Localized network damage related to white matter hyperintensities is linked to worse outcome after severe stroke

White matter hyperintensities of presumed vascular origin (WMH), a manifestation of cerebral small vessel disease, are associated with various clinical sequelae. In stroke patients, total WMH burden is linked to recurrent cerebrovascular events and worse clinical outcome. As WMH also affect the integrity of structural large-scale brain networks, we hypothesize that the extent of WMH-related network damage carries relevant information to explain outcome variability in addition to global WMH volume. Clinical and structural brain imaging data of 33 severely affected acute stroke patients were analysed from two independent cohorts. Imaging data were acquired within the first two weeks after stroke. WMH-related localized and global network damage was derived, involving cortical and subcortical brain regions of an extended motor network. Using ordinal logistic regression analyses, network damage was associated with functional outcome, operationalized by the modified Rankin Scale, at follow-up after three to six months. WMH were linked to a significant disconnection of multiple ipsilesional and contralesional cortical and subcortical brain regions. Global as well as localized periventricular WMH-related network damage affecting distinct brain regions of both hemispheres, including the precentral and the inferior frontal gyrus, areas of the dorsolateral prefrontal cortex, the insula, and multiple subcortical nuclei, was independently associated with a worse outcome after adjustment for baseline symptom burden, age, brain infarct volume and total WMH volume. Total and deep WMH-related network disturbances did not show similar associations. This study shows that periventricular WMH-related network damage affecting specific brain regions of the frontal and insular lobe, and subcortical nuclei is linked to functional outcome in acute stroke patients. This supports the evolving concept of structural brain reserve and underscores the potential significance of pre-existing WMH-related network damage as a crucial factor in comprehending outcome variability after severe stroke.