Central nervous system (CNS) demyelinating syndromes occurring in the context of systemic lupus erythematosus (SLE) may represent a manifestation of neuropsychiatric lupus, or an overlap of SLE and multiple sclerosis (MS). We evaluated prospectively patients presenting with demyelinating syndrome for clinical and serologic evidence of SLE and characterized the evolution of their clinical syndrome to a defined disease.Patients with CNS demyelinating syndromes not fulfilling the criteria for MS were evaluated in a rheumatology unit for features of SLE and followed longitudinally (enrolment period 2016-2020). Clinical, laboratory and neuroimaging data were recorded at every visit, following multidisciplinary evaluation. At end of follow-up, patients were assessed for their final neurologic and rheumatologic diagnosis and classified accordingly.79 patients were included in the study [91.1% female, mean (SD) age at first demyelinating episode 38.4 (10.3), median (IQR) observation period 39 (57) months]. At last follow-up, 38 patients (48.1%) had evolved into MS. Of the remaining, 7 patients (17.1%) had SLE, while 34 (82.9%) had features of systemic autoimmunity without fulfilling classification criteria for SLE. Most common rheumatologic features of these patients were inflammatory arthritis (73.5%), acute cutaneous lupus (47.1%) and positive anti-nuclear antibodies (72.1%). Importantly, these patients were less likely to have elevated IgG index (OR = 0.11, 95%CI 0.04-0.32) and positive oligoclonal bands (OR = 0.21, 95%CI 0.08-0.55).A significant number of patients with demyelination do not fulfill criteria for either MS or SLE at follow-up. These patients exhibit lupus-like autoimmune features and may represent a distinct entity, demyelination with autoimmune features (DAF).