In this longitudinal sample of 129 newborns with neonatal encephalopathy, neonatal seizures and brain injury on MRI were strong risk factors for epilepsy, and the children with epilepsy all had adverse neurodevelopmental outcome.
These results support previous studies suggesting that epilepsy occurs in children with a more severe spectrum of NE. The 25% frequency of epilepsy following neonatal seizures is similar to previous contemporary cohorts that used broad clinical and/or electrographic definitions for neonatal seizures, and lower than studies that required EEG confirmation of seizures(22
). Although duration of follow-up is variable across studies, highest risk within the first year of life is a common feature, as is the high rate of associated neurodevelopmental disabilities(23
Animal studies have begun to elucidate mechanisms by which neonatal seizures can induce persistent enhanced neocortical excitability(29
). Our data also support evidence that severity of seizures is important, which is in keeping with studies by Clancy and Legido, who showed in a mixed cohort that a higher burden of neonatal seizures was a risk factor for epilepsy(22
), and Pisani et al
, who showed a higher rate of epilepsy after status epilepticus when compared with recurrent seizures(30
Severity and pattern of MRI injury are known risk factors for neonatal seizures(6
), and we also show a clear relationship with epilepsy. Children with severe basal ganglia/thalamus pattern of injury and cortical involvement were at highest risk of developing epilepsy. There is controversy from animal studies regarding whether neuronal injury is required for acquired epileptogenesis in the immature brain, or whether seizures alone without neuronal injury can cause changes in excitability sufficient to result in unprovoked seizures beyond the neonatal period(31
). Our finding, that epilepsy occurred only in those children with apparent brain injury on MRI supports, but does not prove, the hypothesis that neuronal injury is, in fact, required to develop epilepsy.
Though our findings do not support a reduced risk of epilepsy in the cooled subjects, the data we present do not exclude this possibility. Since fall 2007, we have treated most newborns at risk for hypoxic-ischemic injury and moderate-severe encephalopathy with therapeutic hypothermia using whole body cooling. Therapeutic hypothermia, which has been shown to reduce death and disability at 18–22 months in several randomized, controlled trials(32
) also has an anti-seizure effect in animal models(36
), although its effect on seizures in human newborns is not clear. Among newborns treated with therapeutic hypothermia at our center, electrographic seizures are present in more than 30%. If neonatal seizures are suppressed in human newborns treated with hypothermia, and neonatal seizures enhance long-term epileptogenesis, the risk of epilepsy in the cooled population may ultimately be reduced. The question of whether hypothermia reduces neonatal seizure burden and/or epileptogenesis should be further explored in larger data sets.
Although this is a large cohort with high-quality neonatal imaging and long-term follow-up, the data are limited in several ways. First, the survey response rate was only 64%. This limitation may have led to an overestimate of the prevalence of epilepsy, since the rate of neonatal seizures was higher in those children whose parents responded to the interview. However, response rate should not affect the relationships between perinatal risk factors, including seizures and MRI findings, and epilepsy. Second, it is possible that there was bias towards diagnosis of epilepsy in some cases of children with ambiguous spells and severe developmental impairment. This may have falsely increased the relationship between MRI injury and neonatal seizures, and epilepsy. Third, since the study’s inception in 1993, we have changed the guidelines for monitoring and treating newborns with encephalopathy. Prior to 2008, video-EEG was used at the discretion of the attending neurologist, usually for 30–60 minute routine recordings. Since 2008, we have monitored all children with NE using continuous video-EEG for the duration of hypothermia and rewarming. In order to understand the true relationship between clinical vs. electrographic seizures and epilepsy, we will need to examine a larger cohort of subjects with long-term conventional video-EEG monitoring.