Original articleAntistreptococcal, neuronal, and nuclear antibodies in Tourette syndrome
Introduction
Streptococcal infection, through an immune-based mechanism, has recently been theorized to contribute to the exacerbation of tics, obsessive-compulsive symptoms, and attention-deficit–hyperactivity disorder (ADHD). In 1998, Swedo et al. [1] described a cohort with the sudden or explosive onset of tics and obsessive-compulsive behaviors as having a temporal association with streptococcal infection. This proposal has in turn led investigators to look for correlations between neuropsychiatric disorders and antistreptococcal and antineuronal antibody titers. Several studies using single-point-in-time measurements have revealed higher mean antistreptolysin O (ASO) titers in patients with Tourette syndrome compared with controls [2], [3], [4]. In one, ASO titers correlated with tic severity [4]. Other investigators, however, have revealed no association between antistreptococcal antibodies and TS [5], [6], [7], but in one report, a correlation was identified with the diagnosis of ADHD [6].
Antineuronal antibodies have also been measured in individuals with TS, with elevated titers reported against human postmortem putamen and rat striatum [5], [7]. However, in these reports the presence of higher immunoreactivity did not correlate with ADHD or obsessive-compulsive behavior. Morshed and colleagues [7] have also suggested that elevated titers of antinuclear antibodies correlate with the diagnosis of Tourette’s Syndrome.
In the current study the findings of previous investigators are reassessed by measuring the following in children and adolescents with the diagnoses of Tourette syndrome, obsessive-compulsive behavior, and ADHD: (1) ASO and antideoxyribonuclease B (anti-DNAse B) titers; (2) antinuclear antibody titers; (3) levels of autoantibodies against human postmortem caudate, putamen, and globus pallidus; and (4) levels of autoantibodies against a neuroblastoma cell line (HTB-10). Previously in this cohort, elevated enzyme-linked immunosorbent assay (ELISA) optical density measurements against putamen were found, but no linear correlation between optical density values and ASO or anti-DNAse B levels was found, although more subjects with higher antistreptococcal titers were diagnosed with Tourette syndrome [5]. This report addresses the proposals that ASO, antiDNAse B, and antinuclear antibodies titers correlate with the neuropsychiatric diagnoses of Tourette syndrome, ADHD, and obsessive-compulsive behavior. Contrary to the reports of several investigators, these diagnoses are hypothesized not to predict single-point-in-time levels of antistreptococcal or antinuclear antibodies.
Section snippets
Subjects
Forty-one outpatients with Tourette syndrome (33 males, 8 females; age range, 7 to 17 years; mean, 11.3 years) were voluntary participants in this hospital-approved study. All fulfilled the diagnostic criteria for Tourette’s syndrome as defined by the Tourette Syndrome Classification Study Group [8]. Patients were not preselected on the basis of a streptococcal infection. Results from ELISA antineuronal antibody analyses from this group have been published [5], [9]. The mean age of tic onset
Mean antistreptococcal antibody titers
Table 1 presents the number of participating individuals in each diagnostic group and the number for whom ASO and anti-DNAse B titers were available. The mean and S.D. of ASO and anti-DNAse B titers in all nonoverlapping groups, which included all possible combinations of diagnostic comorbidity, are presented in Table 2. As shown in the table, no comparison of differences in antistreptococcal antibody titers between unique diagnostic groups produced significant Bonferroni/Dunn adjusted P
Discussion
Immune-based hypotheses have been proposed for some pediatric patients with tic disorders, obsessive-compulsive behavior, and ADHD. Using a postulated role of group A β-hemolytic streptococcal infection, researchers have sought to identify whether individuals with these problems manifest increased levels of antistreptococcal antibodies. In two studies, adults with Tourette syndrome were manifested higher ASO and anti-DNAse B titers than age-matched controls, but there was no association between
Acknowledgements
Supported in part by grants from the National Institutes of Health (5R01NS37706-02) and the National Tourette Syndrome Association.
References (24)
- et al.
Increased anti-streptococcal antibodies in patients with Tourette syndrome
Psychiatry Res
(2000) - et al.
Increased titers of antibodies against streptococcal M12 and M19 proteins in patients with Tourette syndrome
Psychiatry Res
(2001) - et al.
