Early eeg in neonates with mild hypoxic–ischemic encephalopathy: more than meets the eye

You have full access to this article via your institution. Download PDF Neonatal hypoxic–ischemic encephalopathy (HIE) is a key contributor to adverse neurodevelopmental outcomes, with HIE

severity correlating with severity of neurodevelopmental disability. It was previously believed that infants with mild HIE had normal neurodevelopment. However, recent studies suggest that

infants with mild HIE are also at risk for neurodevelopmental impairments.1 A recent multicenter cohort study reported that children with mild HIE have lower cognitive composite scores than

healthy controls at age 2–3 years.2 A systematic review reported adverse neurodevelopmental outcomes in approximately 25% of infants with mild encephalopathy.3 Timing of neurodevelopmental

outcome assessment is also emerging as a key issue in understanding the neurodevelopmental consequences of mild HIE: normal neurodevelopmental outcomes were seen at 2 years of age,4 but

lower Intelligence Quotient scores were observed at 5 years when compared to children without HIE.5 Thus, long-term neurodevelopmental follow-up is critical in infants with mild HIE as

neurodevelopmental impairments may become more apparent with age. Neonates characterized as having mild HIE based on early clinical examinations can have brain injury on magnetic resonance

imaging.6,7 Together, these findings suggest that mild HIE is not as “benign” as previously believed. Advanced neuroimaging and neurophysiologic studies may provide insight into structural

and functional brain abnormalities that contribute to the neurodevelopmental impairments seen in children with mild HIE. With the introduction of therapeutic hypothermia, there has been a

significant reduction in mortality and morbidity of neonates with HIE.8 However, at present, therapeutic hypothermia is the standard of care for infants with moderate-to-severe HIE only and

must be initiated within 6 hours of life. Neonates with mild HIE were excluded from clinical trials of therapeutic hypothermia as it was previously believed that these infants had normal

neurodevelopmental outcomes. Thus, the benefit of therapeutic hypothermia for neurodevelopmental outcomes in infants with mild HIE is unknown. Recently, more centers have begun using

therapeutic hypothermia in neonates with mild HIE, although it is not considered standard of care in this population.9 As reviewed in this recent position paper, rigorous clinical trials are

required to determine whether therapeutic hypothermia improves neurodevelopmental outcomes in newborns with mild HIE.10 Clinical trials of therapeutic hypothermia are difficult to perform

in newborns with mild HIE due in part to challenges in patient selection. As described by Sarnat,11 neonates with mild HIE may appear normal or have subtle findings on early neurological

examinations. The level of encephalopathy increases in severity over time, particularly in the subsequent 2–3 days of life. This evolution in neurological examination findings coupled with

the need to initiate therapeutic hypothermia within the first 6 hours of life presents challenges in using clinical examination to identify newborns with mild HIE for clinical trials. Thus,

biomarkers of mild HIE would be helpful in identifying patients with mild HIE for clinical trials of therapeutic hypothermia. In particular, abnormalities in electroencephalography (EEG)

background and heart rate variability (HRV) have been described in newborns with HIE, with an association between severity of abnormalities in these measures and severity of HIE.12,13

However, early abnormalities in EEG background and HRV in newborns with mild HIE are not yet well described. Identifying early markers of mild HIE using EEG background and HRV could

potentially serve as biomarkers of mild HIE and assist with the selection of appropriate patients for clinical trials of therapeutic hypothermia. In this issue of _Pediatric Research_,

Garvey et al. used qualitative and quantitative analyses to evaluate EEG and HRV abnormalities in the first 6 hours of life in term neonates with mild HIE (_n_ = 58) compared to matched

healthy term newborns (_n_ = 16). Newborns from four prospective studies were included if they met criteria for mild HIE as defined in the PRIME study1; notably, neurophysiologists were not

blinded to patient group. Qualitative analysis of EEG background features revealed at least one abnormality in the EEG recording of 72% infants with mild HIE. The qualitative EEG

abnormalities most predictive of mild HIE were the absence of sleep–wake cycling and the presence of diffuse slow waves.Consistent with qualitative EEG analyses, quantitative measurements of

