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Observational Study
. 2021 Jul 1;78(7):817-825.
doi: 10.1001/jamaneurol.2021.1437.

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

Hannah C Glass  1   2   3 , Janet S Soul  4 , Taeun Chang  5 , Courtney J Wusthoff  6   7 , Catherine J Chu  8 , Shavonne L Massey  9   10 , Nicholas S Abend  9   10   11 , Monica Lemmon  12   13 , Cameron Thomas  14 , Adam L Numis  1   2 , Ronnie Guillet  15 , Julie Sturza  16 , Nancy A McNamara  16 , Elizabeth E Rogers  2 , Linda S Franck  2   17 , Charles E McCulloch  3 , Renée A Shellhaas  16
Affiliations
Observational Study

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

Hannah C Glass et al. JAMA Neurol. .

Erratum in

  • CC-BY Open Access Added.
    [No authors listed] [No authors listed] JAMA Neurol. 2021 Jul 1;78(7):882. doi: 10.1001/jamaneurol.2021.2227. JAMA Neurol. 2021. PMID: 34236400 Free PMC article. No abstract available.

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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Conflict of interest statement

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.

Figures

Figure 1.
Figure 1.. Flow Diagram of Study Participants With Neonatal Onset Acute Symptomatic Seizures
Figure 2.
Figure 2.. Unadjusted Functional Neurodevelopment Among 282 Infants With Acute Symptomatic Neonatal Seizures
Unadjusted Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) scores at 12 months’, 18 months’, and 24 months’ corrected age among 282 infants with acute symptomatic neonatal seizures whose antiseizure medications (ASMs) were discontinued (orange) vs maintained (blue) at the time of discharge from the neonatal seizure admission. The mean (SD) WIDEA-FS score in typically developing children is 109 (17) at 12 months, 152 (16) at 18 months, and 172 (10) at 24 months.
Figure 3.
Figure 3.. Unadjusted Epilepsy-Free Survival Among 282 Infants With Acute Symptomatic Neonatal Seizures
No difference in epilepsy-free survival among infants with acute symptomatic neonatal seizures for whom antiseizure medications (ASMs) were discontinued (orange) vs maintained (blue) at the time of discharge (hazard ratio, 0.8; 95% CI, 0.4-1.5).
See this image and copyright information in PMC

Comment in

References

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