Cerebral White Matter Injury of the Premature Infant—More Common Than You Think

Abstract

Brain injury in the premature infant consists of multiple lesions, principally germinal matrix-intraventricular hemorrhage, posthemorrhagic hydrocephalus, and periventricular leukomalacia (PVL). The last of these now appears to be the most important determinant of the neurologic morbidity observed in survivors of birth weight <1500 g. Indeed, of these very low birth weight infants, ∼10% later exhibit cerebral palsy, and ∼50%, cognitive and behavioral deficits.1–5 The focal necrotic lesions of PVL deep in the cerebral white matter correlate well with the cerebral palsy, whereas the cognitive/behavioral deficits may relate to more diffuse white matter injury observed with PVL (see below). The nature of the relationship between the diffuse white matter injury and the cognitive/behavioral deficits is complex and not entirely understood (see below). The current report of the Hammersmith group by Counsell et al,6 published elsewhere in this issue, addresses the frequency and magnetic resonance imaging (MRI) characteristics of this diffuse white matter abnormality.The study of Counsell et al6 stimulates further a necessary change in the widely held concept of PVL as principally focal necrotic lesions in the periventricular white matter with subsequent cyst formation. This concept is based on the earlier classic neuropathological description in 1962 of the focal necrotic lesions by Banker and Larroche.7 That landmark work led to the appropriate descriptive term for focal softening in the periventricular white matter, ie, PVL. Indeed, innumerable later in vivo clinical and epidemiologic studies of PVL published in the last decade or so have used the ultrasonographic finding of focal periventricular echolucency as the hallmark of PVL (see ref. 1 for review). However, focal necrotic lesions evolving to cysts, readily identified by cranial ultrasonography, are no longer the principal feature of white matter injury in premature infants. Cystic PVL identified by brain imaging is a very uncommon finding in modern neonatal intensive care units. Indeed, in a recent study of 96 consecutive preterm infants by MRI, the findings of cystic PVL were present in only 4.8 By contrast, fully 34 had MRI findings of noncystic white matter injury.8 A smaller series of 32 infants studied by MRI detected no examples of cystic white matter injury, whereas 79% of those imaged at term had MRI findings of noncystic white matter injury.9 Thus, the current concept of PVL must include not only the focal necrotic component deep in periventricular white matter that usually evolves to cyst formation but particularly also a more diffuse noncystic component in central cerebral white matter.The diffuse cerebral white matter injury has been the subject of increased scrutiny recently. For many years, studies of PVL based on conventional neuropathology have noted central cerebral white matter diffuse astrocytosis, often with abnormal glial cells.1,10 However, only recently has this diffuse lesion been clarified by more sophisticated anatomic techniques (see below). Thus, perhaps in describing cerebral white matter injury in current small premature infants, use of the term, “PVL,” which accurately describes the focal softening, would be better replaced by the term “cerebral leukoencephalopathy,” to encompass both the focal component and the more diffuse component. Indeed, over 30 years ago Gilles and Murphy used the term “perinatal telencephalic leukoencephalopathy.”11 For this review, however, rather than using a new term, “cerebral leukoencephalopathy,” I will retain PVL as the encompassing term, to include either the focal component or the diffuse component or both.In marked contrast to the paucity of the finding of cystic PVL in premature infants in modern neonatal intensive care units has been the high frequency of the MRI demonstration, especially by the Hammersmith group, of diffuse white matter abnormality.6,9,12 The abnormality consists principally of MRI signal change, often accompanied by ventricular dilation at term. The frequency of the abnormality on MRI increases as a function of postnatal age. In an earlier report in Pediatrics, the finding of diffuse excessive high signal intensities (DEHSI) on T2-weighted MRI of premature infants (median gestational age, 27 weeks) increased from 21% in the first postnatal week, to 53% in the next several weeks, to 79% at term equivalent.9 This striking result raised the important question of whether this frequent MRI finding represents a biological abnormality, a normal developmental change, or an imaging artifact.Counsell et al6 addressed the question of the nature and significance of DEHSI by using DWI to quantitate at term equivalent the apparent diffusion coefficient (ADC) in cerebral white matter of 50 selected premature infants (median gestational age, 29 weeks).6 ADC is a measure of the overall diffusion of water in the tissue and has been shown to decline in normal cerebral white matter of premat