EEG amplitude, spectral shape, and interhemispheric connectivity revealed significantly increased power in the delta band in neonates with mild HIE compared to healthy term newborns. The

study team did not observe any significant differences in measures of HRV between groups. Overall, the authors demonstrate qualitative and quantitative differences in EEG background,

particularly in sleep–wake cycling and excessive slow wave activity, in infants with mild HIE that can be seen within the first 6 hours of life—during the window for initiation of

therapeutic hypothermia. The findings of the study by Garvey et al. raise important questions and point toward avenues for future research. The authors observed early EEG abnormalities

during a period when the neurological abnormalities in infants with mild HIE are still evolving making it difficult to clinically identify these infants. Their findings suggest that EEG

could be used as an ancillary measure of HIE severity in patients with suspected mild HIE with subtle or even normal neurological examinations in order to select patients for clinical trials

of therapeutic hypothermia. However, in clinical practice, continuous EEG monitoring may not be available or accessible in many centers as it is resource intensive. It would be especially

challenging to initiate continuous EEG monitoring within the timeframe of the first 6 hours of life required to initiate therapeutic hypothermia. Instead, many centers use amplitude EEG

(aEEG) monitoring, which is available as a bedside neuromonitoring tool to clinicians in the Neonatal Intensive Care Unit (NICU). It would be important to determine whether the changes seen

with continuous EEG monitoring are also visualized with aEEG monitoring as it would allow for easier identification and selection of infants with mild HIE, particularly within the timeframe

of the first 6 hours of life required for initiation of therapeutic hypothermia. This may serve as an opportunity to use aEEG as a measure of encephalopathy severity by neonatal transport

teams that are sent by many centers to assess and transfer neonates from delivery hospitals to tertiary care NICUs for therapeutic hypothermia. Garvey et al. observed alterations in EEG

background, particularly in sleep–wake cycling and excessive slow wave activity, in infants with mild HIE compared to healthy term newborns within the first 6 hours of life. Sleep–wake

cycling has long been recognized as an important indicator of the severity of neonatal HIE with the onset of sleep–wake cycling carrying important prognostic information.14 This prior

experience suggests that the early alterations in sleep–wake cycling could be observed with aEEG. The importance of sleep–wake cycling in neonates with mild HIE is especially notable given

the recent recognition that sleep-related reorganization of neural activity on EEG in preterm neonates carries novel prognostic information.15 The association between early sleep–wake

cycling and long-term neurodevelopmental outcomes in neonates with mild HIE warrants further investigation. EEG background abnormalities predict neurodevelopmental outcomes in neonates with

HIE. In particular, EEG background at 36 and 48 h of life has been associated with severity of neurodevelopmental disability in infants with HIE who received hypothermia.13 A normal early

EEG within 6 hours of life has been associated with normal neurodevelopmental outcomes.4 The study by Garvey et al. addresses an important evidence gap: the relationship between

abnormalities in early EEG background and neurodevelopmental outcomes in newborns with mild HIE. Their findings of EEG changes in neonates with mild HIE reinforces that there is more than

meets the eye in this group of neonates. Importantly, early EEG predictors of adverse neurodevelopmental outcomes in newborns with mild HIE could be used to identify infants at highest risk

for neurodevelopmental impairments and targeted for therapeutic trials, such as therapeutic hypothermia. Furthermore, neonates at high risk for adverse outcomes could be followed more

closely with better access to early intervention strategies. Understanding EEG background abnormalities in infants with mild HIE may also provide insight into functional alterations in the

brain that underlie the neurodevelopmental outcomes seen in this population. There is more than meets the clinical “eye” in neonates with mild HIE including early EEG changes and

neurodevelopmental impairments outcomes that were not as benign as previously believed and become more apparent with age.3 The new findings by Garvey et al. suggest a role for early aEEG to

identify neonates with mild HIE for clinical trials as neurologic abnormalities evolve in the first few days of life.11 Early EEG abnormalities in infants with mild HIE may also provide

insight into functional brain alterations contributing to adverse neurodevelopmental outcomes in this population. Given findings in the term HIE population and from neonates born preterm, a

better understanding of the neurobiology of sleep disturbances is warranted. Future studies should also consider longitudinal advanced neuroimaging and neurophysiologic tools to understand

the trajectory of brain changes that underlie the neurodevelopmental abnormalities seen in infants with mild HIE providing further insight into potential interventions. REFERENCES * Chalak,

L. F. et al. Prospective research in infants with mild encephalopathy identified in the first six hours of life: neurodevelopmental outcomes at 18–22 months. _Pediatr. Res._ 84, 861–868

(2018). Article  Google Scholar  * Finder, M. et al. Two-year neurodevelopmental outcomes after mild hypoxic ischemic encephalopathy in the era of therapeutic hypothermia. _JAMA Pediatr._

174, 48–55 (2020). Article  Google Scholar  * Conway, J. M., Walsh, B. H., Boylan, G. B. & Murray, D. M. Mild hypoxic ischaemic encephalopathy and long term neurodevelopmental outcome -

a systematic review. _Early Hum. Dev._ 120, 80–87 (2018). Article  CAS  Google Scholar  * Murray, D. M., Boylan, G. B., Ryan, C. A. & Connolly, S. Early EEG findings in hypoxic-ischemic

encephalopathy predict outcomes at 2 years. _Pediatrics_ 124, 459–467 (2009). Article  Google Scholar  * Murray, D. M., O’Connor, C. M., Anthony Ryan, C., Korotchikova, I. & Boylan, G.

