Multicenter Study

. 2025 Dec;66(12):4844-4856.

doi: 10.1111/epi.18590. Epub 2025 Aug 6.

Postneonatal epilepsy after acute provoked neonatal seizures: Incidence, predictors, and clinical burden in a multicenter cohort followed through early childhood

Adam L Numis^{1

2}, Hannah C Glass^{1

2

3}, Janet S Soul⁴, Courtney J Wusthoff⁵, Shavonne L Massey^{6

7}, Giulia M Benedetti⁸, Catherine J Chu⁹, Cameron Thomas¹⁰, Tayyba Anwar¹¹, Monica E Lemmon^{12

13}, Linda S Franck¹⁴, Madison M Berl¹⁵, Betsy Pilon¹⁶, Stephanie M D Rau⁸, Yi Li¹⁷, Julie Sturza⁸, Charles E McCulloch³, Renée A Shellhaas¹⁸

Affiliations

¹ Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco, San Francisco, California, USA.
² Department of Neurology and Weill Institute for Neuroscience, University of California, San Francisco, San Francisco, California, USA.
³ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.
⁴ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁵ Department of Neurology, University of California, Davis, Sacramento, California, USA.
⁶ Department of Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁷ Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁸ Division of Pediatric Neurology, Department of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.
⁹ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹⁰ Division of Neurology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
¹¹ Department of Neurology, Children's National Hospital, George Washington University School of Medicine, Washington, DC, USA.
¹² Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.
¹³ Department of Population Health Sciences, Duke University School of Medicine, Durham, North Carolina, USA.
¹⁴ Department of Family Health Care Nursing, University of California, San Francisco, San Francisco, California, USA.
¹⁵ Division of Neuropsychology, Children's National Hospital, Washington, DC, USA.
¹⁶ Hope for Hypoxic Ischemic Encephalopathy (HIE), West Bloomfield, Michigan, USA.
¹⁷ Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA.
¹⁸ Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.

PMID: 40770895
PMCID: PMC12779315
DOI: 10.1111/epi.18590

Multicenter Study

Postneonatal epilepsy after acute provoked neonatal seizures: Incidence, predictors, and clinical burden in a multicenter cohort followed through early childhood

Adam L Numis et al. Epilepsia. 2025 Dec.

. 2025 Dec;66(12):4844-4856.

doi: 10.1111/epi.18590. Epub 2025 Aug 6.

Authors

Affiliations

¹ Department of Pediatrics, UCSF Benioff Children's Hospital, University of California, San Francisco, San Francisco, California, USA.
² Department of Neurology and Weill Institute for Neuroscience, University of California, San Francisco, San Francisco, California, USA.
³ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.
⁴ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁵ Department of Neurology, University of California, Davis, Sacramento, California, USA.
⁶ Department of Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁷ Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁸ Division of Pediatric Neurology, Department of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.
⁹ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹⁰ Division of Neurology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
¹¹ Department of Neurology, Children's National Hospital, George Washington University School of Medicine, Washington, DC, USA.
¹² Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA.
¹³ Department of Population Health Sciences, Duke University School of Medicine, Durham, North Carolina, USA.
¹⁴ Department of Family Health Care Nursing, University of California, San Francisco, San Francisco, California, USA.
¹⁵ Division of Neuropsychology, Children's National Hospital, Washington, DC, USA.
¹⁶ Hope for Hypoxic Ischemic Encephalopathy (HIE), West Bloomfield, Michigan, USA.
¹⁷ Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA.
¹⁸ Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.

PMID: 40770895
PMCID: PMC12779315
DOI: 10.1111/epi.18590

Abstract

Objective: Epilepsy is a known potential outcome following acute provoked neonatal seizures, but its onset, treatment patterns, and health care utilization through childhood remain poorly characterized. This study aimed to define the incidence and timing of postneonatal epilepsy, identify perinatal predictors, and describe the clinical burden of epilepsy among survivors of acute provoked neonatal seizures through early childhood.

