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This article focuses on a workup of tumefactive demyelinating lesions and the variants of multiple sclerosis that present with tumefactive lesions: Tumefactive demyelination can also occur in other conditions including autoimmune diseases (eg, Sjogren disease, lupus erythematosus, neuromyelitis optica, associated with aquaporin 4 (AQP4) antibody, acute disseminated encephalomyelitis (ADEM), and myelin oligodendrocyte glycoprotein [MOG] antibody-associated disease), infectious diseases (eg, HIV), malignancy (eg, renal cell carcinoma), related to drugs (eg, fingolimod, tacrolimus), and postinfectious conditions (eg, acute disseminated encephalomyelitis, acute hemorrhage leukoencephalitis)