Neuronal antibody biomarkers for Sydenham's chorea identify a new group of children with chronic recurrent episodic acute exacerbations of tic and obsessive compulsive symptoms following a streptococcal infection.

Harvey S Singer,Kathy Alvarez,Carol B Thompson,Adda Mascaro-Blanco,Syed F Ali,Hilla Ben-Pazi,Madeleine W Cunningham,Ivana Kawikova,Edward L Kaplan,Christina Morris-Berry,Markus Reindl

doi:10.1371/journal.pone.0120499

Abstract

Several autoantibodies (anti-dopamine 1 (D1R) and 2 (D2R) receptors, anti-tubulin, anti-lysoganglioside-GM1) and antibody-mediated activation of calcium calmodulin dependent protein kinase II (CaMKII) signaling activity are elevated in children with Sydenham’s chorea (SC). Recognizing proposed clinical and autoimmune similarities between SC and PANDAS (pediatric autoimmune neuropsychiatric disorder associated with a streptococcal infection), we sought to identify serial biomarker changes in a slightly different population. Antineuronal antibodies were measured in eight children (mean 11.3 years) with chronic, dramatic, recurrent tics and obsessive-compulsive disorder (OCD) associated with a group A β-hemolytic streptococcal (GABHS) respiratory tract infection, but differing because they lacked choreiform movements. Longitudinal serum samples in most subjects included two pre-exacerbation samples, Exac), one midst Exac (abrupt recurrence of tic/OCD; temporally association with a GABHS infection in six of eight subjects), and two post-Exac. Controls included four groups of unaffected children (n = 70; mean 10.8 years) obtained at four different institutions and published controls. Clinical exacerbations were not associated with a significant rise in antineuronal antibody titers. CaMKII activation was increased at the GABHS exacerbation point in 5/6 subjects, exceeded combined and published control’s 95th percentile at least once in 7/8 subjects, and median values were elevated at each time point. Anti-tubulin and anti-D2R titers did not differ from published or combined control group’s 95th percentile or median values. Differences in anti-lysoganglioside-GM1 and anti-D1R titers were dependent on the selected control. Variances in antibody titers and CaMKII activation were identified among the institutional control groups. Based on comparisons to published studies, results identify two groups of PANDAS: 1) a cohort, represented by this study, which lacks choreiform movements and elevated antibodies against D2R; 2) the originally reported group with choreiform movements and elevated anti-D2R antibodies, similar to SC. Increased antibody mediated CaMKII activation was found in both groups and requires further study as a potential biomarker.

Highlights

Sydenham chorea (SC), the neurological manifestation of rheumatic fever, is associated with antibodies against group A β-hemolytic streptococci (GABHS) that cross react with either neuronal extracellular cell surface and/or intracellular antigens [1,2,3,4]
Serial sample evaluations provide the essential opportunity for comparison of clinical exacerbations and antibody levels [32]
A four-fold change in titer between pre-exacerbation and exacerbation points has been used as a measure of change, it is unclear whether a higher or lower alteration provides the optimal degree of significance

Summary

Introduction

Sydenham chorea (SC), the neurological manifestation of rheumatic fever, is associated with antibodies against group A β-hemolytic streptococci (GABHS) that cross react with either neuronal extracellular cell surface and/or intracellular (cytoplasmic or cytoskeletal) antigens [1,2,3,4]. A similar mechanism has been proposed for children who develop the acute fulminant onset of movement and behavioral changes, such as tics and OCD, following a streptococcal infection. This latter group known by the acronym PANDAS (pediatric autoimmune neuropsychiatric disorder associated with a streptococcal infection) was first proposed by Swedo and colleagues in 1998 [5]. The current study attempts to clarify some surrounding issues by characterizing the presence of antibodies associated with SC in a population of individuals with chronic tics and OCD meeting the criteria for PANDAS, but lacking choreiform (piano-playing) movements during symptom exacerbations [10, 14] and possibly having a more “chronic” than relapsing-remitting course [15]. Supporting data from animal models includes: rats immunized with GABHS developed antibodies against D1 and D2 receptors and clinically showed compulsive–like behaviors [19] and passively-transferred serum obtained from GABHS-immunized mice caused behavioral disturbances [20]

Methods

Results

Conclusion