The Pathologic Substrate of Magnetic Resonance Alterations in Multiple Sclerosis

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Multiple sclerosis (MS) pathology is originally defined by the presence of focal white matter lesions, characterized by inflammation, primary demyelination, and reactive glial scaring. More recently, however, it became clear that focal white matter plaques in MS comprise of a broad spectrum of different lesion types, reflecting different stages of activity and different degrees of neurodegeneration or repair. In addition, the MS brain is affected by global changes in the normal-appearing white matter and gray matter. All types of changes in the MS brain and spinal cord occur on the background of inflammation; the type of inflammation, however, differs between different stages and forms of the disease.

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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