Stopping Medication for Seizures Prior to NICU Discharge

Abstract

Source: Glass HC, Soul JS, Chang T, et al Safety of early discontinuation of antiseizure medication after acute symptomatic neonatal seizures. JAMA Neurol. 2021;78(7):817-825; doi:10.1001/jamaneurol.2021.1437Investigators from multiple institutions conducted a prospective observational study to compare outcomes among infants with neonatal seizures whose anti-seizure medications (ASM) were discontinued early (prior to hospital discharge) or maintained following discharge. Study participants were infants with acute symptomatic seizures who were born between July 2015 and March 2018 and were enrolled at 9 Neonatal Seizure Registry (NSRs) centers in the US. Only patients with neonatal seizures documented with continuous conventional electroencephalogram (cEEG) monitoring from a symptomatic cause and who were treated with ASM for the seizures were enrolled. Demographic and clinical data and ASM administration during the neonatal admission were abstracted from the medical record, and participants were followed until 24 months corrected age.The study population was divided into 2 treatment groups based on whether ASM were discontinued prior to hospital discharge or maintained following discharge. The primary study outcome was functional neurodevelopment at 24 months as assessed by the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS), a 50-item questionnaire completed by parents. In typically developing children the mean score is 172 ±10. WIDEA-FS scores among children in the 2 treatment groups were compared with regression analysis. To account for confounding, propensity scores that accounted for multiple patient and clinical characteristics were calculated on study patients and included in regression models. A priori, early discontinuation of ASM was considered to be non-inferior to maintaining therapy after discharge if the difference in mean WIDEA-FS was <-12 points in the propensity score-adjusted analysis. The main secondary outcome was diagnosis of post-neonatal epilepsy. Rates of epilepsy among children in the 2 treatment groups were compared after propensity score adjustment.A total of 303 eligible children were enrolled; 84% were born at ≥37 weeks’ gestation, and 56% were male. Seizure cause was HIE in 43%, ischemic stroke in 26%, intracranial hemorrhage in 18%, and other brain injury in 13%. Overall, 194 (64%) of participants were maintained on ASM after discharge, with 68% of these children treated with phenobarbital. At 24 months, median WIDEA-FS scores were 165 and 161, respectively, for children in the early discontinuation group and those who continued ASM use after discharge. The propensity score-adjusted difference was +4 points (95% CI, -3, +11), meeting the non-inferiority criterion. Among children in the early discontinuation treatment group, 11% developed epilepsy vs 14% of those whose ASM was continued after discharge (adjusted OR, 1.5; 95% CI, 0.7, 3.4).The authors conclude that were no differences in functional neurodevelopment or rate of epilepsy among children with neonatal seizures whose ASM were discontinued before hospital discharge or continued after discharge.Dr Candee has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.The majority of acute seizures in the neonatal period are symptomatic and self-limited.1 While infants with a history of neonatal seizures are at risk for postnatal epilepsy, there is typically a period of latency prior to onset. The ideal duration of ASM treatment for neonatal acute symptomatic seizures is unclear. Despite a 2007 retrospective study by Guillet et al showing that seizure recurrence and developmental disabilities were unaffected by phenobarbital prophylaxis,2 a subsequent 2009 NIH-funded attempt at a randomized placebo-controlled clinical trial of prophylactic phenobarbital in neonates was closed early due to low enrollment.3The current comparative effectiveness study included more than 300 neonates with acute symptomatic seizures, all of whom underwent cEEG monitoring, technology not employed during the earlier study by Guillet et al.2 The primary outcomes, functional neurodevelopment and risk of epilepsy, were no different between the group continued on ASM beyond hospital discharge and the group in which therapy was discontinued. Propensity analysis ensured that factors that might influence whether to continue ASM, such as neurological examination or EEG findings, did not unduly influence the study results. The findings strengthen the argument for discontinuation of ASM therapy after 72 hours of seizure freedom, as recommended by the World Health Organization.4 Widespread enactment of this approach could have significant impact on NICU admission duration, cost of care during the first year of life, and long-term cognitive outcome.While a potential weakness of the study is that the primary outcomes were assessed via parent interview using a standardized telephone survey, the study’s applicability is bolstered by the exclusion of neonates with transient reversible causes or neonatal-onset epilepsy syndromes and by the blinding of research staff administering the surveys.ASM treatment beyond hospital discharge is unnecessary for most neonates with acute symptomatic seizures. (See AAP Grand Rounds. 2021;45[1]:6.)5Clearly ASM can neither mitigate preexisting brain pathology underlying most neonatal seizures nor abrogate the subsequent development of epilepsy.6 Follow-up beyond 24 months of age certainly is needed.