This study demonstrates that continuous video-EEG recording is an important diagnostic and prognostic tool in newborns with HIE undergoing TH. In our cohort, EEG background was associated with early MRI findings throughout the treatment period. A normal EEG was associated with no or mild MRI brain injury at all time points, although a normal background at the beginning of cooling was even more predictive of a favorable MRI outcome (100% specific) than at later time points (93% specific), as the EEG background of one newborn with moderate to severe MRI injury improved from excessively discontinuous to normal over the first 24 hours of monitoring. In contrast, the prognostic value of a BS pattern or extremely low voltage background for moderate to severe injury increased from the beginning of cooling (81% specific) to midcooling and thereafter (100% specific), reflecting 5 newborns with these concerning patterns at the onset of monitoring who rapidly improved by midcooling and were spared from moderate to severe MRI injury. The greatest prognostic value of EEG background in this population for predicting moderate to severe MRI brain injury was not achieved until midcooling, highlighting the importance of continuous monitoring or sequential EEGs in this population.
Our findings are substantiated by prior studies in noncooled infants with HIE, which demonstrated that a normal EEG within the first 2–7 days of life is associated with favorable developmental outcome and a severely abnormal EEG (BS or extremely low voltage) on the second day of life or thereafter is associated with poor outcome.12,–14,24
The few studies that reported EEG background in this population within the first 24 hours of life17,25,26
showed a relatively poor specificity for adverse developmental outcome following a severely abnormal background during the first 12 hours of life because of EEG normalization by 12 to 24 hours of life in some infants with normal outcome. Similarly, in our cohort, a BS or extremely low voltage EEG was not highly predictive for moderate to severe MRI injury until the second day of life, around the time of midcooling. This finding is supported by a prior study evaluating EEG during hypothermia in neonatal HIE by a single sample recorded sometimes in the first 48 hours of life, which found that a background of <5 μV was associated with death or major neurologic disability.15
Similarly, a recent study evaluating the prognostic value of amplitude-integrated EEG in newborns with HIE exposed to normothermia compared to those treated with TH showed that a severely abnormal background pattern in the hypothermia-treated group was not specific for abnormal developmental outcome until 48 hours of life.27
Our findings differ from prior studies of noncooled newborns with HIE in 2 main ways. First, prior studies have shown that a discontinuous EEG in the first several days of life is often associated with poor outcome,28,–31
whereas the majority of newborns in our cohort (73%) with an excessively discontinuous pattern after rewarming had no or only mild MRI injury. While it is difficult to directly compare our study to prior studies given the differences in methodology and the wide range of definitions of discontinuous background in the literature, the outcome of newborns with an excessively discontinuous background appears to be different in newborns treated with hypothermia. Interestingly, clinical encephalopathy on the fourth day of life following TH has also been shown to be less predictive of outcome in cooled infants compared to noncooled infants.8
Second, in comparison to the single study of continuous EEG monitoring in noncooled newborns with HIE which showed improvement of the background pattern over the first 3 days of life in all newborns,17
the background worsened over the course of monitoring in 13% of newborns in our cohort. Whether the EEG differences seen in our cohort of infants with HIE and cooling are attributed to hypothermia itself or the evolution of injury in this population is uncertain.
Electrographic seizures were present in 34% of newborns during TH, and continuous video-EEG revealed that almost 50% of newborns with seizures, including 3 with SE, had seizures without clinical correlate. Although experimental studies showed a potent effect of hypothermia in controlling seizures,32,33
a high incidence of seizures has been reported in children during TH.34
This discrepancy may be related to the earlier and deeper cooling used in animal models.32,33
Most studies rely on clinical evaluation for seizure diagnosis and classification of seizure severity in newborns.35,36
However, it is known that the majority of seizures, especially in critically ill infants, do not have a clinical correlate and will not be recognized without continuous EEG.16,37,38
Moreover, it is often impossible to accurately differentiate between seizure-related and nonseizure movements in infants using clinical evaluation alone.39
While isolated or recurrent seizures were recorded in more than 50% of infants with moderate to severe brain injury, not all were associated with moderate to severe brain injury. In contrast, all newborns with SE had severely abnormal MRI. These results are in keeping with a recent work suggesting that a significantly worse outcome occurs in newborns with SE compared to newborns with recurrent seizures.20
There are several limitations to our study. First, due to the referral pattern at our institution, newborns did not start monitoring at the exact same time in the first day of life. However, in most of our patients, monitoring was initiated within the first 12 hours of life. Second, an excessively discontinuous background by our system encompassed a broad range of interburst intervals. Therefore, it is not surprising that a discontinuous pattern was a relatively poor predictor of MRI brain injury. Third, we used MRI as a short-term outcome measure and do not yet know the long-term outcome in this cohort. It has been reported that hypothermia does not affect the prognostic value of MRI in newborns with HIE.11
However, long-term developmental follow-up of this cohort is needed to confirm our results. Finally, as many patients with poor EEG backgrounds and moderate to severe brain injury were treated with AEDs, we were unable to assess whether depressed background activity was an effect of medication or due to underlying brain injury.
EEG monitoring in newborns is noninvasive, provides data from the entire cortex, and can be easily performed at the bedside. Our findings underscore the importance of continuous EEG monitoring in this population to assist with seizure management and discussions regarding prognosis and goals of care. Even in the setting of hypothermia, EEG remains a strong predictive tool, and its routine use alongside clinical evaluation and MRI is warranted. Establishing consensus on neonatal EEG nomenclature and classification will help future studies on the prognostic value of EEG during TH. Particularly, further analysis and revalidation of the excessively discontinuous pattern in neonates being treated with HIE is warranted. Given emerging data suggesting that seizures may be associated with increased brain injury following neonatal HIE,35,36,40
accurate seizure detection is becoming an important issue in the context of neuroprotection. Future studies that evaluate whether rapid and effective treatment of seizures will improve neurologic outcome will rely on continuous EEG monitoring.