Curr Neurol Neurosci Rep (2012) 12:429435 DOI 10.

1007/s11910-012-0275-6

EPILEPSY (CW BAZIL, SECTION EDITOR)

Continuous Electroencephalography Monitoring in Neonates

Rene A. Shellhaas

Published online: 25 April 2012 # Springer Science+Business Media, LLC 2012

Abstract As more critically ill term and premature neonates are surviving their acute illness, their long-term neurodevelopmental morbidity is being recognized. Continuous monitoring of cerebral function, with electroencephalography or derived digital trends, can provide key information regarding seizures and background patterns, with direct treatment and prognostic implications. Conventional videoelectroencephalography remains the gold standard for neonatal seizure diagnosis and quantification, but can be supplemented by digital trending modalities. Both conventional and amplitude-integrated electroencephalography can provide valuable data regarding the background trends. This review describes indications and methods for continuous electroencephalography monitoring in high-risk neonates. Keywords Electroencephalography . EEG . Intensive care . Neonatal . Seizure . Amplitude-integrated electroencephalography . aEEG . Continuous electroencephalography . Monitoring . Neonates

hypothermia for those with hypoxic-ischemic encephalopathy (HIE), adverse outcomes remain common. Clinical practice varies, depending on the clinicians specialty training and local resources [1], but there is an increasing trend toward neuromonitoring for high-risk term and preterm neonates. It is difficult to distinguish the effects of neonatal seizures from their underlying etiology, and we lack conclusive evidence that treating neonatal seizures improves long-term outcome. However, recent data suggest that neonatal seizures may compound the risk for brain injury and subsequent adverse outcome among those with HIE [2, 3], and increased seizure severity has been correlated with worse outcomes among infants with a range of seizure etiologies [4, 5]. Additionally, in one study, the duration of neonatal seizures was reduced with the introduction of reduced montage electroencephalographic (EEG) monitoring [6], suggesting the possibility that EEG monitoring could lead to improved outcomes by detecting seizures and directing their management.

Indications for Neuromonitoring Introduction Neonates requiring neurointensive care are at high risk for death or long-term neurologic morbidity, including cerebral palsy, developmental delay, and epilepsy. Although an increasing array of interventions are available, such as therapeutic Seizure detection is the most common indication for EEG monitoring. In high-risk populations of neonates, seizures are common [7, 8, 9, 10] and they often lack outward clinical manifestations. Many studies have reported that 50 % or more of all neonatal seizures are subclinical [11, 12, 13, 14]. Since subclinical seizures cannot be detected by bedside clinical observation, their diagnosis relies on EEG. That most neonatal seizures lack outward clinical manifestations should not be surprising, since newborns cannot communicate the sensory phenomena described by older children and adults during seizures (eg, a rising epigastric sensation during temporal lobe seizures, or visual phenomena associated with seizures involving the calcarine

R. A. Shellhaas (*) Department of Pediatrics & Communicable Diseases, Division of Pediatric Neurology, University of Michigan, Room 12-733, C.S. Mott Childrens Hospital, 1540 East Hospital Drive SPC 4279, Ann Arbor, MI 48109-4279, USA e-mail: shellhaa@med.umich.edu

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cortex). Fluctuations in heart rate and/or blood pressure often raise suspicion for seizures in at-risk neonates, but these events in isolation are rarely caused by seizures [7, 15]. Although some neonates do express clinical manifestations of their seizures, especially prior to administration of antiseizure medication [13, 16], accurate distinction between abnormal non-seizure paroxysmal events and clinically apparent seizures is fraught with difficulties. The distinction between clinical seizures and electrographic seizures is critical, as highlighted by two examples from the literature: 1) Initial Apgar scores, pH, lactate, base deficit, need for intubation, and elevated nucleated red blood cells have been studied as predictors of seizures in newborns with HIE. When only clinical seizures were evaluated, these factors appeared to have good positive predictive value (80 %) [17]. However, when stricter electrographic criteria were applied, the positive predictive value was significantly lower (20 %) [18]. 2) In a prospective study of high-risk neonates, neonatal intensive care unit (NICU) staff members were asked to document suspected seizures while conventional videoEEG was recorded. Only 9 % of electrographic seizures (48 of 526) were recognized and documented by NICU staff, while 78 % of documented paroxysmal events (129 of 177) had no electrographic correlate (ie, the events were not seizures) [12]. The gap in the ability to accurately diagnose seizures by clinical observation alone places infants at risk both for under-treatment of ongoing seizures and for over-treatment of events that are, in fact, not seizures. EEG, therefore, improves the precision of seizure quantification, as well as the differential diagnosis of paroxysmal events suspected to be seizures. A sample of events that raise clinical suspicion for seizures, and can be indications for EEG monitoring in newborns, is provided in Table 1. This list is not meant to be comprehensive; rather, it highlights some of the variety of indications for neonatal EEG monitoring. EEG monitoring is resource-intensive, requiring costly equipment, available technologists, and clinical neurophysiologists trained in neonatal EEG interpretation. Not all infants in an intensive care setting can, or should, be monitored. Rather, intensive monitoring should be targeted at patients with high risk for abnormal brain function. Newborn infants with demonstrated acute brain injury, especially those with concomitant encephalopathy, should be considered at high risk for seizures. Examples include infants with intracranial hemorrhage or arterial ischemic stroke. Those with high risk for acute injury, such as infants with encephalopathy who require extracorporeal membrane oxygenation, newborns with meningoencephalitis, or those with birth depression from suspected perinatal asphyxia, may also benefit from EEG

