Perinatal brain damage: The term infant

Abstract

Perinatal brain injury at term is common and often manifests with neonatal encephalopathy including seizures. The most common aetiologies are hypoxic–ischaemic encephalopathy, intracranial haemorrhage and neonatal stroke. Besides clinical and biochemical assessment the diagnostic evaluation rely mostly on EEG and neuroimaging including cranial ultrasound and magnetic resonance imaging. The mechanisms underlying hypoxic–ischaemic brain injury are only partly understood but include excitotoxicity, mitochondrial perturbation, necrosis/apoptosis and inflammation. Neuroprotective treatment of newborns suffering from hypoxic–ischaemic encephalopathy with hypothermia has proven effective and has been introduced as a clinical routine. Ongoing studies are exploring various add-on therapies including erythropoietin, xenon, topiramate, melatonin and stem cells.

Keywords: Brain injury; Diagnosis; Hypothermia; Hypoxia–ischaemia; Neonatal encephalopathy; Neuroprotection; Perinatal.

Fig. 1

Role of mitochondria in hypoxic–ischaemic brain injury. During early reperfusion, extracellular glutamate activates NMDA receptors leading to intracellular accumulation of Ca²⁺ and nitric oxide (NO). NO and mitochondrial Ca²⁺ accumulation (Ca^2 + dysregulation) elicit production of reactive oxygen species (superoxide, O2^.-) which induces respiratory suppression, and contributes to translocation of cytochrome c (CytC) and apoptosis-inducing factor (AIF) from the inner mitochondrial membrane/cristae to the intermembrane space. An increase of pro-apoptotic compared with anti-apoptotic BCL2 family proteins, activation of caspase-2, and interaction of p53 with the outer mitochondrial membrane leads to mitochondrial permeabilisation. The subsequent release of CytC triggers a cascade including assembly of the apoptosome and activation of executional caspases and, leading to degradation of DNA and essential proteins, and resulting in cell death. AIF binds to cyclophilin A (CyA) and the complex translocates to the nucleus and induces chromatinolysis. PSD-95 = postsynaptic density protein 95. nNOS = neuronal NO synthase. CAD = caspase-activated DNase. ICAD = inhibitor of CAD. APAF1 = apoptic peptidase activating factor 1.