Antinuclear antibodies in pediatric acquired demyelinating diseases of the central nervous system

In adults with multiple sclerosis (MS), positive antinuclear antibody (ANA) titers are more common than in age- and sex-matched healthy controls, and the presence of detectable ANA titers in MS correlates with shorter disease duration.^1,2 Based on these findings, a predominant inflammatory phase associated with early MS disease activity leading to a more generalized and intense humoral response has been suggested. ¹

If heightened humoral responses are a feature of early stages of chronic central nervous system (CNS) inflammatory diseases such as MS, we hypothesized that children with MS would be more likely than children with monophasic demyelinating disease to have positive serum ANA titers at presentation with their first attack as a sign of an underlying immune dysregulation.^{1 -3}

We conducted a single-center cohort study of consecutive patients who consented to the pediatric demyelinating disease registry at the Hospital for Sick Children from 2004 to 2012. We included patients with symptom onset before age 17 years 11 months, and a diagnosis of MS (McDonald 2005 and 2010 criteria) or monophasic optic neuritis, transverse myelitis or acute disseminated encephalomyelitis (ADEM). ⁴ For inclusion, patients must have had at least one serum ANA titer measured at initial presentation. Patients with relapsing optic neuritis, transverse myelitis, recurrent or multiphasic ADEM and neuromyelitis optica were excluded due to small numbers and potential differences in the frequency of positive serological autoimmunity. The ANA testing was performed using indirect immunofluorescence on Hep-2 cells, and a titer of ≥1:40 was considered positive. We evaluated seropositivity of ANA titers of ≥1:40 dilution based on use of this threshold in adult MS patients and on conventional practice at our institution of reporting sera at ≥1:40 dilution as ‘positive’.^2,3,5 We included 163 patients in the study (70 with MS, 37 with optic neuritis, 29 with transverse myelitis and 27 with ADEM). The mean (SD) age of the cohort at presentation was 11.9 (4.37) years and 94 (57.7%) were female. Overall, serum ANA titers >1:40 dilution were detected in 42 of 163 children (25.8%), while only 15 (9.2%) had serum ANA titers >1:80 dilution. At a titer of 1:40, children with MS were more likely to have positive ANA titers at onset (35.7%) compared with children with monophasic demyelinating disease (18.3%; p = 0.0118). The likelihood of serum positivity of ANA was particularly low in children with ADEM (7.4%). However, ANA titers did not differ between children with MS and children with monophasic optic neuritis (p = 0.23) or transverse myelitis (p = 0.14). Findings were similar at higher titers with 10 (14.3%) of children with MS affected versus five (5.4%) of those with monophasic illness (p = 0.051).

In summary, 26% percent of children with demyelinating diseases have evidence in serum of ANA at low titer, 9% have higher titers, and ANA positivity is particularly rare in children with ADEM. While interesting to consider as a marker for heightened immune responsiveness, we conclude that the measurement of serum ANA titers is unlikely to distinguish children with MS from children with monophasic demyelination.