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Year : 2016  |  Volume : 5  |  Issue : 1  |  Page : 18-30

Use of Amplitude-integrated electroencephalography in neonates with special emphasis on Hypoxic-ischemic encephalopathy and therapeutic hypothermia

Department of Pediatric Neurology, Gazi University Medical Faculty, Ankara, Turkey

Date of Web Publication6-Jan-2016

Correspondence Address:
Kivilcim Gucuyener
Department of Pediatric Neurology, Gazi University Medical Faculty, Beşevler, 06500 Ankara
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2249-4847.173272

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Recognizing the need for neurological monitoring in critically ill neonates such as the other vital parameters, neonatologists, and neurologists is becoming more familiar and comfortable with the use of amplitude-integrated electroencephalography (aEEG) in the neonatal intensive care unit, with minimal training and can be interpreted by care providers without neurophysiology backgrounds. In its simplest form, aEEG is a processed single-channel electroencephalogram that is filtered and time compressed. Current evidence demonstrates that aEEG is useful to monitor cerebral background activity, diagnose and treat seizures, and predict neurodevelopmental outcomes for preterm and term infants. This review aims to explain the fundamentals behind aEEG and its clinical applications specially referring to neonatal hypoxic-ischemic encephalopathy and hypothermia.

Keywords: Amplitude-integrated electroencephalography, hypothermia, hypoxic-ischemic encephalopathy, neonatal brain monitarization

How to cite this article:
Gucuyener K. Use of Amplitude-integrated electroencephalography in neonates with special emphasis on Hypoxic-ischemic encephalopathy and therapeutic hypothermia. J Clin Neonatol 2016;5:18-30

How to cite this URL:
Gucuyener K. Use of Amplitude-integrated electroencephalography in neonates with special emphasis on Hypoxic-ischemic encephalopathy and therapeutic hypothermia. J Clin Neonatol [serial online] 2016 [cited 2020 Jul 15];5:18-30. Available from: http://www.jcnonweb.com/text.asp?2016/5/1/18/173272

  Introduction Top

Full-array continuous electroencephalography (EEG) monitoring is the gold standard for brain monitoring and detecting seizures,[1] but it's limited availability and complexity in application of leads and its interpretation have restricted its widespread usage in many neonatal intensive care units (NICUs). A potential solution to these problems is offered by amplitude-integrated EEG (aEEG) or cerebral function monitor (CFM) as it is a simplified method of brain monitoring that can be applied by NICU personnel. Today, aEEG is being used to monitor trends in “cerebral function” in newborn infants, since it has been demonstrated to have a high sensitivity and specificity in predicting neurodevelopmental outcomes in term infants with hypoxic-ischemic encephalopathy (HIE) within the first 6 h of life.[2] Additionally, its potential value has been shown in the early enrollment of infants with HIE into trials of neuroprotective interventions such as mild hypothermia.[3] The availability of simultaneous raw EEG tracing alongside the aEEG trace has significantly enhanced the sensitivity and specificity of aEEG in the detection of background and seizure activity.[4] The aEEG has also been used in preterm infants to detect complications such as intraventricular hemorrhage and for prognostication.[5] Novel use of aEEG in newborns with congenital heart disease is also increasing.[6] Importantly, just as continuous monitoring of vital signs, bedside CFM may help to guide decision-making in real time for neonates admitted to NICU.

  Background and Technology Top

aEEG was first introduced in the year 1960 by Prior and Maynard, as a CFM that was used for intraoperative monitoring of brain activity during surgical anesthesia in adults.[7] In the late 1970s, the use of aEEG spread from London to Sweden, and then to the Netherlands where its application evolved mainly to include neonates both term and preterm.[2],[8],[9] Its leaders summarized their experience in the only existing neonatal aEEG reference Atlas.[10] Afterward the technology has evolved over time, but the underlying rationale for aEEG remains unchanged. It provides an easy-to-use, inexpensive modality to monitor brain function at the bedside.

