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Journal Review

Posted in Journal Reviews on 14th Oct 2013

ADEM versus RRMS: Antibodies the answer again?

Acute disseminated encephalomyelitis (ADEM) and relapsing-remitting multiple sclerosis (RRMS) are different forms of autoimmune-mediated demyelination that share the features of polysymptomatic neurological deficits, multifocal white matter lesions and laboratory findings. In some cases the two disorders can be difficult to differentiate and monitoring over time is required for diagnosis. The study from Van Haren et al. explores identifying autoantibody markers that are capable of distinguishing the two entities from one another.

Custom antigen arrays were used to profile anti-myelin-peptide autoantibodies in archived serum derived from patients with paediatric ADEM (15), paediatric MS (11) and adult MS (15). Each of the proteins included in the antigen arrays were selected based on previous publications suggesting possible antigenicity in demyelinating disorders. The adult MS patients were from a single US centre while the paediatric ADEM and MS samples were drawn from various international sites. Not surprisingly the groups were not age matched and there was a higher proportion of females in the adult MS group compared to the other groups. In this study patients were classified as having MS if they fit the 2001 McDonald criteria for lesion dissemination in time and space. ADEM and paediatric MS were distinguished using the International Paediatric MS Study Group definitions.

Over 80% of the serum samples were drawn within 3 months of an acute demyelinating event in the paediatric ADEM and paediatric MS groups, compared to very few in the adult MS group. Using isotype-specific secondary antibodies both IgG and IgM reactivity were profiled in the sera. Specialised computer software was used to confirm differences in autoantibody reactivity profiles between the ADEM and MS samples, and also to generate and validate prediction algorithms based on the autoantibody reactivity profiles.

The study found that sera from ADEM patients contained IgG autoantibodies targeting myelin basic protein, proteolipid protein, myelin-associated oligodendrocyte basic glycoprotein, and alpha-B-crystallin. Alternatively, IgM autoantibodies targeting myelin basic protein, proteolipid protein, myelin-associated oligodendrocyte basic glycoprotein and oligodendrocyte-specific protein, were present in the MS samples (adult and paediatric). Nearly all the differentiating IgG-targeted antigens tested showed higher autoantibody reactivity among ADEM patients, while the same was true for IgM-targeted antigens and MS patients. In this study ADEM was characterised by class-switched IgG responses to proteins, supporting the notion that the immune system is primed during a prodromal illness that often precedes demyelination in this condition.

No difference in autoantibody profiles were noted between the adult and paediatric MS groups. Using the prediction algorithms (encompassing the autoantibody reactivity profiles), ADEM serum could be distinguished with a sensitivity of 62-86% and specificity of 56-79%, and MS serum with a sensitivity of 40-87% and specificity of 62-86%.

This study yielded results that are promising in terms of using combined profiles of serum IgG and IgM autoantibodies to identify myelin antigens that may assist in differentiating MS from ADEM. However, further biological assays are needed to further assess the pathogenic potential of these antibodies and to establish their clinical utility. From a practical perspective the future development of a diagnostic assay would certainly prove useful in those cases where clinico-radiological differentiation is difficult, as accurate and rapid diagnosis has distinct treatment and management implications. Further research in this area may also improve our understanding of the pathogenesis of these two disorders.

Van Haren K, Tomooka BH, Kidd BA, et al. Serum autoantibodies to myelin peptides distinguish acute disseminated encephalomyelitis from relapsing-remitting multiple sclerosis. Mult Scler. 2013 April 23. doi: 10.1177/1352458513485653

Heidi Beadnall, Brain and Mind Research Institute, The University of Sydney, Royal Prince Alfred Hospital

ACNR 2013: Published online 14th October.