Periventricular leukomalacia or PVL is one of the most important causes of disability in premature infants and is the most common cause of permanent motor dysfunction or cerebral palsy in this group.4 PVL is generally considered as a developmentally determined ischemic syndrome of premature infants with a peak incidence between27-30 weeks gestation.4 However, as clinical study of the disorder has intensified, etiologies such as maternal and neonatal infection have also emerged as important causes.54 Nevertheless, it is appropriate to condsider PVL here as an important cause of ischemic injury in the developing brain.
PVL was originally described in postmortem brain by Banker and Larroche as symmetric bilateral necrosis of periventricular white matter that is most severe around the frontal horns and in the occipital-parietal region around the ventricular trigone.55 As neuroimaging with head ultrasound and then MRI scanning developed, PVL could be studied in more detail in living infants and a greater variety of lesions was apparent.56 PVL associated with cystic lesions in the white matter can often be observed to develop in premature infants with serial imaging in the postnatal pe-riod.56 In this type, there may be little evidence of pathology initially after birth, but serial ultrasound images first reveal enhanced echogenicity around the ventricles and then formation of cysts.57 These cysts eventually collapse after several weeks, as the surrounding white matter reorganizes, simultaneously enlarging the ventricular space filled by cerebrospinal fluid. In many cases, the formation of these periven-tricular cysts is probably caused by ischemia in the periventricular white matter, which may be more vulnerable because of the anatomy of its arterial supply.58 Although the role of systemic hypotension has been proposed as a cause of PVL, this theory currently appears to have less support than the hypothesis of impaired intra-cerebral arterial autoregulation.59 Premature infants cannot regulate the diameter of intracerebal arterioles to maintain constant perfusion pressure in the face of variations in systemic pressure as well as older babies. Careful studies with Doppler ultrasound suggest that there is a strong correlation between fluctuations in cerebral perfusion in sick premature infants and development of PVL.60
Ischemia may cause white matter necrosis through excitotoxic mechanims that parallel those involved in neuronal damage.61 Immature oligodendroglia that synthesize and maintain myelin are vulnerable to high concentrations of glutamate that may be released in white matter during ischemia, in part because they are more vulnerable to damage from oxidative stress.62 The enhanced vulnerability of immature oligo-dendroglia during a critical point in their development has been proposed as one of the factors that makes premature infants most vulnerable to PVL during a relatively narrow time window of gestational age.63 Excitotoxic mechanisms may also be a link to death of oligodendroglia from inflammatory cytokines stimulated by infection.54 Both agents such as endotoxin and overstimulation of excitatory amino acids may stimulate proinflammatory cascades that kill oligodendroglia by apoptotic mechanism. This mechanistic interaction between glutamate-mediated excitotoxicty stimulated by ischemia and inflammatory cascades stimulated by infectious agents, as well as the association between infection and alterations in blood pressure, probably contribute to the interactions between these two mechanisms to cause PVL.54
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