monitoring. Since infants who require pharmacologic paralysis cannot demonstrate any clinical sign associated with seizures, those with comorbid risk for brain injury can also be considered candidates for EEG monitoring. Newborns with suspected cerebral dysgenesis or neonatal epilepsy syndromes are also clearly at risk for seizures and should be considered for EEG monitoring. For additional discussion of indications for neonatal EEG monitoring, readers are referred to the American Clinical Neurophysiology Societys recently published guideline [20].

Methods for Continuous EEG Monitoring in Neonates Conventional Video-EEG Conventional video-EEG remains the gold standard for neonatal seizure detection and quantification. A modified International 1020 System for electrode placement is recommended (Fig. 1) [20], with additional extracerebral leads including a respiratory channel and electrocardiogram, to assist with assessment of behavioral state and identification of extracerebral artifacts. Extraoculogram and surface electromyography leads are often helpful, but are not always required (Fig. 2). The American Clinical Neurophysiology Society offers guidelines for the minimum standards for EEG recording [21]. Timelocked video monitoring is strongly recommended for the differential diagnosis of paroxysmal clinical events and is often useful for distinguishing artifacts [20]. A bedside observer is also of utmost importance, as this individual can alert the EEG reviewer to clinically relevant events by pressing a patient event marker, entering the event on the digital EEG file at the bedside, and/or documenting in a flow sheet. Such events could be typical paroxysmal episodes, administration of neuroactive medications, or other interventions such as chest percussion (which can cause artifact on the EEG). Duration of Monitoring In general a 60-minute, routine-length neonatal EEG is adequate for assessment of the interictal background. The duration is longer than that recommended for a typical older child or adult, since it is imperative that the recording be of sufficient length to capture both wakefulness and sleep, if such state modulation exists. However, a routine-length EEG is generally not considered sufficient to screen for neonatal seizures among high-risk patients [20]. Rather, it is recommended that high-risk neonates be monitored with EEG for 24 h to evaluate for seizures. Studies have indicated that most seizures will occur within 24 h of EEG monitoring [7, 22], although among neonates with HIE who are treated with therapeutic hypothermia, some data suggest that continuing monitoring through the cooling and

Curr Neurol Neurosci Rep (2012) 12:429435 Table 1 Indications for EEG monitoring

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Evaluation of abnormal paroxysmal events, such as: Focal tonic, focal clonic, multifocal clonic episodesa Intermittent forced eye deviation Myoclonus Unexplained apnea Unexplained autonomic instability (eg, paroxysmal tachycardia or hypertension) Brainstem-release phenomena (eg, oral automatisms or bicycling movements) Other abnormal movements Surveillance for subclinical seizures Initial diagnosis Assessment of response to anti-seizure medicationsb Evaluation for seizure recurrence during or after weaning of anti-seizure medications Assessment of EEG background abnormalities Assist in estimating prognosis Amplitude-integrated electroencephalography is well suited for this purpose Serial routine-length conventional electroencephalography may also be adequate

These are the most reliable manifestations of clinically apparent neonatal seizures [19]

More than 50 % of neonates may demonstrate electroclinical dissociation (clinical signs vanish while electrographic seizures continue) after phenobarbital or phenytoin are administered [13] EEG electroencephalographic

rewarming period is most appropriate [8, 9]. While few published data are available to support this practice, many centers recommend continuing EEG monitoring until the newborn infant has been seizure-free for 24 h, except in circumstances when this is either not feasible or deemed by the treating clinicians not to be in the infants best interest [20]. When EEG is requested to determine whether abnormal paroxysmal events correspond to electrographic seizures, the appropriate duration of monitoring is variable. If the episodes have no obvious EEG correlate, it is recommended that the EEG continue until several typical events have been captured. If the inter-event EEG background is stable and the events are not seizures, then monitoring for this purpose can be discontinued.

