The differential diagnosis between multiple sclerosis and acute disseminated encephalomyelitis has major prognostic and therapeutic implications for the patient. As originally defined, acute disseminated encephalomyelitis is an acute monophasic disease that requires early anti-inflammatory treatment, whereas long-term immunomodulatory therapies are considered unnecessary due to the self-limiting nature of the disease. In contrast, multiple sclerosis in most patients is a long-lasting chronic disease, characterized by relapses and remissions, which may finally transform into a progressive disease. Thus, long-term immunomodulatory or imunosuppressive treatment must be considered. The distinction between these two entities is particularly important in patients presenting with severe or fulminant disease onset. In recent years, new diagnostic criteria have been developed for acute disseminated encephalomyelitis (DeSeze et al. , 2007; Krupp et al. , 2007; Tenembaum et al. , 2007) and multiple sclerosis (McDonald et al. , 2001; Polman et al. , 2005), which may help the neurologist to differentiate these diseases at their initial presentation. Although these criteria in overall are useful, they are far from perfect. Major problems appear in patients with a very aggressive disease onset and widespread brain lesions, in whom the distinction between acute disseminated encephalomyelitis and early multiple sclerosis may become apparent only after prolonged follow-up of the individual patient. Furthermore, although recurrent or even relapsing forms of acute disseminated encephalomyelitis have been described in recent years, these disease entities are, as yet, poorly defined from the perspective of neuropathology (Tenembaum et al. , 2007). Pathology is generally regarded as the gold standard in defining different forms of inflammatory demyelinating diseases (Adams and Kubik, 1952; Alvord, 1985; Wegner, 2005). Classical acute disseminated encephalomyelitis is predominantly an inflammatory disease, in which demyelination is sparse and restricted to …