The practice of initiating immunomodulatory treatment immediately after a clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS) emphasizes the need to distinguish between disseminated encephalomyelitis (DEM) and MS. Their clinical, genetic, imaging, and histopathological characteristics establish that they are distinct disease entities. Acute and recurrent DEM are more common in children, but also occur in adults. DEM is polysymptomatic and includes signs and symptoms rarely encountered in MS, such as fever, alterations of the state of consciousness, cognitive and aphasic symptoms, and meningism. Cerebrospinal oligoclonal bands are rare. Magnetic resonance imaging (MRI) is the best means of distinguishing between DEM and MS. In the former, the lesion load is heavy, thalamus or basal ganglia are often affected, and early in the disease most of the lesions are usually larger than those of MS and enhance with gadolinium. The MRI spinal cord lesions are longer than three vertebral segments, and define neuromyelitis optica (NMO). Antibodies against aquaporin-4 are present in some NMO, but are also found in cases of MS and DEM. Most NMO are forms of DEM, not MS, and are identical with the 'Oriental' or 'optico-spinal' form of MS.