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•MOG and AQP4+ NMOSD can present clinical and radiological features similar to RRMS.•Brain and spinal cord MRI criteria may help separate these diseases with high sensitivity and positive predictive value.•Brain and spinal cord criteria were less sensitive separating MOG/AQP4+ NMOSD from CIS and POMS compared to RRMS.•In patients not fulfilling radiological criteria, antibody testing should be considered from the beginning to avoid diagnostic pitfalls and guide therapeutic efforts.