Cerebral 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 (); and non-cystic PVL, in which the focal necroses are microscopic and evolve principally to glial scars (). A third form of cerebral white matter abnormality consists of diffuse astrogliosis without focal necroses (). That the latter is the mildest form of injury in a spectrum that includes cystic PVL as the most severe form seems likely but has not yet been established conclusively. Cystic and non-cystic PVL are most clearly related to subsequent neurological deficits. Cystic PVL is now rare; non-cystic PVL accounts for most of the cerebral white matter injury in premature infants today.2, 3, 6
Figure 1 Schematic diagram of the three major forms of white matter abnormality in premature infants. Cystic (A) and non-cystic (B) periventricular leukomalacia exhibit the two components of the lesion—that is, focal necrosis deep in the white matter and (more ...)
Recently the term ‘‘encephalopathy of prematurity’’ has been used for the constellation of neuronal abnormalities observed in premature infants, especially those with cerebral white matter injury.7
These grey matter abnormalities, identified initially by volumetric MRI studies, include defective growth of the cerebral cortex and deep nuclear structures, in particular the thalamus and basal ganglia.6–9
A recent neuropathological study of 41 premature infants identified neuronal loss and gliosis in the thalamus in 40–55% of infants, in the basal ganglia in 30–50% and in the cerebral cortex in 10–30%.10
Importantly, the neuronal deficits were observed predominantly in brains with PVL, nearly entirely non-cystic, and were uncommon in brains with only diffuse white matter gliosis or normal white matter. The neuronal abnormalities may be particularly important in the genesis of the cognitive deficits subsequently observed in premature infants. The combination of PVL and the neuronal deficits constitutes the ‘‘encephalopathy of prematurity’’.7, 10
It is beyond the scope of this review to discuss the potential relationship of the white matter injury to the neuronal abnormalities—that is, whether cause–effect or association. Indeed, a fertile topic for future research is the delineation of the relationships between the involvement of the neuronal-axonal unit and the spectrum of white matter disturbance in PVL. In the remainder of this review, we focus on the pathogenesis of the white matter injury per se, with a particular focus on the pre-OL.