References for this Review were obtained from personal reprint files, supplemented by PubMed searches, with varying search periods (from 1980 to November, 2008). PubMed searches were initiated with all the topical areas covered in the Review. The full list of search terms is available from the author on request and included “periventricular leukomalacia”, “cerebral white matter injury”, “subplate neurons”, “cerebral cortex”, “axonal development”, “oligodendroglial development”, “neuronal
ReviewBrain injury in premature infants: a complex amalgam of destructive and developmental disturbances
Introduction
The enormity of the problem of encephalopathy in premature infants relates in substantial part to the large number of affected infants. Every year in the USA, approximately 63 000 infants are born with a very low birthweight (VLBW; ≤1500 g).1 This group represents 1·5% of all livebirths, a proportion that has increased gradually over the past decade. The importance of encephalopathy in this large group is indicated by the subsequent occurrence of cognitive, behavioural, attentional, or socialisation deficits in 25–50%, and of major motor deficits (eg, cerebral palsy) in 5–10%.2, 3, 4, 5, 6, 7, 8 Cognitive deficits without major motor deficits are by far the dominant neurodevelopmental sequelae in infants with VLBW. Particular note should be made of the increasingly important contribution to this burden of disability by the most premature infants. Because of sharply increased survival (50–70%) in recent years, these extremely premature infants comprise a substantial proportion of infants with VLBW in many centres. Disability in this subset exceeds 50% in most studies.8, 9, 10, 11, 12
The neuropathological correlates of this encephalopathy include various lesions, most notably periventricular leukomalacia (PVL; figure 1), and accompanying neuronal/axonal deficits that involve the cerebral white matter, thalamus, basal ganglia, cerebral cortex, brainstem, and cerebellum. Severe germinal matrix haemorrhage–intraventricular haemorrhage (GMH-IVH), particularly with periventricular haemorrhagic infarction (PHI; figure 1), is an important, albeit quantitatively less common, lesion in premature infants. Imaging studies indicate that 50% or more of infants with VLBW show findings consistent with PVL and apparent neuronal/axonal disease, whereas severe GMH-IVH with PHI occurs in only approximately 5%.8 (Importantly, the occurrence of PHI can rise to as much as 20–30% in infants below 750 g.) Thus, the emphasis of this Review is on PVL and neuronal/axonal disease, because quantitatively, this constellation seems to account for most of the brain injury and the resulting neurological sequelae. The term “encephalopathy of prematurity” is proposed for this combination. However, the emerging role for severe GMH-IVH with PHI, especially in the smallest infants, is discussed briefly.
The pathogenesis of PVL has been reviewed in detail elsewhere,8, 13 and will not be discussed here. The main initiating pathogenetic mechanisms are ischaemia and inflammation, the latter often due to maternal intrauterine infection or postnatal sepsis. These two upstream mechanisms often co-exist and can potentiate each other. The main downstream mechanisms are excitotoxicity and free-radical attack. Various maturation-dependent factors, including a propensity for premature infants to experience episodes of cerebral ischaemia and infection or inflammation, and an intrinsic susceptibility to excitotoxicity and free-radical accumulation, converge to accentuate vulnerability. The cellular targets of these pathogenetic mechanisms are discussed below.
The thesis of this Review is that the encephalopathy of prematurity is a complex amalgam of primary destructive disease and secondary maturational and trophic disturbances. Recent delineation of the extraordinary array of rapidly developing neurobiological processes that occur at 20–40 weeks of gestation in the human brain provides new insights into the bases for the likely maturational/trophic disturbances. I will first review the neuropathology of the encephalopathy of the premature infant, then describe the brain developmental events that occur in the premature period, and finally discuss the likely interrelations of destructive and developmental mechanisms in the genesis of the encephalopathy.
Section snippets
Neuropathology
The main neuropathological processes in the premature infant—PVL and neuronal/axonal disease—have been defined in recent years both in vivo by MRI and post mortem by advanced histological and immunocytochemical techniques. The neuropathology of severe GMH-IVH with PHI, a venous infarction, has been well delineated by conventional histological approaches and by cranial ultrasonography and is described in standard sources.8
Brain development during the premature period
The neuropathology of brain injury in the premature infant as described above occurs against a background of multiple active developmental events that take place at 24–40 weeks of gestation and involve pre-OLs, microglia, axons, subplate neurons, the proliferative cerebral dorsal subventricular zone (SVZ) and ventral germinative epithelium of the ganglionic eminence (GE), thalamus, cortex, and cerebellum. Because of the very active and complex characteristics of these events, they are likely to
Combination of destructive and developmental disturbances
The ultimate degree of brain abnormality in survivors of premature birth is likely to depend on a combination of destructive and impaired trophic/maturational mechanisms. The relative importance of these two mechanisms and the nature and extent of their interactions are central issues. The trophic/maturational mechanisms include cell–cell interactions that can involve intercellular trophic support, retrograde effects, and anterograde effects (eg, Wallerian degeneration, trans-synaptic
Conclusions
Brain abnormality in the premature infant is unlikely to consist of a straightforward addition of destructive non-haemorrhagic and haemorrhagic lesions, such as PVL and, less commonly, GMH-IVH with PHI. Recent insights into the full spectrum of the encephalopathy of prematurity and into the remarkable series of developmental events that occur in the brain during this period indicate a complex amalgam of destructive and developmental mechanisms. Although further clarification of this amalgam is
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