The technical basis behind aEEG is similar to that of the conventional EEG, the recording measures differences in electrical potentials between electrodes and displays, changes in electrical activity over time. The aEEG represents the processed EEG signal from one- or two-channel, which has been filtered and rectified and then displayed on a semi logarithmic scale. From 0 to 10 µV the scale is linear and from 10 to 100 µV the scale is logarithmic. In this way, a signal at lower amplitude is enhanced, whereas a signal at higher amplitude is attenuated. Low (<2 Hz) and high frequencies (>15 Hz) of the EEG signal are attenuated, and a time-compressed trace is obtained so that typically 6 cm of recording represents 1-h on the x-axis.[10] It is known as the lower margin of the aEEG trace reflects EEG “continuity” and the upper margin reflects EEG wave amplitude [Figure 1]. CFM devices also have an impedance monitoring system to record the state of conductivity of the electrodes and to indicate the occurrence of artifacts [Figure 1].
Figure 1: (a) Upper margin: Represents amplitude, lower margin: Represents continuity, (b) impedance: Measures the state of conductivity of the electrodes, detects artifacts

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In aEEG, a minimum of three electrodes are placed on the scalp, two of which are located on the biparietal region (P3–P4) and the third electrode as a ground (reference) electrode. Additional electrodes can be placed in the central regions (C3 and C4); use of additional channels can improve the sensitivity of neonatal seizure detection [Figure 2].
Figure 2: Biparietal and central electrodes (either jel or needle electrodes are used)

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Two studies have compared the two techniques and found the bihemispheric method to be superior, especially in infants with unilateral brain injury.[11],[12] Parietal and central regions represent the most appropriate location for detecting EEG abnormalities caused by diffuse systemic hypo perfusion, given that it overlies the apex of vascular watershed regions of the brain. Also, most new machines can also display the raw EEG tracing, which facilitates interpretation for artifact and seizure detection.[4] Mostly disposable self-adhesive and pregelled or needle electrodes are used. Skin preparation with a skin abrasive paste such as Nuprep (Bio-Medical Instruments, Warren, MI, USA) is required with the adhesive electrodes and these electrodes need to be replaced or re-injected with conducting gel after 24–48 h. The needle electrodes are quick and easy-to-use, can be securely attached and function well for several days. The aEEG tracing obtained with either type of electrode is identical.

  Amplitude-Integrated Electroencephalography Interpretation and Classification Top

aEEG is usually displayed alongside the source EEG tracing; generally each half of the screen displays one another. It is a graphical display, in which the x-axis represents time and the y-axis represents EEG amplitude. The EEG signal is plotted as a single vertical line representing 15 s sample of data, where the highest point of the vertical line is the maximum and the lowest point is the minimum amplitude. As recording proceeds, a dense band showing the range of activity over time is created.

The width of the band indicates the variability of the amplitude. The appearance of the band is related to the level of continuity; in preterm babies (the EEG is discontinuous) encephalopathic babies, the lower edge of the band falls and the band is wider. In severe discontinuity and burst suppression, the band is very narrow. If the cerebral activity is absent, the result is almost a straight line.

On most monitors, the other half of the screen displays the raw EEG, which can be useful for detailed analysis of seizures or artifacts [Figure 1]. The CFM can detect and record events that could potentially affect the aEEG, such as the administration of medication, therapeutic interventions (as cares or patting), and seizure. This time-synchronized information is highly useful for those reviewing the aEEG at later times to distinguish potential causes of aEEG change. While interpreting aEEG, we have to look for the background pattern, sleep-wake cycling (SWC), and the existence of seizures.

Background pattern

The background activity is the dominant pattern of electrical activity in the whole aEEG tracing. It may vary with arousal, medication exposure, and gestational age. The aEEG background can be characterized by both bay patterns and amplitude. Initial descriptions of the aEEG were based on pattern recognition. A simple amplitude-based classification was created by al Naqeeb et al. method that could be used by clinicians inexperienced in EEG assessment for the selection of infants for trials of neuroprotective therapy with cooling:[13]

  1. Normal amplitude: The upper margin of band of aEEG activity >10 µV and the lower margin >5 µV
  2. Moderately abnormal amplitude: The upper margin of band of aEEG activity >10 µV and the lower margin ≤5 µV
  3. Severely abnormal amplitude: The upper margin of the band of aEEG activity <10 µV and lower margin <5 µV.