B. Early EEG grade and outcome at 5 years after mild neonatal hypoxic ischemic encephalopathy. _Pediatrics_ 138, e20160659 (2016). Article  Google Scholar  * Gagne-Loranger, M., Sheppard,

M., Ali, N., Saint-Martin, C. & Wintermark, P. Newborns referred for therapeutic hypothermia: association between initial degree of encephalopathy and severity of brain injury (what

about the newborns with mild encephalopathy on admission?). _Am. J. Perinatol._ 33, 195–202 (2015). Article  Google Scholar  * Walsh, B. H. et al. The frequency and severity of magnetic

resonance imaging abnormalities in infants with mild neonatal encephalopathy. _J. Pediatr._ 187, 26.e1–33.e1 (2017). Article  Google Scholar  * Jacobs, S. E. et al. Cooling for newborns with

hypoxic ischaemic encephalopathy. _Cochrane Database Syst. Rev._ CD003311 (2013). * Chawla, S., Bates, S. V. & Shankaran, S. Is it time for a randomized controlled trial of hypothermia

for mild hypoxic-ischemic encephalopathy? _J. Pediatr._ 220, 241–244 (2020). Article  Google Scholar  * El-Dib, M. et al. Should therapeutic hypothermia be offered to babies with mild

neonatal encephalopathy in the first 6 h after birth? _Pediatr. Res._ 85, 442–448 (2019). Article  Google Scholar  * Sarnat, H. B. & Sarnat, M. S. Neonatal encephalopathy following fetal

distress: a clinical and electroencephalographic study. _Arch. Neurol._ 33, 696–705 (1976). Article  CAS  Google Scholar  * Andersen, M., Andelius, T. C. K., Pedersen, M. V., Kyng, K. J.

& Henriksen, T. B. Severity of hypoxic ischemic encephalopathy and heart rate variability in neonates: a systematic review. _BMC Pediatr._ 19, 242 (2019). Article  Google Scholar  *

Weeke, L. C. et al. Role of EEG background activity, seizure burden and MRI in predicting neurodevelopmental outcome in full-term infants with hypoxic-ischaemic encephalopathy in the era of

therapeutic hypothermia. _Eur. J. Paediatr. Neurol._ 20, 855–864 (2016). Article  Google Scholar  * Osredkar, D. et al. Sleep-wake cycling on amplitude-integrated electroencephalography in

term newborns with hypoxic-ischemic encephalopathy. _Pediatrics_ 115, 327–332 (2005). Article  Google Scholar  * Tokariev, A. et al. Large-scale brain modes reorganize between infant sleep

states and carry prognostic information for preterms. _Nat. Commun._ 10, 1–9 (2019). Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS S.P.M. receives support from the

Bloorview Children’s Hospital Chair in Paediatric Neuroscience. T.S. is supported by the CIHR Canada Graduate Scholarship, Ontario Ministry of Health Clinician Investigator Program and the

Sickkids Research Institute Clinician Scientist Training Program. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Division of Neurology, Department of Paediatrics, The Hospital for Sick

Children and University of Toronto, Toronto, ON, Canada Thiviya Selvanathan & Steven P. Miller Authors * Thiviya Selvanathan View author publications You can also search for this author

inPubMed Google Scholar * Steven P. Miller View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Steven P. Miller.

ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional

claims in published maps and institutional affiliations. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Selvanathan, T., Miller, S.P. Early EEG in

neonates with mild hypoxic–ischemic encephalopathy: more than meets the eye. _Pediatr Res_ 90, 18–19 (2021). https://doi.org/10.1038/s41390-021-01514-6 Download citation * Received: 17 March

2021 * Accepted: 21 March 2021 * Published: 06 April 2021 * Issue Date: July 2021 * DOI: https://doi.org/10.1038/s41390-021-01514-6 SHARE THIS ARTICLE Anyone you share the following link

with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt

content-sharing initiative