In this cohort of 56 newborns with moderate-severe HIE who were cooled using whole body hypothermia,status epilepticus, multifocal seizures, and seizures that were resistant to a single loading dose of 20mg/kg of phenobarbital were associated with moderate-severe injury on neonatal MRI. Newborns whose electrographic seizures never had an obvious clinical correlate were as likely to have moderate-severe injury as those who had electrographic seizures with a clinical correlate.
Previous studies have demonstrated that electrographic seizures are a risk factor for adverse outcome in the setting of HIE, with rates of death and disability ranging from 60-100%[5
]. We show that seizures remain a risk factor for adverse outcome in the setting of therapeutic hypothermia, However, children with seizures that are easily treated with a first line agent may be spared moderate or severe brain injury, suggesting that the outcome following seizures is not uniformly poor in children treated with therapeutic hypothermia. This finding is consistent with preclinical models of therapeutic hypothermia that showneuroprotectionin spite of alack of reduction in the number of delayed seizures[33
The finding that a greater burden of seizures was important corroborates results by Van Rooijet al, who reported a relationship between seizure duration detected with aEEGand degree of MRI injury.Pisaniet al also found that status epilepticuswas a stronger risk factor than recurrent seizures for adverse neurodevelopmental outcome,and McBride et al, showed that having >75 seizures was associated with microcephaly, severe CP, and failure to thrive[5
In this study, newborns with subclinical seizures diagnosed with video-EEG monitoring were as likely to have MRI injury as those whose seizures had clinical signs. This finding supports data fromBjorkmanet al, who examined newborn piglets subjected to a hypoxic-ischemic insult, and found that animals with seizures had worse MRI, histological injury and neurobehavior when compared withthose without seizures, even if the seizures had no obvious clinical signs[34
]. In addition, Connell et al showed that seizures detected using a two-channel recorder were equally likely to be associated with adverse neurodevelopmental outcome whether or not they were associated with clinical signs[35
The finding that seizure onset beyond the first 12 hours of life is not only common in newborns with HIE, but is associated with moderate-severe injury on MRI challenges conventional clinical thinking about the relationship between timing of onset of neonatal seizures and severity of insult. Rafayet al found that seizures within the first 12 hours of life were more likely to indicate HIE thanstroke[36
]. Only 14% of newborns in that cohort had seizure onset after 12 hours of life, compared with 82% of our cohort. However, the later onset of seizures in the more severely affected newborns is in keeping with the fetal sheep model, where longer duration of ischemia was associated with more prolonged EEG suppression, and delayed transition to epileptiform activity[37
]. The reasons for the difference may include the following: (1) EEG versus clinical diagnosis ofseizures; (2) use of continuous EEG monitoring; or (3) differences in the evolution of energy failure, injury and seizures in newborns who are treated with therapeutic hypothermia.
Though our study is strengthened by high quality data acquisition, it is not without limitations. First, monitoring was initiated, on average, at 10 hours of life, and so we may have missed very early onset seizures in some subjects, including those with moderate-severe brain injury. EEG recording in the first hours of life was not possible due to factors including delayed recognition of neurological signs, need for transport from a referring center, patient access, and the time required to place a full montage. Nonetheless, monitoringwas initiated within 12 hours of life in 75% of subjects. Furthermore there was no difference in timing of onset of recording among those with and without brain injury. Given the usual course for neonatal seizures, we believe that it is unlikely that neonates with moderate-severe injury had early seizures that spontaneously resolved prior to the onset of monitoring only to recur at a later time point. However, this possibility does not change the clinically relevant findingthat late emergence of seizures is associated with injury.Second, the long-term clinical outcome data for this cohort arenot yet available. Rutherford et al reported that MRI remains highly predictive of outcome in newborns treated with hypothermia[38
], suggesting that the MRI results are likely to remain predictive as this cohort matures into childhood. Finally, the small number of subjects with seizures prohibits multivariable analysis.
The results of this study have implications for diagnosis, treatment and counseling for neonatal seizures that occur in the setting of therapeutic hypothermia. The high rate of electrographic seizures with onset after the first 12 hours of life suggests that short-term, intermittentEEG recording - as is routine in many centers –is inadequate for detecting the full burden of electrographic seizures in cooled newborns. Further, the similar severity of brain injury in newborns with electroclinical seizures as compared with those with seizures withoutclinical correlate supports the need for randomized controlled trials to evaluate the practice of treating only infants with convulsive seizures. Finally, these data may aid counseling for families regarding prognosis in newborns with seizures in the setting of therapeutic hypothermia.