Methods: This prospective, multicenter cohort study followed neonates with acute provoked seizures from the Neonatal Seizure Registry (NSR-II) in an extended follow-up through early childhood (Developmental Functional Evaluation). Neonatal clinical and neuroimaging data were collected, and epilepsy outcomes (including semiology, treatments, and health care use) were assessed annually through at least 5 years via structured interviews and medical record review. Kaplan-Meier and Cox proportional hazards models evaluated epilepsy risk, with data censored at loss to follow-up.

Results: Among 282 neonates evaluated for epilepsy in NSR-II, 183 (65%) continued into the extended follow-up study. Across the entire follow-up period through early childhood, 50 (18%) developed epilepsy, with a cumulative incidence of 21.6% (95% confidence interval [CI] = 16.7%-27.7%). Earlier epilepsy onset was associated with ≥3 days of neonatal seizures (hazard ratio [HR] = 2.8, 95% CI = 1.5-5.2), abnormal discharge neurological exam (HR = 2.4, 95% CI = 1.3-4.4), and deep gray/brainstem injury (HR = 2.4, 95% CI = 1.2-4.7). Prematurity (<37 weeks) was associated with later epilepsy onset (HR = 3.7, 95% CI = 2.0-6.8). Half (50%) of children with epilepsy developed intractable epilepsy, and 40% required intensive care unit admission. Despite this, only one child received vagus nerve stimulation, and none underwent other epilepsy surgeries.

Significance: These findings highlight the early and persistent epilepsy risk after neonatal seizures. Preterm infants face increased risk later in childhood compared to infants born at term. Risk factor stratification may improve early surveillance, guide clinical decisions, and support family counseling. The underutilization of epilepsy surgery in this cohort suggests multifactorial barriers that warrant further investigation.

Keywords: acquired epilepsy; epidemiology; intractable epilepsy; neonatal seizures; prematurity.

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Conflict of interest statement

C.J.W. receives a stipend as editor for Neurology. B.P. reports a relationship with Hope for HIE that includes employment. R.A.S. reports a relationship with Pediatric Epilepsy Research Foundation that includes board membership and employment; a relationship with the Epilepsy Study Consortium that includes consulting or advisory roles; and a relationship with UpToDate that includes royalties for authorship of topics related to neonatal seizures. The remaining authors have no conflicts of interest. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Figures

**FIGURE 1**
Seizure semiology among 47 children with epilepsy after acute provoked neonatal seizures. (A) Seizure semiology prior to 2 years of age. (B) Seizure semiology from 3 to 8 years of age. (C–F) Temporal profile of (C) epileptic spasms, (D) tonic seizures, (E) tonic–clonic seizures, and (F) focal impaired awareness seizures (FIAS). In panels C–F, vertical black lines indicate censoring due to loss to follow‐up or study completion. NSR, Neonatal Seizure Registry.

**FIGURE 2**
Kaplan–Meier failure curves showing cumulative incidence of postneonatal epilepsy. (A) Three or more days of electroencephalographically (EEG) confirmed neonatal seizures, (B) deep gray or brainstem injury on neonatal magnetic resonance imaging, and (C) abnormal neurological examination at the time of hospital discharge were each associated with earlier onset postneonatal epilepsy, whereas (D) premature birth was associated with later onset postneonatal epilepsy. CI, confidence interval.

**FIGURE 3**
Multivariate Cox proportional hazards regression for development of postneonatal epilepsy through early childhood. Plotted with 95% confidence intervals.

**FIGURE 4**
Association of prematurity with development of postneonatal epilepsy, stratified by presence of risk factors identified from multivariate Cox proportional hazards regression (3 or more days of electroencephalographic [EEG] seizures, deep gray or brainstem injury on magnetic resonance imaging, abnormal discharge neurologic exam, and severely abnormal EEG background). Data are plotted as a percentage of participants with a given number of risk factors within the term cohort (n = 238) or preterm cohort (n = 44).

See this image and copyright information in PMC

References

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Postneonatal epilepsy after acute provoked neonatal seizures: Incidence, predictors, and clinical burden in a multicenter cohort followed through early childhood

Affiliations

Postneonatal epilepsy after acute provoked neonatal seizures: Incidence, predictors, and clinical burden in a multicenter cohort followed through early childhood

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical