Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by immune inflammation in the tissues of various organs. SLE is associated with generalized pathology of the microcirculatory bed and systemic disorganization of connective tissue. There are many options of the clinical course of the disease. Anamnestic, clinical, and laboratory data can be associated with certain diagnostic difficulties. Erythema, follicular hyperkeratosis, atrophy, infiltration, telangiectasia, absence of palpatory tenderness are typical clinical signs of lupus erythematosus. Identification of the systemic form of the disease may pose certain difficulties, and SLICC criteria (2012) should be used to verify it. This disease is diagnosis when biopsy confirms lupus nephritis with antinuclear factor (ANF), a-DNA, or if there are four criteria, including one immunological criterion (any of a-DNA, ANF, a-SM, cardiolipin antibodies — a-CL, C3, C4) and one clinical criterion. The article describes the development of SLE in a patient with organic lesion of the central nervous system (epilepsy accompanied by pronounced cognitive decline). The clinical aspects of differential diagnosis with Senear—Usher syndrome and toxicoderma were discussed. The diagnosis of SLE was verified by pathological examination. Acantholytic cells were not detected. Enzyme immunoassay was performed in order to exclude Senear—Usher syndrome by determining autoantibodies to recombinant antigens (Euroimmun ELISA test systems) desmoglein-1, desmoglein-3 in blood serum (negative result was obtained).