Demyelinating Diseases: Multiple Sclerosis
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Demyelination is characterized by destruction of normal myelin with an elative preservation of axons. Demyelinating diseases encompass among others multiple sclerosis (MS), neuromyelitis optica (Dévic disease), acute disseminated encephalomyelitis (ADEM), and acute hemorrhagic leukoencephalopathy (AHL).
Three types of MS exist including classical (Charcot type), acute (Marburg type), and concentric (Balo type). The classical MS Charcot type is clinically characterized by relapsing remitting (RRMS), secondary progressive (SPMS), primary progressive (PPMS), and relapsing progressive (PRMS) attacks. Symptoms include sensory disturbances (numbness, tingling, itching, burning), walking difficulties (due to fatigue, weakness, spasticity, loss of balance, and tremor), vision problems (diplopia, blurred, and pain on eye movement), intestinal and urinary system dysfunction (constipation and bladder dysfunction), cognitive and emotional impairment (inability to learn and depression), dizziness and vertigo, and sexual problems. Secondary and tertiary symptoms might develop.
On MR imaging, multiple white matter lesions with dissemination in time and space are noticed. Asymmetric bilateral hyperintensities common in periventricular location, callososeptal or juxtacortical and in supra- and/or infratentorial location are prevalent. A perpendicular arrangement to lateral ventricles following deep medullary veins is known as “Dawson fingers.” As disease proceeds, plaques show confluence.
Demyelinated plaques are well-demarcated regions of gray discoloration of variable size, shape, number, and distribution. Histologic variation in appearance is due to the age of the lesion, disease activity, and the presence or absence of remyelination. Areas of demyelination show destructed myelin, and perivascular inflammation with lymphocytes and macrophages. Active, inactive, and shadow plaques are distinguished. Cortical lesions in multiple sclerosis affect the cerebral cortex, cerebellar cortex, and hippocampus. They consist of complete loss of myelin, axonal preservation like preserved phosphorylated neurofilament-reactive profiles, ramified microglia, rarely macrophages, sparse lymphocytes, and degeneration of cortical neurons, axons, and synapses.
Pathogenetic mechanisms include among others autoimmune processes, inflammation (innate immunity, microglia and macrophages, adaptive immunity, T-cells, regulatory T-cells, B-cells, and interleukin 1ß), infective processes (viruses—molecular mimicry, measles, rubella, etc.), and environmental factors. Expression analyses showed dysregulation of genes associated with inflammation, genes associated with cell death, DNA damage and DNA repair, p53 function, and genes involved in reaction to tissue injury and association with tissue repair, RNA metabolism, and regulation of transcription or translation. MS risk variants are determined as changed single nucleotide polymorphisms (SNP) of genes involved in human methylation pathways, microRNAs.
Treatment consists in using immunosuppression with methylprednisolone and as long-term treatment interferon beta-1b, glatiramer acetate, and azathioprine. Prognosis depends on the classical type (i.e., RRMS, SPMS, PPMS, and PRMS) or acute Marburg type. Development of progressive multifocal leukoencephalopathy (PML) after JC virus infection under natalizumab is possible.
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