Elsevier

The Lancet Neurology

Volume 8, Issue 1, January 2009, Pages 110-124
The Lancet Neurology

Review
Brain injury in premature infants: a complex amalgam of destructive and developmental disturbances

https://doi.org/10.1016/S1474-4422(08)70294-1Get rights and content

Summary

Brain injury in premature infants is of enormous public health importance because of the large number of such infants who survive with serious neurodevelopmental disability, including major cognitive deficits and motor disability. This type of brain injury is generally thought to consist primarily of periventricular leukomalacia (PVL), a distinctive form of cerebral white matter injury. Important new work shows that PVL is frequently accompanied by neuronal/axonal disease, affecting the cerebral white matter, thalamus, basal ganglia, cerebral cortex, brain stem, and cerebellum. This constellation of PVL and neuronal/axonal disease is sufficiently distinctive to be termed “encephalopathy of prematurity”. 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. This Review integrates the fascinating confluence of new insights into both brain injury and brain development during the human premature period.

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

Search strategy and selection criteria

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

References (211)

  • TE Inder et al.

    Defining the nature of the cerebral abnormalities in the premature infant—a qualitative magnetic resonance imaging study

    J Pediatr

    (2003)
  • K Deguchi et al.

    Characteristic neuropathology of leukomalacia in extremely low birth weight infants

    Pediatr Neurol

    (1997)
  • Y Arai et al.

    Expression of β-amyloid precursor protein in axons of periventricular leukomalacia brains

    Pediatr Neurol

    (1995)
  • SZ Meng et al.

    Early detection of axonal and neuronal lesions in prenatal-onset periventricular leukomalacia

    Brain Dev

    (1997)
  • K Deguchi et al.

    Periventricular leukomalacia: relation to gestational age and axonal injury

    Pediatr Neurol

    (1999)
  • M Anjari et al.

    Diffusion tensor imaging with tract-based spatial statistics reveals local white matter abnormalities in preterm infants

    NeuroImage

    (2007)
  • SJ Counsell et al.

    Thalamo-cortical connectivity in children born preterm mapped using probabilistic magnetic resonance tractography

    NeuroImage

    (2007)
  • CD Kroenke et al.

    Diffusion MR imaging characteristics of the developing primate brain

    NeuroImage

    (2005)
  • JP Boardman et al.

    Abnormal deep grey matter development following preterm birth detected using deformation based morphometry

    NeuroImage

    (2006)
  • JA Martin et al.

    Annual summary of vital statistics: 2006

    Pediatrics

    (2008)
  • LJ Woodward et al.

    Object working memory deficits predicted by early brain injury and development in the preterm infant

    Brain

    (2005)
  • K Kobaly et al.

    Outcomes of extremely low birth weight (<1 kg) and extremely low gestational age (<28 weeks) infants with bronchopulmonary dysplasia: effects of practice changes in 2000 to 2003

    Pediatrics

    (2008)
  • M Allin et al.

    Cognitive maturation in preterm and term born adolescents

    J Neurol Neurosurg Psychiatr

    (2008)
  • JJ Volpe

    Neurology of the newborn

    (2008)
  • N Marlow et al.

    Neurologic and developmental disability at six years of age after extremely preterm birth

    N Engl J Med

    (2005)
  • NS Wood et al.

    The EPICure study: associations and antecedents of neurological and developmental disability at 30 months of age following extremely preterm birth

    Arch Dis Child

    (2005)
  • N Marlow et al.

    Motor and executive function at 6 years of age after extremely preterm birth

    Pediatrics

    (2007)
  • D Wolke et al.

    Specific language difficulties and school achievement in children born at 25 weeks of gestation or less

    J Pediatr

    (2008)
  • O Khwaja et al.

    Pathogenesis of cerebral white matter injury of prematurity

    Arch Dis Child Fetal Neonatal Ed

    (2008)
  • SP Miller et al.

    Comparing the diagnosis of white matter injury in premature newborns with serial MR imaging and transfontanel ultrasonography findings

    AJNR Am J Neuroradiol

    (2003)
  • TE Inder et al.

    Abnormal cerebral structure is present at term in premature infants

    Pediatrics

    (2005)
  • LJ Woodward et al.

    Neonatal MRI to predict neurodevelopmental outcomes in preterm infants

    N Engl J Med

    (2006)
  • RL Haynes et al.

    Nitrosative and oxidative injury to premyelinating oligodendrocytes is accompanied by microglial activation in periventricular leukomalacia in the human premature infant

    J Neuropath Exp Neurol

    (2003)
  • SA Back et al.

    Selective vulnerability of preterm white matter to oxidative damage defined by F(2)-isoprostanes

    Ann Neurol

    (2005)
  • S Robinson et al.

    Neonatal loss of gamma-aminobutyric acid pathway expression after human perinatal brain injury

    J Neurosurg

    (2006)
  • SS Billiards et al.

    Myelin abnormalities without oligodendrocyte loss in periventricular leukomalacia

    Brain Pathol

    (2008)
  • Z Yang et al.

    Sustained neocortical neurogenesis after neonatal hypoxic/ischemic injury

    Ann Neurol

    (2007)
  • DK Thompson et al.

    Perinatal risk factors altering regional brain structure in the preterm infant

    Brain

    (2007)
  • BS Peterson et al.

    Regional brain volume abnormalities and long-term cognitive outcome in preterm infants

    JAMA

    (2000)
  • C Nosarti et al.

    Adolescents who were born very preterm have decreased brain volumes

    Brain

    (2002)
  • M Allin et al.

    Effects of very low birthweight on brain structure in adulthood

    Dev Med Child Neurol

    (2004)
  • P Fearon et al.

    Brain volumes in adult survivors of very low birth weight: a sibling-controlled study

    Pediatrics

    (2004)
  • GA Lodygensky et al.

    Structural and functional brain developmental after hydrocortisone treatment for neonatal chronic lung disease

    Pediatrics

    (2005)
  • KN Segovia et al.

    Arrested oligodendrocyte lineage maturation in chronic perinatal white matter injury

    Ann Neurol

    (2008)
  • TE Inder et al.

    White matter injury in the premature infant: a comparison between serial cranial ultrasound and MRI at term

    AJNR Am J Neuroradiol

    (2003)
  • T Debillon et al.

    Limitations of ultrasonography for diagnosing white matter damage in preterm infants

    Arch Dis Child Fetal Neonatal Ed

    (2003)
  • SJ Counsell et al.

    Diffusion weighted imaging of the brain in preterm infants with focal and diffuse white matter abnormality

    Pediatrics

    (2003)
  • JJ Volpe

    Cerebral white matter injury of the premature infant—more common than you think

    Pediatrics

    (2003)
  • LE Dyet et al.

    Natural history of brain lesions in extremely preterm infants studied with serial magnetic resonance imaging from birth and neurodevelopmental assessment

    Pediatrics

    (2006)
  • JE Bell et al.

    Brain damage and axonal injury in a Scottish cohort of neonatal deaths

    Brain

    (2005)
  • Cited by (1908)

    • Preterm birth: A neuroinflammatory origin for metabolic diseases?

      2024, Brain, Behavior, and Immunity - Health
    View all citing articles on Scopus
    View full text