The Pathologic Substrate of Magnetic Resonance Alterations in Multiple Sclerosis
Section snippets
Focal white matter lesions
Focal MS lesions can be present in any location of the CNS. However, since they arise around veins and venules,2, 4 areas of the CNS with high venular density are more frequently affected than others. Such predilection sites are the periventricular and the subcortical white matter of the forebrain, the optic nerves and chiasm, the cerebellar peduncles and the lateral columns of the spinal cord.18
MS plaques are sharply demarcated focal white matter lesions, characterized by primary
Axonal injury and widening of the extracellular space
Axonal destruction within the plaques is an important feature of MS pathology because axonal destruction appears to be the major substrate for permanent functional deficit.25 The extent of axonal destruction is variable between different lesions within a given patient and between different patients; the variation ranges from 20% to more than 80%. Most pronounced acute axonal injury occurs during the active stage of the lesion.26, 27, 28 In active lesions, an average reduction of axonal density
Remyelination
Although evidence for remyelination in MS lesions has been provided in the earliest neuropathological accounts of this disease,3 it was believed for a long time, that repair of myelin is sparse or absent in white matter lesions of the CNS. However, systematic ultrastructural studies provided unequivocal evidence for myelin repair within the lesions.21, 32, 33 Furthermore, these studies showed that remyelinated lesions may become affected by new demyelinating attacks.34 Remyelination is seen in
Blood brain barrier damage and inflammation
Assessing blood–brain barrier (BBB) damage in MS lesions through the leakage of gadolinium (Gd) became a very useful tool to determine the activity of the disease process in clinical diagnosis and therapeutic trials.43, 44, 45 There is good agreement between studies showing that Gd-enhancement is a characteristic feature of newly forming lesions in the brain and spinal cord. Brain biopsies in early MS lesions have shown that Gd-enhancement is associated with inflammation.46, 47 Based on these
BBB damage and active demyelination
Active white matter lesions, which are defined by Gd-enhancement, are frequent in the early stages of MS, but they are rather rare in the progressive stage. In the progressive stage, up to three enhancing lesions have been described per scan and time point in the entire brain45, 54. In contrast, in pathology, active demyelination is described in more than 50% of all lesions in patients with primary or secondary progressive MS.57, 58 Thus, there is a major discrepancy between the active lesions
Focal white matter changes preceding the appearance of a demyelinating lesion
For a long time, it was assumed that focal disturbance of the BBB, as seen on Gd-enhanced MR imaging scans, is the initial event in the formation of a new white matter lesion of MS.43, 44, 60 However, subsequent studies, performing serial MR imaging investigations separated by small time intervals, showed that, at least in some lesions, subtle changes in the white matter can be seen in areas, which days to weeks later develop into classical Gd-enhancing active lesions. These changes consisted
Diffuse changes in the normal-appearing white matter
Diffuse signal abnormalities on MR imaging scans, global reduction of N-acetyl aspartate, or other quantitative MR indices are seen in the NAWM, in particular from patients with progressive MS. The extent of these changes in the NAWM can only partly be explained as a secondary consequence of axonal destruction in focal white matter lesions.13, 54, 64, 65, 66 Only a few studies have concentrated on the neuropathology of tissue damage in the NAWM.
One explanation for the appearance of tissue
Cortical and gray matter pathology
MS is commonly regarded as a disease affecting the white matter exclusively. It has, however, been noted already in early studies that gray matter, and in particular the cerebral cortex, is affected by demyelination.18, 76, 77 Although cortical demyelination can so far hardly be seen directly on MR imaging, cortical atrophy and subtle changes in cortical MTR have been reported in MS patients, in particular in the progressive stage of the disease.14, 78 The current view in neuropathology is that
Neuromyelitis Optica (Devic's Disease)
A specific subtype of MS-like inflammatory-demyelinating diseases is neuromyelitis optica (NMO).94, 95 Originally described as a monophasic disease, it recently became clear that the disease process in NMO can also affect other brain regions and chronic relapsing disease courses are frequent. Characteristic features of this disease are longitudinally extensive lesions in the spinal cord, expanding over several cord segments.96 In contrast to classical MS,97 NMO lesions in the spinal cord target
Summary
Neuropathology is generally regarded as the gold standard for defining MS lesions in diagnosis and research. However, the neuropathologist's view of MS was for a long time restricted to focal white matter lesions, the classical MS plaques. Detailed cross-sectional and longitudinal MR imaging studies in MS patients, however, have identified aspects of MS pathology that could not be explained by the plaque-centered view of the disease and that have stimulated intense research efforts aimed at
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Quantitative susceptibility mapping of both ring and non-ring white matter lesions in relapsing remitting multiple sclerosis
2022, Magnetic Resonance ImagingCitation Excerpt :With respect to the relationship of susceptibility of QSM+ non-RLs and EDSS, the significance of the correlation remains unclear. We hypothesize that high susceptibility lesions may represent an acute focus of inflammation and demyelination contributing to disability because active lesions are highly associated with ongoing axonal injury [6,29]. This relationship may also be complicated by effect modifiers such as age and disease duration, as suggested in Filippi et al. [30].
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