A key goal of neonatal neurocritical care is improved outcomes, and brain monitoring plays an essential role. The recent NEST trial1 reported no outcome benefits using aEEG monitoring compared to clinical seizure identification among neonates treated for seizures. However, the study failed to prove the effects of monitoring on seizure treatment in the first place.
Neonates with acute neurological disorders, such as encephalopathy due to hypoxia-ischemia, will commonly undergo continuous electroencephalography (EEG) monitoring to assess brain recovery and detection of seizures. EEG monitoring is necessary for a reliable diagnosis and monitoring of neonatal seizures2, because the majority of EEG-confirmed neonatal seizures have no clinical signs, while EEG monitoring may confirm that many clinical events are non-epileptic in origin3. The International Neonatal Consortium, European Medicines Agency, US Food and Drug Administration, Brighton Collaboration, the International League Against Epilepsy, and American Clinical Neurophysiology Society agree that all studies involving the treatment of neonatal seizures should evaluate seizures from the EEG recordings2,4,5.
Before these international recommendations, it was common for clinicians to question the added value of (a)EEG monitoring in newborn care. The NEST trial1 attempted to address this question by assessing whether neurodevelopmental outcomes are improved by treating seizures with the aid of amplitude-integrated EEG monitoring (aEEG) compared to treating seizures identified by clinical recognition only. The underlying assumption was that seizure identification and management reduces secondary brain injury and improves neurodevelopment (Fig. 1), and that aEEG facilitates seizure diagnosis and treatment. The study found no evidence of improved neurodevelopmental outcomes, and secondary analyses showed reduced cognitive outcomes in the group with aEEG monitoring. The secondary outcome findings can be linked to many well-established confounders, only some of which were mentioned in the paper. However, the most surprising finding of this study is the lack of difference in overall seizure burden between groups treated with aEEG monitoring support versus those with clinical consideration only.
It is now widely recognized that (a)EEG monitoring and seizure treatment should commence as early as possible because the seizure burden peaks during the first 24 h in infants with hypoxic-ischemic encephalopathy (the primary cause of neonatal seizures) with subsequent gradual resolution6,7. This spontaneous resolution of seizures over time means that a late start of treatment would require prohibitively large study cohorts and only show a treatment response with limited clinical significance8. In the NEST study, aEEG was initiated after 24 h; therefore, NEST likely missed the bulk of the seizure burden, and it only assessed the remains of the spontaneously decaying seizures. Thus, the NEST study design per se precluded an opportunity to see an actual treatment effect in either study arm8.
In addition to missing seizures due to the late onset of aEEG monitoring, the EEG assessment method per se used in the NEST study introduces a major confounder in seizure burden estimates (Fig. 1). Although aEEG is often useful for clinical brain monitoring, including the recognition of longer seizures, international guidelines have established that the aEEG alone cannot provide accurate enough estimates of seizure burden. The NEST study amplifies this bias by only considering the longer seizures that were evident on the compressed aEEG trace that likely led to a considerable proportion of the seizure burden going undetected, untreated, and not accounted for in the analyses. Moreover, the report does not provide key details regarding the aEEG, for instance, which recording channels were used, how aEEG review was actually done at the bedside, whether seizure detection algorithms were (or were not) used, when treatment(s) were administered, and how seizure burden and response to treatment were subsequently quantified. Furthermore, analyses of aEEG background patterns are not reported despite their strong associations with outcome9.
Overall, the NEST study portrays a grand challenge in all contemporary medical research. The rapidly changing clinical landscape and accumulating research data make it difficult to design new studies with influential results. This is particularly true for neonatal research where the use of long-term neurodevelopment outcomes results in very long study cycles. Consequently, the initial study question may have lost its relevance by the time the trial is completed. In the case of NEST, the concurrently accumulated evidence rendered the initial study question a classic straw man hypothesis: The study was designed to test the hypothesis that aEEG improves neurodevelopmental outcomes by improving seizure identification and seizure management, thereby reducing seizure burden (Fig. 1). Instead, the study shows that aEEG begun >24 h after delivery did not affect treatment practices and outcomes, but it does not really address the question of whether or how early use of EEG monitoring impacts treatment success, i.e., seizure burden en route to better outcomes. Notably, this situation is changing rapidly worldwide, with further training of personnel as well as more widespread use of EEG devices with adequately validated algorithms for automated seizure detection10.
