Relapsing–remitting and primary progressive MS have the same cause(s) – the neuropathologist’s view: 1

Abstract

Multiple sclerosis (MS) presents with different clinical manifestations, including acute MS, relapsing–remitting (RRMS), secondary progressive (SPMS) and primary progressive MS (PPMS). The clinical manifestations in these different forms of MS as well as the response to anti-inflammatory treatment of patients vary profoundly, and therefore the question has been proposed whether the cause and disease mechanisms are the same or differ between patient subgroups or stages of the disease. However, the pathology of the disease in the different forms does not support this concept. The pathology of MS is defined by a spectrum of tissue alterations in the central nervous system. This includes plaques of primary demyelination and astrocytic scar formation in the white and gray matter that when active arise around inflamed veins. In addition diffuse inflammation, microglia activation, axonal and neuronal loss and reactive gliosis affect the normal-appearing white and gray matter. These changes finally result in profound tissue loss, reflected by brain atrophy. All these features are essential criteria for the pathological diagnosis of MS and are, thus, seen in all patients, irrespective of their clinical course. However, their extent and relative contribution to the global pathology seen in a given MS patient is variable, and this variability in quantitative terms also reflects different clinical disease courses. 1 Inflammation is a key element of MS pathology. Inflammatory infiltrates mainly consist of T-lymphocytes and a much lower number of B-cells and plasma cells. Activation of microglia cells and macrophages is associated with active demyelination and neurodegeneration. The inflammatory reaction is most intense in patients at early disease stages and declines with patient age and disease duration. 2 Thus, in comparison to early (acute or RR) MS, the extent of inflammation is lower in patients with secondary progressive MS (SPMS) and even lower in PPMS. 3 However, active demyelination and neurodegeneration is invariably associated with inflammation. In patients in whom inflammation has declined to levels seen in agematched controls, active demyelination is absent and axonal injury too has declined to levels seen in the respective controls. 2 Furthermore, persistent meningeal inflammation is associated with active demyelination and neurodegeneration in the cortex not only in the early stages of MS, 4 but also in patients with SPMS or PPMS. 5,6 The inflammatory response in part is fuelled by a new influx of inflammatory cells from the circulation, and this process is associated with blood-brain barrier injury, reflected by gadolinium (Gd)-enhancement in magnetic resonance imaging (MRI). Part of the inflammatory response, however, occurs in the brain parenchyme and around blood vessels in the absence of blood-brain barrier disruption. 7 While inflammation, which is associated with blood-brain barrier damage, is mainly present in patients with acute and RRMS, it becomes rare in patients who have entered the progressive phase of the disease. The opposite is seen with inflammation, which is compartmentalized behind a normal (repaired) blood-brain barrier. This is more pronounced in patients with progressive compared to those with early MS. A similar shift is also seen in the quantitative relation of different types of tissue injury between early relapsing and late progressive MS. 8 New focal white matter lesions are frequent in the early stages of MS, but become rare in patients with progressive disease. In contrast, slowly expanding focal white matter lesions, the number and size of cortical lesions and the extent of diffuse injury in the normal-appearing white and gray matter increase with age and disease duration. Thus, the differences in the pathology between RRMS, SPMS and PPMS are of quantitative, but not of qualitative nature. Recent data suggest that oxidative injury and subsequent mitochondrial damage may play an important role in driving demyelination and neurodegeneration in the MS brain. 9 Oxidative injury can be induced by inflammation, resulting in oxdidative burst, and can further be amplified by various mechanisms that are related to brain aging and preexisting neurodegeneration. Thus, it is proposed that MS starts with the invasion of inflammatory cells from the peripheral