Early‐life epilepsy after acute symptomatic neonatal seizures: A prospective multicenter study

Abstract

Objective We aimed to evaluate early‐life epilepsy incidence, seizure types, severity, risk factors, and treatments among survivors of acute neonatal seizures. Methods Neonates with acute symptomatic seizures born 7/2015‐3/2018 were prospectively enrolled at nine Neonatal Seizure Registry sites. One‐hour EEG was recorded at age three months. Post‐neonatal epilepsy and functional development (Warner Initial Developmental Evaluation of Adaptive and Functional Skills – WIDEA‐FS) were assessed. Cox regression was used to assess epilepsy‐free survival. Results Among 282 infants, 37 (13%) had post‐neonatal epilepsy by 24‐months [median age of onset 7‐months (IQR 3–14)]. Among those with post‐neonatal epilepsy, 13/37 (35%) had infantile spasms and 12/37 (32%) had drug‐resistant epilepsy. Most children with post‐neonatal epilepsy had abnormal neurodevelopment at 24‐months (WIDEA‐FS >2SD below normal population mean for 81% of children with epilepsy vs 27% without epilepsy, RR 7.9, 95% CI 3.6–17.3). Infants with severely abnormal neonatal EEG background patterns were more likely to develop epilepsy than those with mild/moderate abnormalities (HR 3.7, 95% CI 1.9–5.9). Neonatal EEG with ≥3 days of seizures also predicted hazard of epilepsy (HR 2.9, 95% CI 1.4–5.9). In an adjusted model, days of neonatal EEG‐confirmed seizures (HR 1.4 per day, 95% CI 1.2–1.6) and abnormal discharge examination (HR 3.9, 95% CI 1.9–7.8) were independently associated with time to epilepsy onset. Abnormal (vs. normal) three‐month EEG was not associated with epilepsy. Significance In this multicenter study, only 13% of infants with acute symptomatic neonatal seizures developed post‐neonatal epilepsy by age 24‐months. However, there was a high risk of severe neurodevelopmental impairment and drug‐resistant seizures among children with post‐neonatal epilepsy. Days of EEG‐confirmed neonatal seizures was a potentially modifiable epilepsy risk factor. An EEG at three months was not clinically useful for predicting epilepsy. These practice changing findings have implications for family counseling, clinical follow‐up planning, and future research to prevent post‐neonatal epilepsy.

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

“…One of the concerns of unnecessary continuation of ASMs is that preclinical models have demonstrated neuronal apoptosis and disruption of synaptic development when mammals are exposed to ASMs. 2,3 The data presented in this study 1 do not appear support the preclinical data regarding functional neurodevelopment.…”

“…We found no added benefit for centralized review to estimate risk of infantile spasms and other epilepsies. 3,4 Further, if centralized review adds rigor, we would not alter our recommendations to discontinue ASM, since the medications currently used to treat acute neonatal seizures do not prevent epilepsy (and are not appropriate to treat infantile spasms).…”

EBNEO Commentary: Safety of early discontinuation of anti‐seizure medication in neonates

“…5 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 et al had found that in neonates with seizures, initial neurocritical care (hypothermia programme, continuous EEG monitoring, seizure management guidelines and ongoing staff education) is important in determining the dose of ASM and 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.…”

Seizure prediction in 1117 neonates leveraging EMR-embedded standardized EEG reporting

“…Additionally, among neonates with HIE, seizures have been associated with an increased risk for subsequent neurobehavioral problems and epilepsy. 2,[4][5][6][7] Due to the high risk of seizures in this population, guidelines recommend that neonates with HIE undergo continuous EEG monitoring (CEEG) liberally during the therapeutic hypothermia and return to normothermia periods, which often last 4-5 days. 8,9 However, this practice is resource-intensive and not feasible for all neonates who might benefit, 10 as many neonates receive care in neonatal intensive care units without CEEG capability and approaches to remote CEEG are new and not yet widely available.…”