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Safety of Early Discontinuation of Antiseizure Medication After Acute Symptomatic Neonatal Seizures

Educational Objective
To examine whether discontinuation of antiseizure medication after resolution of acute symptomatic neonatal seizures and prior to hospital discharge affects functional development or incidence of epilepsy at age 24 months.
1 Credit CME
Key Points

Question  Is discontinuation of antiseizure medication (ASM) after resolution of acute symptomatic neonatal seizures and prior to discharge from the hospital associated with functional neurodevelopment or epilepsy at 24 months?

Findings  In this comparative effectiveness study of 303 children with neonatal seizures from 9 centers, 64% had ASM maintained at hospital discharge. No difference was found between ASM maintenance and discontinuation groups in functional neurodevelopment or epilepsy; 13% of children developed epilepsy, including more than one-third with infantile spasms.

Meaning  These results support discontinuing ASMs for most neonates with acute symptomatic seizures prior to discharge from the hospital, an approach that may represent an evidence-based change in practice for many clinicians.

Abstract

Importance  Antiseizure medication (ASM) treatment duration for acute symptomatic neonatal seizures is variable. A randomized clinical trial of phenobarbital compared with placebo after resolution of acute symptomatic seizures closed early owing to low enrollment.

Objective  To assess whether ASM discontinuation after resolution of acute symptomatic neonatal seizures and before hospital discharge is associated with functional neurodevelopment or risk of epilepsy at age 24 months.

Design, Setting, and Participants  This comparative effectiveness study included 303 neonates with acute symptomatic seizures (282 with follow-up data and 270 with the primary outcome measure) from 9 US Neonatal Seizure Registry centers, born from July 2015 to March 2018. The centers all had level IV neonatal intensive care units and comprehensive pediatric epilepsy programs. Data were analyzed from June 2020 to February 2021.

Exposures  The primary exposure was duration of ASM treatment dichotomized as ASM discontinued vs ASM maintained at the time of discharge from the neonatal seizure admission. To enhance causal association, each outcome risk was adjusted for propensity to receive ASM at discharge. Propensity for ASM maintenance was defined by a logistic regression model including seizure cause, gestational age, therapeutic hypothermia, worst electroencephalogram background, days of electroencephalogram seizures, and discharge examination (all P ≤ .10 in a joint model except cause, which was included for face validity).

Main Outcomes and Measures  Functional neurodevelopment was assessed by the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) at 24 months powered for propensity-adjusted noninferiority of early ASM discontinuation. Postneonatal epilepsy, a prespecified secondary outcome, was defined per International League Against Epilepsy criteria, determined by parent interview, and corroborated by medical records.

Results  Most neonates (194 of 303 [64%]) had ASM maintained at the time of hospital discharge. Among 270 children evaluated at 24 months (mean [SD], 23.8 [0.7] months; 147 [54%] were male), the WIDEA-FS score was similar for the infants whose ASMs were discontinued (101 of 270 [37%]) compared with the infants with ASMs maintained (169 of 270 [63%]) at discharge (median score, 165 [interquartile range, 150-175] vs 161 [interquartile range, 129-174]; P = .09). The propensity-adjusted average difference was 4 points (90% CI, −3 to 11 points), which met the a priori noninferiority limit of −12 points. The epilepsy risk was similar (11% vs 14%; P = .49), with a propensity-adjusted odds ratio of 1.5 (95% CI, 0.7-3.4; P = .32).

Conclusions and Relevance  In this comparative effectiveness study, no difference was found in functional neurodevelopment or epilepsy at age 24 months among children whose ASM was discontinued vs maintained at hospital discharge after resolution of acute symptomatic neonatal seizures. These results support discontinuation of ASM prior to hospital discharge for most infants with acute symptomatic neonatal seizures.

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Article Information

Accepted for Publication: March 18, 2021.

Published Online: May 24, 2021. doi:10.1001/jamaneurol.2021.1437

Correction: This article was corrected on July 8, 2021, to add CC-BY Open Access.

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Glass HC et al. JAMA Neurology.

