Diffusely abnormal white matter in multiple sclerosis

Abstract

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 T 2 -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 T 2 imaging would enable retrospective DAWM identification and analysis.

Prognostic relevance of MRI in early relapsing multiple sclerosis: ready to guide treatment decision making?

“…Apart from focal inflammation, MS, in particular in progressive stages, is also characterized by diffuse inflammation that can appear on conventional MRI as areas of slightly increased T2-hyperintensity. 35 – 37 Various quantitative MRI methods to detect diffuse neuroinflammation have been described. On positron emission tomography, several radioligands binding to the 18-kDa translocator protein and 11 C-acetate label activated microglia and astrocytes, respectively.…”

“… 57 , 100 , 102 , 142 – 144 Loss of correlation of lesion load to present disability and future deterioration reflects an increasing and uncontrollable variance, introduced, for example, by strategic lesions, 145 , 146 damage to specific networks, 144 , 147 spinal cord involvement, 36 and diffuse pathology. 35 – 37 For these reasons, the predictive capabilities of MRI should be applied in early RRMS and strongly guide initial treatment decisions.…”

Predictive MRI Biomarkers in MS—A Critical Review

“…The diffusely abnormal white matter (DAWM) has poorly defined boundaries and a signal intensity that lies between NAWM and classic WML. This MRI finding is very common when searched for, being present in a significant proportion (around 40%) of MS patients across all clinical subtypes [ 89 ].…”

Characteristics of cerebral blood flow in an Eastern sample of multiple sclerosis patients: A potential quantitative imaging marker associated with disease severity

“…However, it cannot provide quantitative analysis of brain function in MS patients and does not correlate strongly with clinical status ( 22 , 23 ). Except the pathologic changes in DWM, growing evidence suggests a more widespread and subtle form of disease activity also occurs in NAWM and GM ( 24 , 25 ), which may have an association with clinical manifestation. Conventional MRI is not sensitive to the pathology affecting CNS tissue outside DWM (i.e., in NAWM and GM).…”