The other currently recommended classification combines the pattern of the tracing with measurement of the amplitude:[14]

  1. Continuous pattern: Continuous activity with the lower amplitude around 5–10 µV and maximum amplitude 10–50 µV
  2. Discontinuous pattern: Discontinuous background with minimum amplitude <5 µV and maximum amplitude >10 µV
  3. Burst suppression pattern: Discontinuous background with minimum amplitude at 0–2 µV and bursts with amplitude >25 µV
  4. Low voltage pattern: Continuous background of very low voltage (around or <5 µV)
  5. Inactive, flat pattern: Primarily inactive background <5 µV.

The two methods of interpreting aEEG background pattern have the same prognostication performance in neonates with HIE [15] [Figure 3].
Figure 3: Two methods used for classifying amplitude-integrated electroencephalography (a): ( i) Amplitude-based classification: Normal amplitude. (ii) Pattern based classification: Continuous normal voltage. (b): (i) Amplitude-based classification: Moderatly abnormal amplitude, (ii) Pattern based classification: Discontinous normal voltage. (c): (i) Amplitude-based classification: Severly abnormal amplitude, (ii) Pattern based classification: Burst suppression. (d): (i) Amplitude-based classification: Severly abnormal amplitude, (ii) Pattern based classification: Continuous low voltage, (e): (i) Amplitude-based classification: Severly abnormal amplitude, (ii) Pattern based classification: Flat trace

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Preterm newborns normally have discontinuous aEEG backgrounds with increasing continuity as the gestational age increases. This is reflected by changes in the aEEG activity band with increasing gestational age.[16] By 36 weeks gestational age, the aEEG should look similar to that of a term infant.

Sleep-wake cycling

SWC refers to cyclic fluctuation in the amplitude and degree of discontinuity as the neonate is in various stages of sleep or wakefulness. On aEEG, this is reflected by the presence of smooth sinusoidal variation, mostly in the minimal amplitude. Broadening of the bandwidth represents the discontinuity of quiet sleep, whereas the narrow bandwidth regions represent the lower voltage, more continuous activity during wakefulness or active sleep [Figure 4]. Sleep-wake cycles can be classified as absent, immature, or developed. With the use of aEEG, SWC can be clearly identified as early as 30 weeks gestation and is indicative of better short-term outcome in preterm babies.[17],[18] This cyclicity is often abolished by sedative drugs or following cerebral insults and is sometimes disturbed transiently after some medical or nursing interventions.[19]
Figure 4: Normal trace: Sleep-wake cycling, upper margin >10 μV, lower margin >5 μV, limited variability

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The aEEG background and amplitude can be transiently suppressed after phenobarbital and benzodiazepines, chloral hydrate, and opiates.[20] Also, profound depression of the aEEG has been reported following treatment with fentanyl or large doses of midazolam.[21],[22] The background and amplitude can also be affected by extracerebral factors such as electrocardiogram, respiration, and high-frequency oscillation ventilation. Consequently, the raw EEG signal should always be assessed to find out the reason for the artifacts [23] [Figure 5]a and [Figure 5]b.
Figure 5: (a) Gross artifact due to detached electrodes abnormal high impedance in lower half of slide – cerebral function monitor trace cannot be interpreted. (b) Probable pulse artifact that is abolished by change of position of head

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Since it is impossible to observe the infant continuously and the clinical manifestations are often subtle or even absent, detection of seizures can be difficult in neonates. The electrographic characteristics are variable and the most usual pattern is of a focus of repetitive stereotyped sharp and slow waves migrating from one area of the cortex to another. Neonatal electrical seizures most frequently arise from central or temporal foci with a minimum a duration of at least 10 s and are readily detected with a single pair of central cross-cerebral electrodes, but bilateral recording is preferable in infants with suspected unilateral cerebral infarction or hemorrhage.[24] Several studies examined the utility of aEEG in comparison with conventional and/or video-EEG in this infant population,

