Effect of Treatment of Clinical Seizures vs Electrographic Seizures in Full-Term and Near-Term Neonates: A Randomized Clinical Trial

March 14, 2022

MANUSCRIPT CITATION

Hunt RW, Liley HG, Wagh D, Schembri R, Lee KJ, Shearman AD, Francis-Pester S, deWaal K, Cheong JYL, Olischar M, Badawi N, Wong FY, Osborn DA, Rajadurai VS, Dargaville PA, Headley B, Wright I, Colditz PB; Newborn Electrographic Seizure Trial Investigators. Effect of Treatment of Clinical Seizures vs Electrographic Seizures in Full-Term and Near-Term Neonates: A Randomized Clinical Trial. JAMA Netw Open. 2021 Dec 1;4(12):e2139604. doi: 10.1001/jamanetworkopen.2021.39604. PMID: 34919132.

REVIEWED BY

Elizabeth Sewell, MD, MPH
Children’s Healthcare of Atlanta and Emory University School of Medicine

Atul Malhotra, MD, PhD
Monash Children’s Hospital and Monash University

TYPE OF INVESTIGATION

Treatment

QUESTION

In term or near-term neonates with seizures (P), does treatment of all electrographic and clinical seizures (I) compared to treatment of only clinical seizures (C) improve survival free of disability (O) at 2 years of age (T)?

METHODS

  • Design: Randomized controlled trial
  • Allocation: Randomization was stratified by site and diagnosis using computer-generated block randomization with variable block sizes
  • Blinding: Neither clinicians nor parents could be blinded to study
  • Follow-up period: 2 years
  • Setting: 13 participating centers across 3 countries (Australia, Austria, and Singapore) between March 2012 and February 2016
  • Patients: 212 infants
    • Inclusion criteria: Neonates more than 35 weeks’ gestational age who were less than 48 hours of age who had a diagnosis of either:
      • Neonatal encephalopathy including coma, stupor, or depressed mental state
      • HIE with at least two of following: (1) apgar score less than 5 at 5 minutes of birth, (2) cord blood gas or arterial blood gas within 1 hour of birth with pH of less than 7.1 or base excess less than -12, or (3) need for ongoing respiratory support at 10 minutes after birth
      • Suspected neonatal seizures from any cause
    • Exclusion criteria: Diagnosis of nonconvulsive status epilepticus or cerebral dysgenesis subsequently diagnosed on neuroimaging
  • Intervention: Treatment of all electrographic and clinical seizures versus treatment of clinical seizures alone (aEEG covered). The paper states that clinicians adhered to specific diagnostic criteria for electrographic seizures but this was not detailed in the paper; aEEG monitors did have automated seizure detection software that was utilized. Seizures were treated according to a standard algorithm with phenobarbital as first-line treatment and phenytoin as second-line treatment.
  • Outcomes:
    • Primary Outcome: Neurodevelopmental assessments at 2 years of age by blinded assessors using Bayley Scales of Neurodevelopment, 3rd edition, as well as medical assessment and parental history
    • Secondary Outcomes:
      • Components of the primary outcome including death, cognitive disability, motor disability, language disability, deafness, blindness, and cerebral palsy
      • Time to suck feeds
      • Seizures
      • MRI
  • Analysis and Sample Size:
    • Researchers anticipated 40% background rate of death or neurodisability and approximately 50% of included neonates will have seizures due to HIE. Researchers calculated sample size based on a 12% reduction in death or severe disability anticipated with the electrographic seizure treatment group.
    • With 80% power and two-sided 0.05 significance, a goal of 260 neonates in each group was calculated to determine a significant difference in outcome.
    • The trial was concluded early due to a lack of equipoise at some sites as the trial progressed so that 212 infants were randomized.
  • Patient follow-up: 172 infants (81%) with follow-up data analyzed for primary outcome

MAIN RESULTS

Seizure Etiology (Total N = 212) (N, %):

