Cerebral Function Monitoring In Neonatal Intensive Care Units

Aysen Orman, Nilay Hakan, Atika Çağlar, Mustafa Aydin

Aysen Orman, Atika Çağlar, Mustafa Aydin, Department of Pediatrics-Neonatology, Firat University School of Medicine, Elazig, Turkey
Nilay Hakan, Department of Pediatrics-Neonatology,SitkiKocman University School of Medicine, Mugla, Turkey

Conflict-of-interest statement: The author(s) declare(s) that there is no conflict of interest regarding the publication of this paper.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http: //creativecommons.org/licenses/by-nc/4.0/

Correspondence to: Mustafa Aydin, MD, Department of Pediatrics-Neonatology, Firat University School of Medicine, 23119, Elazig, Turkey.
Email: dr1mustafa@hotmail.com
Telephone: +90 (424) 233 35 55
Fax: +90 (424) 238 80 96

Received: June 19, 2018
Revised: November 27, 2018
Accepted: November 30, 2018
Published online: December 23, 2018


AIM: Cerebral function monitoring with amplitude-integrated electroencephalography (aEEG) device is a method for continuous monitoring of brain activity that is increasingly use in neonatal intensive care units.

METHODS: In its simplest form, aEEG is a processed single-channel EEG that is filtered and time-compressed.Several classifications are currently in use to describe patient’s tracings, voltage criteria, pattern recognition, cyclicity, and the presence of seizures.

RESULTS: The main usage of the aEEG currently is for select newborns with birth asphyxia who benefit from therapeutic hypothermia and for predict of their long-term neurological prognosis. The early aEEG traces of preterm infants also predict of their neurodevelopmental outcome. Current evidences demonstrated that aEEG is useful for define cerebral background activity, detect seizures, monitor treatment effects and predict neurodevelopmental outcomes of newborns. The main advantages of this device are its simplicity for both application and interpretation on one hand and the possibility of continuous long-term monitoring with real time assessment of clinical events on the other.

CONCLUSION: aEEG is a safe and reliable method for the bedside monitoring of neonatal cerebral function and it can also provide information about long-term neurological prognosis.

Key words: Cerebral function monitoring; Amplitude-integrated electroencephalography; Newborn infant; Treatment; Prognosis

© 2018 The Author(s). Published by ACT Publishing Group Ltd. All rights reserved.

Orman A, Hakan N, Çağlar A, Aydin M. Cerebral Function Monitoring In Neonatal Intensive Care Units. International Journal of Neurology Research 2018; 4(1): 464-471 Available from: URL: http://www.ghrnet.org/index.php/jnr/article/view/2366


The amplitude-integrated electroencephalogram (aEEG) is a filtered and time-compressed EEG traces that can be used for long-term cerebral function monitoring (CFM) in patients of all ages. The difficulty of using conventional electroencephalogram (cEEG) in neonatal intensive care units (NICUs) has led to the introduction of the aEEG as an auxiliary device for CFM. Nevertheless, cEEG remains the gold standard in identification and localization of neonatal seizures.

The aEEG device was originally developed by Maynard and Prior in 1960[1,2]. It has been used in different age groups until now ranging from open heart surgeries to premature infants follow up in NICUs[3,4]. Currently, it is mostly used for decision making about starting therapeutic hypothermia and clinical follow-up offull-term neonates with perinatal hypoxic ischemic encephalopathy (HIE). aEEG has also been shown to be useful in predicting neurodevelopmental outcomeof neonates with HIE. Another area where aEEGis used is the identification of seizures and the assessment of the effectiveness of used therapies[5,6]. Recently, it has also been used to determine the effects of pulmonary hypertension and congenital heart diseases on the brain.

Studies have shown that there is a good correlation between aEEGand conventional EEG signals. The aEEG is usually recorded from one or two channels derived from parietal, central, or frontal electrodes. Therefore, it is considered as a single-channel EEG monitor[7,8]. aEEG is based upon cEEG that is recorded with two or four scalp electrodes, depicting the amplitude of the raw EEG on a time-compressed semi-logarithmic scale. The electrodes of the device are placed on biparietal P3-P4 or central C3-C4 localizations (Figure 1)[9]. The signals from these regions are amplified first and then recorded at a rate of 6 cm per hour after being filtered through various filters to purify the artifacts caused by muscle activities or surrounding electronic devices[10]. aEEG can be affected by other technical factors such as respiratory movements, interelectrode distance, head skin edema, electrocardiographic artifacts, and high frequency ventilation. Muscle or movement artefacts can result in a broad band or sudden changes activity recordings. Repetitive movements cause a similar appearance to seizure activity. Therefore, the artifacts should always be excluded and EEG traces without artifacts should be evaluated[11]. Hence, it is also important to control the impedance of the aEEG, which reflects the quality of contact between the skin and the electrode. Poor contact or low impedance can cause to emergence of artifacts and so artificially increase of the voltage of aEEG. Silver-silver electrodes and coaxial cables which traditionally used in the original aEEG device reduce the artefacts that are caused by motion or equipment[12,13].

