Primum non nocere: are seizure medications safe in neonates?

Commentary One of the most challenging questions in the neonatal intensive care unit (NICU) is how neonatal seizures should be treated. Currently used drugs work approximately half the time – good news for some patients but not for others (1). Medications designed for a physiologically older age group (i.e., non-neonates) may be less effective in neonates due to differences (compared with older patients) in pharmacoki-netics (e.g., absorption and elimination). Just as important, the role played by GABA (traditionally considered to be an inhibitory neurotransmitter) is less clear in neonates (2). At the same time, drugs currently used to treat seizures in neonates may carry a risk of adverse effects in the developing brain, including cell death and abnormal behavior and development (3, 4). These effects need to be considered against the risks of ongoing seizure activity. In general, the longer the exposure to a drug, the greater the risk of adverse reactions. But can one dose of a medication make much of a difference? Forcelli et al. explore this question and conclude that even a single exposure to certain seizure medications can have a prolonged adverse effect. There may however, be safer alternatives. Forcelli et al. studied electrophysiological and morphologic changes in medium spiny neurons (MSNs) from the striatum of rat pups after exposure to seizure drugs on postnatal day 7 (P7) or P10. The authors chose this cell population because of their prior work showing neurons in this region are susceptible to cell death after seizure drug exposure (3). MSNs receive input from both excitatory glutamatergic and inhibitory GABAergic neurons and integrate both cortical and subcortical signals before producing activity that impacts motor function, including motor learning and memory (5). The authors studied phenobarbital, phenytoin, and la-motrigine. Phenobarbital is the most commonly used seizure medicine in neonates, and phenytoin is a widely-used second choice (6). Lamotrigine has been shown to be relatively safe during pregnancy but is not typically used for acute treatment of neonatal seizures because of the need for gradual dose titration, which can take 2-3 months (due to the risk of Stevens-Johnson syndrome), well beyond the neonatal period (la-motrigine used in this study was supplied by GlaxoSmithKline, Research Triangle Park, NC, which also provided funding for the Forcelli study) (7). Although the lower dose of phenobarbital used in this study (37.5 mg/kg in rats vs 20-40 mg/kg typically OBJECTIVE: Drug exposure during critical periods of brain …