This study uses conventional, continuous EEG monitoring to describe the incidence of electrographic seizures among term neonates receiving therapeutic hypothermia for hypoxicischemic encephalopathy. Using the definitive standard for seizure detection, we found 65% of subjects had electrographic seizures during or immediately after treatment with hypothermia. This finding is consistent with the “pre-hypothermia” literature, which describes seizures in 22%-64%, suggesting that hypothermia as employed for hypoxic-ischemic encephalopathy does not substantially affect the incidence of seizures.1,2,6
Among neonates receiving hypothermia, initial data from 20 term neonates receiving selective head cooling for hypoxicischemic encephalopathy found 19 had seizures on amplitude-integrated EEG during cooling, all of which were nonconvulsive seizures.13
We did not identify as high an incidence of seizures in our group. The reason for the discrepant results is not obvious. This finding may be a result of differences in study populations, as each study was a single-institution group, and thus there may be inherent differences in the patient populations between hospitals. We also cannot exclude the possibility that the results diverge because of differences between how whole-body cooling and selective head cooling influence seizure pathophysiology; these results could occur if selective head cooling were somehow to elicit an increase in electrographic seizures as compared to whole-body cooling or historical normothermia. Finally, our results may be different because of differences between seizure detection with amplitude-integrated EEG and conventional video EEG recording. Although amplitude-integrated EEG systems generally allow access to a raw single-channel EEG tracing for further review, these records overall can be subject to higher degrees of artifact than conventional multichannel EEG.24,25
Such artifact may mislead the bedside clinician in the diagnosis of seizures. Further research is needed to resolve the difference between the findings, as the results have important clinical management implications. If seizures are nearly universal, as previously reported,13
then prophylactic administration of anti-seizure medications might be considered for any neonate undergoing therapeutic hypothermia. Conversely, if seizures are common but not universal, as our data suggest, management might involve EEG monitoring with anti-seizure medication administered only when seizures are detected.
This study demonstrated a relatively wide range in the time of first seizure onset, from about 6-95 hours of life, with a mean time of first seizure at 35 hours. although about half of patients with seizures had the onset of seizures within 24 hours after birth, a substantial number had seizure onset much later. Furthermore, approximately a third of those with seizures experienced temporary cessation of seizures for more than 24 consecutive hours, only to have seizures later recur. This finding is a departure from previous reports. Later seizure recurrence may happen because hypothermia delays injury and thus seizure occurrence, but seizures may also have occurred because we performed continuous EEG monitoring for a longer duration than previous studies and thus may have been more sensitive for detection of seizure recurrence. Further work is needed to confirm rates of seizure recurrence after 24 hours in high-risk neonates. If our findings are generalized, they would suggest that limiting continuous EEG to the first 24 hours after birth or discontinuing EEG upon initial seizure resolution could miss important clinical information.
This study has several limitations. First, this was an observational study. All subjects received hypothermia, and so a basis for comparison can be drawn only from historical data in the literature. These historical data suggest seizures occur in 22%-64% of neonates with hypoxic-ischemic encephalopathy without cooling.1,2,6
However, we do not have a direct comparison group, and thus we cannot conclusively demonstrate whether hypothermia influences seizure occurrence or influences the timing of seizure occurrence. Furthermore, although consecutive enrollment and prospective data collection protect against selection bias, there was no control for clinical care administered during the period in question. For example, a substantial number of patients received anti-seizure medications either before or during continuous EEG at the discretion of the treating physician, which could influence both the incidence and timing of seizures. The general practice in our institution is to treat with anti-seizure medications with the goal of electro-graphic seizure termination. Other treatment algorithms might have resulted in different occurrences of seizures. Second, this was a single institution study with a limited number of subjects; larger studies including patients at other sites under different treatment algorithms are needed to confirm and generalize our findings. Third, this study examined only the presence and time of onset of electrographic seizures. Further research is needed to characterize the exact seizure burden and other EEG features in this population, and to better understand their effects on clinical outcomes. Finally, MRIs were not performed in a standardized manner, thereby precluding systematic analysis of neuroimaging findings and seizure occurrence.
In conclusion, this prospective study of a consecutive cohort identified electrographic seizures in 65% of neonates receiving therapeutic hypothermia for hypoxic-ischemic encephalopathy. Of those with seizures, 47% had exclusively nonconvulsive seizures, and 23% had status epilepticus. The range of time to seizure onset was wide, spanning several days, including during hypothermia, rewarming, and upon return to normothermia. Many patients had only nonconvulsive seizures, which would not have been detected even with careful clinical observation. Although electrographic seizures were common, they were not universal, suggesting standard administration of anti-seizure medications to neonates with hypoxic-ischemic encephalopathy is not warranted anticipatorily. At the same time, given the relatively high incidence of seizures in this group, EEG monitoring should be carefully considered. The optimal duration of monitoring is unclear, though our results suggest it may be beneficial to extend EEG monitoring beyond the first 24 hours for neonates receiving hypothermia for hypoxic-ischemic encephalopathy.