Pathological Heterogeneity of Idiopathic Central Nervous System Inflammatory Demyelinating Disorders C. Lucchinetti 1 Introduction . 20 2 Heterogeneity of Multiple Sclerosis White Matter Lesions . 21 2.1 Stages of Lesions . 21 2.2 MS Plaque Types . 22 2.3 Inflammation and Immune Effector Heterogeneity in MS . 24 2.4 Evidence for Immunopathogenic Heterogeneity in Multiple Sclerosis . 27 2.5 Immunopathologic Heterogeneity May Be Stage-Dependent . 30 3 Remyelination in MS . 31 4 The Clinicopathologic Spectrum of CNS Idiopathic Inflammatory Demyelinating Disorders . 32 4.1 Acute Disseminated Encephalomyelitis . 33 4.2 Marburg Variant of Acute MS . 34 4.3 Tumefactive MS . 35 4.4 Balo Concentric Sclerosis. 35 4.5 Neuromyelitis Optica . 36 Conclusions . 38 References . 38 Abstract The last decade has seen a resurgence of interest in MS neuropathology. This resurgence was partly fueled by the development of new molecular and histochemical tools to examine the MS lesion microscopically, as well as technological advances in neuroimaging, which permit a dynamic assessment of lesion formation and disease progression. The heterogeneous pathology of MS in relation to stage of lesion activity, phase of disease, and clinical course is discussed. Pathological studies reveal that the immune factors associated with multiple differ- ent effector mechanisms contribute to the inflammation, demyelination, and tissue injury observed in MS lesions. While many agree that pathological heterogeneity exists in white matter demyelinated lesions, it is uncertain whether these observa- tions are patient-dependent and reflect pathogenic heterogeneity or, alternatively, C. Lucchinetti Mayo Clinic College of Medicine , 200 First St. SW, Rochester, MN 55905, USA e-mail: [email protected] M. Rodriguez (ed.), Advances in Multiple Sclerosis and Experimental 19 Demyelinating Diseases. Current Topics in Microbiology and Immunology 318. © Springer-Verlag Berlin Heidelberg 2008 20 C. Lucchinetti are stage-dependent with multiple mechanisms occurring sequentially within a given patient. Evidence supporting both concepts is presented. Remyelination is present in MS lesions; however, the factors contributing to the extent of repair and oligodendrocyte survival differ depending on the disease phase. A variable and patient-dependent extent of remyelination is observed in chronic MS cases and will likely need to be considered when designing future clinical trials aimed to promote CNS repair. MS is one member of a spectrum of CNS idiopathic inflam- matory demyelinating disorders that share the basic pathological hallmark of CNS inflammatory demyelination. Advances based on recent systematic clinicopatho- logic-serologic correlative approaches have led to novel insights with respect to the classification of these disorders, as well as a better understanding of the underlying pathogenic mechanisms. 1 Introduction Multiple sclerosis (MS) is an inherently heterogeneous disorder with respect to its clinical, radiographic, and genetic features. Its basic pathology consists of multifocal central nervous system (CNS) lesions characterized by inflammation, demyelination, astrogliosis, variable remyelination preservation, and relative axonal preservation. MS represents only one member of a family of CNS idio- pathic inflammatory demyelinating disorders (IIDDs), all similarly characterized by focal demyelination, and includes acute disseminated encephalomyelitis (ADEM), acute MS (Marburg variant), Balo’s concentric sclerosis (BCS), and neuromyelitis optica (NMO). Largely due to similarities with experimental autoimmune encephalomyelitis (EAE), the role of CD4 + T cells has been emphasized in MS pathogenesis. However, accumulating in vitro and in vivo studies challenge the traditional view that MS is purely a CD4 + T cell-mediated autoimmune disease and suggest that the events involved in MS immunopathogenesis may be more complex than pre- viously recognized. Furthermore, the advent of more sophisticated histological and molecular tools to study MS pathology has contributed to evolving concepts regarding disease initiation and progression. Although all MS lesions are charac- terized by destruction of myelin sheaths, they display a significant degree of pathological heterogeneity with respect to the topography of the lesions, the severity and character of the inflammatory response, the extent of remyelination and the degree and pattern of oligodendrocyte and axonal injury. It is debatable whether these observations reflect patient-dependent pathogenic heterogeneity or, alternatively, are stage-dependent with multiple mechanisms contributing to the observed pathological heterogeneity. This chapter will focus on the concept of MS pathological heterogeneity with respect to