Neonatal Seizures: Diagnosis, Etiologies, and Management

Julie Ziobro, MD, PhD; Renée A. Shellhaas, MD, MS


Semin Neurol. 2020;40(2):246-256. 

In This Article

Pathophysiology of Neonatal Seizures

The immature brain is susceptible to acute symptomatic seizures due to multiple age-related pathophysiologic mechanisms which lead to excess excitation and reduced inhibition. This concept is supported by rodent models in which relative excessive excitation confers a much lower seizure threshold in the immature brain compared with adult animals tested with the same chemoconvulsant agent.[6]

In the mature nervous system, gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter. When GABA binds to the GABAa receptors of mature neurons, there is an influx of chloride; this results in neuronal membrane hyperpolarization and inhibition of action potentials. In immature neurons, however, GABAa-receptor activation leads to a net chloride efflux and further depolarization of the neuronal membrane; this increases the likelihood of firing an action potential. Reversal of the chloride gradient is mediated primarily by the membrane cation chloride cotransporters: the early expression of sodium–potassium–chloride cotransporter 1 (NKCC1), which imports chloride,[7] and the delayed expression of potassium–chloride cotransporter 2 (KCC2), which exports chloride.[8] Immature nervous systems have a relatively higher expression of NKCC1 than KCC2. When the KCC2 chloride cotransporter becomes dominant in the late preterm to early term period, the chloride gradient shifts to that seen in mature neurons. When NKCC1 predominates, GABA binding to the postsynaptic receptor will cause depolarization and excitation due to chloride efflux.[7] This will also trigger inward calcium currents and remove the voltage-dependent magnesium block from N-methyl-D-aspartate (NMDA) receptors, promoting calcium entry and activation of second messengers that also increase brain excitability and seizure risk.[9,10]

In addition to the decrease in neuronal inhibition, there is enhanced excitation in the immature brain. Glutamate is the primary excitatory neurotransmitter with developmentally regulated receptor expression.[11] Glutamate binds to NMDA, AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), and kainite receptors. During development, the GluN2B subunit of the NMDA receptor is widely expressed across many brain regions. The GluN2B subunit enhances calcium influx and thus confers longer excitatory postsynaptic currents compared with the mature neuronal response to glutamate.[9]

Physiologic, use-dependent synaptogenesis is at its peak during the neonatal period—the developmental stage with the highest density of synapses and dendritic spines. This amplified excitation in the developing brain is necessary for numerous activity-dependent developmental processes, such as neurogenesis, cell migration and differentiation, synapse formation, and circuit development, but also leaves the immature brain exquisitely susceptible to seizures.[6,9,10,12]