Diffusely Abnormal White Matter in Chronic Multiple Sclerosis

Abstract

Background: Diffuse abnormalities in the white matter (WM), ie, the so-called diffusely abnormal WM (DAWM), as observed on magnetic resonance imaging (MRI), may contribute to the development of clinical disability in multiple sclerosis (MS). Underlying pathologic and MRI characteristics of DAWM are largely unknown.Objectives: To explore and describe the histopathologic and radiologic characteristics of DAWM in chronic MS.Design: An MRI and histopathologic postmortem correlative study. Methods:We analyzed 17 formalin-fixed hemispheric brain slices from 10 patients with chronic MS using histopathologic analysis and qualitative and quantitative MRI. A region-of-interest approach was applied to compare radiologically defined DAWM, normal-appearing WM, and focal WM lesions and to correlate quantitative MRI measures with histopathologic findings. Main Outcome Measures:The DAWM consisted of extensive axonal loss, decreased myelin density, and chronic fibrillary gliosis, all of which were substantially abnormal compared with normal-appearing WM and significantly different from focal WM lesion pathology. Increased T1-and T2-relaxation times and decreased fractional anisotropy values were found in DAWM regions of interest, in association with extensive axonal loss and reduced myelin density. Increased T1-and T2relaxation times were associated with chronic gliosis.Conclusions: This study classifies DAWM in chronic MS as an abnormality that is different from normalappearing WM and focal WM lesions, most likely resulting from the cumulative effects of ongoing inflammation and axonal pathology. As such, DAWM is likely to substantially contribute to disease progression and may prove to be an important new disease marker in clinical trials focusing on the neurodegenerative aspects of MS.

Dynamic Imaging of Individual Remyelination Profiles in Multiple Sclerosis

“…These findings mirror postmortem evidence showing that the lesion edge surrounding areas are characterized by a partial decrease in myelin density with an intermediate level between discrete lesions and NAWM,28, 29, 30, 31 and that the severity of myelin destruction inside lesions becomes progressively worse from the periphery to the center 28…”

Diffusely Abnormal White Matter in Progressive Multiple Sclerosis: In Vivo Quantitative MR Imaging Characterization and Comparison between Disease Types

“…These abnormalities have been referred to as dirty WM, dirty-appearing WM, or DAWM. [1][2][3][4] The use of varying criteria renders comparisons among these studies difficult. A previous article has proposed a set of MR imaging criteria to define DAWM, applied them in a postmortem setting, and concluded that the use of these specific criteria yields only areas with truly diffuse pathology, without including multifocal lesional pathology.…”

“…A previous article has proposed a set of MR imaging criteria to define DAWM, applied them in a postmortem setting, and concluded that the use of these specific criteria yields only areas with truly diffuse pathology, without including multifocal lesional pathology. 4 Recently, these areas of DAWM have been characterized histopathologically and were found to contain tissue changes indicating a chronic pathology, including axonal loss, myelin loss, and chronic isomorphic gliosis. 4,5 However, the severity of these changes may vary among patients.…”

“…4 Recently, these areas of DAWM have been characterized histopathologically and were found to contain tissue changes indicating a chronic pathology, including axonal loss, myelin loss, and chronic isomorphic gliosis. 4,5 However, the severity of these changes may vary among patients. On the basis of previous histopathology and MR imaging results, DAWM is believed to represent a separate pathologic entity in MS, 4,5 in addition to MR imagingϪvisible focal WM lesions, focal lesions in the gray matter, and subtle changes in the so-called normal-appearing brain tissue.…”

“…4,5 However, the severity of these changes may vary among patients. On the basis of previous histopathology and MR imaging results, DAWM is believed to represent a separate pathologic entity in MS, 4,5 in addition to MR imagingϪvisible focal WM lesions, focal lesions in the gray matter, and subtle changes in the so-called normal-appearing brain tissue. Because DAWM pathology appears to be chronic, most likely reflecting secondary axonal degeneration, one could hypothesize that monitoring DAWM in vivo may give important information on the progression of the disease.…”