Antiepileptic drug treatment strategies in neonatal epilepsy.
The highest risk of seizures across the lifespan is in the neonatal period. The enhanced excitability of the immature brain compared to the mature brain is related to the sequential development and expression of essential neurotransmitter signaling pathways. During the neonatal period there is an overabundance of excitatory receptors, and γ-amino-butyric acid (GABA) is potentially depolarizing, as opposed to hyperpolarizing in the older brain. While this enhanced excitability is required for regulation of activity-dependent synapse formation and refining of synaptic connections that are necessary for normal brain development, enhanced excitability predisposes the immature brain to seizures. In addition to being common, neonatal seizures are very difficult to treat; antiepileptic drugs used in older children and adults are less efficacious, and possibly detrimental to brain development. In an effort to target the unique features of neurotransmission in the neonate, bumetanide, an NKCC1 inhibitor which reduces intraneuronal Cl(-) and induces a significant shift of EGABA toward more hyperpolarized values in vitro, has been used to treat neonatal seizures. As the understanding of the pathophysiology of genetic forms of neonatal epilepsy has evolved there have been a few successful attempts to pharmacologically target the mutated protein. This approach, while promising, is challenging due to the findings that the genetic syndromes presenting in infancy demonstrate genetic heterogeneity in regard to both the mutated gene and its function.
University of Vermont College of Medicine, Burlington, VT, United States.
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Hernan
University of Vermont College of Medicine, Burlington, VT, United States. Electronic address: gregory.holmes@uvm.edu.
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Holmes
D000328:Adult; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D002648:Child; D004827:Epilepsy / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007231:Infant, Newborn
D000927:Anticonvulsants
Antiepileptic drugs; EEG; GABA; Hyperexcitability; Neurodevelopment