In the central nervous system, myelin is formed by processes of oligodendrocytes, which wrap around the axons and insulate them, forming myelin sheaths and allowing saltatory conduction. This form of conduction allows a fast propagation of action potentials along the axons. Myelin is therefore important for normal functioning of the CNS. ‘Demyelination’ refers to the loss of myelin with a relative preservation of axons. The basic histopathological evaluation of demyelinating lesions therefore requires at least two stainings: one for myelin and one for axons. If the loss of myelin is greater than that of axons, it can be described as demyelination. A myelin staining technique in widespread use is Luxol fast blue (LFB), which is also sometimes called ‘Klüver-Barrera’, which leads to a blue staining of myelin. A typical axonal staining is Bielschowsky silver impregnation, which leads to a black staining of axons and dendrites, i.e., nerve cell processes.
Axons are also usually lost to a certain extent in demyelinating lesions, but in a primary demyelinating lesion, myelin loss in an active lesion exceeds the axonal loss, and is often complete in the presence of a relatively well-preserved axonal meshwork in the tissue, especially in multiple sclerosis, the most common inflammatory demyelinating disease (IDD). If axons are also profoundly lost, the lesion might be necrotic rather than merely demyelinating. Necrosis typically also leads to a loss of other brain tissue constituents, such as astrocytes and microglia, while there is usually a profound macrophage resorption of the tissue. Although most lesions in the context of IDDs do not lead to brain parenchymal necrosis, some IDDs such as MOGAD or NMO (see below) may lead to severely destructive lesions and even necrosis (Misu et al, 2013; Hoftberger et al, 2020). A prototypic CNS condition which leads to necrosis formation is ischemic stroke.
As the name implies, demyelination in IDDs occurs in a context of inflammation. Traditionally, and particularly in daily neuropathological practice, ‘brain inflammation’ refers to a pathological state of the brain in which elevated lymphocyte numbers are present in the perivascular spaces and/or the brain parenchyma itself. However, the inflammation may in fact consist of cellular and humoral factors, and the various IDDs show profoundly different involvement of cellular and humoral inflammatory factors. Nevertheless, elevated numbers of lymphocytes (CD3+ T cells, CD20+ B cells) are practically always found in inflammatory demyelinating lesions. Conversely, granulocytes (neutrophilic or eosinophilic) are found in only a subset of IDDs (particularly active NMO lesions) (Misu et al, 2013), and are usually completely absent in cases such as lesions of multiple sclerosis (MS) (Lassmann et al, 2007). Humoral factors such as antibodies and factors in the complement system might also be present in IDDs, but consideration must always be given as to whether these have a truly pathogenic role, such as the AQP4 antibodies and the complement system in NMO (Misu et al, 2007; Bradl et al, 2009), or whether they merely reflect epiphenomena without any significant pathogenicity, like some antibodies with various newly described targets in MS (Vietzen et al, 2023). Since inflammation as a whole plays a crucial pathogenic role in IDDs, it typically responds well to anti-inflammatory treatments. The different inflammatory reactions in the various IDDs are also reflected – and in part confirmed - by their different response to those treatments.
IDDs encompass diseases such as multiple sclerosis (MS), Myelin Oligodendrocyte Glycoprotein antibody associated disease (MOGAD), and Neuromyelitis optica (NMO), which will be introduced here, focusing on the neuropathology of these diseases, i.e., their appearances in histopathology and the pathogenic implications arising from those appearances.