Glass HC, Soul JS, Chang T, Wusthoff CJ, Chu CJ, Massey SL, Abend NS, Lemmon M, Thomas C, Numis AL, Guillet R, Sturza J, McNamara NA, Rogers EE, Franck LS, McCulloch CE, Shellhaas RA. Safety of Early Discontinuation of Antiseizure Medication After Acute Symptomatic Neonatal Seizures. JAMA Neurol 2021;78(7):817-25. PMID: 34028496
Dr Natasha Keerthika Russell BSc(Hons), DCH, MD
Senior Registrar, Paediatrics
Mackay Base Hospital, Queensland Health, Australia
Dr Gopakumar Hariharan MD FRACP
Senior Lecturer, James Cook University
Mackay Base Hospital, Queensland Health, Australia
TYPE OF INVESTIGATION
In neonates with seizures (P), does discontinuation of antiseizure medication (ASM) prior to discharge from the hospital (I) compared to those neonates who had ASM continued post discharge (C) affect neurodevelopment or risk of epilepsy (O) at 24 months of age(T)?
- Design: Prospective observational comparative effectiveness study
- Allocation: Not Applicable
- Blinding: The WIDEA-FS developmental assessment tool was administered by research staff blinded to the child’s medication history and duration of ASM treatment
- Follow-up period: 24 months
- Setting: Infants born between July 2015 – March 2018 with neonatal seizures enrolled from 9 US Neonatal Seizure Registry centres
- Patients: 303 neonates
- Inclusion Criteria:
- A known seizure cause such as hypoxic-ischaemic encephalopathy, ischaemic stroke, intracranial haemorrhage, or other acute brain injury AND
- cEEG-confirmed seizure OR Treated with an ASM for a seizure
- Exclusion Criteria:
- Events not typical of seizures or those excluded by EEG
- Neonatal-onset epilepsy syndromes diagnosed at birth or after hospital discharge
- Inclusion Criteria:
- Intervention: Duration of ASM treatment dichotomized as ASM discontinued vs ASM maintained at the time of hospital discharge.
- Primary outcome
- Neurodevelopment at age 24 months by Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) (Functional impairment when the WIDEA-FS total score was greater than 2 SDs below the mean for age).
- Secondary outcomes:
- Incidence of post-neonatal epilepsy as defined by International League Against Epilepsy criteria
- Primary outcome
- Analysis and Sample Size:
- With a 80% power and two-sided 0.05 significance, 116 neonates were required to identify a statistically significant difference in neurodevelopmental scores between neonates who had ASM discontinued at discharge and those neonates who had ASM maintained.
- Propensity adjustment undertaken for seizure cause, gestational age, therapeutic hypothermia, worst EEG background during first 24 hours of recording, days of electrocardiographic seizures and discharge neurologic examination.
- Neurodevelopmental assessment was powered for propensity-adjusted noninferiority for early ASM discontinuation
- Patient follow-up: 282 with follow-up data (93% of total) and 270 with the primary outcome measure (89% of total)
Seizure Etiology (Total N= 303) (N, %)
- Hypoxic-ischaemic encephalopathy (130, 43%)
- Ischaemic Stroke (79, 26%)
- Intracranial haemorrhage (55, 18%)
- Other acute brain injury (39, 18%)
ASM Status (Total N= 303) (N, %)
- ASM maintained on discharge (194, 64%) (range across study centres, 10%-95%; P < .001)
- Duration of ASM post-discharge- Median of 4 months (IQR, 3-8 months;P < .001)
- Initial loading ASM administered- Phenobarbital (90%), Levetiracetam (6%)
- Anti-seizure medication at discharge – Phenobarbital monotherapy (68%), Levetiracetam monotherapy (13%), Polytherapy not specified (20%)
Primary Outcome: Neurodevelopment
- No difference in those with ASM discontinued vs ASM maintained at 24 months (28% ASM discontinued vs 37% ASM maintained; (odds ratio, 0.6; 95% CI, 0.4-1.1;P = .11)
- Propensity- adjusted difference in scores at 24 months: 4 points (2%) higher among infants whose ASM was discontinued (90% CI, −3 to 11)
Secondary Outcome: Epilepsy
- No difference in post-neonatal epilepsy in neonates with ASM discontinued (11%) vs ASM maintained (14%) (odds ratio, 0.8; 95% CI, 0.4-1.6; P = .49)
- No difference in timing of epilepsy onset between ASM discontinued group vs ASM maintained group (hazard ratio, 0.8; 95% CI, 0.4-1.5)
Discontinuation of anti-seizure medication in neonates prior to discharge from the hospital appears to be safe. At 24 months of age, neurodevelopmental outcome and the incidence of epilepsy were similar between those who had ASM discontinued compared to those who continued to be on ASM.
