Diffusely abnormal white matter in multiple sclerosis

MRI enables detailed in vivo depiction of multiple sclerosis (MS) pathology. Localized areas of MS damage, commonly referred to as lesions, or plaques, have been a focus of clinical and research MRI studies for over four decades. A nonplaque MRI abnormality which is present in at least 25% of MS patients but has received far less attention is diffusely abnormal white matter (DAWM). DAWM has poorly defined boundaries and a signal intensity that is between normal-appearing white matter and classic lesions on proton density and T₂ -weighted images. All clinical phenotypes of MS demonstrate DAWM, including clinically isolated syndrome, where DAWM is associated with higher lesion volume, reduced brain volume, and earlier conversion to MS. Advanced MRI metric abnormalities in DAWM tend to be greater than those in NAWM, but not as severe as focal lesions, with myelin, axons, and water-related changes commonly reported. Histological studies demonstrate a primary lipid abnormality in DAWM, with some axonal damage and lesser involvement of myelin proteins. This review provides an overview of DAWM identification, summarizes in vivo and postmortem observations, and comments on potential pathophysiological mechanisms, which may underlie DAWM in MS. Given the prevalence and potential clinical impact of DAWM, the number of imaging studies focusing on DAWM is insufficient. Characterization of DAWM significance and microstructure would benefit from larger longitudinal and additional quantitative imaging efforts. Revisiting data from previous studies that included proton density and T₂ imaging would enable retrospective DAWM identification and analysis.