Seizures In Neonates With Cardiopulmonary Disease: The Case For Continous EEG Monitoring And Further Studies
Susan Nicolson MD, Jim DiNardo MD, Viviane Nasr MD, Lindsey Loveland Baptist, MD
Today’s Pediatric Anesthesia Article of the Day is brought to us by our cardiac anesthesia team. They’ve been doing a fantastic job and I wanted to take this moment to thank them for their efforts. Because of the SPPM, CCAS, and SPA meetings starting tomorrow, the PAAD will be going on a one week hiatus. Although not my intention to become Jimmy Olsen, I’ll try to summarize some of the meeting highlights from Tampa on my return. Myron Yaster MD
Original article
Massey SL, Glass HC, Shellhass RA, Bonifacio S, Chang T, Chu C, Cilio MR, Lemmon ME, McCulloch CE, Soul JS, Thomas C, Wusthoff CJ, Xiao R, Abend NS. Characteristic of Neonates with Cardiopulmonary Disease Who Experience Seizures: A Multicenter Study. J Pediatr 2022; 242: 63-72. PMID: 34728245
Seizures in neonates are a manifestation of brain dysfunction and injury. Seizures have been well characterized for neonates with acute brain injuries such as perinatal asphyxia, ischemic stroke, intracranial hemorrhage and CNS infections. Much less is known about seizures in neonates with underlying cardiopulmonary disease, defined in this paper as congenital heart disease (CHD), congenital diaphragmatic hernia (CDH) and exposure to extracorporeal membrane oxygenation (ECMO). Neonates with cardiopulmonary disease may have abnormal brain development or abnormal brain function due to cardiopulmonary pathophysiology and/or complications associated with lifesaving technology [cardiopulmonary bypass (CPB), ECMO] ref 1-3. These scenarios may result in acute acquired brain injury that may manifest as seizures. Single center studies of neonates with cardiopulmonary disease have reported clinical and subclinical (EEG only) seizure incidence ranging from 1-20% ref 4,5.
Massey and colleagues examined a prospective cohort of the Neonatal Seizure Registry (NSR-1) looking at consecutive neonates (less than 44 weeks postmenstrual age at the time of seizure onset) with clinical or EEG confirmed seizures at 6 sites between January 2013 and April 2015. The study aimed to compare clinical presentation, continuous EEG (cEEG) strategies, seizure characteristics, management and outcomes in neonates with and without cardiopulmonary disease. These sites adhered to the American Clinical Neurophysiology Society’s guideline for cEEG in neonates, which recommends cEEG for differential diagnosis of suspicious clinical events and screening for subclinical seizures in high-risk neonatal populations ref 6. High-risk neonatal populations include those with acute etiologies such as intracranial hemorrhage or infection, neonates with cardiopulmonary disease including CHD requiring surgical repair with CPB or requiring ECMO. The study cohort of 354 neonates included 83 (23%) with cardiopulmonary disease and 271 (77%) without. The cardiopulmonary disease cohort included 73 neonates (88%) with CHD, 5 neonates (6%) with CDH and 26 neonates (31%) who required ECMO. Multiple cardiopulmonary disease diagnoses occurred in 20 neonates (24%). Surgical intervention occurred in 48 out of 73 neonates with CHD at a median of 81 hours of age. CPB was used in 29 (60%) of those undergoing surgery for a median duration of 95 minutes with deep hypothermic circulatory arrest in 12 (25%) for a median duration of 38 minutes. The cohort of neonates without cardiopulmonary disease included 144 (53%) with HIE, 55 (20%) with ischemic stroke, 44 (15%) with intracranial hemorrhage and 28 (10%) with intracranial infection.
Several important differences were found in seizure presentation between neonates with and without cardiopulmonary disease. Neonates with cardiopulmonary disease were:
· More likely to experience subclinical (EEG only) seizures (40% vs 21%, p< 0.001)
· More likely to experience seizures later in the clinical course (around the time of reparative surgery)
Treatment response was similar in both neonates with and without cardiopulmonary disease, including high rates of incomplete response to initial loading of antiseizure medications (66% vs 67%). Phenobarbital was the most prescribed antiseizure medication in all neonates. Although neonates with cardiopulmonary disease received a higher total loading dose of phenobarbital (40 vs 30 mg/kg), the 2 groups had comparable drug levels. Neonates with cardiopulmonary disease were more likely to receive levetiracetam as both the initial loading and as an antiseizure medication during their hospitalization. The optimal balance between safety and seizure efficacy of antiseizure medications in patients with CHD requires further evaluation.
Although the raw rates of in-hospital mortality were higher in the cardiopulmonary disease cohort (30% vs 14%), neonates with and without cardiopulmonary disease had similar rates of in-hospital death per time when accounting for their differential hospitalization durations. Within the cardiopulmonary disease cohort, the high rates of in-hospital mortality were driven by neonates who required ECMO or had multiple cardiopulmonary disease diagnoses.
This large multicenter cohort of neonates with and without cardiopulmonary disease experienced high rates of seizures, particularly EEG only seizures, which were often resistant to initial antiseizure medication. These findings provide additional evidence for neonatal guidelines that recommend protocol-driven cEEG monitoring in high risk neonatal populations, including those with cardiopulmonary disease disease. Neonates with cardiopulmonary disease are often sedated and some paralyzed in the peri-operative period, limiting the utility of a neurologic exam. Without cEEG, subclinical seizures would not be detected and seizure burden could not be accurately assessed or treated.
Given that many cardiac anomalies occur in the context of genetic conditions and/or concurrent brain malformations, it is challenging to assess whether neonatal seizures in this population arise from an acute symptomatic cause, an endogenous congenital case that predisposes to epilepsy or both. An additional consideration is the role of the maternal-fetal-placental environment and its interplay with underlying genetic predispositions. The NSR-1 cohort did not collect prenatal data, including markers of maternal health, nor assess for brain lesions with neuroimaging. Future studies on neonates with CHD need to capture the neonate’s genetic, pre-natal/fetal and placental profile, include pre and post procedure neuroimaging and cEEG to better determine the etiology of the seizures. The duration of antiseizure medication may differ by etiology. Early termination of antiseizure medication may be appropriate with acute symptomatic etiologies and prolonged mediation may be required with epilepsy.
References:
1. Licht DJ et al. Brain maturation is delayed in infants with complex congenital heart defect. J Thorac Cardiovasc Surg 2009; 137: 529-36.
2. Miller Sp et al. Abnormal brain development in newborns with congenital heart disease. N Engl J Med 2007; 357: 1928-38.
3. Peyvandi S et al. The association between cardiac physiology, acquired brain injury and postnatal brain growth in critical congenital heart disease. J Thorac Cardiovasc Surg 2018; 155: 291-300.
4. Clancy RR et al. Electrographic neonatal seizures after infant heart surgery. Epilepsia 2005; 46: 84-90/
5. Naim MY et al. Subclinical seizures identified by postoperative electroencephalographic monitoring are common after neonatal cardiac surgery. J Thorac Cardiovasc Surgery 2015; 150: 169-78.
6. Shelhaas RA et al. The American Clinical Neurophysiology Society’s Guideline on continuous electoencephalography monitoring in neonates. JClin Neurophysiol 2011; 28: 611-7.