Discontinuing Antiseizure Medications After Acute Symptomatic Neonatal Seizures

The developing brain is particularly vulnerable to internal and external stressors, and it is no surprise that clinicians in the field of neonatal neurology fiercely debate the urgency of treating neonatal seizures while at the same token advocate minimizing exposure to potentially toxic antiseizure medications (ASMs). In this issue of Neurology® Clinical Practice, Carrasco et al.¹ explored the evidence for early discontinuation of ASMs after acute symptomatic seizures in neonates and provide a pragmatic framework for clinicians to use in practice.

Neonatal seizures occur in 1.8–3.5 per 1,000 live births, and majority are due to an acute brain injury—hypoxic ischemic encephalopathy, perinatal stroke, intracranial hemorrhage, or infection.² The seizures that occur in the acute phase of brain injury are provoked and do not meet the criteria for epilepsy. However, compared with the general population, these neonates are at an increased risk of developing postneonatal epilepsy (PNE) later in life, a risk of nearly 25%.³ Carrasco et al. reinforce that the use of ASMs such as phenobarbital beyond the acute period is deemed prophylactic and the benefits do not outweigh the risks in these cases. Continuing phenobarbital after discharge does not significantly reduce the development of epilepsy or adverse functional neurodevelopmental outcomes compared with neonates who discontinued phenobarbital before discharge.^4-7 Furthermore, early exposure to phenobarbital is associated with increased apoptotic cell death in the brain and altered hippocampal synaptic development in animal studies, as well as a drop in IQ scores seen in early studies of infants treated with daily phenobarbital after provoked febrile seizures.^7-9

Despite this growing evidence, there is much consternation surrounding the early discontinuation of ASMs after acute symptomatic seizures. Neonatal seizures are considered an emergency and require prompt recognition and treatment. This coupled with high rates of subclinical seizures in this population amplifies clinicians' fears about stopping ASMs too prematurely and relying only on clinical features of seizure recurrence. Carrasco et al. help assuage these uncertainties by providing an approach for early discontinuation of ASMs based on brain injury severity and EEG markers. Regardless of etiology, ASMs discontinuation should commence once a neonate with mild to moderate brain injury is seizure free for at least 3 days. A follow-up EEG within 48 hours can ensure success of the medication wean. Neonates with severe brain injury as evidenced by MRI and/or the EEG background are at the highest risk of developing PNE, often in the first year of life, and more prone to developing refractory and severe types of epilepsy such as infantile spasms early in life.^3,10 Carrasco et al. recommend more discretion in these severe cases and a separate approach to their ASM management. If a neonate with severe brain injury is seizure free for at least 3 days, discontinuation of medications such as phenobarbital and phenytoin can be attempted. However, this may be more successful if neonates are transitioned to less toxic medications such as levetiracetam.¹¹ After discharge, this cohort requires close outpatient follow-up and can benefit from surveillance EEGs in the first year of life.

Some helpful additions to the pathway outlined by Carrasco et al. could include the length of the follow-up EEG and guidance on how to wean off multiple ASMs before discharge. For example, an EEG that captures both the awake and sleep states is more valuable in discerning future seizure risk. It is also known that nearly 2/3 of neonates with seizures have an incomplete response to the first ASM and require a second-line medication.¹² In such cases, one option could be to stop one ASM at a time starting with phenobarbital.

Early biomarkers of PNE still remain to be elucidated, and ongoing research may help close this gap and provide an even more stratified pathway in the future. However, the current evidence and years of clinical experience substantiate early discontinuation or transition to more favorable ASMs in neonates with acute symptomatic seizures. Close follow-up and adequate family education on seizures in susceptible populations are equally paramount. In addition, in settings with limited availability of pediatric neurologists and EEGs, transition to levetiracetam is a reasonable option in the interim. Clinicians across disciplines caring for neonates with seizures should feel supported and empowered by this issue and strongly consider the guidelines presented by Carrasco et al. on behalf of the Newborn Brain Society.

Study Funding

The authors reports no targeted funding.

Disclosure

Site PI and EEG lead for HIKMA-NEMA phenobarbital trial, NCT04320940. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.