Group A streptococcal infections and tic disorders in an Italian pediatric population
J Pediatr
(2001) - et al.
Antibodies against neural, nuclear, cytoskeletal, and streptococcal epitopes in children and adults with Tourette syndrome, Sydenham’s chorea, and autoimmune disorders
Biol Psychiatry
(2001) - et al.
Antibodies against a neuron-like (HTB-10 neuroblastoma) cell in children with Tourette syndrome
Biol Psychiatry
(1999) - et al.
Obsessive-compulsive symptomatology in children with Tourette syndrome
J Am Acad Child Adolesc Psychiatry
(1987) - et al.
Children’s Yale-Brown Obsessive Compulsive ScaleReliability and validity
J Am Acad Child Adolesc Psychiatry
(1997) - et al.
Striatal antibodies in children with Tourette syndromeMultivariate discriminant analysis of IgG repertoires
J Neuroimmunol
(2001) - et al.
Anti-striatal antibodies in Tourette syndrome cause neuronal dysfunction
J Neuroimmunol
(2000) - et al.
Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood
Lancet
(1999)
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infectionsClinical description of the first 50 cases
Am J Psychiatry
Antibodies against human putamen in children with Tourette syndrome
Neurology
Cited by (62)
Tourette Syndrome and Tic Disorders
2016, Handbook of Behavioral NeuroscienceCitation Excerpt :Some have identified a relationship between titers and severity of clinical symptoms (Cardona and Orefici, 2001). Other studies have not found a relationship between streptococcal-related titers and TS (Loiselle et al., 2003). Two longitudinal studies showed that there was little association between clinical exacerbations and a new GABHS infection (Kurlan et al., 2008; Leckman et al., 2011).
The role of immune mechanisms in Tourette syndrome
2015, Brain ResearchMaternal history of autoimmune disease and later development of tourette syndrome in offspring
2015, Journal of the American Academy of Child and Adolescent PsychiatryA personal 35 year perspective on Gilles de la Tourette syndrome: Assessment, investigations, and management
2015, The Lancet PsychiatryCitation Excerpt :The controversy surrounding PANDAS, the infectious cause, the immunological cause and thus treatment of Tourette's syndrome (eg, with antibiotics and intravenous γ globulin injections) continues. There are publications in support of an association between Tourette's syndrome and a streptococcal infection,133 others that are inconclusive,134 and publications against an association.135 Most agree now that Tourette's syndrome and PANDAS are completely different entities, and that instead of infections as such playing a major part in the aetiopathology of Tourette's syndrome, immunogenic factors could contribute to the expression of Tourette's syndrome among other genetic and extragenetic or environmental factors and thus issues of immunity are probably important (panel).136
Immune-mediated animal models of Tourette syndrome
2013, Neuroscience and Biobehavioral ReviewsCitation Excerpt :Whether anti-neuronal antibodies can be detected in subjects with TS and related disorders is a matter of some controversy (Hoekstra et al., 2002; Martino et al., 2009b; Murphy et al., 2010a; Robertson and Stern, 1998; Singer et al., 2008). Although many studies support the presence of anti-CNS IgG autoantibodies in at least a subset of subjects with TS (Cheng et al., 2012; Church et al., 2003; Kiessling et al., 1993, 1994; Laurino et al., 1997; Loiselle et al., 2003; Martino et al., 2011, 2007; Morer et al., 2008; Morshed et al., 2001; Rizzo et al., 2006; Singer et al., 1998, 1999; Wendlandt et al., 2001; Yeh et al., 2012, 2006; Zykov et al., 2009), some studies have found the levels of IgG autoantibodies in TS or PANDAS sera to be indistinguishable from those of controls (Brilot et al., 2011; Kawikova et al., 2010; Kirkman et al., 2008; Morris et al., 2009; Singer et al., 1998, 2005a) and a temporal relationship to documented GAS infection or the presence of anti-GAS antibodies has not always been evident (Kawikova et al., 2010; Loiselle et al., 2003; Martino et al., 2011; Singer et al., 2008, 1998, 1999). One study found lower levels of antibodies against a panel of neuronal targets previously identified in TS and/or OCD, but only in antibodies of the IgA isotype (Kawikova et al., 2010).