Chronic and early MS lesions. Chronic MS lesions have a sharp border with the surrounding normal appearing white matter [NAWM; LFB-PAS staining; (a)]. Frequently, the demyelinated lesion centre is hypocellular while the lesion border and the normal appearing white matter show an increased number of macrophages and/or microglia (immunohistochemistry for the macrophage/microglial marker KiM1P (b) and insert). Early MS lesions with pattern I are characterized by a sharp border with the NAWM [LFB-PAS staining; (c)]. The inflammatory infiltrates are dominated by foamy macrophages [immunohistochemistry for KiM1P (d)], which may contain myelin degradation products in their cytoplasm (immunohistochemistry for the myelin protein MBP (insert in d)). T cells are diffusely distributed within the parenchyma of the lesion (e), but may also be found perivascularly in NAWM [immunohistochemistry for CD3; (f)]. Pattern III lesions show an ill-defined lesion border [LFB-PAS staining; (g)]. In areas of active demyelination and NAWM, numerous dying oligodendrocytes (arrows) with condensed nuclei are observed [immunohistochemistry for CNP; (h)]. The insert in h shows a higher magnification of a CNP-positive oligodendrocyte with a condensed nucleus. In NMO, a loss of astrocytes and glial fibres [immunohistochemistry for GFAP; (i)] as well as a perivascular deposition of complement is observed [immunohistochemistry for C9neo; (j)]

Different demyelinating diseases. ADEM is characterized by very limited perivascular demyelination [LFB-PAS; (a)] and perivascular infiltrates that consist mostly of foamy macrophages [immunohistochemistry for KiM1P; (b)]. In vanishing white matter, a diffuse loss of myelin is observed [LFB-PAS; (c)]. The number of oligodendrocytes in affected white matter areas is markedly reduced [immunohistochemistry for CNPase (d)]. In contrast to early MS lesions, the demyelinated lesions are infiltrated by relatively few macrophages [immunohistochemistry for KiM1P; (e)]. In X-linked adrenoleukodystrophy, numerous bizarre astrocytes can be found within the lesions (arrows in f) as well as lymphocytic perivascular infiltrates (arrowhead in f; haematoxylin and eosin staining). The lesion areas are completely demyelinated (g) and in macrophages needle-like inclusions may be found (insert in g). In Alexander’s disease large CNS areas with an almost complete loss of myelin are found [immunohistochemistry for MBP; (h)]. The histopathological characteristic of Alexander’s disease is numerous GFAP-positive Rosenthal fibres [immunohistochemistry for GFAP; (i)]

PML, SSPE and viral encephalitis. PML lesions may be characterized by a sharp lesion border [LFB-PAS; (a)]. The histopathological hallmarks are bizarre astrocytes (immunohistochemistry for GFAP; insert in a) and viral inclusion bodies in oligodendrocytes and astrocytes [immunohistochemistry with antibodies recognizing JC antigens; (b)]. SSPE is characterized by demyelinated lesions often accompanied by extensive axonal loss [immunohistochemistry for MAG; (c)]. In oligodendroglial nuclei, viral inclusions can be found, which are intensively eosinophilic [haematoxylin and eosin; (d)]. Measles virus antigen can be identified by immunohistochemistry (e). In acute viral encephalitis, e.g. in acute measles encephalitis, marked perivascular infiltrates are observed while the myelin is not affected [LFB-PAS staining; (f)]. In this patient, measles virus antigen could be detected in oligodendroglial nuclei (insert in f). The perivascular infiltrates may be dominated by B cells [immunohistochemistry for the B cell marker CD20; (g)]

In vasculitis, the infiltrates are localized within the vessel wall and consist mostly of T cells [immunohistochemistry for the T cell marker CD3; (a)]. Frequently, the vessel wall is destroyed [reticulin staining; (b)]. Noncaseating granulomas consisting of multinucleated giant cells and epitheloid cells surrounded by a lymphocytic wall are the histological hallmarks of neurosarcoidosis (c). In CNS lymphomas, a perivascular accumulation of neoplastic B cells is characteristic [haematoxylin and eosin; (d)]. The high proliferation index in lymphomas may help to distinguish lymphomas from vasculitis or viral encephalitis. However, occasionally also cases of vasculitis and encephalitis show a marked proliferation. The detection of a monoclonal B cell population by PCR confirms the suspected diagnosis of a B cell lymphoma [immunohistochemistry for the proliferation marker Ki67; (e)]

Flow chart for the diagnosis of MS and its most important differential diagnosis. ADEM acute disseminated encephalomyelitis, CPM central pontine myelinolysis, AHL acute haemorrhagic necrotizing leukoencephalitis; MBD Marchiafava-Bignami disease, MS multiple sclerosis, PML progressive multifocal leukoencephalopathy, RTF Rosenthal fibres, SSPE subacute sclerosing panencephalitis, VWM vanishing white matter disease