Figure 1 Determination of localizations to place electrodes.

A special bandpass filter enhances frequencies between 2 and 15 Hz. Frequencies < 2 Hz and > 15 Hz are attenuated in order to eliminate artefacts. Amplitudes < 10 μV are displayed on a linear scale and amplitudes >10 μV on a logarithmic scale. The lowest-detected amplitude is shown as the lower border, and the highest amplitude is shown as the upper border. By this means, even small changes in the lower amplitude remain visible, while an overloading of the display at high amplitudes is avoided. Due to time compression, 5 - 6 cm on the time scale represents 1 h, thus making the review of brain activity for hours and even days possible[14,15]. The visible information in the aEEG traces is limited to changes of the amplitude. Modern devices offer the possibility of viewing the raw EEG, so the frequency and morphology of the raw EEG curve can also be considered for interpretation. This helps to distinguish between artefacts and real seizure activity during suspicious sections of the aEEG band. Broad-band filter often rejects the less than 2 activities per second[14].

Although aEEG offers the possibility for continuous CFM in neonates, itgives less information than a cEEG. The cEEG, using the international 10-20 system of electrode placement, is considered the gold standard for detecting electro-clinical or electrographic seizures, but the short duration of routine EEG may miss clinical or electrographic seizures. Moreover, it requires the compensator equipment and evaluation by a specialized neurologist. Another EEG monitoring protocol is continuous video-EEG. The American Clinical Neurophysiology Society guideline recommends that continuous EEG monitoring combined with synchronized video-EEG can be used for high-risk patients, including those with HIE, to screen for seizure activity. However, aEEG is straightforward to apply and can be monitored by neonatologists or nurses. More than half of neonatologists are utilize aEEG with practice variations by NICU settings[16]. But, in the study of Rakshasbhuvankar et al. where aEEG and conventional video EEG was compared[17], aEEGhad low (33. 7%) sensitivity for detecting the seizures lasting less than 5 minutes.

Hence, this review aims to explain the fundamentals and clinical applications of the aEEGfor clinical practitioners.

aEEG classification

The standard aEEG contains minimum and maximum peak variability of the filtered EEG amplitude. It appears as an activity band passing slowly on the display screen. The width of the band indicates the variability in the aEEG amplitude. In healthy newborns, there are regular changes in the width of the band according to the sleep-wake state and fluctuatesbetween approximately 10 and 40 μV (Figure 2A)[18,19]. The interpretation of the EEG is basically based on the sleep-wake cycles (SWCs) and the presence of seizures (Table 1).

Figure 2 Background aEEGpatterns: A, normal pattern in a full-term neonate (lower limit > 5 μV and upper limit > 10-25 μV); B, normal aEEG voltage in which the sleep-wake patterns are observed (* REM period and ** non-REM period).

Table 1 aEEG interpretation (background, presence of seizures, sleep-wake cycle).
Background Seizure activitySleep-wake cycle
Low voltageStatus epilepticus 
Flat tracing --
CNV: Continuous normal voltage; DNV: Discontinuous normal voltage

aEEG traces

Background activity in the aEEG trace is an indicator of electrical activity. Background activity varies with gestational age and drug exposure. In small preterm babies, the aEEG background is discontinuous with episodes of high amplitude activity alternate with low amplitude activity. As the gestational age increases, the aEEG background pattern becomes continuous as in full-term babies[20]. The aEEG background patterns are classified according to the upper and lower limit values of the activity bands (Table 2).

