Is Late Prevention of Cerebral Palsy in Extremely Preterm Infants Plausible?

Abstract

Preterm birth continues to be associated with neurodevelopmental problems including cerebral palsy. Cystic white matter injury is still the major neuropathology underlying cerebral palsy, affecting 1-3% of preterm infants. Although rates have gradually fallen over time, the pathogenesis and evolution of cystic white matter injury are still poorly understood. Hypoxia-ischemia (HI) remains an important contributor yet there is no established treatment to prevent injury. Clinically, serial ultrasound and magnetic resonance imaging studies typically show delayed development of cystic lesions 2 to 4 weeks after birth. This raises the important and unresolved question as to whether this represents slow evolution of injury occurring around the time of birth, or repeated injury over many weeks after birth. There is increasing evidence that tertiary injury after HI can contribute to impairment of white and grey matter maturation. In the present review, we discuss preclinical evidence that severe, cystic white matter injury can evolve for many weeks after acute HI and is associated with microglia activity. This suggests the intriguing hypothesis that the tertiary phase of injury is not as subtle as often thought and that there may be a window of therapeutic opportunity for one to two weeks after hypoxic-ischemic injury to prevent delayed cystic lesions and so further reduce the risk of cerebral palsy after preterm birth.

Tumour necrosis factor blockade after asphyxia in foetal sheep ameliorates cystic white matter injury

“…Fewer foetuses (two versus four foetuses) in the UCO-Etanercept developed a pattern of white matter atrophy and ventriculomegaly, representing the most severe pattern of injury. 11 , 15 Those that did develop this pattern showed markedly less loss of intact white matter area, albeit with a modest increase in the area of cystic lesions compared with the UCO-vehicle group ( Table 3 ).…”

“…The start of Etanercept infusions was designed to correspond with the estimated beginning of the tertiary phase of injury from 72 h onwards. 15 The spacing between the infusions was chosen to broadly reflect the systemic half-life of Etanercept of 4–5 days. 20 , 26 The dose of Etanercept was extrapolated and adjusted for relative body and brain size from studies in humans and rats.…”

“…7 , 14 These data suggest that substantial white matter cell death can occur in the ‘tertiary’ phase of injury, from about 72 h after HI onwards. 15 In neonatal rodents there is evidence that programmed necrosis is initiated by membrane-bound death receptor activation by the tumour necrosis factor (TNF) family of cytokines, 16 and can evolve over weeks after HI. 17 Consistent with these data, in the preterm foetal sheep no apoptotic cell death or caspase-3 expression was seen before emergence of cystic WMI, and cystic injury was preceded by exuberant local microgliosis.…”

Cerebral Oxygenation and Metabolism After Hypoxia-Ischemia

“…This is followed by a phase of secondary deterioration of oxidative metabolism, cytotoxic edema and ultimately bulk cell death lasting for ∼72 h ( 11 ). Even after this time, there is considerable evidence for tertiary evolution of ongoing injury and dysmaturation, but also ongoing repair processes that may last for weeks to months ( 12 , 13 ). These phases of evolving injury after HI are associated with characteristic neurophysiological and cerebral perfusion changes.…”

“…The secondary phase after HI resolves after 3–4 days into a tertiary phase involving persistent inflammation, delayed evolution of cystic injury and repair and reorganization processes ( 12 , 13 , 71 ). On the one hand these processes are essential for reorganizing the brain, but the very prolonged exposure to inflammation raises the intriguing possibility that there could be an extended therapeutic window of opportunity to improve recovery.…”