Fig. 1 The International 1020 System for electroencephalography electrode placement, modified for neonates, includes the electrode positions in the boxes. Additional extracerebral channels, including respiratory and electrocardiogram tracings, are also necessary. Extraocular and surface electromyography leads are often useful, but not always required

Longitudinal assessment of encephalopathy can be complimented by serial routine-length EEGs. These recordings, which must be of sufficient duration to capture sleep-wake cycling, provide the clinician with information about the evolution of a chronic encephalopathy. For example, serial assessments of a preterm infants EEG should demonstrate maturation of normal graphoelements and subsiding discontinuity, with increasingly well-defined sleep-wake cycling. An infant whose EEG background patterns demonstrate features consistent with those expected for infants of 2 or more weeks younger postmenstrual age is said to have a dysmature EEG (eg, if a 36-week postmenstrual age infants EEG background is more consistent with that of a typical 33-week infant, the EEG is dysmature). Persistently dysmature or frankly abnormal patterns are negative prognostic indicators [23]. In general, the longer the EEG background remains abnormal, the worse the infants neurodevelopmental prognosis. There is evidence that therapeutic hypothermia modifies the EEG background evolution among neonates with HIE. In this particular circumstance, it may be reasonable to continue conventional (or reduced-array) EEG monitoring throughout cooling and rewarming, both for seizure detection and for evaluation of background trends over time, since the data can assist with estimating prognosis. For example, the absence of sleep-wake cycling on amplitudeintegrated electroencephalography (aEEG) after 24 h of age is a poor prognostic indicator for infants with HIE who are not cooled [24], but the window for emergence of sleepwake cycling lengthens to 48 h for those undergoing hypothermia therapy [25]. Persistence of severe background abnormalities, such as burst suppression, beyond 24 to 30 h of life corresponded to high risk of severe brain imaging abnormalities in a study assessing conventional EEG monitoring among infants receiving therapeutic hypothermia [8].

432 Fig. 2 This conventional electroencephalography was recorded from a term infant with hypoxic-ischemic encephalopathy, using the International 1020 System for electrode placement, modified for neonates, along with extracerebral channels including respiratory (not functioning in this screenshot), electrocardiogram, chin electromyography, and extraoculograms. The black arrows indicate a focal seizure at the central vertex (Cz electrode) with spread to the right central region (C4 electrode). This seizure had no clinical correlate

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Amplitude-Integrated EEG aEEG transforms raw EEG by filtering low (<2 Hz) and high (>15 Hz) frequencies, rectifying and smoothing the signal, with a semilogarithmic amplitude compression displayed at 6 cm/h [26, 27]. aEEG can be recorded independently from, or in parallel with, conventional EEG. If a single-channel aEEG is to be recorded in isolation, the parietal electrode positions are recommended (P3 and P4; Fig. 1), since these are over the cerebrovascular watershed zones [26] and may detect more seizures than electrodes positioned over the frontal regions [28]. Most modern aEEG devices utilize dual-channel recordings, recorded from central-parietal channels (C3P3 and C4P4). In some NICUs, both aEEG and conventional EEG are assessed simultaneously. Most often, this is accomplished by displaying the digital trend on the bedside monitor for review by the patients primary medical team, while the full conventional EEG is recorded and interpreted offline by a clinical neurophysiologist. This best of both worlds scenario allows clinical staff to identify concerning changes in the aEEG background patterns and then contact the clinical neurophysiologist for confirmation of the findings. More recently, conventional EEG monitoring groups have suggested employing eight-channel aEEG displays for rapid detection of background changes and seizures [29, 30]. aEEG can provide prognostically significant data regarding the electrographic background in neonates. The signal is displayed on a markedly compressed time scale, which allows the reviewer to assess background trends for multiple hours of recording on a single screen (Fig. 3). This modality has been studied in numerous clinical scenarios, including prematurity [31, 32], HIE [25, 33], congenital heart disease [34], and so forth. The advantage of this modality is that it is relatively simple to implement, and does not necessarily require the skills of an experienced clinical neurophysiologist. However, there is an important learning curve and a

