Acute disseminated encephalomyelitis and multiple sclerosis

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 narrow perivenous sleeves. This pathological process is widespread throughout the nervous system, giving rise to large and diffuse or multifocal lesions in magnetic resonance imaging. In contrast, inflammation in multiple sclerosis is associated with focal confluent plaques of primary demyelination showing variable degrees of axonal injury and loss (Callen et al., 2009). Thus, the distinctive pathological criterion distinguishing acute disseminated encephalomyelitis and multiple sclerosis is the presence, or not, of confluent versus perivenous demyelination. A study reported in the current issue (Young et al., page 333), aims at validating clinical diagnostic criteria, including magnetic resonance imaging and cerebrospinal fluid parameters, against the pathological gold standard described above. The authors make use of a large collection of biopsy and autopsy material from patients with inflammatory demyelinating diseases, which have been collected at the Mayo Clinic during the last decades, together with very detailed clinical information on these patients. Individuals with disorders subsumed under the spectrum of neuromyelitis optica were excluded. The main result from this study is that, when taken as a whole, the diagnostic criteria for acute disseminated encephalomyelitis, defined by the International Paediatric Multiple Sclerosis Study Group (Krupp et al., 2007; Tenembaum et al., 2007), matched the pathological diagnosis of acute disseminated encephalomyelitis with a sensitivity of 80% and a specificity of 91%. Three patients manifested pathological features of both perivenous and confluent demyelination. When these patients were included, sensitivity dropped to 77%. However, when individual criteria for acute disseminated encephalomyelitis were applied to the cohort with multiple sclerosis-like confluent demyelination, the overlap was higher. Multifocal brain MRI lesions were seen in 61%, polysymptomatic presentation in 75% and encephalopathy in 22% of the patients with multiple sclerosis-like confluent demyelination. Despite this overlap in initial clinical presentation, the disease remained monophasic in all patients with pure perivenous demyelination, whereas most of those with confluent demyelination subsequently developed further disease exacerbations and/or fulfilled the McDonald criteria for the diagnosis of multiple sclerosis at follow-up. In conclusion, this study shows that the clinical criteria for differentiation of acute disseminated encephalomyelitis and multiple sclerosis are imperfect, and it reveals considerable overlap in the clinical presentation between these two disorders. There are several possible explanations for this situation. Pathological studies have long since shown that perivenous and confluent demyelination may overlap in patients with the Marburg type of acute multiple sclerosis (Adams and Kubik, 1952). This combination is also clearly seen in the present study, which doi:10.1093/brain/awp342 Brain 2010: 133; 317–319 | 317