The impact of treating electrographic seizures in hypoxic ischemic encephalopathy (HIE) is unknown.
Neonates ≥36 weeks with moderate or severe HIE were randomly assigned to either treatment of electrographic seizures alone (ESG) or treatment of clinical seizures (CSG). Conventional EEG video was monitored in both groups for up to 96 hours. Cumulative electrographic seizure burden (SB) was calculated in seconds and converted to log units for analysis. MRI scans were scored for severity of brain injury. Infants underwent neurodevelopmental evaluation at 18 to 24 months. Statistical analyses were performed by using SAS 9.3 version (SAS Institute, Inc, Cary, NC).
Thirty-five of 69 neonates (51%) who were randomly assigned and included in the study developed seizures (15 in ESG and 20 in CSG). Excluding infants with status epilepticus, median SB (interquartile range) in seconds in ESG (n = 10) was lower than in CSG (n = 16) (449 [113–2070] vs 2226 [760–7654]; P = .02). ESG had fewer seizures with shorter time to treatment (P = .04). Twenty-four of 30 (80%) surviving infants with seizures underwent neurodevelopmental evaluation at 18 to 24 months. Increasing SB in the combined cohort was significantly associated with higher brain injury scores (P < .03) and lower performance scores across all 3 domains on BSID III (P = .03).
In neonates with HIE, EEG monitoring and treatment of electrographic seizures results in significant reduction in SB. SB is associated with more severe brain injury and significantly lower performance scores across all domains on BSID III.
Dear Editor
We thank Drs. Wilkinson and Stenson for their comments on our clinical trial. As they point out, and as we state in our article, our study was not powered, a priori, to address the impact of treating EEG seizures on neurodevelopmental outcomes. This will need a larger multicenter effort. The reason we discuss the ethical dilemma around such a potential trial is based on clinical practice recommendations from the American Clinical Neurophysiology Society (ACNS)1 . These guidelines, while acknowledging lack of data on the long term benefit of this practice, nevertheless recommend EEG monitoring for at least 24 hours in all infants admitted with neonatal encephalopathy. In a recent review published from the Children’s Hospital Neonatal Consortium (CHNC) Database, a collaborative neonatal database of 27 regional NICUs from Children’s Hospitals across the USA, 78% of infants admitted for neonatal encephalopathy and therapeutic hypothermia underwent conventional EEG and/or amplitude integrated EEG monitoring in the first 24 hours of life2 . At least in the USA, there is no longer equipoise in the neonatal intensive care and pediatric neurology community on the benefits of EEG monitoring in neonatal hypoxic-ischemic encephalopathy (HIE). We acknowledge and agree with Drs. Wilkinson and Stenson on the importance of answering the question of the long-term benefits of EEG monitoring in neonatal HIE with a large, appropriately powered, randomized clinical trial, but such a trial would only be feasible in a country/region where equipoise still exists in clinical practice on the benefits of EEG monitoring in neonatal HIE.
References:
1. Shellhaas 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(6):611-7.
2. Massaro AN, Murthy K Zaniletti I et al. Short-term outcomes after perinatal hypoxic ischemic encephalopathy: a report from the Children's Hospitals Neonatal Consortium HIE focus group. J Perinatol. 2015; 35(4):290-6
Dear Editor,
The paper by Sreenivasakumar et al(1) is a valuable addition to the small existing randomized trial literature on monitoring and treatment of seizures in newborn infants. It confirms findings from previous studies that greater seizure burden is associated with more severe brain injury, and that pharmacological treatment reduces electrical seizures.
However, in their discussion the authors argue that their findings support routine electroencephalogram (EEG) monitoring of newborn infants with hypoxic ischaemic encephalopathy (HIE), and infer that because of “ethical concerns” large multi-centre trials of EEG monitoring should not occur. Neither of these conclusions is justified by the evidence presented.
The most important question that determines whether we should routinely monitor infants with HIE with aEEG is not ‘can aEEG detect more seizures than clinical monitoring alone?’ or does ‘treatment of electrical seizures reduce the electrical seizure burden?’ The key question is whether treating electrical seizures in this way makes a difference to the long term neurological outcome. And this trial, like the previous small (n=33) randomized trial,(2) does not show that this more intensive approach improves outcome.
The previous study by Van Rooji et al did not compare brain injury on MRI or neurodevelopmental outcome between groups.(2) Sreenivasakumar et al do not report a comparison between treatment groups of the severity of MRI injury either. They do report neurodevelopmental testing results in 53 surviving infants. There was no difference between groups in cognitive, motor, or language composite scores on Bayley assessment.
Why did the authors find no difference in developmental outcome despite a reduced seizure burden? Perhaps because the study was underpowered to detect such a difference. However, it is also possible that treatment of electrical seizures makes no difference to outcome because the damage is already done; alternatively, any benefit of reducing seizure burden may be outweighed by the toxicity of current anticonvulsants.
The important ethical reason not to conduct a large randomized trial of monitoring and treatment of electrical seizures in newborn infants would be if there were already clear evidence of overall benefit from this treatment or of harm. However, this evidence does not exist. Indeed, the data from Sreenivasakumar et al makes the case for a large multi-centre trial more compelling if anything – since it shows that there is not unequivocal benefit of EEG monitoring and treatment.
It is vital that we neonatologists learn from our history.(3) It is a mistake to jump from promising basic science and indirect evidence to routine treatment in the absence of good trial evidence. Large randomized trials of EEG monitoring and treatment in newborn infants with HIE would not be easy (2) – but they are essential.
Associate Professor Dominic Wilkinson
Consultant Neonatologist, John Radcliffe Hospital, Oxford, UK
Director of Medical Ethics, Oxford Uehiro Centre for Practical Ethics, University of Oxford
Dominic.wilkinson@philosophy.ox.ac.uk
@Neonatalethics
Professor Ben J Stenson
Consultant Neonatologist, Royal Infirmary of Edinburgh, Edinburgh, UK
1. Srinivasakumar P, Zempel J, Trivedi S, Wallendorf M, Rao R, Smith B, Inder T,
Mathur AM. Treating EEG Seizures in Hypoxic Ischemic Encephalopathy: A Randomized
Controlled Trial. Pediatrics. 2015 Nov;136(5):e1302-9.
2. van Rooij LG, Toet MC, van Huffelen AC, et al. Effect of treatment of subclinical neonatal seizures detected with aEEG: randomized, controlled trial. Pediatrics. 2010;125(2).
3. Robertson, A. F. Reflections on errors in neonatology III. The “experienced” years, 1970 to 2000. Journal of Perinatology 2003 23(3), 240–249.