rigorous curriculum for continuous quality improvement is strongly suggested [35]. In many NICUs the neonatologists perform and analyze aEEG independently, although ideally the clinical neurophysiology service should be involved. aEEG background is interpreted according to a simple system, based on the amplitude of the upper and lower margins of the band [36], or a complex pattern recognition system [27], which utilizes terminology adapted from conventional EEG parlance. Both systems have merits, with increased interindividual reliability using the simple system [37] but richer texture in interpretation via the complex system. Although aEEG is clearly useful for electrographic background interpretation, its use for seizure detection is more controversial. For many years, researchers have reported that aEEG can be used to detect some seizures [38], but the limitations of this technique are now being appreciated [28, 3941]. Neonatal seizures are, by nature, brief and spatially restricted [42]. More than half of neonatal seizures last less than 90 s, which translates to a deflection of about 1.4 mm on a typical aEEG screen display [41]. Although the addition of dual aEEG channels with display of the corresponding raw EEG improves seizure detection [40], a significant learning curve remains, and novices are less likely than experts to detect seizures [41]. Note, too, that the raw aEEG tracing remains subject to the filtering and other processing inherent to aEEG, so its appearance is somewhat different from a single channel recorded using conventional EEG. Detailed review of the literature is required to make certain important distinctions regarding the accuracy of aEEG for seizure detection. Most studies report relatively good specificity, but the sensitivity for seizure detection is generally quite low. Some studies discuss the sensitivity of this method for detecting seizure-positive records (ie, at least one seizure detected in a given aEEG tracing containing seizures), while others report the sensitivity and specificity

Curr Neurol Neurosci Rep (2012) 12:429435 Fig. 3 This sample amplitudeintegrated electroencephalography (aEEG) screenshot was recorded from a term neonate with hypoxic-ischemic encephalopathy. Ten seconds of raw EEG tracing are displayed above approximately 3 h of the corresponding left and right hemisphere aEEG traces

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for the detection of individual seizures. Using single-channel aEEG, without the corresponding raw EEG, results in a 25 % to 38 % sensitivity for detecting seizure positive aEEG records [39, 41] and 25 % to 56 % for individual seizure detection [40, 41]. Expert aEEG readers sensitivity is better than novices [41]. Adding a second aEEG channel, along with the raw EEG, improved sensitivity to 76 %, with 78 % specificity, for two expert reviewers [40]. Given the limited ability to identify seizures, aEEG is not considered an equivalent substitute for conventional EEG monitoring for the purpose of seizure detection, although it is likely better than no electrographic monitoring at all. The consistently high specificity is reassuring, since this implies that few infants would be treated based on aEEG monitoring when they do not, in fact, have seizures. Other Methods for Digital EEG Trend Analysis Since conventional EEG monitoring generates a tremendous amount of data and trained clinical neurophysiologists are rarely available for real-time 24-h/day assessments, many centers are turning to digital trend analysis techniques to complement and streamline EEG interpretation. Research specific to neonatal EEG is lacking, compared with the literature for older individuals, but this is clearly an area of great scientific and clinical interest. Envelope Trend Analysis Envelope trend analysis relies on the EEGs amplitude. This modality presents the median EEG amplitude for successive epochs, thereby reducing noise created by brief high-

amplitude artifacts. Envelope trend can identify some neonatal seizures [43], but brief seizures that are of low amplitude or are associated with movement artifact are difficult to detect reliably. Further study is required before this comes into widespread practice. Density Spectral Array Density spectral array uses fast Fourier transform and displays the spectral power of the recorded EEG. Time is plotted on the x-axis, with frequency on the y-axis, and power represented by a grayscale or color code. The neurophysiologist can select the specific electrodes of interest, or the power can be averaged for a set of electrodes (eg, an entire hemisphere). Analysis of the raw EEG is required to confirm seizures detected with this method, since artifacts can lead to increased power and result in false-positives. Spectral edge frequency varies with sleep-wake cycling in healthy term neonates [44]. This modality has been evaluated in isolation [30] and in conjunction with aEEG [45], to allow for efficient interpretation at the bedside, with promising results. Automated Seizure Detection Automated seizure detection is the focus of many research teams [4648]. Neonatal-specific algorithms are required, since electrographic features of neonatal EEG are distinct from those of older individuals. Currently, commercially available algorithms are in use both for conventional EEG and aEEG, but they lack specificity and sensitivity. This is an area of great interest and active innovation.

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Curr Neurol Neurosci Rep (2012) 12:429435 7. Clancy RR, Sharif U, Ichord R, Spray TL, Nicolson S, Tabbutt S, et al. Electrographic neonatal seizures after infant heart surgery. Epilepsia. 2005;46(1):8490. 8. Nash KB, Bonifacio SL, Glass HC, Sullivan JE, Barkovich AJ, Ferriero DM, et al. Video-EEG monitoring in newborns with hypoxic-ischemic encelphalopathy treated with hypothermia. Neurology. 2011;76:55662. This is one of the first studies to systematically evaluate conventional EEG monitoring among neonates with HIE who are treated with therapeutic hypothermia. The authors utilize neonatal brain MRI as a surrogate marker for outcome. 9. Wusthoff CJ, Dlugos DJ, Gutierrez-Colina A, Wang A, Cook N, Donnelly M, et al. Electrographic seizures during therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy. J Child Neurol. 2011;26(6):7248. 10. Brouwer AJ, Groenendaal F, Koopman C, Nievelstein RJ, Han SK, De Vries LS. Intracranial hemorrhage in full-term newborns: a hospital-based cohort study. Neuroradiology. 2010;52(6):56776. 11. Clancy RR, Legido ADL. Occult neonatal seizures. Epilepsia. 1988;29:25661. 12. Murray DM, Boylan GB, Ali I, Ryan CA, Murphy BP, Connolly S. Defining the gap between electrographic seizure burden, clinical expression and staff recognition of neonatal seizures. Arch Dis Child Fetal Neonatal Ed. 2008;93:F18791. This work provides important data regarding the difficulty in accurately diagnosing neonatal seizures via clinical observation alone. Seizures were significantly under-detected by bedside caregivers, while nonseizure events were frequently misinterpreted as seizures. 13. Scher MS, Alvin J, Gaus L, Minnigh B, Painter MJ. Uncoupling of EEG-clinical neonatal seizures after antiepileptic drug use. Pediatr Neurol. 2003;28:27780. 14. Scher MS, Aso K, Beggarly ME, Hamid My, Steppe DA, Painter MJ. Electrographic seizures in preterm and full-term neonates: clinical correlates, associated brain lesions, and risk for neurologic sequelae. Pediatrics. 1993;91:12834. 15. Cherian PJ, Blok JH, Swarte RM, Govaert P, Visser GH. Heart rate changes are insensitive for detecting postasphyxial seizures in neonates. Neurology. 2006;67(12):22213. 16. Pisani F, Copioli C, Di Gioia C, Turco E, Sisti L. Neonatal seizures: relation of ictal video-electroencephalography (EEG) findings with neurodevelopmental outcome. J Child Neurol. 2008;23(4):3948. 17. Perlman JM, Risser R. Can asphyxiated infants at risk for neonatal seizures be rapidly identified by current high-risk markers? Pediatrics. 1996;97(4):45662. 18. Murray DM, Ryan CA, Boylan GB, Fitzgerald AP, Connolly S. Prediction of seizures in asphyxiated neonates: correlation with continuous video-electroencephalographic monitoring. Pediatrics. 2006;118(1):416. 19. Fenichel GM. Neonatal neurology. 4th ed. Philadelphia: Churchill Livingstone Elsevier; 2007. 20. Shellhaas RA, Chang T, Tsuchida T, Scher MS, Riviello JJ, Abend NS, et al. The American Clinical Neurophysiology Societys Guideline on Continuous Electroencephalography Monitoring in Neonates. J Clin Neurophysiol. 2011;28(6):6117. This guideline reflects the state of the art in neonatal EEG monitoring and represents the consensus of an international committee of experts in neonatal neurology. The article details indications and methodology for EEG monitoring, including technical considerations and clinical applications. 21. Epstein CM. Guidelines two: minimum technical standards for pediatric electroencephalography. J Clin Neurophysiol. 2006;23 (2):926. 22. Laroia N, Guillet R, Burchfiel J, McBride MC. EEG Background as predictor of electrographic seizures in high-risk neonates. Epilepsia. 1998;39(5):54551.

Conclusions Although neonates with acute and chronic cerebral dysfunction are at high risk for mortality and neurodevelopmental morbidity, there are opportunities to modify their outcomes. Interventions, such as therapeutic hypothermia, are emerging, and new treatments for neonatal seizures are on the horizon. Certain subpopulations of neonates have substantial risk for seizures, most of which are subclinical, and these seizures may amplify underlying brain injury and impact long-term prognosis. The only way to accurately diagnose and quantify these seizures is through EEG, with long-term conventional EEG monitoring as the diagnostic modality of choice. aEEG can be employed as a complementary tool, and is particularly useful for the assessment of electrographic background evolution over time. Other digital trending modalities are emerging, and may supplement and streamline EEG interpretation. With an increasingly keen focus on clinical neonatal neurology, and an active and rich research environment, there is hope that outcomes for these high-risk patients will be optimized.

Disclosure Conflicts of interest: R.A. Shellhaas: has received grant support from NICHD (5K23HD068402-02), Child Neurology Foundation Shields Fellowship Award, and University of Michigans Janette Ferrantino Award and Woodson Biostatistics Fund.

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