Corresponding Author: Hannah C. Glass, MDCM, MAS, Department of Neurology, University of California, San Francisco, 675 Nelson Rising Ln, PO Box 0663, San Francisco, CA 94143 (hannah.glass@ucsf.edu).

Author Contributions: Drs Glass and McCulloch had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Glass and Shellhaas are the co–primary investigators of the listed Patient-Centered Outcomes Research Institute (PCORI) contract.

Concept and design: Glass, Chang, Wusthoff, Chu, Massey, Abend, Lemmon, Thomas, Guillet, Rogers, Franck, Shellhaas.

Acquisition, analysis, or interpretation of data: Glass, Soul, Chang, Wusthoff, Chu, Massey, Abend, Lemmon, Thomas, Numis, Sturza, McNamara, Rogers, McCulloch, Shellhaas.

Drafting of the manuscript: Glass, Shellhaas.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Glass, Sturza, McCulloch.

Obtained funding: Glass, Shellhaas.

Administrative, technical, or material support: Glass, Chang, Wusthoff, Chu, Thomas, Numis, McNamara, Franck, Shellhaas.

Supervision: Glass, Wusthoff, Chu, Thomas, Rogers, Shellhaas.

Other - co-investigator for grant : Guillet.

Conflict of Interest Disclosures: Dr Glass reported grants from PCORI and grants from the Pediatric Epilepsy Research Foundation during the conduct of the study and grants from the National Institutes of Health (NIH) and Cerebral Palsy Alliance during the conduct of the study outside the submitted work. Dr Soul reported grants from UCB Pharma outside the submitted work. Dr Chang reported grants from PCORI during the conduct of the study. Dr Wusthoff reported grants from PCORI during the conduct of the study. Dr Chu reported grants from the NIH during the conduct of the study and grants from Biogen Inc and personal fees from Sleep Med Inc outside the submitted work. Dr Abend reported receiving royalties from Demos, consultation fees from the Epilepsy Foundation, grants from the NIH, and grants from UCB Pharma outside the submitted work. Dr Lemmon reported grants from the NIH during the conduct of the study and payment for expert testimony from the Department of Justice Medicolegal Team outside the submitted work. Dr Thomas reported grants from the NIH during the conduct of the study. Dr Numis reported grants from the National Institute of Neurological Disorders and Stroke (NINDS) (K23NS105918) outside the submitted work. Dr Guillet reported grants from PCORI during the conduct of the study and grants from the Neonatal Research Network at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the NIH as site alternate PI with salary support; grants from the National Institute of Diabetes and Digestive and Kidney Diseases of the NIH as coinvestigator with salary support; and grants from the Clinical & Translational Science Institute at the University of Rochester as a Member of Education Directorate with salary support outside the submitted work. Dr McNamara reported grants from the Spasm Prediction After Symptomatic Neonatal Seizures in the SPASM Study Pediatric Epilepsy Research during the conduct of the study. Dr McCulloch reported grants from the NIH and grants from PCORI during the conduct of the study. Dr Shellhaas reported grants from PCORI during the conduct of the study; personal fees from UpToDate for authorship related to neonatal seizures; personal fees from The Epilepsy Study Consortium as a consultant, personal fees from American Academy of Neurology as Associate Editor of Neurology, grants from the NIH, and grants from the Pediatric Epilepsy Research Foundation outside the submitted work. No other disclosures were reported.

Funding/Support: PCORI supported this study (2015C2-1507-31187).

Role of the Funder/Sponsor: The funding organization had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank the Neonatal Seizure Registry Parent Advisory Panel and representatives from Casey’s Circle, Hand to Hold, and Hope for HIE (hypoxic-ischemic encephalopathy), whose members contributed valuable perspectives regarding study design, implementation, and interpretation. The authors acknowledge Donna Ferriero, MD, MS (University of California, San Francisco), and Faye Silverstein, MD (University of Michigan), for their contributions to the Neonatal Seizure Registry. No compensation was received. We are grateful for the hard work of the clinical research coordinators at each study center.

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