Table 2 Classification of background activity in aEEG (lower and upper limit values of activity bands).
Background Lower limitUpper limitInterpretation
CNV > 5 μV> 10-25 μVNormal
DNV< 5 μV> 10 μVLow amplitude can be variable
Burst-suppression< 5 μV -Amplitude can rise to 25 μV with burst
Low voltage< 5 μV< 5 μVThere may be some variables
Flat tracing< 5 μV < 5 μVIsoelectric line
CNV: Continuous normal voltage; DNV: Discontinuous normal voltage

Two major factors in the classification of aEEG traces are voltage and pattern. Voltages in the trace are classified as normal, abnormal, and low. Interpretation of the aEEG usually involves three categories; (a) classification of the background pattern, (b) SWC and (c) presence of seizure activity. Hence, aEEG traces observed in full-term neonates can be evaluated under six main groups[21]:

1. SWCs: Normal voltage seen in healthy babies is characterized by wide awake and narrow sleep bands. The normal SWC seems to curl up and down like a snake with narrowing and expanding traces. The lower limit of the aEEG pattern should be > 5 μV and the upper limit should be > 10 μV. Narrow band occurs during rapid eye movement (REM) period and wide band during non-REM period (Figure 2B)[22]. The absence of SWCs may also suggest presence of immature brain. The presence and quality of SWCs reflect the severity of the hypoxic-ischemic insult. But, there may be significant changes in the SWCs regardless of the severity of encephalopathy in newborns underwent perinatal asphyxia. In addition, the time of onset of SWC has a predictive value for neurodevelopmental outcome[23]. However, further studies are needed in this respect.

2. Wave-pattern: It is seen before the completely normal trace appears in infants who recovering from hypoxic-ischemic injury. Voltage is normal, but lower (< 5 μV) and upper (> 10 μV) voltage fluctuations are seen.

3. Absence of sleep-wake pattern: It occurs after mild injuries and often following a normal sleep-wake cycle pattern. There are abnormal voltage band traces of fixed width.

4. Burst-suppression: It is seen in moderate or severe injuries. The longer it takes, worse the prognosis. Short-duration high-voltage bursts occur on a low-voltage trace that producewide bands where the upper limit can be < 5 μV and the upper limit can exceed 10 μV (Figure 3)[24].

5. Isoelectric line: It is seen after severe hypoxic ischemic injury and predicts the poor prognosis. There are low-voltage traces which showing no fluctuation on an inactive background < 5 μV (Figure 4)[25].

6. Seizure: The seizures must be continued for at least ten minutes in order to be visible in the aEEG. Seizures can also be subclinical (subtle). It is difficult to distinguish short-term seizures from artefacts in aEEG traces. During the seizure, upper limit may be as high as 50 μV, so increased voltage changes are observed on the above-mentioned traces. If repeated frequently, a “saw-tooth” appearance will occur (Figure 5)[26].

Figure 3 Burst suppression pattern (arrow showing a burst in raw EEG).

Figure 4 Isoelectric line and artifacts (arrows).

Figure 5 ”Saw-tooth” appearance due to frequent seizures (arrows) and moderately abnormal aEEG trace after phenobarbital (asterisks).

aEEG in clinical practice

Currently, aEEG is often used in the NICUsettingsto detect seizures and predict the prognosis in full-term neonates with HIE. However, it is increasingly used for the determination of neurodevelopmental effects of persistent pulmonary hypertension and congenital heart diseases[27].

aEEG in patients with HIE

During the neonatal period, aEEG has been generally studied in full-term neonates who developed HIE secondary to perinatal asphyxia. It is known that aEEG patterns are the early predictor of brain damage in these patients. Low voltage and flat isoelectric activity are associated with poor prognosis[28]. Many studies reported that aEEG traces within the first 6-12 hours period of hypoxic-ischemic insult are very valuable[29,30]. In the total body hypothermia (TOBY)study, aEEG was used as an adjunct to determine patients who should undergo to therapeutic hypothermia. After the use of aEEG in these trials, many centers have added aEEG to their clinical protocols for evaluating the severity of encephalopathy and deciding on brain cooling therapy.

Marics et al[31] retrospectively assessed the causes and prevalence of false-positive interpretation of aEEG in newborns with moderate to severe HIE. The muscle artefacts can especially lead to an incorrect evaluation of aEEG traces. Because the seizures are common in the first 1-2 days of life in newborns with HIE, aEEG or video EEG is recommended in these patients[32,33]. The aEEG is interpreted by measuring the waves’ amplitude and monitoring the pattern (Table 3, Figure 6)[22].

Figure 6 Interpretation of theaEEGtraces by wave amplitude and pattern.

