Neonatal brain injury : pathophysiology and current therapeutic options

Perinatal brain injury is a major contributor to neonatal morbidity and mortality and is a common cause of disability with devastating impact on individuals and families. The mechanisms involved in the genesis of brain lesions depend of the the gestational age at which brain development is altered. In the term infant, the most common pathology implicated in brain damage is hypoxic-ischemic encephalopathy (HIE). HIE is the consequence of an excitotoxic cascade leading to cortical and/or basal ganglia lesions. Therapeutic hypothermia induced in the 6 hours following HIE reduces the risk of death or major neurodevelopmental disability in the neonate with moderate or severe encephalopathy and is the only neuroprotective treatment available in clinical practice. Research is now being focused on other promising strategies such as xenon, allopurinol, N-acetyl cystein, melatonin, anticonvulsant, erythropoietin or stem cell transplantation. In the preterm infant, diffuse white matter injury (dWMI) is the main pathological condition associated with neurological impairment. Based on experimental models, pathophysiological mechanisms of dWMI potentially include infection/inflammation, hypoxia-ischemia and oxidative stress. Experimental studies suggest a sensitizing effect of systemic inflammation that makes the perinatal brain more vulnerable to further insults. Antenatal magnesium sulfate therapy given to women at risk of preterm birth substantially reduced the risk of motor disorders in childhood but is unfortunately unable to reduce long term cognitive impairment or behavioural disorders. Antenatal steroids and caffeine therapy for apnea of prematurity are two other treatments with positive impact on neurodevelopment. Randomized controlled trials studying erythropoietin or melatonin are currently under process. Finally, research performed at the University of Liege suggests that Estetrol (E4), an estrogen synthetized exclusively by the human foetus, has neuroprotective properties in animal models of HIE as well as in inflammatory-induced dWMI