Seizure Burden and Neurologic Outcomes After Neonatal Encephalopathy

Abstract

Background and Objectives:Seizures are common during neonatal encephalopathy, but the contribution of seizure burden to outcomes remains controversial. This study aims to examine the relationship between electrographic seizure burden and neurological outcomes after neonatal encephalopathy.Methods:This prospective cohort study recruited newborns ≥36 weeks PMA around 6 hours of life between August 2014 to November 2019 from a Neonatal Intensive Care Unit. Participants underwent continuous electroencephalography for at least 48 hours, brain MRI within 3-5 days of life, and structured follow-up at 18 months. Electrographic seizures were identified by board-certified neurophysiologists, and quantified as total seizure burden and maximum hourly seizure burden. A medication exposure score was calculated based on all anti-seizure medications given during NICU admission. Brain MRI injury severity was classified based on basal ganglia and watershed scores. Developmental outcomes were measured using the Bayley Scales of Infant Development, 3rdEdition. Multivariable regression analyses were performed, adjusting for significant potential confounders.Results:Of 108 enrolled subjects, 98 subjects had cEEG and MRI data collected, of which 5 were lost to follow-up, and 6 died before age 18 months. All subjects with moderate-severe encephalopathy completed therapeutic hypothermia. cEEG-confirmed neonatal seizures occurred in 21(24%) newborns, with a total seizure burden mean of 12.5 ± 36.4 minutes, and a maximum hourly seizure burden mean of 4 ± 10 min/hr. After adjusting for MRI brain injury severity and medication exposure, total seizure burden was significantly associated with lower cognitive (-0.21, 95%CI -0.33 – -0.08, p=0.002) and language (-0.25, 95%CI -0.39 – -0.11, p=0.001) scores at 18 months. Total seizure burden of 60 minutes was associated with 15-point decline in language scores, and 70 minutes for cognitive scores. However, seizure burden was not significantly associated with epilepsy, neuromotor score, or cerebral palsy (p>0.1).Discussion:Higher seizure burden during neonatal encephalopathy was independently associated with worse cognitive and language scores at 18 months, even after adjusting for exposure to anti-seizure medications and severity of brain injury. These observations support the hypothesis that neonatal seizures occurring during neonatal encephalopathy independently contribute to long-term outcomes.

Continuous versus Routine Electroencephalography in the Intensive Care Unit: A Review of Current Evidence

“…Several independent analyses have outlined that seizures/SE density over time correlates with worsening clinical prognosis in adults [49] and children [50,51]. However, association does not imply causality.…”

Temporal evolution of electrographic seizures in newborn infants with hypoxic-ischaemic encephalopathy requiring therapeutic hypothermia: a secondary analysis of the ANSeR studies

“… 31 A high seizure burden has previously been linked to adverse outcomes despite encephalopathy severity and antiseizure medication, highlighting the need for rapid seizure detection and treatment in the management of newborns with hypoxic-ischaemic encephalopathy. 17 , 18 , 19 , 20 The persistence of seizures during rewarming and beyond is not fully understood and is understudied. 32 , 33 , 34 The current study has shown different seizure evolution patterns in newborn infants with hypoxic-ischaemic encephalopathy that correlated with EEG background severity.…”

“… 13 , 14 , 15 , 16 Previous studies have shown a correlation between high seizure burden and death or long-term disability, or a combination of these outcomes, in infants with hypoxic-ischaemic encephalopathy, independent of the background severity and antiseizure medication. 17 , 18 , 19 , 20 The effect of seizures after the active cooling phase is not yet fully understood, but studies have suggested an association between seizures in the rewarming period and abnormal outcomes. 13 , 14 All previous published studies either analysed small numbers of infants with hypoxic-ischaemic encephalopathy or detected seizures by amplitude-integrated EEG monitoring, which is known to have limitations for the detection of all seizures in newborn infants.…”

Treatment of seizures in the neonate: Guidelines and consensus‐based recommendations—Special report from the ILAE Task Force on Neonatal Seizures

“…However, because studies focused on associations between seizure burden and outcome, as opposed to the impact of seizure reduction on outcome, the available data could not establish whether clinical efforts to reduce seizure burden are associated with improved outcomes. Given indirect evidence, 31,70,71,73,75,90,101 experts agreed that treatment of neonatal seizures (including electrographic-only seizures) to achieve a lower seizure burden may be associated with improved outcomes. In many low-and middleincome settings, lack of access to EEG or aEEG precludes recognition of electrographic seizures or leads to misinterpretation of clinical events, potentially adding to seizure burden or overuse of ASM, with effects on outcomes for neonates in these regions.…”