Pathogenesis of cerebral white matter injury of prematurity

Abstract

Cerebral white matter injury, characterised by loss of premyelinating oligodendrocytes (pre-OLs), is the most common form of injury to the preterm brain and is associated with a high risk of neurodevelopmental impairment. The unique cerebrovascular anatomy and physiology of the premature baby underlies the exquisite sensitivity of white matter to the abnormal milieu of preterm extrauterine life, in particular ischaemia and inflammation. These two upstream mechanisms can coexist and amplify their effects, leading to activation of two principal downstream mechanisms: excitotoxicity and free radical attack. Upstream mechanisms trigger generation of reactive oxygen and nitrogen species. The pre-OL is intrinsically vulnerable to free radical attack due to immaturity of antioxidant enzyme systems and iron accumulation. Ischaemia and inflammation trigger glutamate receptor-mediated injury leading to maturation-dependent cell death and loss of cellular processes. This review looks at recent evidence for pathogenetic mechanisms in white matter injury with emphasis on targets for prevention and treatment of injury.Cerebral white matter injury in the premature infant is a problem of enormous importance. For example, in the USA each year approximately 60 000 infants (1.5% of the 4 000 000 yearly live births) are born with a birth weight less than 1500 g, 1 and based on MRI data at least 50% exhibit some degree of cerebral white matter injury, 2, 3 as defined later. This injury likely accounts for the predominance of neurological deficits observed in the approximately 90% of infants who survive. These deficits in survivors include cerebral palsy in 5-10% and importantly, cognitive/behavioural/attentional deficits in about 50%. 4, 5 Although other pathologies occur in premature infants-for example, severe intraventricular haemorrhage, periventricular haemorrhagic infarction, hydrocephalus, cerebellar disease-cerebral white matter injury seems to be the predominant lesion. Prevention of this injury requires insight into pathogenesis, and recent research holds promise that preventive interventions will be found. PERIVENTRICULAR LEUKOMALACIA AND ENCEPHALOPATHY OF PREMATURITYCerebral white matter injury is the term used in this review for the full spectrum of periventricular leukomalacia (PVL). PVL has two components-that is, focal necrosis deep in the white matter with loss of all cellular elements, and a more diffuse component in central cerebral white matter with loss of pre-myelinating oligodendrocytes (pre-OLs), astrogliosis and microglial infiltration. 2 PVL occurs in two overlapping forms: cystic PVL, in which the focal necroses are macroscopic and evolve to multiple cysts ( fig 1A); and non-cystic PVL, in which the focal necroses are microscopic and evolve principally to glial scars ( fig 1B). A third form of cerebral white matter abnormality consists of diffuse astrogliosis without focal necroses ( fig 1C). That the latter is the mildest form of injury in a spectrum that includes cystic Correspondence to: Dr J J ...

Respiratory support for premature neonates in the delivery room: effects on cardiovascular function and the development of brain injury

“…As a clinical correlate, diffuse "microstructural" white matter injury within the corpus callosum in infants born at <33 wk gestation is clinically associated with poor cognitive function at 19 years of age (61). Interestingly, the pattern of white matter injury associated with increased systemic proinflammatory mediators is similar to that described in response to infection/inflammation in animal studies (58,59,62) and is consistent with that in infants with periventricular leukomalacia associated with higher plasma or cerebral spinal fluid cytokine expression (63)(64)(65). The inflammatory response of the brain to mechanical ventilation is more common in, but not limited to, the white matter, with PPV in male rats increasing c-fos expression, an indicator of neuronal activation, in gray matter, which was further amplified by high V T ventilation within the retrosplenial cortex and thalamus (55).…”

“…Considering that systemic proinflammatory cytokines can readily cross the blood-brain barrier (45,57), the circulating cytokines can elicit and exacerbate an inflammatory response within the brain. This can result in increased number of infiltrating inflammatory cells, activation of resident microglia (which causes local amplification of proinflammatory cytokines), increased oxidative stress, and subsequent diffuse white matter gliosis within the periventricular white matter, subcortical white matter, and corpus callosum (Figure 4) (4,58,59). This brain inflammatory environment, notably an increase in activated microglial cells, is a prominent feature of neuropathologies and can be correlated with brain cell death (60).…”

Chorioamnionitis: a multiorgan disease of the fetus?

“…The activated microglia generate free radicals and induce the ultimate death of the antioxidant-deficient immature oligodendrocytes. 27 Combined, these two processes result in morphological white matter lesions and the impairment of myelination, one of the most serious complications of WMD in preterm infants. 28 Pathogenetically important is the fact that the immature fetal brain becomes sensitized to hypoxia-ischemia during antenatal infection.…”

Stem Cell Therapy in Pediatric Neurological Disabilities

“…In cerebral palsy, white matter injury also known as periventricular leukomalacia (PVL) is one of the major pathologies observed [16]. Stem cells differentiate into neurons, oligodendrocytes and astrocytes which replace and repair the white matter injury in CP [17] (Figure 2).…”