Seizures in the newborn occur in approximately 1 per 1000 to 3.5 per 1000 live, full-term births and are a common cause for admission to the neonatal intensive care unit (NICU).1 Neonatal seizures indicate the presence of acute brain injury, including hypoxic-ischemic encephalopathy or stroke, congenital brain malformations, or genetic epileptic syndromes. A high cumulative seizure burden during the newborn period is associated with increased risk of death and neurodevelopmental disability.2 Given concerns about the risk that ongoing seizures drive intensification of seizure activity and may cause additional injury to the brain, neonatal seizures are often treated aggressively with anticonvulsant medications. Most neonatal seizures are subclinical, ie, electroencephalographic (EEG) epileptogenic discharges occur without any temporally related clinical motor or autonomic symptoms, and, moreover, the diagnosis of clinical seizures in neonates is highly unreliable. Therefore, neuromonitoring with amplitude-integrated EEG (aEEG) or continuous EEG (cEEG) has become the standard of care among tertiary NICUs.3 Yet, while EEG monitoring in the NICU enables precision-guided approaches to diagnosis and therapy, an unresolved question in neonatology and neonatal neurology is whether the treatment of subclinical electrographic seizures is beneficial.
Management of neonatal seizures is complicated by uncertainty surrounding the efficacy and adverse effects of anticonvulsants in neonates.4 Clinicians are faced with the dilemma of balancing the competing risks of seizure-related excitotoxicity and drug-related effects on the developing brain. The treatment of subclinical electrographic seizures is intended to mitigate neuronal injury and neuroinflammation fueled by ongoing seizure activity. However, this benefit is largely theoretical, as anticonvulsants come with potential adverse effects on neurodevelopment. Phenobarbital, for example, is often first-line therapy for neonatal seizures, despite limited efficacy and evidence suggesting a pro-apoptotic effect in neurons.4 Second-line anticonvulsants are similarly associated with adverse cognitive effects.4 Therefore, it is imperative that we rationalize the dose and duration of anticonvulsant administration during critical periods of neurodevelopment, and that our management decisions are based on well-executed studies that show the drug interventions do more good than harm.
Hunt et al5 describe a study in which a heterogenous population of 212 neonates at high risk for seizures at less than 48 hours of age were randomized to receive anticonvulsant therapy for either all clinically and electrographically detected seizures or for clinical seizures alone. The authors did not find that treatment of both clinical and electrographic seizures led to superior survival or neurodevelopmental outcomes at 2 years of age compared with the treatment of clinical seizures. In fact, the study found that infants who received treatment for electrographic seizures had evidence of worse cognitive outcomes. This is the largest study to date comparing 2 current clinical approaches to neonatal seizure management in the NICU. The inclusion of patients at an early stage in the disease with a range of seizure etiologies is highly pragmatic and reflects clinical practice, in which the precise cause of the seizures is often unknown at the time of treatment initiation. The primary outcome of death or disability at 2 years of age, with disability defined as a BSID-III score 2 SDs below the population mean, cerebral palsy, low visual acuity, or deafness requiring amplification is also clinically relevant, and improvements in any component of this composite outcome would surely drive clinical decision-making.
A limitation to the study by Hunt et al5 is that the decision to treat seizures was based on aEEG rather than cEEG. aEEG displays a time-compressed, 1- or 2-channel trend of the EEG and is more reliable for seizure identification than clinical examination. While we understand that cEEG is highly resource and labor intensive and is certainly not as widely available as aEEG, the American Clinical Neurophysiology Society guideline recommends that cEEG monitoring be used for high-risk patients.6 Many institutions around the world now use cEEG rather than aEEG as the criterion standard of diagnosis in neonates with seizures. Given that aEEG has lower sensitivity than cEEG, as outlined by the authors of the present study, it is possible that subclinical seizures were underdiagnosed and undertreated in the intervention arm of the present study, reducing the contrast between treatment arms. However, given the concern of worse neurodevelopmental outcomes in infants receiving more aggressive anticonvulsant therapy, it is unlikely that more drug exposure would have been beneficial.
Despite the limited generalizability to NICUs that predominantly use cEEG, this study suggests that more is not always better when it comes to anticonvulsant therapy for neonatal seizures. We propose that this study should prompt renewed dialogue between neonatologists and neurologists about the necessity of anticonvulsant medication in the absence of clinical seizures and recommend that in groups of children where equipoise exists, further clinical trials should be undertaken. Certainly, this study should not dampen enthusiasm for neuromonitoring in neonates, as cEEG can have important implications for management and prognosis. Nonetheless, the trial by Hunt et al5 adds to ongoing literature suggesting that more anticonvulsant therapy does not lead to improved outcomes. In fact, a recent comparative effectiveness study found that the continuation of antiepileptic therapy upon NICU discharge for infants with acute symptomatic seizures was not associated with improved neurodevelopmental outcomes.7
Understanding the impact of neonatal seizure burden on long-term neurodevelopmental outcomes is a research priority. The key to therapeutic success is likely the immediate management of the underlying cause where possible, and the appropriate use of antiseizure treatment. This trial underscores that medical management of critically ill infants should be based on empirical evidence to ensure safe and effective treatment while minimizing untoward adverse effects and complications. Future collaborative studies need to investigate whether drug therapy guided by cEEG, over aEEG, contributes to meaningfully improved neurodevelopmental outcomes, preferably at the child’s primary school age. The current lack of evidence-based clinical management protocols for neonatal seizures and the paucity of clinical studies examining long-term morbidities of anticonvulsant therapy remain a significant barrier to consistent, high-quality care of vulnerable infants.
Published: December 17, 2021. doi:10.1001/jamanetworkopen.2021.40677
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Offringa M et al. JAMA Network Open.
Corresponding Author: Martin Offringa, MD, PhD, The Hospital for Sick Children, 686 Bay St, Toronto, ON, M5G 0A4, Canada (email@example.com).
Conflict of Interest Disclosures: None reported.
et al; Newborn Electrographic Seizure Trial Investigators. Effect of treatment of clinical seizures vs electrographic seizures in full-term and near-term neonates: a randomized clinical trial. JAMA Netw Open
. 2021;4(12):e2139604. doi:10.1001/jamanetworkopen.2021.39604Google Scholar