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 63000 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%.2–8
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.8–12
The neuropathological correlates of this encephalopathy include various lesions, most notably periventricular leukomalacia (PVL; ), 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; ), 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.
Cystic and non-cystic periventricular leukomalacia (PVL) and germinal matrix haemorrhage–intraventricular haemorrhage (GMH-IVH) and GMH-IVH with periventricular haemorrhagic infarction (PHI)
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.