Table 3 Comments on background activity of the aEEG.
Pattern 1 Minimum amplitude 5-10 μV and maximum amplitude 10-50 μV in the continuous background
Pattern 2 Minimum amplitude < 5 μV and maximum amplitude > 10 μV in the discontinuous background
Pattern 3 Minimum amplitude 0-2 μV and burst amplitude > 25 μV in the discontinuous background
Pattern 4 Very low voltage < 5 μV in the continuous background
Pattern 5 Inactive, flat background activity of < 5 μV

Effects of hypothermia on aEEG traces

There is a direct correlation between the degree of hypothermia and the suppression in the aEEG amplitude. Periodic complexes at 30 °C, suppression at 25 °C, “burst” activity and an isoelectric line at 17 °C emerge in the aEEG. However, hypothermia in which the internal temperature of the body is cooled to 33-34 °C in the case of HIE does not affect the aEEG traces. The initiation of hypothermia to babies with HIE who have moderate to severe abnormal aEEG patterns within the first 6 hours after birth positively affects the neurological outcomes. In a study which comparedcooled infants with non-cooled infants the positive predictive value of aEEG was low (64-75%) within 6 hoursafter birth; but it reached to 80% in both groups within 24-36 hours after birth[34]. In another study, it was reported that possibility of severe neurological damage was high (>80%) in patients having severe suppression in aEEG in the first 48 hours of life[35]. It is still unclear that whether the recovery time of pathological findings in aEEG is changed by cooling therapy.

aEEGfor detection of neonatal seizures

Seizures in the newborns are often difficult to detect because they are generally subclinical[36]. This may be detrimental to the immature brain and may negatively affect the long-term neurodevelopmental outcomes. Neonatal seizures are rarely idiopathic; they are commonly a manifestation of serious central nervous system diseases. Main causes of seizure in neonates are HIE (30-50%), intracranial hemorrhages (10-17%), hypocalcemia (6-15%), hypoglycemia (6-10%), central nervous system infections (5-14%), infarcts (7%), inborn error metabolism(3%) and idiopathic (10%)[37].

The electrographic features of the neonatal seizures are quite diverse. Interhemispheric bilateral synchronized seizures are rare. Electrical seizures in the newborn infants are usually originated from central or temporal foci. In general, the seizure pattern of repetitive sharp spikes and slow waves that originated from one focus and travel from one side of the cortex to another is frequently encountered. Therefore, aEEG has been a major curiosity in the detection of seizures, the selection of anticonvulsant treatment and the evaluation of effectiveness of treatment. The limited number of electrodes applied duringaEEG monitoring may failto detect the spatially distributed seizure activities. This reduces the sensitivity of aEEG in neonatal seizures[38]. However, it may be difficult to detect the seizure in a time-compressedaEEG screening if the neonatal seizure duration is short (60% of seizures last around 90 seconds)[23].

Nonetheless, specificity is more reliable; very few false positive results have been reported in systematic studies[39]. Shellhaas et al[39]evaluated the effects of aEEG on neonatal seizure and reported that aEEG had no effect on the use of antiepileptic drugs and ordering of neuroimaging studies but reduced unnecessary treatments initiated accidentally by considering clinical seizure. Epileptic seizures are more frequent in neonatal period compared to older children. They usually occur in case of encephalopathy and have a very wide etiology. In a study, Mastrangelo et al. [40] compared the cEEG and aEEG in terms of electrographic seizure detection in neonates with acute neonatal encephalopathy and reported that aEEG could be easily recognized prolonged electrophysiologic seizures, but missed half of short single seizures. Reliability of the aEEG in terms of detecting seizures has been questioned by many authors. Because aEEG is sensitive to amplitude changes, but insensitive to frequency changes, discharges which do not make a significant increase in amplitude maybe missed[41]. A wide range of sensitivities (26% to 76%) have been reported in studies conducted to determine neonatal seizures[42,43]. The visible information in amplitude changes duringaEEG monitoring is limited. Modern aEEG devices offer the ability to display raw EEG, so the frequency and morphology of the raw EEG curve can also be interpreted, andalso, it helps to differentiate artifacts from true seizure activitiesin the EEG band[6,23,36]. Some aEEG devices records the patient’s video simultaneously for better interpretation of seizure and artifacts. It can detect unrecognized seizures due to long recording time. Therefore, the aEEG is not intended to replace cEEG, but to complete it[6,22]. Eventually, use of EEG and aEEGtogether is recommended in cases of hypoxiaand/orintractable seizures[44].

