fund.

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