finding that aEEG was not only reliable but also complemented cEEG in the diagnosis of neonatal seizures. A pilot study on the feasibility of aEEG in one NICU center showed that 73% of seizures >30 s and 87% >60 s were detected by the aEEG seizure algorithm.[25] The presence of the raw EEG signal on the aEEG monitor may add more value to seizure detection. Shah et al. made a study comparing single-channel aEEG, two-channel aEEG, and two-channel aEEG combined with the raw EEG signal. Interobserver agreement was high (0.67) with sensitivity and specificity approaching 80% when two-channel aEEG was combined with simultaneous raw EEG. When reviewers examined both the aEEG and corresponding EEG tracing, sensitivity for seizure identification increased from 41% to 56% up to 76%.[4] Also in another study of the 851 neonatal seizures detected on conventional EEG, Shellhaas and Clancy showed that 78% originated in the cross-cerebral C3–C4 channel and 81% from the centrotemporal or midline vertex electrodes.[26],[27]

Generally, the peak-to-peak amplitude of an electrographic neonatal seizure is greater than the amplitude of the interictal background, thus most electrographic neonatal seizures on aEEG are characterized as an abrupt, transient, sharp rise in the lower margin, often accompanied by a smaller rise in the upper margin with narrowing of the bandwidth.

Hellstrom–Westas et al. categorize seizures as single, repetitive (more frequent than 30 min intervals), and status epilepticus (SE) (ongoing activity >30 min) [Figure 6]. The interpretation of the raw EEG tracing is important and should show simultaneous seizure activity indicated by repetitive spikes or sharp waves. Multivariate analyses indicated that the expertise with amplitude-integrated EEG interpretation, increasing individual seizure duration, higher seizure amplitude, and larger number of seizures per hour improves the odds of seizure detection on single-channel amplitude-integrated EEG.[28] The aEEG is often used to monitor the response to treatment with anticonvulsants, which is especially useful in infants who are sedated or treated with paralytic agents which suppress or abolish the clinical manifestations of seizures.
Figure 6: Frequent seizures

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Sometimes it is difficult differentiate an artifact from an activity in aEEG in clinical practice. The range of recorded artifact obtained by the assistance of raw EEG tracings varies anywhere between 12% and 60% among published values. Artifacts commonly mistaken for seizures on aEEG include arousal patterns, mechanical ventilation, patient interventions such as patting or chest physiotherapy, sucking or chewing, and electrode artifacts.[26]

An ECG signal will result in elevation of the lower margin of the aEEG tracing, there could also be an artifact from pulsation of the recording electrode causing a repetitive movement. Muscle or movement artifact can result in an artificially broadband or in an abrupt change in the band of activity [Figure 5]a and [Figure 5]b.

  Amplitude-Integrated Electroencephalography and Neonatal Encephalopathy Top

In neonatal encephalopathy either due to hypoxia, ischemia, or hypoglycemia or to any other reason, if the insult becomes severe enough, the EEG becomes depressed as a result of the compromised neuronal function that is not specific for a certain type of insult. Since the most frequent cause of neonatal encephalopathy is HIE, most of the clinical studies of the CFM have been carried out in infants with HIE. Infants with mild HIE with a continuous or slightly discontinuous aEEG with absent cyclicity [Figure 7] and [Figure 8] are more likely to have the good outcome, while infants with severe HIE have a severely abnormal aEEG background (low voltage, inactive), absent of SWC and have a high risk for adverse outcome (death or severe handicap) [Figure 9]. However, the outcome is more uncertain in infants with burst suppression; there is an almost 50% chance that the infant will survive without handicap if the aEEG background becomes continuous within the first 24 h.[29] In infants with moderate HIE, the time at onset and the quality of SWC is associated with outcome. The onset of normal SWC within the first 36 h was associated with normal outcome while infants with later onset of SWC or abnormal SWC were more likely to have neurological handicap.[30]
Figure 7: Moderately abnormal trace with burst suppression pattern

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Figure 8: Two-channel amplitude-integrated electroencephalography trace moderately abnormal background seizures predominant on the left side

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Figure 9: Two-channel amplitude-integrated electroencephalography trace severely abnormal background seizures predominant on the left side

