Neonatal seizures: an update on mechanisms and management

Abstract

The lifespan risk of seizures is highest in the neonatal period. Current therapies have limited efficacy. Although the treatment of neonatal seizures has not changed significantly in the last several decades, there has been substantial progress in understanding developmental mechanisms that influence seizure generation and responsiveness to anticonvulsants. This article provides an overview of current approaches to the diagnosis and treatment of neonatal seizures, and some of the recent insights about the pathophysiology of neonatal seizures that may provide the foundation for better treatment are identified.

Figure 1. Electroencephalographic appearance of neonatal seizures

Electrical seizure activity begins in the midline central region (CZ) and then shifts to the left central region (C3). Toward the end of the seizures, as the electrical activity persists in the left central region, the midline central region becomes uninvolved. This electrical seizure activity occurred in the absence of any clinical seizure activity in this 40-week gestational age female infant with hypoxic-ischemic encephalopathy. She was initially comatose and hypotonic and, at the time of EEG recording, had been treated with phenobarbital. (Reprinted with permission from [136])

Figure 2. Schematic depiction of developmental profile of glutamate and GABA receptor expression and function

Equivalent developmental periods are displayed for rats and humans on the top and bottom x-axes, respectively. Activation of GABA receptors is depolarizing in rats early in the first postnatal week and in humans up to and including the neonatal period. Functional inhibition, however, is gradually reached over development in rats and humans. Prior to full maturation of GABA-mediated inhibition, the NMDA and AMPA subtypes of glutamate receptors peak between the first and second postnatal weeks in rats and in the neonatal period in humans. Kainate receptor binding is initially low and gradually rises to adult levels by the fourth postnatal week. Neonatal seizures emerge within the “critical period” of synaptogenesis and cerebral development. Abbreviations: AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionate; GABA, γ-aminobutyric acid; NMDA, N-methyl-D-aspartate; P, postnatal day. Reprinted from [45]. Permission obtained from Nature Reviews Neurology **.

Figure 3. Dynamics of synaptic transmission at cortical synapses in the neonatal period

Depicted are an excitatory glutamatergic synapse (left panel) and a GABAergic inhibitory synapse (right panel). Presynaptic release of glutamate results in depolarization (excitation) of the postsynaptic neuron (left panel) by activation of NMDA and AMPA receptors. In contrast, release of GABA (right panel) results in hyperpolarization (inhibition) when the post synaptic neuron expresses sufficient quantities of the Cl⁻ transporter KCC2, but depolarization (excitation) when intracellular Cl⁻ accumulates due to unopposed action of the Cl⁻ importer NKCC1. The immature glutamatergic receptors (left panel) are comprised of higher levels of NR2B, NR2C, NR2D, and NR3A subunits of the NMDA receptor, enhancing influx of Ca²⁺ and Na⁺ compared to mature synapses. In addition, AMPA receptors are relatively deficient in GluR2 subunits, resulting in relatively increased Ca²⁺ permeability compared to mature synapses. Hence specific NMDA receptor antagonists and AMPA receptor antagonists may prove to be age-specific therapeutic targets for treatment development. In addition, while GABA_A receptor activation normally results in hyperpolarization and inhibition at mature synapses, due to the coexpression of NKCC1 and KCC2, the expression of KCC2 is low in the neonatal period compared with later in life and thus Cl⁻ levels accumulate intracellularly and opening of GABA_A receptors allows the passive efflux of Cl⁻ out of the cell, resulting in paradoxical depolarization. In addition, GABA_A receptor subunit expression in the immature brain is typified by higher levels of the α4 subunit, which is functionally associated with diminished benzodiazepine sensitivity. Both these attributes of the GABA_A receptor make classical GABA agonists such as barbiturates and benzodiazepines less effective in the neonatal brain. The NKCC1 channel blocker bumetanide has anticonvulsant efficacy when administered with phenobarbital, suggesting a synergistic effect.