Why is this issue important to raise? We believe that there is a risk that the NEST study question per se may lead clinicians to erroneously conclude that EEG monitoring is unhelpful in neonatal neurological management. This misleading effect may be worse in low- and middle-income countries where the current upskilling of neonatal units is calling for de novo implementation of brain monitoring routines. Notably, the authors of NEST study concluded that “EEG remains the reference standard for the detection of neonatal seizures, and essential in the validation of neonatal research.” This important statement carries the readership onto the grand challenge question of neonatal neurological care: Why monitor the neonatal brain? Routine clinical practice has shown that EEG monitoring of neonates supports and guides individualized patient care by providing a functional measure of brain recovery after injury, reliable detection of seizures, and surveillance of sleep-wake cycling, as well as many other context-relevant observations9,10,11. In addition, several novel aEEG and EEG biomarkers are being developed that hold promise for making EEG a proximal outcome measure for individualized patient care, benchmarking clinical trials, as well as predicting later neurodevelopmental compromise. These benefits are irrefutable and widely acknowledged, and conceivably, trying to measure their links to neurodevelopmental outcomes without considering the possible intermediary or causal mechanisms is unproductive. Indeed, there is a widely shared bedside experience in neonatal intensive care units that trusts in a well-known mechanism, the latent Hawthorne effect11,12: mere attention to the newborn brain leads to improved newborn care.
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Acknowledgements
We thank the following organizations for supporting research of authors in this article: European Union’s Horizon 2020 programme, Finnish Academy (337788, 332017), Sigrid Juselius Foundation, National Health and Medical Research Council of Australia, National Institute of Health Research (NIHR; UK), the Evelyn Trust (UK), NIH U54 NS100064 and NS43209, U.S. Department of Defense (W81XWH-18-1-0612), the Heffer Family and the Segal Family Foundations, and the Abbe Goldstein/Joshua Lurie and Laurie Marsh/Dan Levitz families. The views expressed are those of the author(s) and not necessarily those of the funders.
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S.V. is an unpaid advisor for Stratus and ANT. R.M.P. is an investigator for studies with UCB and does consultancy work for Kephala LTD, Ireland. She served as a Speaker and/or on Advisory Boards for Natus, GW, Eisai, and UCB. G.B.B. has a consultancy with UCB and Nihon Kohden to provide advice on neonatal EEG monitoring. She is a co-founder of a start-up company Kephala LTD, which provides EEG reviewing services for industry and academia. M.R.C. serves as a Speaker and/or on Advisory Boards for Eisai, UCB, and Biocodex, and does consultancy work for Sanofi Aventis. J.M.W. receives an honorarium for her role as Associate Editor for Epilepsia, advisory board for South African branch of Sanofi. S.A. receives an honorarium for his role as associate Editor for Epilepsia. He has served as consultant or received honoraria for lectures from Angelini Pharma, Biocodex, Biomarin Encoded, Eisai, GRINtherapeutics, GW Pharma, Neuraxpharma, Nutricia, Orion, UCB Pharma, Ultragenyx, Xenon, Zogenix. He has been an investigator for clinical trials for Eisai, Marinus, Takeda, UCB Pharma, Xenon, and Zogenix. K.P.V. received an honorarium from Medlink Neurology and Dravet Syndrome Foundation. C.D.H. receives an honorarium for his role as Associate Editor of the Journal of Clinical Neurophysiology, and has consulted on clinical trial design and conduct for UCB Biopharma and Takeda Pharmaceuticals. R.A.S. receives royalties from UpToDate for authorship of topics related to neonatal seizures; serves as Associate Editor for Neurology; and is a consultant for the Epilepsy Study Consortium. Her research is supported by NIH and the Pediatric Epilepsy Research Foundation. S.L.M. is serving as Associate Editor of Neurobiology of Disease. He is on the editorial board of Brain and Development, Pediatric Neurology, Annals of Neurology, MedLink, and Physiological Research. He receives compensation from Elsevier for his work as Associate Editor in Neurobiology of Disease and from MedLink for his work as Associate Editor; and royalties from two books he co-edited. N.J.S., L.H.-W., L.S.d.V., N.S.A., and F.B. declare no competing interests.
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Vanhatalo, S., Stevenson, N.J., Pressler, R.M. et al. Why monitor the neonatal brain—that is the important question. Pediatr Res 93, 19–21 (2023). https://doi.org/10.1038/s41390-022-02040-9
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DOI: https://doi.org/10.1038/s41390-022-02040-9
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