Pathology of multiple sclerosis: where do we stand?

Abstract

Purpose of review: This article summarizes the pathologic features of multiple sclerosis (MS) and other inflammatory demyelinating diseases and discusses neuropathologic studies that have yielded novel insights into potential mechanisms of demyelination.

Recent findings: The pathologic hallmark of MS consists of focal demyelinated plaques within the CNS, with variable degrees of inflammation, gliosis, and neurodegeneration. Active MS lesions show a profound pathologic heterogeneity with four major patterns of immunopathology, suggesting that the targets of injury and mechanisms of demyelination in MS may be different in different disease subgroups. Recent pathologic studies have suggested that the subarachnoid space and cortex may be initial sites and targets of the MS disease process, that inflammatory cortical demyelination is present early in MS, and that meningeal inflammation may drive cortical and white matter injury in some MS patients.

Summary: MS is heterogeneous with respect to clinical, genetic, radiographic, and pathologic features; surrogate MRI, clinical, genetic, serologic, and/or CSF markers for each of the four immunopatterns need to be developed in order to recognize them in the general nonbiopsied MS population. Inflammatory cortical demyelination is an important early event in the pathogenesis of MS and may be driven by meningeal inflammation. These observations stress the importance of developing imaging techniques able to capture early inflammatory cortical demyelination in order to better understand the disease pathogenesis and to determine the impact of potential disease-modifying therapies on the cortex.

Figure 1-1

Immunopattern II multiple sclerosis lesion. A, Demyelination demonstrated as loss of immunohistochemical (IHC) staining. The myelin protein proteolipid protein (PLP) (arrow indicates a perivascular inflammatory infiltrate) (scale bar = 250 μm). B, The myelin protein myelin oligodendrocyte glycoprotein (scale bar = 250 μm). C, The myelin protein myelin-associated glycoprotein (scale bar = 250 μm). D, Active demyelination evidenced by the presence of myelin-laden macrophages (arrows) (PLP IHC, scale bar = 50 μm); E, Sea of macrophages (IHC for KiM1P, a panmacrophage marker, scale bar = 100 μm). F, T-cell perivascular inflammatory infiltrate (arrow) (IHC for cluster of differentiation 3, a marker common to all lymphocytes, scale bar = 50 μm). G, Complement activation on axons (black arrows) and phagocytosis of complement-opsonized myelin debris by macrophages (white arrow) (IHC for neoepitope on the complement component C9 of the terminal lytic complex, scale bar = 50 μm). H, Reactive astrocyte (arrows) and Creutzfeldt-Peters cells (reactive astrocytes with abundant cytoplasm and fragmented nuclear inclusions arranged in a circular pattern) (inset) (hematoxylin and eosin stain, scale bar = 100 μm, inset scale bar = 50 μm). I, Relative axonal preservation within the multiple sclerosis lesion (arrows indicate the lesion’s edge) (Bielschowsky stain, scale bar = 100 μm).

Figure 1-2

Immunopattern III multiple sclerosis/Baló concentric sclerosis. Demyelination is characterized by A, a preferential loss of the myelin protein myelin-associated glycoprotein (MAG) seen on MAG immunohistochemical (IHC) staining (scale bar = 1.5 mm), while other myelin proteins such as B, proteolipid protein (PLP) (PLP IHC, scale bar = 1.5 mm), and C, myelin oligodendrocyte glycoprotein (MOG) (MOG IHC, scale bar = 1.5 mm), are partially preserved.

Figure 1-3

Pathology of multiple sclerosis cortical onset. A, Subpial cortical lesion visualized as the absence of proteolipid protein (PLP) immunohistochemical (IHC) staining; arrows indicate the border between the cortical lesion and the normally myelinated gray matter and white matter (PLP IHC, scale bar = 500 μm). B, Active demyelination (black arrows indicate myelin-laden macrophages) in the cortical lesion (white arrow indicates a neuron) (PLP IHC, scale bar = 50 μm). C, Macrophage infiltration (IHC for cluster of differentiation [CD] 68, a macrophage marker, scale bar = 100 μm). D, Perivascular and parenchymal infiltration with T cells visible as CD3-positive brown-stained cells (CD3 IHC, scale bar = 100 μm). E, Axonal injury evidenced by the presence of axonal swellings (arrows) in a lesional area with relative axonal preservation (IHC for neurofilament protein, scale bar = 50 μm). F, Injured neurons (black arrows) scattered among normal-appearing neurons (white arrows) (hematoxylin and eosin, scale bar = 50 μm). G, Macrophages/microglia (brown-stained cells) present in the upper cortex and meninges (CD68 IHC, scale bar = 100 μm). H, Meningeal inflammation with T lymphocytes (brown-stained cells) (CD3 IHC, scale bar = 50 μm). I, Most T cells are cytotoxic T cells as evidenced by their brown CD8 immunohistoreactivity (IHC for CD8, a marker of cytotoxic lymphocytes, scale bar = 50 μm).