white matter lesions, the fate of the oligodendrocyte and extent of repair, and it will elaborate upon the heteroge- neous clinicopathological spectrum of the CNS idiopathic inflammatory demyelinating disorders. Pathological Heterogeneity of Idiopathic Central Nervous System 21 2 Heterogeneity of Multiple Sclerosis White Matter Lesions MS pathology varies with respect to the demyelinating stage of the lesion as well as with disease duration. MS neuropathological studies are largely skewed toward the analysis of either very early lesions derived from fulminant autopsy cases, brain biopsies when the diagnosis was still in question, or very late chronic lesions from patients who died with longstanding disease. This essentially provides snapshots from which investigators attempt to draw dynamic conclusions regarding disease evolution and progression. However, pathological information is limited regarding the preclinical phase of the disease and the transition phase, when patients convert from relapsing to progressive disease. 2.1 Stages of Lesions A variety of criteria have been used to stage the activity of MS lesions including the extent and activation state of lymphocytes and macrophages, the presence of MHC class II antigens, and the presence of adhesion molecules or cytokines. However, these approaches do not reliably distinguish inflammatory from demyeli- nating activity, and it is not uncommon to find inflammatory MS lesions with no signs of active demyelination. Pathological studies investigating demyelinating mechanisms must therefore rely on a precise definition of demyelinating activity. At a minimum, the presence of luxol-fast blue (LFB+) myelin degradation products within the macrophage cyto- plasm is a reliable indicator of ongoing demyelination [54]. A more rigorous approach to demyelination staging in MS lesions has been proposed based on the structural profile and chemical composition of myelin degradation products within macrophages in correlation to the expression of macrophage differentiation markers (Fig. 1 ) [18]. The time sequence of myelin degradation in macrophages is based on the evaluation of EAE lesions [55] as well as recent in vitro studies analyzing the sequential breakdown of myelin by human monocytes [37]. Whenever myelin sheaths are destroyed, macrophages or microglia cells take up the remnants. Minor myelin proteins, such as myelin oligodendrocyte glycoprotein (MOG) or myelin- associated glycoprotein (MAG), rapidly degrade within macrophages 1 to 2 days after phagocytosis. In contrast, major myelin proteins, such as myelin basic protein (MBP) and proteolipid protein (PLP), may persist in macrophages for 6–10 days. In later stages, the macrophages contain sudanophilic and periodic acid Schiff (PAS)- positive granular lipids that may persist in the lesion up to several months. Macrophages expressing distinct markers of macrophage activation and differentiation (myeloid related protein [MRP14], a member of the S100 family of calcium-binding proteins, and 27E10) infiltrate early active demyelinating MS lesions. Their cytoplasms con- tain myelin degradation products immunoreactive for both MOG and MAG. These minor myelin proteins disappear within late active MS lesions; however, myelin 22 C. Lucchinetti Fig. 1 Staging of demyelinating activity. MS lesions can be classified into early active (EA), late active (LA), and inactive (IA) stages based on the type of myelin degradation products present in the macrophage cytoplasm debris is still immunoreactive for MBP and PLP. Macrophages within inactive, com- pletely demyelinated areas no longer contain either minor or major myelin proteins; however, PAS+ debris may still be present. Early remyelinating lesions are charac- terized by clusters of short, thin, irregularly organized myelin sheaths with greater MAG or CNPase reactivity relative to MOG or PLP, and PAS+ macrophages may be present. Evidence for areas of early remyelination occurring concurrently with active demyelination can also be observed. This staging classification scheme provides a dynamic topographical framework for analyzing lesion evolution. In any MS brain, a variety of lesions at different stages of demyelinating activity may be present. Furthermore, a single MS lesion may have multiple areas of differing demyelinating activity. However, it is impor- tant to acknowledge that this staging approach may fail to capture events in lesion evolution preceding myelin degradation. Using these stringent criteria, the inci- dence of actively demyelinating lesions in MS brains is quite low, especially in brain bank material largely consisting of longstanding chronic MS cases. 2.2 MS Plaque Types Based on the topographical distribution of the macrophages and their immunoreac- tivity