    • HIE receiving hypothermia (153, 72%)
    • Arterial Ischemic Stroke (21, 10%)
    • Extra-axial hemorrhage (16, 8%)
    • Sinovenous thrombosis (3, 2%)
    • Genetic epilepsies (3, 2%)
    • Hypoglycemia (2, 1%)
    • Unknown (11, 5%)

Primary Outcome (Total N = 172)

    • No significant difference in odds of death or disability in neonates with clinical and electrographic seizures treated compared to those with only clinical seizures treated (44% vs. 31%, OR 1.83, 95% CI 0.96-3.49)
    • Remained not significant when seizure burden was accounted for (N=143, aOR 1.79, 95% CI 0.87-3.67)
    • Remained not significant in subgroup analysis of infants with HIE (N=128, aOR 1.77, 95% CI 0.84-3.73)

Secondary Outcomes

    • Lower cognitive scores in survivors of electrographic and clinical seizure treatment group compared to the clinical seizure only treatment group (N=162, mean [SD] scores 97.4 [17.7], mean difference -6.5, 95% CI -1.2 to -11.8, p=0.02)
    • No difference in time to full suck feeds in survivors of electrographic and clinical seizure treatment group compared to the clinical seizure only treatment group (N=200, hazard ratio 0.98, 95% CI 0.57-1.71, p=0.97)
    • No significant difference in odds of electrographic seizures in neonates with clinical and electrographic seizures treated compared to those with only clinical seizures treated (N=174, 86% vs. 83%, OR 1.28, 95% CI 0.56-2.97)
    • No significant difference in total seizure burden in neonates with clinical and electrographic seizures treated compared to those with only clinical seizures treated (N=174, 848 vs. 613, OR 1.61, 95% CI 0.82-3.12)
    • 86% of neonates with electrographic and clinical seizures treated versus 69% of neonates with only clinical seizures treated received anticonvulsant medication (OR no reported)
    • No significant difference in odds of postneonatal epilepsy in neonates with clinical and electrographic seizures treated compared to those with only clinical seizures treated (N=171, 6% vs. 4%, OR 1.55, 95% CI 39-6.14, p=0.53)
    • No significant difference in MRI brain injury scores in neonates with clinical and electrographic seizures treated compared to those with only clinical seizures treated (N=181, mean [SD] score 10.18 [10.15] vs. 9.37 [8.6], mean difference 0.96, 95% CI -1.82-3.74, p=0.50)

CONCLUSION

In a group of neonates with acute symptomatic seizures, treatment of electrographic and clinical seizures with currently used anticonvulsants did not significantly reduce the risk of death or disability at 2 years compared to treatment of only clinical seizures.

COMMENTARY

The aim of this trial was to evaluate whether aggressive treatment of electrographic seizures in addition to clinical seizures improved neurodevelopmental outcomes compared to treatment of only clinical seizures.1  Authors took a pragmatic approach to seizure diagnosis by utilizing amplitude-integrated EEGs (aEEG). 598 infants were assessed for eligibility and 212 infants were randomized, after excluding infants who did not meet inclusion criteria or declined to participate.  Forty infants were lost to follow-up or had incomplete data on the primary outcome, thus 172 (81%) were included in the analysis.  They found no difference in death or severe disability at 2 years for infants who had both electrographic and clinical seizures treated versus those who had only clinical seizures treated. These results remained consistent even after adjusting for seizure burden and HIE. Additionally, there was no significant difference in presence of electrographic seizures, cumulative ASM dose, or brain injury on MRI between groups. While not significant, seizure burden was higher in the electrographic seizure group despite randomization, which is concerning as that could negatively impact outcome.

