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

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.

Figure 1.. Germinal matrix and intraventricular haemorrhage in human preterm infants.

a | Grade I germinal matrix haemorrhage. Microscopic image of hematoxylin-eosin stained section showing haemorrhage (arrowheads) confined to the germinal matrix and not extending to the ventricle in a 25-week preterm infant at postnatal day 3. Arrows indicate the ependymal layer. b | Grade II intraventricular haemorrhage (IVH). Coronal section of the forebrain of a 25-week infant showing blood (block arrows) in the germinal matrix and lateral ventricle. c | Grade II IVH. Coronal section of the forebrain of a 24 week infant with IVH and ventricular dilatation (red arrows). d | Grade IV periventricular haemorrhagic infarction (PHVI). Coronal section of the forebrain of a 28 week preterm infant revealing IVH with ventricular dilatation of ventricle (red arrow) as well as an infarct dorsal to the ventricle (PVHI, block arrow).

Figure 2.. Sequential neuroimaging studies of a preterm infant with bilateral intraventricular haemorrhage and periventricular haemorrhagic infarction.

a | Cranial ultrasound (coronal view) shows a bilateral germinal matrix haemorrhage (arrowheads) and periventricular haemorrhagic infarction (PVHI), seen as a large echogenic lesion in the white matter (arrows) in a preterm infant of 29 weeks gestational age. b | A T2-weighted MRI sequence performed on day 10 confirmed the PVHI (arrows) and also shows some abnormalities (arrowhead) in the white matter on the contralesional side. c | A subsequent T1-weighted MRI scan performed at term-equivalent age shows an area of cavitation (arrows) and asymmetry of myelination of the posterior limb of the internal capsule (PLIC). d | A direction-encoded collar map confirms asymmetry of the PLIC (seen as blue, rostral-caudal direction), with lower fractional anisotropy suggestive of reduced myelination on the affected side.

Figure 3.. Degenerating axons and reduced numbers of myelinated axons in an animal model of IVH.

a | Representative brain coronal section immunolabeled with amyloid-β precursor protein (APP)-specific antibody showing swelling along contiguous axons (varicosity, arrowhead) or terminal bulbs suggesting axonal damage in periventricular corona radiata of premature rabbit kits (embryonic day (ED) 29; term 32 days) with intraventricular haemorrhage (IVH) at postnatal day 1 and day 3, but not in day 3 controls without IVH. b | Fluoro-Jade-C-labelled coronal section showing neurofilaments and varicosities (arrowheads) in the periventricular corona radiata of prematurely born rabbit kits with IVH at postnatal day 7 and day 14, but not in day 14 controls without IVH. c | Electron micrograph showing fewer myelinated axons (yellow arrows) in the corona radiata of a kit with IVH compared to a control kit without IVH, both at postnatal day 14. Features of axonal degeneration can also be seen in the corona radiata of the kit with IVH, including an intra-axonal vacuole (orange arrowhead), granular disintegration to total loss of microtubules and rupture of the axolemma (black arrows). Scale bar 1μm.

Figure 4:. Mechanisms and treatment options for white matter injury.

Intraventricular haemorrhage (IVH) results in the collection of blood in cerebral ventricles, clot lysis and the subsequent release of haemoglobin, iron, thrombin and complement. These blood products induce oxidative stress, glutamate excitotoxicity and inflammation, which are the main pathological reactions that result in damage to oligodendrocyte progenitor cells (OPCs), reduced myelination. In addition, IVH causes mass effects that compress the brain region around the ventricle and damage the blood–brain barrier. Therapeutic strategies to improve myelination have been classified into three categories: removal of blood products; inhibition of inflammation, glutamate excitotoxicity and oxidative stress; and promotion of proliferation and maturation of OPCs. BMP, bone morphogenetic protein; COX2, cyclo-oxygenase 2; TNF, tumour necrosis factor.

Figure 5:. IVH induces apoptosis of oligodendrocyte progenitor cells and reduces myelination of the white matter.

a | Coronal sections of the periventricular white matter of the frontal lobe of the forebrain of a preterm (born at ED29; term 32 days) rabbit kit with intraventricular haemorrhage (IVH) on postnatal day 2 and a premature human infant (born at gestational age 27 weeks) on postnatal day 3 with IVH. Both sections were immunolabelled with O4 antibody (red) and TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling, which detects DNA breaks) staining (green). Apoptotic O4-positive and TUNEL-positive cells are shown (arrowheads). Scale bar 20 μm. b | Representative coronal section of the forebrain of an ED29 rabbit kit with IVH on postnatal day 14 immmunolabelled with an antibody targeting myelin basic protein versus a control kit without IVH, also on day 14. Reduced myelination is evident in the corona radiata of the kit with IVH. ED, embryonic day; V, ventricle. Scale bar 100 μm.

Figure 6:. Regulation of oligodendrogenesis.

Key signalling pathways that regulate the production and maturation of oligodendrocyte progenitor cells (OPCs) are likely to be affected by intraventricular haemorrhage (IVH)-induced injury to OPCs. (1) Bone morphogenetic proteins (BMPs) activate BMP receptors 1 and 2 and phosphorylate downstream SMAD proteins (SMAD1, SMAD5, SMAD8) to induce transcription of the DNA-binding protein inhibitors ID2 and ID4, which suppresses both the specification and maturation of OPCs. (2) Sonic hedgehog protein (SHH) binds to protein patched homolog 1 (PTC1) resulting in activation of smoothened homolog (SMO). Stimulation of SMO increases the levels of zinc finger proteins GLI1 and GLI2. This upregulation of GLI1 and GLI2 and degradation of transcriptional activator GLI3 contribute to the upregulation of oligodendrocyte transcription factor 2 (OLIGO2), which promotes oligodendrogenesis. (3) Notch activation releases the notch protein intracellular domain (NICD), which then translocates to the nucleus and induces the transcription of Notch-targeted genes. Notch activation inhibits the differentiation of OPCs. (4) Wnt activation results in dissociation of the β-catenin destruction complex. The resultant rise in cytoplasmic levels of β-catenin, and its translocation to the nucleus, induces transcription of Wnt target genes. IVH downregulates this Wnt signaling. APC, adenomatous polyposis coli protein; CK1, casein kinase 1 isoform-α; CSL, a family of transcription factors; GSK3B, glycogen synthase kinase-3β; LRP, lipoprotein receptor-related protein; PKA, protein kinase A; STK36, serine/threonine-protein kinase 36, also known as fused homolog; SUFUH, supressor of fused homolog; TCF7L2, transcription factor 7-like 2.