Neurobiology of periventricular leukomalacia in the premature infant

Brain injury in the premature infant is a problem of enormous importance. P eriventricular leukomalacia (PVL) is the major neuropathologic form of this brain injury and underlies most of the neurologic morbidity encountered in survivors of premature birth. Prevention of PVL now seems ultimately achie vable because of recent neurobiologic insights into pathogenesis. The patho genesis of this lesion relates to three major interacting factors. The firs t two of these, an incomplete state of development of the vascular I supply to the cerebral white matter, and a maturation-dependent impairment in reg ulation of cerebral blood flow underlie a propensity for ischemic injury to cerebral white matter. The third major pathogenetic factor is the maturati on-dependent vulnerability of the oligodendroglial (OL) precursor cell that represents the major cellular target in PVL. Recent neurobiologic studies show that these cells are exquisitely vulnerable to attack by free radicals , known to be generated in abundance with ischemia-reperfusion. This vulner ability of OLs is maturation-dependent, with the OL precursor cell highly v ulnerable and the mature OL resistant, and appears to relate to a developme ntal window characterized by a combination of deficient antioxidant defense s and active acquisition of iron during OL differentiation. The result is g eneration of deadly reactive oxygen species and apoptotic OL death. Importa nt contributory factors in pathogenesis interact with this central theme of vulnerability to free radical attack. Thus, the increased likelihood of PV L in the presence of intraventricular hemorrhage could relate to increases in local iron concentrations derived from the hemorrhage. The important con tributory role of maternal/fetal infection or inflammation and cytokines in the pathogenesis of PVL could be related to effects on the cerebral vascul ature and cerebral hemodynamics, to generation of reactive oxygen species, or to direct toxic effects on vulnerable OL precursors. A key role for elev ations in extracellular glutamate, caused by ischemia-reperfusion, is sugge sted by demonstrations that glutamate causes toxicity to OL precursors by b oth nonreceptor- and receptor-mediated mechanisms. The former involves an e xacerbation of the impairment in antioxidant defenses, and the latter, an a lpha -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptor-m ediated cell death. Most importantly, these new insights into the pathogene sis of PVL suggest potential preventive interventions. These include avoida nce of cerebral ischemia by detection of infants with impaired cerebrovascu lar autoregulation, e.g. through the use of in vivo near-infrared spectrosc opy, the use of free radical scavengers to prevent toxicity by reactive oxy gen species, the administration of alpha -amino-3-hydroxy-5-methyl-4-isoxaz olepropionic acid/kainate receptor antagonists to prevent glutamate-mediate d injury, or the use of maternal antibiotics or anticytokine agents to prev ent toxicity from maternal/fetal infection or inflammation and cytokines.