Perinatal White Matter Injury: Connecting Histology, Pathophysiology and Neurodevelopmental Outcomes

The first descriptions of perinatal white matter injury and its proposed relationship to adverse neurological outcomes were published over 150 years ago. Initial studies highlighted the significance of prematurity in the development of this pathology. Although prematurity remains a significant risk factor in the development of perinatal white matter injury today, it can be seen in many clinical settings and is associated with hypoxic/ischaemic insults and inflammation. White matter injury is typically divided into the focal form, white matter necrosis (or periventricular leukomalacia) and the diffuse form, often referred to as diffuse white matter gliosis. Diffuse white matter gliosis is characterised by a proliferation of reactive astrocytes throughout the cerebral white matter and is associated with injury to pre-oligodendrocytes that results in the arrest of maturation and delayed myelination in surviving infants. White matter necrosis causes focal injury to the cellular components of the affected white matter as well as axons. However, axonal injury is also present in the diffuse form of white matter injury, even in the absence of necrosis, and the location of pre-oligodendrocytes correlates with sites of white matter injury, suggesting that the diffuse and focal forms of perinatal white matter injury may exist on a spectrum rather than as completely distinct entities. This review focuses on the macroscopic and microscopic features of white matter injury and how these relate to the proposed pathophysiology of this disease and adverse neurodevelopmental outcomes. Areas of uncertainty and future challenges are also discussed.