Novel Therapeutics for Neonatal Seizures

Abstract

Neonatal seizures are a common neurologic emergency for which therapies have not significantly changed in decades. Improvements in diagnosis and pathophysiologic understanding of the distinct features of acute symptomatic seizures and neonatal-onset epilepsies present exceptional opportunities for development of precision therapies with potential to improve outcomes. Herein, we discuss the pathophysiology of neonatal seizures and review the evidence for currently available treatment. We present emerging therapies in clinical and preclinical development for the treatment of acute symptomatic neonatal seizures. Lastly, we discuss the role of precision therapies for genetic neonatal-onset epilepsies and address barriers and goals for developing new therapies for clinical care.

Keywords: Antiseizure medication; Bumetanide; Hypoxic-ischemic encephalopathy; KCNQ2; Levetiracetam; Phenobarbital.

Fig. 1

Graphic illustration of sites of action for the currently available antiseizure medications used for neonatal seizures (black text, blue boxes) and therapeutics in preclinical development (red italics text, pink boxes). Note that in the neonatal brain, chloride efflux through GABA_A receptors (black arrow) predominates due to the chloride gradient created from relative greater expression of NKCC1 versus KCC2. In the adult brain, this chloride gradient is reversed, allowing for chloride influx (red arrow) through the GABA_A receptor. The TrkB pathway is activated following ischemia, leading to hypofunction of the KCC2 channel. Treatment with TrkB pathway modulators have been shown to improve KCC2 function in preclinical models of neonatal hypoxic–ischemic injury and reverse seizure refractoriness to phenobarbital, suggesting a future role as adjunctive therapy for refractory acute symptomatic seizures in neonates. Figure created with BioRender.com