EEG sharp waves are a biomarker of striatal neuronal survival after hypoxia-ischemia in preterm fetal sheep

Hamid Abbasi,Laura Bennet,Paul P. Drury,Christopher A. Lear,Charles P. Unsworth,Joanne O. Davidson,Alistair J. Gunn

doi:10.1038/s41598-018-34654-7

Abstract

The timing of hypoxia-ischemia (HI) in preterm infants is often uncertain and there are few biomarkers to determine whether infants are in a treatable stage of injury. We evaluated whether epileptiform sharp waves recorded from the parietal cortex could provide early prediction of neuronal loss after HI. Preterm fetal sheep (0.7 gestation) underwent acute HI induced by complete umbilical cord occlusion for 25 minutes (n = 6) or sham occlusion (control, n = 6). Neuronal survival was assessed 7 days after HI by immunohistochemistry. Sharp waves were quantified manually and using a wavelet-type-2-fuzzy-logic-system during the first 4 hours of recovery. HI resulted in significant subcortical neuronal loss. Sharp waves counted by the automated classifier in the first 30 minutes after HI were associated with greater neuronal survival in the caudate nucleus (r = 0.80), whereas sharp waves between 2–4 hours after HI were associated with reduced neuronal survival (r = −0.83). Manual and automated counts were closely correlated. This study suggests that automated quantification of sharp waves may be useful for early assessment of HI injury in preterm infants. However, the pattern of evolution of sharp waves after HI was markedly affected by the severity of neuronal loss, and therefore early, continuous monitoring is essential.

Highlights

Worldwide, hypoxic-ischemic (HI) intrapartum insults were associated with approximately 1,150,000 cases of HI encephalopathy in 2010, 8.5 per 1,000 live births, and in turn with high rates of death and neurodevelopmental disability[1]
Hypothermia, and potentially other treatments that act through similar pathways, is only effective when started during the latent phase after HI; efficacy is rapidly lost with increasing delay after HI as previously reviewed[3]
We have shown in preterm fetal sheep that during the latent phase there is intense epileptiform transient activity, including spikes, sharps, slow-waves, which correlated with subcortical neuronal loss[6,19,20,21,22,23,24,25]

Summary

Introduction

Hypoxic-ischemic (HI) intrapartum insults were associated with approximately 1,150,000 cases of HI encephalopathy in 2010, 8.5 per 1,000 live births, and in turn with high rates of death and neurodevelopmental disability[1]. Electroencephalographic (EEG) and amplitude integrated EEG (aEEG) monitoring within 6 hours after HI can predict neurological outcome in term infants, but in many mild and moderate cases may only be a reliable indicator towards the end of the latent phase, when the efficacy of early therapies such as therapeutic hypothermia is becoming limited[13,15,16,17]. There is clinical evidence that in the neonatal period these waveforms are associated with increased risk of disability[26,27] Clinical use of this finding will require automated quantification of numbers of transients, in contrast with visual assessment and counting in early studies[6,28,29]. Numbers of sharp waves within each epoch were correlated with neuronal survival assessed 7 days after HI in utero

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Results

Conclusion