Effect of neonatal seizure burden and etiology on the long-term outcome: data from a randomized, controlled trial
Sara K. Trowbridge
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Contribution: Conceptualization, Data curation, Formal analysis, Methodology, Writing - original draft, Writing - review & editing
Search for more papers by this authorLois O. Condie
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Contribution: Data curation, Formal analysis, Methodology, Writing - review & editing
Search for more papers by this authorJessica R. Landers
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Contribution: Data curation, Formal analysis, Methodology, Project administration, Writing - review & editing
Search for more papers by this authorAnn M. Bergin
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Contribution: Data curation, Formal analysis, Investigation, Methodology, Supervision, Writing - review & editing
Search for more papers by this authorPatricia E. Grant
Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Contribution: Data curation, Formal analysis, Writing - review & editing
Search for more papers by this authorKalpathy Krishnamoorthy
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
Contribution: Data curation, Formal analysis, Investigation, Writing - review & editing
Search for more papers by this authorValerie Rofeberg
Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA
Contribution: Formal analysis, Methodology, Writing - review & editing
Search for more papers by this authorDavid Wypij
Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA
Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA
Contribution: Formal analysis, Methodology, Writing - review & editing
Search for more papers by this authorKevin J. Staley
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
Contribution: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Writing - review & editing
Search for more papers by this authorCorresponding Author
Janet S. Soul
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Correspondence Janet S. Soul, Department of Neurology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Email: [email protected]
Contribution: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Writing - original draft, Writing - review & editing
Search for more papers by this authorfor the Boston Bumetanide Trial Group
Search for more papers by this authorSara K. Trowbridge
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Contribution: Conceptualization, Data curation, Formal analysis, Methodology, Writing - original draft, Writing - review & editing
Search for more papers by this authorLois O. Condie
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Contribution: Data curation, Formal analysis, Methodology, Writing - review & editing
Search for more papers by this authorJessica R. Landers
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Contribution: Data curation, Formal analysis, Methodology, Project administration, Writing - review & editing
Search for more papers by this authorAnn M. Bergin
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Contribution: Data curation, Formal analysis, Investigation, Methodology, Supervision, Writing - review & editing
Search for more papers by this authorPatricia E. Grant
Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Contribution: Data curation, Formal analysis, Writing - review & editing
Search for more papers by this authorKalpathy Krishnamoorthy
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
Contribution: Data curation, Formal analysis, Investigation, Writing - review & editing
Search for more papers by this authorValerie Rofeberg
Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA
Contribution: Formal analysis, Methodology, Writing - review & editing
Search for more papers by this authorDavid Wypij
Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Department of Cardiology, Boston Children's Hospital, Boston, Massachusetts, USA
Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA
Contribution: Formal analysis, Methodology, Writing - review & editing
Search for more papers by this authorKevin J. Staley
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
Contribution: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Writing - review & editing
Search for more papers by this authorCorresponding Author
Janet S. Soul
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
Correspondence Janet S. Soul, Department of Neurology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Email: [email protected]
Contribution: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Writing - original draft, Writing - review & editing
Search for more papers by this authorfor the Boston Bumetanide Trial Group
Search for more papers by this authorAbstract
Background
Neonatal seizures are common, but the impact of neonatal seizures on long-term neurologic outcomes remains unclear. We addressed this question by analyzing data from an early-phase controlled trial of bumetanide to treat neonatal seizures.
Methods
Neonatal seizure burden was calculated from continuous video-electroencephalogram data. Neurologic outcome was determined by standardized developmental tests and postneonatal seizure recurrence.
Results
Of 111 enrolled neonates, 43 were randomized to treatment or control groups. There were no differences in neurologic outcomes between treatment and control groups. A subgroup analysis was performed for 84 neonates with acute perinatal brain injury (57 hypoxic–ischemic encephalopathy [HIE], 18 stroke, 9 intracranial hemorrhage [ICH]), most of whom (70%) had neonatal seizures. There was a significant negative correlation between seizure burden and developmental scores (p < 0.01). Associations between seizure burden and developmental scores were stronger in HIE and stroke groups compared with ICH (p < 0.05).
Conclusion
Bumetanide showed no long-term beneficial or adverse effects, as expected based on treatment duration versus duration of neonatal seizures. For neonates with perinatal brain injury, higher neonatal seizure burden correlated significantly with the worse developmental outcome, particularly for ischemic versus hemorrhagic brain injury. These data highlight the need for further investigation of the long-term effects of both neonatal seizure severity and etiology.
Conflict of Interest
The authors declare no conflict of interest.
Open Research
Data Availability Statement
The data sets generated during and/or analyzed during the current study are not publicly available due to the protection of patient data but are available from the corresponding author upon reasonable request.