Use of aEEG in preterm infants

The use of aEEG in preterm infants has become an active research area. aEEGbackground activity in preterm infants was found to be more irregular compared tofull-term newborns. There are more frequent bursts and low voltage times on the aEEG signal[45,46]. aEEG is quite irregular during the 24-25th gestational week, and the irregular amplitude and width gradually decrease as the maturity increases[47,48]. Full-band aEEG analysis identifies specific unusual findings in preterm infants. Some findings such as the “delta brush” and “saw-tooth” occur at specific gestational ages. Sleep-wake state in aEEG differs from 30th gestational week and evolves exactly at the 37th gestational week[49].

Effects of drugs onaEEG traces

Several drugs affect the background of aEEG amplitude. Sedatives like chloral hydrate, opiates andanticonvulsant drugs like phenobarbital and benzodiazepines temporarily suppress the EEG. Fentanyl and high dose midazolam treatments can cause deep depression in aEEG. Therefore, aEEG assessment made within 30-60 minutes after drug exposure may result in misinterpretation of the encephalopathydegree[50-52].

aEEG in prediction of prognosis

The diagnostic value of cEEG on brain damage has been proven by conducted studies. aEEG has a high diagnostic value in neonates developed encephalopathy within the few hours after birth. It has been reported that aEEG is a good tool as other clinical, radiological and neurophysiological evaluations in terms of predicting neurodevelopmental outcomes in newborns with HIE[53].

Features showing good prognosis: (1) Presence of normal background activity pattern; (2) Even if the aEEG trace initially is abnormal, return to normal within 48 hours during cooling and within 24 hours during normothermia; (3) The presence of SWCs or the beginning of SWCs within the first 36 hours after birth.

Features showing poor prognosis: (1) Abnormal background pattern; (2) Interrupted pattern and low voltage; (3) An amplitude of < 5 μV within the first postnatal 3 days; (4) Absence of SWC; (5) Status epilepticus; (6) Prolonged and marked moderate to severe voltage disturbances.

However, further studies exploring the predictive value of aEEG and/or video EEG monitoring on short- and long-term outcomes in high-risk neonates are needing.

CFM using near infrared spectroscopy (NIRS)

aEEG and NIRS may be useful in examining cerebral electrical activity and cerebral hemodynamic changes during therapeutichypothermia[54,55]. NIRS is a technique which developed on the basis of relative transparency of light on the biological tissues. Thin-layer of the skin, skull and cerebral tissue of neonates allow the NIRS lightsof 700-1000 nanometer wavelengths to penetrate easily. Reflections of the NIRS light through the cerebral tissue are sent to the detector which presentsabout 2-3 cm depth[56]. NIRS are based upon the principle of absorbing the light by oxygenated and deoxygenated hemoglobin at different wavelengths and use to continuously monitor of cerebral hemodynamics in clinical practice for measuring changes in different concentrations[37]. Previous studies have reported that changes in cerebral oxygenation in the patients with HIE are associated with the severity of brain injury[57]. Delayed perfusion at the beginning of the secondary energy failurein hypoxic cases causes low cerebral oxygenation and cerebral vasodilatation. This suggests that the increase in brain oxygenation measured by NIRS is associated with poor prognosis[58,59].

Ancora et al. [57] evaluated the neurodevelopmental outcome of cooled neonates with HIE byaEEG and NIRS and reported that aEEG lost its positive predictive value within the first 24 hours of life. But, the tissue oxygenation index assessed by NIRS has been reported to be useful for early prediction of infants who benefit from therapeutic approach[60]. NIRS has the potential to guide clinical management by monitoring brain oxygenation and perfusion for preventing brain damage, and avoiding unnecessary treatment. It can also provide important information about the prognosis of these babies.

In conclusion, aEEG is widely used in many developed countries around the world because it is easily accessible and helps patient management. As it has relatively low and variable sensitivity and specificity than a cEEG, it cannot replace that technique. Rather, it completes the existing means for cerebral diagnostics such as cEEG, ultrasound, and magnetic resonance imaging. There is good evidence for the prediction of outcome after birth asphyxia in full-term infants, and the aEEG has been established as a tool to identify infants who will benefit from cooling[22,61,62]. In preterm infants, there is also good evidence that long-term neurological prognosis can be predicted by early aEEG recordings. However, to date, this knowledge does not result in consequences for clinical decision making in this infant population. It is likely that aEEG will become a standard tool in NICUs in the future.


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