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  Amplitude-Integrated Electroencephalography as a Prognostic Tool Top

Before the hypothermia therapy

Many studies have shown that aEEG background activity is known to be a sensitive predictor of brain injury and later neurodevelopmental outcome in term babies with HIE. Several studies have shown that 6 to 12 h of life is the period during which the aEEG background is most valuable.[2],[9],[13] Sensitivities in these studies range from 91% to 100% with positive predictive values (PPVs) of nearly 85%. One study showed that both the early aEEG and clinical examination within the first 12 h of birth increased the PPV and specificity compared with either method alone.[31] An early normal or slightly abnormal aEEG/EEG background pattern is almost mostly associated with good outcome.[2],[9],[13],[32] Many cases with the recovery of EEG activity within 24 h of birth also make a good clinical recovery.[29],[33] Therefore, the prognostic accuracy of the aEEG is dependent on the timing of the assessment. A burst suppression pattern, continuous low voltage, or flat trace persisting beyond 24–36 h indicates a high probability of an abnormal neurodevelopmental outcome at 18–24 months.[2],[9],[13],[31],[32] A recent systematic review reported that aEEG performed within 24 h of birth has a sensitivity of 93% (95% confidence interval [95% CI]: 85–97%) and specificity of 91% (95% CI: 67–98%).[34] The duration of monitoring may be important as well, as several studies advocate longer monitoring beyond 24 h due to a later normalization of the abnormal aEEG background pattern. ter Horst et al. recorded aEEG traces from asphyxiated infants during the first 72 h. The likelihood ratio for burst suppression or continuous low activity or flat trace for predicting adverse outcome was 2.7 (95% CI: 1.4–5.0) during the first 6 h and increased to 19 (95% CI: 2.8–128) between 24 and 36 h but was insignificant after 48 h. Normal voltage patterns were predictive of normal neurologic outcomes up to 48 h.[32] van Rooij et al. showed that in infants with severely abnormal patterns at 6 h, recovery to normal by 24 h resulted in mild or no disability in 61% of infants.[29] Like the aEEG background activity changes, neonates with HIE have noticeable differences in SWC with regard to the severity of encephalopathy. A shorter time of onset, increased duration of active sleep, and quality of SWC can all provide prognostic value in these cases.[2],[9] Osredkar et al. reported that in asphyxiated neonates, SWC appearing before 36 h after birth was associated with better outcome.[30]

After hypothermia therapy

Should aEEG be used to determine which neonates to cool?

Therapeutic hypothermia (TH) is now standard of care in patients with neonatal asphyxia to reduce secondary neuronal death that occurs after the initial insult. Infants with moderate encephalopathy are those who most likely benefit from TH and; aEEG has been used to help identify these neonates. The aEEG was used to help the selection of patients in the CoolCap trial of selective head cooling with mild systemic hypothermia as well as a biomarker of the outcome.[3] In the sub-analysis, those infants with evidence of moderate encephalopathy on aEEG (i.e., a discontinuous pattern) benefited from hypothermia, whereas those with evidence of severe encephalopathy (i.e., burst suppression, continuous low voltage, or flat trace) on aEEG did not show significant benefit. Selective head cooling was found to decrease the risk of death or severe neurodevelopmental disability at 18 months of age.[3] The total body hypothermia for neonatal encephalopathy (TOBY) trial likewise used aEEG for entry criteria in subject selection to receive cooling therapy. The results showed similar findings; more of those infants with severe abnormal aEEG died or had a severe disability than those of with moderately abnormal aEEG traces.[35] Following the use of aEEG in these pioneering trials, although another major trial did not use aEEG for entry criteria for subject selection,[36] many centers now use aEEG in their clinical protocols for evaluating the severity of encephalopathy and in deciding which neonates might benefit from cooling. However, there is still some debate ongoing whether aEEG should be used as selection criteria for the subjects to be cooled or not after a study by Sarkar et al. which found up to 30% of infants with normal aEEG tracings taken during the first 6 h but clinical signs of encephalopathy had early death or abnormal magnetic resonance imaging (MRI) findings and thus could potentially benefit from TH?[37] Thus, for neonates with suspected HIE, aEEG can be a useful adjunct for assessing the degree of severity in selecting patients for TH, but it should not be used as the sole criteria, current criteria for eligibility for cooling treatment rely primarily on the clinical assessment of encephalopathy.[38]

