Elsevier

Neuroscience

Volume 166, Issue 1, 10 March 2010, Pages 157-167
Neuroscience

Clinical Neuroscience
Research Paper
Seizures are associated with brain injury severity in a neonatal model of hypoxia–ischemia

https://doi.org/10.1016/j.neuroscience.2009.11.067Get rights and content

Abstract

Hypoxia–ischemia is a significant cause of brain damage in the human newborn and can result in long-term neurodevelopmental disability. The loss of oxygen and glucose supply to the developing brain leads to excitotoxic neuronal cell damage and death; such over-excitation of nerve cells can also manifest as seizures. The newborn brain is highly susceptible to seizures although it is unclear what role they have in hypoxic-ischemic (H/I) injury. The aim of this study was to determine an association between seizures and severity of brain injury in a piglet model of perinatal H/I and, whether injury severity was related to type of seizure, i.e. sub-clinical (electrographic seizures only) or clinical (electrographic seizures+physical signs). Hypoxia (4% O2) was induced in anaesthetised newborn piglets for 30 min with a final 10 min period of hypotension; animals were recovered and survived to 72 h. Animals were monitored daily for seizures both visually and with electroencephalogram (EEG) recordings. Brain injury was assessed with magnetic resonance imaging (MRI), 1H-MR spectroscopy (1H-MRS), EEG and by histology (haematoxylin and eosin). EEG seizures were observed in 75% of all H/I animals, 46% displayed clinical seizures and 29% sub-clinical seizures. Seizure animals showed significantly lower background amplitude EEG across all post-insult days. Presence of seizures was associated with lower cortical apparent diffusion coefficient (ADC) scores and changes in 1H-MRS metabolite ratios at both 24 and 72 h post-insult. On post-mortem examination animals with seizures showed the greatest degree of neuropathological injury compared to animals without seizures. Furthermore, clinical seizure animals had significantly greater histological injury compared with sub-clinical seizure animals; this difference was not apparent on MRI or 1H-MRS measures. In conclusion we report that both sub-clinical and clinical seizures are associated with increased severity of H/I injury in a term model of neonatal H/I.

Section snippets

Animals

Large White newborn piglets (n=42) were obtained from the University of Queensland Gatton Piggery. Average age and weight was 17.0 h (±1.3) and 1.47 kg (±0.03) respectively. Approval for this study was obtained from the University of Queensland Animal Experimentation Ethics Committee and was carried out in accordance with National Health and Medical Research Council guidelines (Australia). Care was taken to minimize the number of animals used and to ensure no undue pain or distress.

Hypoxia/ischemia

The H/I

Results

Thirty-eight animals received H/I. Ten animals developed clinical seizures that were unresponsive to anticonvulsant treatment and in accordance with University of Queensland Animal Ethics were euthanased prior to the 72 h endpoint; these animals were excluded from further analysis consistent with our aim (to study survivable H/I brain injury and seizures) as complete EEG, clinical seizure and MRI/1H-MRS data were not available. The surviving H/I animals (n=28) were grouped for statistical

Discussion

In this study we demonstrate that seizures are associated with increasing severity of brain injury following a global H/I insult in the neonatal term piglet. Whilst damage was apparent in all H/I animals as determined from in vivo measures and neuropathology, the greatest degree of brain injury was observed in animals with seizures compared to animals in which seizure activity was absent. In our model 75% of all H/I animals developed seizures post-insult which we observed as clinical seizures

Acknowledgments

We wish to thank LED Wallis and NJ Stevenson for assistance with experiments and analysis. Financial support was provided by The National Health and Medical Research Council (Australia) (grant ID: 351501).

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    Authors contributed equally to the work contained in this manuscript.

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