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  • Review Article
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White matter injury in infants with intraventricular haemorrhage: mechanisms and therapies

Nature Reviews Neurology volume 17, pages 199–214 (2021)Cite this article

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Abstract

Intraventricular haemorrhage (IVH) continues to be a major complication of prematurity that can result in cerebral palsy and cognitive impairment in survivors. No optimal therapy exists to prevent IVH or to treat its consequences. IVH varies in severity and can present as a bleed confined to the germinal matrix, small-to-large IVH or periventricular haemorrhagic infarction. Moderate-to-severe haemorrhage dilates the ventricle and damages the periventricular white matter. This white matter injury results from a constellation of blood-induced pathological reactions, including oxidative stress, glutamate excitotoxicity, inflammation, perturbed signalling pathways and remodelling of the extracellular matrix. Potential therapies for IVH are currently undergoing investigation in preclinical models and evidence from clinical trials suggests that stem cell treatment and/or endoscopic removal of clots from the cerebral ventricles could transform the outcome of infants with IVH. This Review presents an integrated view of new insights into the mechanisms underlying white matter injury in premature infants with IVH and highlights the importance of early detection of disability and immediate intervention in optimizing the outcomes of IVH survivors.

Key points

  • Intraventricular haemorrhage (IVH) results in periventricular white matter injury (WMI) in premature infants of 23–32 weeks gestation; survivors can develop neurodevelopmental sequelae, including cerebral palsy, cognitive deficits and hydrocephalus.

  • IVH triggers robust inflammation around the cerebral ventricles, damages axons and induces both apoptosis and maturational arrest of oligodendrocyte progenitors, leading to reduced myelination of white matter.

  • A constellation of blood-induced reactions, including oxidative stress, glutamate excitotoxicity, inflammation, deranged signalling pathways and alteration of the extracellular matrix, contribute to WMI in infants with IVH.

  • The early diagnosis of neurobehavioural impairments, timely referral to deficit-specific early intervention and family-centred care are crucial to optimizing the neurodevelopmental outcomes of these infants.

  • Neuroimaging studies are important for the early diagnosis of neurodevelopmental impairments, predicting outcomes and evaluating the efficacy of therapeutic interventions in both individual patients and clinical trials.

  • New therapies being tested in preclinical models might reduce cerebral inflammation and promote myelination; ongoing clinical trials are investigating stem cell treatment and the endoscopic removal of clots.

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Fig. 1: Germinal matrix and IVH in human preterm infants.
Fig. 2: Sequential neuroimaging studies of a preterm infant with bilateral IVH and PVHI.
Fig. 3: Degenerating axons and reduced numbers of myelinated axons in an animal model of IVH.
Fig. 4: Mechanisms and treatment options for white matter injury.
Fig. 5: IVH induces apoptosis of oligodendrocyte progenitor cells and reduces myelination of white matter.
Fig. 6: Regulation of oligodendrogenesis.

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Acknowledgements

The authors sincerely thank Robert Hevner, University of California San Diego, CA, USA, for the images of brain slices from a human premature infant with IVH in Figs 1a and 1b. The authors also sincerely thank George Kleinman, New York Medical College, Valhalla, NY, USA, and Peter Nikkels, University Medical Center, Utrecht, the Netherlands, for the images of brain slices from a human premature infant with IVH in Figs 1c and 1d, respectively. The authors are grateful to Joseph Volpe, Harvard University, Boston, MA, USA, for a critical review of the manuscript. The authors’ research work is supported by NIH grants RO1 NS110760 and R21NS102897 (both to P.B.).

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  1. Division of Neonatology, Children’s Hospital at Montefiore, Bronx, NY, USA

    Praveen Ballabh

  2. Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, NY, USA

    Praveen Ballabh

  3. Department of Neonatology, University Medical Center Utrecht, Utrecht, The Netherlands

    Linda S. de Vries

  4. Department of Neonatology, Leiden University Medical Center, Leiden, The Netherlands

    Linda S. de Vries

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Ballabh, P., de Vries, L.S. White matter injury in infants with intraventricular haemorrhage: mechanisms and therapies. Nat Rev Neurol 17, 199–214 (2021). https://doi.org/10.1038/s41582-020-00447-8

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