  Does Amplitude-Integrated Electroencephalography Predict Neurodevelopmental Outcome in Neonates Receiving Therapeutic Hypothermia for Hypoxic-Ischemic Encephalopathy? Top

Although the predictive value of aEEG/EEG will change in neonates with HIE receiving TH, aEEG can still help to predict neurodevelopmental outcome. An early normal continuous or merely discontinuous aEEG background pattern at 3–6 h with SWC will be associated with good outcome, but delayed recovery of abnormal traces may also be associated with a good outcome.[39],[33] Hallberg et al.[39] recorded aEEG/EEG during cooling in 23 term babies; all 5 infants with a normal background pattern at 6 h had a normal outcome however not only 10/15 infants with initial burst suppression or a worse aEEG pattern at 6 h but also 4/10 infants with severely abnormal aEEG pattern at 24 h normalized between 36 and 48 h had a good outcome at 1-year. Severe aEEG background patterns were only predictive of adverse outcome after 36 h. Thoresen et al. compared the predictive value of aEEG/EEG in cooled and noncooled infants.[33] The PPV of an abnormal aEEG between 3–6 h was 84% in noncooled and 59% in cooled babies. Infants with good outcome had normalized background pattern by 24 h in the noncooled group and 48 h when treated with hypothermia. Thus, there are many neonates with abnormal aEEG background at 3–6 h that go on to have normal outcomes following hypothermia. Similarly, Shankaran et al. found an abnormal trace at 36 h was associated with poor outcome with an OR of 10.7.[40] Azzopardi et al., by analyzing the results of the randomized TOBY trial, showed that the predictive value of aEEG within 6 h of birth was lower in the cooled group than in the noncooled group, both in infants with moderate as well as in those with severe suppression of the aEEG and the best PPV was obtained when the low voltage and flat trace patterns were combined as the most severely abnormal patterns (PPV of 59% vs. 71% for the cooled and noncooled groups, respectively).[41] Furthermore, the presence of SWC on early aEEG can also help to predict the neurodevelopmental outcome. The study by Thoresen et al. found that the median time of onset of SWC associated with good outcome was 24 h in the noncooled group and 36 h among neonates receiving TH. Never developing SWC was strongly predictive of poor outcome.[33] All the findings from these studies suggested that the altered predictive value is a consequence of the hypothermia intervention and cooling has a beneficial effect in infants with a wide spectrum of severity of encephalopathy. Thus, aEEG is one of the good biomarkers that may help us when counseling parents about the need for TH and the likely outcome of affected infants [Figure 10].
Figure 10: (a-e) The evaluation of amplitude-integrated electroencephalography trace before, during hypothermia, at rewarming and after rewarming. (a) Severely abnormal trace (flat low amplitude burst with low amplitude evolving to moderately abnormal trace), (b) moderately abnormal trace and cooling starts, (c) normal continuous trace during cooling and rewarming is done, (d) discontinuous normal voltage, (e) continuous normal voltage with sleep-wake cycling

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  Seizures and Hypoxic-Ischemic Encephalopathy Top

Hypothermia treatment and seizures in hypoxic-ischemic encephalopathy, does therapeutic hypothermia has an anti-epileptogenic effect?

Neonatal seizures are associated with an increased incidence of brain injury and long-term neurodevelopmental delay.[42] Approximately, 50–75% of neonatal seizures at term are due to HIE, and between 20% and 50% of neonates with seizures experience later epilepsy.[43],[44] Prior to hypothermia area electrographic seizures were reported in more than half of neonates with HIE, SE was a frequent cause and the overall seizure burden was high.[45] Animal and human studies suggested that neonatal seizures in the setting of HIE could lead to long-term neurodevelopmental deficits.[46],[47] There is increasing evidence that seizures themselves may be harmful to the developing brain, and confer a risk for adverse outcomes independent of the severity of hypoxic-ischemic injury detected on MRI.[44],[48],[49]

