The classic histopathologic lesions found in MS are focal sclerotic white matter plaques. Though located throughout the CNS, they tend to appear in the optic nerve, periventricular white matter (particularly the corpus callosum), juxtacortical border, cerebellum, brainstem, and the cervical spine with longitudinal extension of no more than two vertebral segments and axial involvement of less than one-half [6]. It is not known why these locations are preferentially affected but they are so characteristic that diagnosis utilizing MRI criteria is based upon them [35].

White matter plaques are typically centered around large- or medium-sized veins, with areas of high venous density frequently affected. They exhibit a finger-like perivenular extension pattern, classically termed Dawson’s fingers. Periventricular lesions may exhibit strip-like patterns of demyelination. In the spinal cord, lesions are fan-shaped with the tips located at the subpial surface. In cortical lesions, large subpial band-like lesions can be found. In sum, these patterns suggest pathogenic factors emanating from the vasculature, meninges, or CSF [2].

White matter lesions in the acute phase of disease demonstrate the disruption of the blood-brain barrier (BBB), allowing for visualization with gadolinium contrast enhancement on MR imaging [36]. The formation of new white matter lesions acts as a radiologic sign for continued inflammatory disease activity and thus serves as a biomarker for assessing the efficacy of immunomodulatory therapy both in clinical trials and practice [37].

Lymphocyte activation is presumed to play a major role in the formation of white matter lesions [38, 39]. In active lesions, macrophages and activated microglial cells are the most numerous inflammatory cells [40], but the process is initiated by an initial wave of CD8⁺ T cells, followed by CD4⁺ T cells, B cells, plasma cells, and additional macrophages [6, 41, 42].

On post-mortem tissue, four different types of white matter lesion pathology have been described [2, 6]. Pattern 1 (present in 10 % of patients with MS, with higher incidence in those with <1 year disease history) shows sharply demarcated lesion edges with a perivascular T-cell infiltrate, active demyelination, activated microglia, and macrophages full of myelin. Pattern 2 (seen in 55 % of patients) shows more severe T-cell and macrophage infiltration, with IgG deposition and complement (C9neo) antigen in areas of demyelination. Pattern 3 (30 % of patients) has poorly defined borders, dying oligodendrocytes, inflamed vessels with loss of myelin associated glycoprotein (MAG) and CNPase reactivity and a rim of spared myelin. Pattern 4 is found only in PPMS patients and rarely at that (5 % of patients), characterized by infiltrating T cells and macrophages with oligodendrocyte degeneration in the white matter adjacent to the active lesion.

Disagreement over whether individual patients tend to have one type of lesion pathology exists, although over time, all four types become fully demyelinated and converge toward a final sclerotic endpoint. Whereas acute plaques exhibit uniform myelin destruction with macrophages laden with myelin degradation products at early stages of digestion, more chronic plaques demonstrate an inactive center with a surrounding rim of macrophages engorged with early myelin degradation products [4]. Slowly expanding active lesions have an inactive center with surrounding macrophages, though the myelin digestion is advanced or complete in most of these cells. The acute and chronic plaques are found in early MS, whereas the slowly expanding active plaques are more common in progressive stages of MS [30, 43].

As noted, breakdown of the BBB, as detected by contrast permeability of gadolinium on MRI, precedes the formation of a lesion [44]. However, it is important to note that gadolinium enhancement is not sensitive in detecting small breaches of the BBB, which can be found with organic dyes on post-mortem tissue [45]. These breaches are widespread throughout chronic lesions and NAWM and, along with diffuse ultrastructural changes, suggest increased vascular permeability (including the separation of endothelial cells, increased transendothelial transport marker, dysferlin, and disorganization of astrocytic foot processes) [43]. Taken together, this supports the presence of widespread chronic inflammatory changes not limited to active lesions in the MS brain.

Inflammatory lesions are believed to be driven by peripheral activation of T cells demonstrating upregulated expression of α4 integrin, which mediates binding to vascular cell adhesion molecules (VCAMs) on endothelial cells and transmigration through the BBB [46]. Within the CNS parenchyma, T cells secrete pro-inflammatory cytokines which activate microglia, which then secrete additional cytokines drawing more T cells, macrophages, and dendritic cells to the lesion.

Active demyelination occurs as macrophages engulf myelin fragments and accumulate lysosomal myelin degradation products within days to weeks of lesion formation [47]. Variable degrees of axonal injury may be found alongside the disintegrated myelin sheaths and apoptotic cell death of oligodendrocytes may occur [2].

Demyelination is observed in all types of white matter lesions, though types I and II are characterized by damage to the myelin sheaths and types III and IV exhibit oligodendrocyte death [6, 48]. Damage to myelin sheaths may be secondary to toxic effects of activated macrophages or by autoantibody-mediated attack on myelin components. Autoantibodies are more commonly present in patients with RRMS, though specific autoantigens (such as anti-MOG) have not been shown to be unique to MS [49]. Death of oligodendrocytes is likely multifactorial and may be secondary to hypoxia, toxic injury from macrophages and mitochondrial failure [50, 51].

Contrary to classical medical teaching, axonal injury is found to occur in MS lesions, often as an early event [2, 8]. It has been proposed that two separate mechanisms are involved in axonal damage. The first is an early fulminant injury related to the mediators of the acute inflammatory reaction, possibly including cytotoxic T cells, macrophages, excitotoxic changes in the extracellular milieu or axonal membrane, or intrinsic neuronal changes induced by the denuded axon, leading to deficiencies in mitochondrial function and transport [52]. The second process involves a slow degeneration in chronic plaques that may be mitigated by remyelination [8].