Figure 1-4

MRI of multiple sclerosis cortical onset. A, Prebiopsy axial T1-weighted image with contrast showing enhancement of the cortical lesion (arrow). Inset shows that contrast enhancement is within the cortical gray matter (arrowheads indicate the gray/white matter junction). B, Axial T2-weighted image 69 months after biopsy showing the appearance of new periventricular white matter lesions. C, Sagittal fluid-attenuated inversion recovery (FLAIR) image 69 months after biopsy showing the appearance of multiple new white matter lesions, with two of the lesions involving the corpus callosum.

Figure 1-5

Pathology of a neuromyelitis optica (NMO) lesion located in the ventral medulla. A, Destructive hypercellular lesion; arrows indicate the border between the lesion that shows atypical hematoxylin and eosin (HE) staining (area below arrows) and normal-appearing white matter with preserved HE staining (area above arrows) (HE, scale bar = 500 μm). B, Demyelinated lesion; arrows indicate the border between lesion that shows loss of proteolipid protein (PLP) immunohistoreactivity (area below arrows) and normal-appearing white matter with preserved PLP immunohistoreactivity (area above arrows) (PLP immunohistochemical [IHC] staining, scale bar = 500 μm). C, Active demyelination (arrows indicate myelin-laden macrophages) (PLP, scale bar = 50 μm). D, The lesion shows macrophage infiltration (KiM1P IHC, scale bar = 250 μm). E, Loss of aquaporin-4 (AQP4) is characteristic for active NMO lesions; arrows indicate the border between lesion that shows loss of AQP4 immunohistoreactivity (area below arrows) and increased AQP4 immunohistoreactivity seen at the lesion’s edge (area above arrows) (AQP4 IHC, scale bar = 250 μm). F, Loss of glial fibrillary acidic protein (GFAP) is also frequently encountered in NMO-active demyelinating lesions; arrows indicate the border between the lesion that shows loss of GFAP immunohistoreactivity (area below arrows) and normal GFAP immunohistoreactivity of the normal-appearing white matter surrounding the lesion (area above arrows) (GFAP IHC, scale bar = 500 μm). G, Loss of aquaporin in the area postrema (arrow) (AQP4 IHC, scale bar = 250 μm). H, Macrophage/microglia infiltration in the area postrema (KiM1P IHC, scale bar = 100 μm). I, Area postrema blood vessels (asterisks) with thickened and hyalinized walls (HE; scale bar = 50 μm). J, Active NMO lesions with loss of AQP4 immunoreactivity seen as the disappearance of the perivascular rim or rosette AQP4 pattern (asterisks) and loss of AQP4 outlining of the astrocytic surface (arrows) (AQP4 IHC; scale bar = 50 μm). K, Increased AQP4 immunoreactivity outlining the cytoplasmic surface of reactive astrocytes (arrows) with preservation of the typical perivascular distribution (asterisks) at the border of the NMO lesion (AQP4 IHC; scale bar = 50 μm). L, Increased AQP4 immunoreactivity outlining the cytoplasmic surface of reactive astrocytes (arrows) with preservation of the typical perivascular distribution (asterisks) within an active multiple sclerosis lesion (AQP4 IHC; scale bar = 50 μm).

Figure 1-6

MRI of neuromyelitis optica. A, Sagittal, and B, axial fluid-attenuated inversion recovery (FLAIR) images demonstrating heterogeneous T2-hyperintense corpus callosum and periventricular lesions with poorly defined margins. C, 2 months later, and, D, 17 months later, sagittal T2-weighted images of the cervical spinal cord and posterior fossa. Note the longitudinally extensive central T2-hyperintense lesion of the spinal cord on both images (arrows). Spinal cord atrophy is appreciated as a more narrow appearance of the cord in panel D.

Figure 1-7

Pathology of acute disseminated encephalomyelitis. A, Sleeves of perivascular demyelination (Luxol fast blue/periodic acid–Schiff staining) seen as the disappearance of the normal blue staining of the myelin conferred by the Luxol fast blue (several blood vessels with perivascular demyelination are marked with asterisks) (scale bar = 500 μm). B, Sleeves of perivascular demyelination (asterisks mark several blood vessels with perivascular loss of proteolipid protein [PLP]) (PLP, scale bar = 500 μm). C, Infiltration with macrophages (KiM1P, scale bar = 500 μm). D, Perivascular inflammatory infiltrate with neutrophils (arrows) (hematoxylin and eosin, scale bar = 50 μm); E, Cortical microglial aggregate (arrows) (KiM1P, scale bar = 100 μm). F, The cortex in the region of the microglial aggregate does not show cortical demyelination (PLP, scale bar = 500 μm).