There is lack of consensus regarding continuation of antiseizure medication (ASM) in neonates who had seizures during their intensive care stay.1,2 Current evidence is insufficient to determine the association of neonatal seizures and its impact on long term neurodevelopment.3 Controversy exists in terms of the appropriate anticonvulsant for continuation at the time of discharge from the hospital. 4
The observational comparative effectiveness study by Glass et al demonstrates the safety of discontinuation of ASM in neonates prior to discharge from the intensive care unit. There was no difference noted in neurodevelopment scores in neonates whose ASM was discontinued at discharge compared to those who had their seizure medication continued. Total scores as well as the the prosensity adjusted difference in scores on the WIDEA-FS were 4 points higher in the ASM discontinued group raising the possibility of risk of harm from continuation of ASM. However, the variability in the the ASM exposure amongst the neonates followed up makes it difficult to interpret the reported neurodevelopmental outcomes.
Although there is evidence of increased risk of post-neonatal seizure disorder with neonatal seizures, evidence is lacking on the relationship between early discontinuation of ASM and seizure disorder. The study by Glass et al demonstrates that the risk of postneonatal seizures is similar between those who had ASM discontinued versus maintained. The study by Fitzgerald et al further supports that the incidence of future seizure disorders was not increased with discontinuation of ASM prior to discharge in neonates with hypoxic ischemic encephalopathy treated with hypothermia.
The findings from the study by Shelhaas et al suggest that severity of acute symptomatic seizures and its successful control is a predictor of developing later epilepsy.6 Wietstock at al had found that in neonates with seizures, initial neurocritical care (hypothermia program, continuous EEG monitoring, seizure management guidelines and ongoing staff education) is important in determining the dose of ASM as well as the duration of maintenance ASM therapy.7 Incorporating these factors in future studies could provide information on safety of discontinuing ASM, and its relation to risk of postneonatal seizure disorders.
Majority of neonates with seizures in the study were treated with phenobarbital on discharge. Although Phenobarbital has been used extensively in neonates, it can be associated with adverse neurodevelopmental outcomes. 8 A previous study by Sharpe et al showed superiority of phenobarbital to levetiracetam in treating neonatal seizures, however demonstrating higher rates of adverse outcomes with phenobarbital. 9 As such, more long-term neurodevelopmental follow up studies are needed to establish whether levetiracetam could be a preferred anticonvulsant in the neonatal period.
The study provides clinically pertinent evidence on safety of discontinuing ASM at discharge and, neurodevelopment outcomes of these neonates discharged from intensive care. Further sufficiently powered multicentre prospective studies with standardised neurodevelopmental follow up beyond 24 months of age to establish the the safety and superiority of this approach for neonates of all gestations are warranted. This may provide evidence on reducing unnecessary exposure to post-neonatal ASM thereby further improving the developmental outcomes.
- Pisani F, Facini C, Pavlidis E, Spagnoli C, Boylan G. Epilepsy after neonatal seizures: literature review. Eur J Paediatr Neurol. 2019;19(1):6-14.
- Hellström-Westas L, Boylan G, Ågren J. Systematic review of neonatal seizure management strategies provides guidance on anti-epileptic treatment. Acta Paediatr. 2015;104(2):123-9.
- De Haan TR, Langeslag J, van der Lee JH, van Kaam AH. A systematic review comparing neurodevelopmental outcome in term infants with hypoxic and vascular brain injury with and without seizures. BMC Pediatr. 2018;18(1):147.
- Le VT, Abdi HH, Sánchez PJ, Yossef L, Reagan PB, Slaughter LA, et al. Neonatal antiepileptic medication treatment patterns: A decade of change. Am J Perinatol. 2021;38(5):469-76.
- Fitzgerald MP, Kessler SK, Abend NS. Early discontinuation of antiseizure medications in neonates with hypoxic-ischemic encephalopathy. Epilepsia 2017;58(6):1047-53.
- Shellhaas RA, Wusthoff CJ, Numis AL, Chu CJ, Massey SL, Abend NS, et al. Early-life epilepsy after acute symptomatic neonatal seizures: A prospective multicenter study. Epilepsia. 2021;62(8):1871-82.
- Wietstock SO, Bonifacio SL, McCulloch CE, Kuzniewicz MW, Glass HC. Neonatal neurocritical care service is associated with decreased administration of seizure medication. J Child Neurol. 2015;30(9):1135-41.
- Maitre NL, Smolinsky C, Slaughter JC, Stark AR. Adverse neurodevelopmental outcomes after exposure to phenobarbital and levetiracetam for the treatment of neonatal seizures. J Perinatol. 2013 ;33(11):841-6.
- Sharpe C, Reiner GE, Davis SL, Nespeca M, Gold JJ, Rasmussen M, et al; NEOLEV2 INVESTIGATORS. Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial. Pediatrics. 2020;145(6):e20193182.