Advanced imaging techniques and detailed pathological studies have established that cortical demyelination is common in MS and often is not correlated to the extent or locations of WM lesion load [24, 28]. Cortical lesions correlate clinically with cognitive deficits and increase the risk for seizures to develop [53, 54]. It is not known whether cortical demyelination shares the same pathophysiologic precipitant as white matter disease, whether it occurs primarily from a distinctive demyelinating process, secondarily to remote changes of the white matter tracts or both. Cortical neuron loss does tend to appear globally rather than in regional areas correlating to white matter lesions [55].

Notably, though not readily apparent on MR imaging, GM lesions exhibit lymphocytic infiltration (including myelin-laden macrophages, T cells, and B cell follicular structures), BBB breakdown, and meningeal inflammation on post-mortem tissue, suggesting that inflammatory events underlie the formation of these lesions [56]. Indeed, the magnitude of active demyelination and neurodegeneration correlates with the amount of meningeal inflammation. Of note, cortical demyelination is present in RRMS though it becomes more prominent in PPMS and SPMS, and does not appear to be correlated with the extent and degree of white matter lesions [24].

Grossly normal-appearing white matter (NAWM) shows abnormal pathology as well, particularly in patients with SPMS and PPMS [27]. Changes consistent with a diffuse inflammatory process (activation of microglia cells and diffuse axonal injury independent of demyelination) have been described and these changes do not correlate with the focal white matter lesion load [24].

Progressive gray matter damage and cortical atrophy have also been described with an average of 10 % global cortical thinning in post-mortem MS brains compared to controls [57]. Retrograde degeneration of focal WM lesions may contribute to cortical atrophy but cannot fully explain the degree and location of diffuse cortical atrophy as it does not correlate with the white matter lesion burden. Similarly, the regional distribution of cortical demyelinating plaques is likely insufficient to directly account for the widespread cortical changes [24].

Whether cortical atrophy causes global white matter changes or in turn, is a result of anterograde and retrograde degeneration of axons is not known. Both processes may occur in parallel.

As described elsewhere in this book, progressive forms of MS are characterized clinically by gradual accumulation of disability and a poor clinical response to available immunosuppressive and immunomodulatory therapies that are effective in RRMS. Pathologically, PPMS and SPMS exhibit fewer new focal white matter plaques and demonstrate more slowly expanding lesions, cortical demyelination, diffuse damage and axonal injury of the NAWM, with widespread microglial activation and brain atrophy [2]. Therefore, progressive MS may involve distinctive inflammatory mechanisms that are more widespread and insulated from immunotherapies of the systemic circulation.

Remyelination in plaques is demonstrated by the presence of pale thinly myelinated lesions, termed “shadow plaques” in post-mortem tissue [58]. These lesions are characterized by an increased number of oligodendrocyte precursor cells (OPC) and mature oligodendrocytes [59]. The presence of remyelinated plaques seems to occur in some patients but not in others, and the extent of remyelination may differ between lesions within an individual [2]. Cases with high levels of remyelination have been observed equally among patients with RRMS, SPMS, and PPMS, suggesting that inter-individual differences may determine the capacity for remyelination, though no genetic polymorphisms have yet been found [60].

In chronic MS, maturing oligodendrocytes are rare, suggesting that a block in differentiation exists. Possible deficits may be in failure to activate, failure to recruit, or failure to differentiate. Several inhibitory factors have been identified, which prevent OPCs from contacting an axon, expressing myelin-specific genes and ensheathing an axon, key steps in the functional differentiation of OPCs [61, 62]. Interestingly, remyelination is more commonly observed in cortical lesions rather than subcortical, cerebellar, or spinal cord white matter lesions, suggesting that there is a more permissive environment in the cortex.

Remyelinated plaques are susceptible to subsequent new demyelinating attacks and appear to be more susceptible to new demyelination than normal-appearing white matter [58]. MR imaging is able to detect poorly myelinated lesions though there is no currently available neuroimaging marker to differentiate early demyelinating lesions from incompletely remyelinated plaques [63].

Variability is one of the hallmarks of the clinical picture of MS. Some patients have a mild course with little activity or progression over many decades, while for others the course may be aggressive with significant neurological decline over a few years. However, despite the unpredictable nature of symptom frequency and intensity, patients often experience comparable patterns of disease.

As described elsewhere, MS symptoms manifest in two major ways: through relapses or progressive disease. Lesions in the optic nerve, posterior fossa, and spinal cord most commonly cause a clinical relapse. Because of their inflammatory nature, they typically evolve over days to weeks, plateau, and then improve, again over days to weeks. While some relapses do leave a residual deficit, most often the symptom intensity is significantly less than at the peak of the relapse. It may take 1–2 years for a relapse to recover to the fullest extent. Relapses often occur in a focal manner; however, some patients with a very active inflammatory response may present with multi-focal symptoms correlating to multiple lesions that have simultaneously formed. Progressive symptoms are quite different in that they occur as a result of neurodegeneration, and cause gradual worsening occurring over months and years. Throughout the course of their disease, many patients with MS also experience the subtle development of chronic symptoms that are related to the condition, yet are difficult to place into the relapsing or progressive categories.