References
- 1Glass HC, Shellhaas RA, Wusthoff CJ, et al. Contemporary profile of seizures in neonates: a prospective cohort study. J Pediatr. 2016; 174: 98-103.
- 2Rennie JM, de Vries LS, Blennow M, et al. Characterisation of neonatal seizures and their treatment using continuous EEG monitoring: a multicentre experience. Arch Dis Childhood Fetal Neonatal Ed. 2019; 104: F493-F501.
- 3Malone A, Anthony Ryan C, Fitzgerald A, Burgoyne L, Connolly S, Boylan GB. Interobserver agreement in neonatal seizure identification. Epilepsia. 2009; 50: 2097-2101.
- 4Glass HC, Wusthoff CJ, Shellhaas RA, et al. Risk factors for EEG seizures in neonates treated with hypothermia. Neurology. 2014; 82: 1239-1244.
- 5Scher MS, Alvin J, Gaus L, Minnigh B, Painter MJ. Uncoupling of EEG-clinical neonatal seizures after antiepileptic drug use. Pediatr Neurol. 2003; 28: 277-280.
- 6Shellhaas RA, Chang T, Tsuchida T, et al. The American Clinical Neurophysiology Society's Guideline on continuous electroencephalography monitoring in neonates. J Clin Neurophysiol. 2011; 28: 611-617.
- 7van Rooij LGM, Toet MC, van Huffelen AC, et al. Effect of treatment of subclinical neonatal seizures detected with aEEG: randomized, controlled trial. Pediatrics. 2010; 125: e358-e366.
- 8Lemmon ME, Bonifacio SL, Shellhaas RA, et al. Characterization of death in infants with neonatal seizures. Pediatr Neurol. 2020; 113: 21-25.
- 9McBride MC, Laroia N, Guillet R. Electrographic seizures in neonates correlate with poor neurodevelopmental outcome. Neurology. 2000; 55: 506-514.
- 10Glass HC, Glidden D, Jeremy RJ, Barkovich AJ, Ferriero DM, Miller SP. Clinical neonatal seizures are independently associated with outcome in infants at risk for hypoxic–ischemic brain injury. J Pediatr. 2009; 155: 318-323.
- 11Murray DM, Boylan GB, Ryan CA, Connolly S. Early EEG findings in hypoxic–ischemic encephalopathy predict outcomes at 2 years. Pediatrics. 2009; 124: e459-e467.
- 12Srinivasakumar P, Zempel J, Trivedi S, et al. Treating EEG seizures in hypoxic ischemic encephalopathy: a randomized controlled trial. Pediatrics. 2015; 136: e1302-e1309.
- 13Kharoshankaya L, Stevenson NJ, Livingstone V, et al. Seizure burden and neurodevelopmental outcome in neonates with hypoxic–ischemic encephalopathy. Dev Med Child Neurol. 2016; 58: 1242-1248.
- 14Fitzgerald MP, Massey SL, Fung FW, Kessler SK, Abend NS. High electroencephalographic seizure exposure is associated with unfavorable outcomes in neonates with hypoxic–ischemic encephalopathy. Seizure. 2018; 61: 221-226.
- 15Basti C, Maranella E, Cimini N, et al. Seizure burden and neurodevelopmental outcome in newborns with hypoxic–ischemic encephalopathy treated with therapeutic hypothermia: a single center observational study. Seizure. 2020; 83: 154-159.
- 16Wirrell EC, Armstrong EA, Osman LD, Yager JY. Prolonged seizures exacerbate perinatal hypoxic–ischemic brain damage. Pediatr Res. 2001; 50: 445-454.
- 17Yager JY, Armstrong EA, Miyashita H, Wirrell EC. Prolonged neonatal seizures exacerbate hypoxic-ischemic brain damage: correlation with cerebral energy metabolism and excitatory amino acid release. Dev Neurosci. 2002; 24: 367-381.
- 18Soul JS, Bergin AM, Stopp C, et al. A pilot randomized, controlled, double-blind trial of bumetanide to treat neonatal seizures. Ann Neurol. 2021; 89: 327-340.
- 19Bayley N. Bayley Scales of Infant and Toddler Development. 3rd ed. PsychCorp; 2006.
- 20Sparrow SS, Cicchetti V, Balla A. Vineland adaptive behavior scales. 2nd ed. American Guidance Service; 2005.
- 21Palisano RJ, Rosenbaum P, Bartlett D, Livingston MH. Content validity of the expanded and revised Gross Motor Function Classification System. Dev Med Child Neurol. 2008; 50: 744-750.