TH is the only effective treatment currently available for neonates with HIE and has become the standard of care reducing morbidity and mortality.[50] Question is whether cooling reduces the incidence of seizures in neonates with HIE. Animal studies indicate that cooling therapy is associated with less epileptiform activity and fewer seizures. According to a fetal sheep model of severe hypoxia-ischemia, cooling was associated with a reduction in the number of epileptiform discharges in the first 6 h after asphyxia and a reduction in both early and late seizure amplitude.[51] Hypothermia also had anticonvulsant properties in an epilepsy model of rats treated with clinic acid.[52] Numerous studies have shown that seizures frequently occur with HIE at presentation, during cooling, and with rearming. The CoolCap Study reported seizures in 60% of the infants,[3] but whole body cooling study found that 45% of the infants had seizures at time of enrollment.[36] During or immediately following hypothermia, electrographic or clinical seizures were noted in 30% to 90% of the infants.[53],[54],[55],[56]

Although meta-analyses of randomized controlled trials fail to show an effect of cooling on seizures in neonates,[50],[57] single-center observational studies indicate that TH can decrease the incidence of seizure and seizure burden.[58],[59],[60] Low et al. found that hypothermia did not reduce the total number of seizures in a hypothermic group compared with a normothermic group with moderate HIE but demonstrated that the total number of minutes seizing was reduced in the hypothermic group (60 vs. 203 min), but this result was not valid for the severe HIE group.[61] Another study conducted by Srinivasakumar et al. confirmed these results by showing that TH was associated with reduced electrographic seizure burden in babies with moderate but none in those severe HIE and in neonates with mild or moderate brain injury but not in those severe brain injury as seen in MRI.[62] Perinatal stoke has also been associated with a significantly lower frequency of seizures when treated with TH.[63]

Glass et al. reported on a cohort of infants with HIE from three different centers who underwent TH and continuous EEG monitoring. Monitoring was initiated within the 1st day of life and continued for at least 24 h. Seizures occurred in nearly half of the infants in this study, with most of them developing during the period of cooling. They found that the early EEG background, rather than clinical signs of encephalopathy, or any other perinatal risk factors, was the most predictive of seizures.[61] Another recent study also examined the relationship between TH and the seizure burden in a cohort of neonates with HIE who had admitted to the center either before or after the cooling program had started. Cooled newborns with moderate encephalopathy were much less likely to have either clinical or electrographic seizures compared to noncooled newborns (cooled: 26% vs. noncooled: 61%, P < 0.001), but there was no difference in the risk of seizures among newborns with severe encephalopathy (cooled: 87% vs. noncooled: 83%, P = 0.8).[62]

All the above data support preclinical and clinical studies that suggest TH may have anti-epileptogenic effects. The use of aEEG is now part of the standard protocol in many centers in HIE management and this method provides the possibility of increasing the diagnosis of electrographic seizures with or without clinical seizures where the gold standard continuous video-EEG monitoring is not available.

Seizure onset and hypothermia treatment

In one study of neonates with HIE, the authors reported a mean age of electrographic seizure onset of 35 h with more than half of the patients having seizure onset at <24 h of age and the latest age of electrographic seizure onset was defined as 95 h.[55] Low et al. showed that there was no statistically significant difference in the time of seizure onset in a group of neonates undergoing TH compared to a normothermic group (normothermic: 18 [12–22] h vs. hypothermic: 13 [11–22] h).[59] In another study where the neonates were under hypothermia treatment due to HIE, it was shown that a median age of seizure onset was at 18 h and the latest age of electrographic seizure onset was 62 h.[61] New or recurrent seizures during the re-warming period (after 72 h) have also been described in several studies an entity that should be kept in mind.[53],[61],[63] In the study done by Shah et al., seizures were the most frequent in 6–12 h after birth, followed by a diminution in seizure frequency over the following 2 days with a significant increase in the incidence of seizures on the 4th day, coinciding with rewarming period.[64]