Not all electrographic seizures are accurately recognized by clinicians with visual assessment alone, leading to both under-diagnosis and inappropriate administration of anti-seizure medications (ASMs) for non-epileptogenic events.2  Commonly used ASMs have been associated with neurotoxicity in animal models and some clinical studies.3-5  There is biologic plausibility that seizures can have negative impacts on the brain and body.6  It is primarily seizure burden, more so than the discrete number of seizures, that has correlated with adverse neurodevelopmental outcomes.7 In a study of seizures in neonates with hypoxic-ischemic encephalopathy (HIE), continuous EEG monitoring and treatment with ASMs decreased seizure burden however unfortunately the study did not evaluate neurodevelopmental outcomes.8  Following this publication, the diagnosis and treatment of seizures in neonates has shifted dramatically, and standard of care has since evolved to treatment of all electrographic seizures when possible.9  Subsequent recruitment for the study by Hunt et al had to end prematurely due slow enrollment secondary to loss of equipoise of treating clinicians.1 Thus, the study is ultimately unable to make definitive conclusions on the impact of treatment of electrographic versus clinical seizure treatment on neurodevelopmental outcomes.

While siezure burden trended higher in the electrographic seizure group, it was not significantly different between groups.  Since seizure burden has been linked to outcome, it may not be surprising that there was no significant difference in neurodevelopment between groups.  Other limitations include lack of continuous EEG, which remains the gold standard for seizure diagnosis, and the number of infants (18%) without follow up data. Additionally, as authors pointed out, only 84% of the study population had electrographic seizures, which underscores a primary limitation to the study with the lower sensitivity and specificity of aEEGs that is partially dependent on clinician experience. Furthermore, in the group of infants who were treated for clinical seizures, only 69 infants received ASMs but 78 infants had electrographic seizures. This highlights the challenge of diagnosing and treating seizures with clinical observation alone (as done in this study with aEEGs being covered), since not all infants with concerning clinical movements have electrographic seizures. Also, while the number of infants exposed to phenobarbital was similar between groups, more infants in the electrographic seizure group were exposed to phenytoin.

Ultimately, the results of this paper are not conclusive to change current practice recommendations for seizure management in newborns. However, this study does highlight some of the challenges of studying seizure diagnosis and management in neonates, as well as the minimal long-term neurodevelopmental data available for newborns with seizures treated with ASMs. Unfortunately, previous efforts for a trial (NCT01089504) looking at long-term effects of phenobarbital failed recruitment but ongoing research is needed on seizure management and neurodevelopmental outcomes in newborns.

REFERENCES

  1. Hunt 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 Netw Open. 2021;4(12):e2139604.
  2. Murray DM, Boylan GB, Ali I, Ryan CA, Murphy BP, Connolly S. Defining the gap between electrographic seizure burden, clinical expression and staff recognition of neonatal seizures. Archives of Disease in Childhood-Fetal and Neonatal Edition. 2008;93(3):F187-F191.
  3. Bittigau P, Sifringer M, Genz K, et al. Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci U S A. 2002;99(23):15089-15094.
  4. Maitre NL, Smolinsky C, Slaughter JC, Stark AR. Adverse neurodevelopmental outcomes after exposure to phenobarbital and levetiracetam for the treatment of neonatal seizures. Journal of Perinatology. 2013;33(11):841-846.
  5. Farwell JR, Lee YJ, Hirtz DG, Sulzbacher SI, Ellenberg JH, Nelson KB. Phenobarbital for febrile seizures—effects on intelligence and on seizure recurrence. New England Journal of Medicine. 1990;322(6):364-369.
  6. Vespa PM, Miller C, McArthur D, et al. Nonconvulsive electrographic seizures after traumatic brain injury result in a delayed, prolonged increase in intracranial pressure and metabolic crisis. Crit Care Med. 2007;35(12):2830-2836.
  7. McBride MC, Laroia N, Guillet R. Electrographic seizures in neonates correlate with poor neurodevelopmental outcome. Neurology. 2000;55(4):506-513.
  8. Srinivasakumar P, Zempel J, Trivedi S, et al. Treating EEG Seizures in Hypoxic Ischemic Encephalopathy: A Randomized Controlled Trial. Pediatrics. 2015;136(5):e1302-1309.
  9. Pressler RM, Cilio MR, Mizrahi EM, et al. The ILAE classification of seizures and the epilepsies: Modification for seizures in the neonate. Position paper by the ILAE Task Force on Neonatal Seizures. Epilepsia. 2021;62(3):615-628.
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