- 22Kwon JM, Guillet R, Shankaran S, et al. Clinical seizures in neonatal hypoxic–ischemic encephalopathy have no independent impact on neurodevelopmental outcome: secondary analyses of data from the neonatal research network hypothermia trial. J Child Neurol. 2011; 26: 322-328.
- 23Lee J, Croen LA, Lindan C, et al. Predictors of outcome in perinatal arterial stroke: a population-based study. Ann Neurol. 2005; 58: 303-308.
- 24Guillet R, Kwon J. Seizure recurrence and developmental disabilities after neonatal seizures: outcomes are unrelated to use of phenobarbital prophylaxis. J Child Neurol. 2007; 22: 389-395.
- 25Ronen GM, Buckley D, Penney S, Streiner DL. Long-term prognosis in children with neonatal seizures: a population-based study. Neurology. 2007; 69: 1816-1822.
- 26Pisani F, Orsini M, Braibanti S, Copioli C, Sisti L, Turco EC. Development of epilepsy in newborns with moderate hypoxic–ischemic encephalopathy and neonatal seizures. Brain Dev. 2009; 31: 64-68.
- 27Glass HC, Hong KJ, Rogers EE, et al. Risk factors for epilepsy in children with neonatal encephalopathy. Pediatr Res. 2011; 70: 535-540.
- 28Wusthoff CJ, Kessler SK, Vossough A, et al. Risk of later seizure after perinatal arterial ischemic stroke: a prospective cohort study. Pediatrics. 2011; 127: e1550-e1557.
- 29Fox CK, Glass HC, Sidney S, Smith SE, Fullerton HJ. Neonatal seizures triple the risk of a remote seizure after perinatal ischemic stroke. Neurology. 2016; 86: 2179-2186.
- 30Clancy RR, Legido A. Postnatal epilepsy after EEG-confirmed neonatal seizures. Epilepsia. 1991; 32: 69-76.
- 31Shellhaas RA, Wusthoff CJ, Numis AL, et al. Early-life epilepsy after acute symptomatic neonatal seizures: a prospective multicenter study. Epilepsia. 2021; 62: 1871-1882.
- 32Smit E, Liu X, Gill H, Sabir H, Jary S, Thoresen M. Factors associated with permanent hearing impairment in infants treated with therapeutic hypothermia. J Pediatr. 2013; 163: 995-1000.
- 33Laptook AR, Shankaran S, Tyson JE, et al. Effect of therapeutic hypothermia initiated after 6 hours of age on death or disability among newborns with hypoxic–ischemic encephalopathy. JAMA. 2017; 318: 1550-1560.
- 34Mizrahi EM, Clancy RR. Neonatal seizures: early-onset seizure syndromes and their consequences for development. Ment Retard Dev Disabil Res Rev. 2000; 6: 229-241.
- 35Tekgul H, Gauvreau K, Soul J, et al. The current etiologic profile and neurodevelopmental outcome of seizures in term newborn infants. Pediatrics. 2006; 117: 1270-1280.
- 36Garfinkle J, Shevell MI. Prognostic factors and development of a scoring system for outcome of neonatal seizures in term infants. Eur J Paediatr Neurol. 2011; 15: 222-229.
- 37Hammond EJ, Ramsay RE, Villarreal HJ, Wilder BJ. Effects of intracortical injection of blood and blood components on the electrocorticogram. Epilepsia. 1980; 21: 3-14.
- 38Huang LT, Cilio MR, Silveira DC, et al. Long-term effects of neonatal seizures: a behavioral, electrophysiological, and histological study. Dev Brain Res. 1999; 118: 99-107.
- 39Glass HC, Nash KB, Bonifacio SL, et al. Seizures and magnetic resonance imaging-detected brain injury in newborns cooled for hypoxic–ischemic encephalopathy. J Pediatr. 2011; 159(5): 731-735.
- 40Nash KB, Bonifacio SL, Glass HC, et al. Video-EEG monitoring in newborns with hypoxic–ischemic encephalopathy treated with hypothermia. Neurology. 2011; 76: 556-562.
- 41Shah DK, Wusthoff CJ, Clarke P, et al. Electrographic seizures are associated with brain injury in newborns undergoing therapeutic hypothermia. Arch Dis Child Fetal Neonatal Ed. 2014; 99: F219-F224.
- 42van Handel M, Swaab H, de Vries LS, Jongmans MJ. Long-term cognitive and behavioral consequences of neonatal encephalopathy following perinatal asphyxia: a review. Eur J Pediatr. 2007; 166: 645-654.
- 43Hunt RW, Liley HG, Wagh D, et al. Effect of treatment of clinical seizures vs electrographic seizures in full-term and near-term neonates: a randomized clinical trial. JAMA Network Open. 2021; 4:e2139604.
Citing Literature