Status epilepticus and hypothermia

SE is seen in neonates with both moderate and severe HIE.[58],[47] A recent study of 56 term neonates with SE demonstrated a correlation between longer seizure duration and adverse neurodevelopmental outcomes, specifically in a subgroup of 48 HIE neonates. In a study by Wusthoff et al., 23% of the neonates with HIE and neonatal seizures undergoing TH continued to have SE.[54] SE was observed in 10% of the hypothermic neonates in a study by Glass et al.[55] In a group undergoing TH studied by Srinivasakumar et al., 5/19 of neonates with SE were noted to have severe brain injury on MRI.[59] Nash et al. also reported that 4 of 15 neonates treated with TH had status SE and moderate-to-severe brain injury.[65] It is important to notice that neonates with HIE undergoing TH may have periods of SE that may be a risk factor for brain injury.

Given the altered profile of neonatal seizures in babies with HIE and the possibility of sedation makes seizure detection even more important and challenging in these population. Additionally, in neonates with HIE, we do not know which clinical features are going to predict which neonate is going to have a seizure and because clinical observation is not adequate for a correct diagnosis; recent guidelines have suggested that neuromonitoring should be available for seizure detection in all neonates undergoing TH for HIE either by continuous video-EEG or aEEG.[66],[67]

Seizure treatment during therapeutic hypothermia

Treatment of neonatal seizures is to prevent clinical deterioration, further brain damage, poor neurodevelopmental outcomes, and to reduce the risks of future epilepsy.[48],[67] There are no randomized controlled trials comparing the effects of seizure treatment versus no seizure treatment on short- or long-term neurodevelopmental outcomes. The 2007 Cochrane review concluded that “anticonvulsant therapy to term infants in the immediate period following perinatal asphyxia cannot be recommended for routine clinical practice, other than in the treatment of prolonged or frequent clinical seizures.”[68] Regardless of etiology, most of the clinicians recommends phenobarbital as the first-line antiepileptic drug to treat neonatal seizures.[69],[70],[71] Phenobarbital and phenitoin were found to be equally effective in less than half of the patients in a randomized control trial of 59 neonates with seizures [72] and up to date, no evidence is shown to suggest that phenobarbital improves the benefit of TH in infants with HIE.[73] Luckily, the majority of the data so far suggest that hypothermia does not significantly affect the clearance of phenobarbital when along with TH in those babies.[74],[75] If seizures continue after an initial treatment with phenobarbital, then a second dose of phenobarbital is recommended. The second-line treatments recommended for ongoing seizures are phenitoin, leveteracetam, and lidocaine. Midazolam bolus and infusion are recommended as a third line of treatment for refractory seizures.[69], 70, [75],[76],[77] van den Broek et al. showed that lidocaine clearance was reduced by 24% in neonates having TH as compared to controls, and the authors suggest a modified lidocaine protocol with a shortened infusion time for the babies with refractory seizures under hypothermia treatment.[78] Only a small study investigated the effect of hypothermia on the clearance of midazolam infusion and found no effect.[79] Topiramate was also effectively used in neonates undergoing hypothermia for HIE, and the drug plasma concentrations was found in the reference rage.[80]

Hypothermia and improved monitoring can contribute to improved neurologic outcomes among cooled neonates with moderate encephalopathy by reducing seizure burden and leading to a decrease in the use of unnecessary anticonvulsant medications. More studies are necessary to clarify the role of aEEG monitoring in this population, as well as the mechanisms underlying reduced seizure risk associated with TH and related long-term neurologic outcomes.

  Conclusion Top

The use of aEEG has proved to be of clinical value in sick neonates; it does not replace the standard EEG but should be used as a complement to EEG in high-risk infants in NICUs. The aEEG trace in term infants with newborn encephalopathy is sensitive and specific for early prediction of later neurodevelopmental outcomes. This in turn reflects the degree of encephalopathy and cerebral abnormality on MRI. Digital aEEG monitors that provide one or two-channel of raw EEG with the aEEG trace have been shown to detect 80% of all electrographic seizures in the newborn. In addition to predicting neurodevelopmental outcomes and seizure detection, it is hoped that aEEG might be able to give us a better understanding of how different interventions may affect brain activity either.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10]


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