Streptococcal upper respiratory tract infections and exacerbations of tic and obsessive-compulsive symptoms: a prospective longitudinal study.

OBJECTIVE: The objective of this blinded, prospective, longitudinal study was to determine whether new group A ß hemolytic streptococcal (GABHS) infections are temporally associated with exacerbations of tic or obsessive-compulsive (OC) symptoms in children who met published criteria for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). A group of children with Tourette syndrome and/or OC disorder without a PANDAS history served as the comparison (non-PANDAS) group. METHOD: Consecutive clinical ratings of tic and OC symptom severity were obtained for 31 PANDAS subjects and 53 non-PANDAS subjects. Clinical symptoms and laboratory values (throat cultures and streptococcal antibody titers) were evaluated at regular intervals during a 25-month period. Additional testing occurred at the time of any tic or OC symptom exacerbation. New GABHS infections were established by throat swab cultures and/or recent significant rise in streptococcal antibodies. Laboratory personnel were blinded to case or control status, clinical (exacerbation or not) condition, and clinical evaluators were blinded to the laboratory results. RESULTS: No group differences were observed in the number of clinical exacerbations or the number of newly diagnosed GABHS infections. On only six occasions of a total of 51 (12%), a newly diagnosed GABHS infection was followed, within 2 months, by an exacerbation of tic and/or OC symptoms. In every instance, this association occurred in the non-PANDAS group. CONCLUSIONS: This study provides no evidence for a temporal association between GABHS infections and tic/OC symptom exacerbations in children who meet the published PANDAS diagnostic criteria.

Association between intracellular infectious agents and Tourette's syndrome.

The underlying pathophysiological mechanisms in Tourette's syndrome (TS) are still unclear. Increasing evidence supports the involvement of infections, possibly on the basis of an altered immune status. Not only streptococci but also other infectious agents may be involved. This study investigates the association between the neurotrophic agents Chlamydia, Toxoplasma and TS. 32 patients with TS and 30 healthy matched controls were included. For each individual, IgA/IgG antibody titers against Chlamydia trachomatis/pneumoniae and Toxoplasma gondii were evaluated and analyzed with Fisher's exact test. We found a significantly higher rate of TS patients with elevated antibody titers against Chlamydia trachomatis (P = 0.017) as compared to controls. A trend toward a higher prevalence in the Tourette's group was shown for Toxoplasma (P = 0.069). In conclusion, within the TS patients a higher rate of antibody titers could be demonstrated, pointing to a possible role of Chlamydia and Toxoplasma in the pathogenesis of tic disorders. Because none of these agents has been linked with TS to date, a hypothesis is that infections could contribute to TS by triggering an immune response. It still remains unclear whether tic symptoms are partly due to the infection or to changes in the immune balance caused by an infection.

Antineuronal antibodies in a group of children with obsessive-compulsive disorder and Tourette syndrome.

An autoimmune hypothesis has been suggested for early onset obsessive-compulsive disorder and Tourette syndrome. The term: Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) has been proposed as an aetiological subtype of OCD and TS, related to a Group A beta haemolytic streptococcal (GABHS) infection that triggers an autoimmune response. Antineural antibodies have been studied and found in the sera of some patients with these disorders, and they are thought to cross-react with streptococcal and basal ganglia antigens. The present study included 32 prepubertal-onset OCD patients, 21 with TS diagnosis (some of them meeting criteria for PANDAS) and 19 normal children, all aged between 9 and 17 years. Antibodies were assayed by immunohistochemistry and immunoblot. Special attention was paid to the methodology and a high serum dilution was used to minimize non-specific binding. No anti-basal ganglia antibodies were detected by immunohistochemistry in any of the samples. Two proteins, with approximate molecular weights of 86 kDa and 55 kDa, were found in sera from 7 patients. Though the study supports the hypothesis of an autoimmune process underlying OCD or TS in some patients, further research is needed.

Association between streptococcal infection and obsessive-compulsive disorder, Tourette's syndrome, and tic disorder.

OBJECTIVE: Reports have suggested that streptococcal infection may be etiologically related to pediatric autoimmune neuropsychiatric disorders (PANDAS), but there are few good epidemiologic studies to support this theory. Using population-based data from a large West-Coast health maintenance organization, we assessed whether streptococcal infection was associated with increased risk for obsessive-compulsive disorder (OCD), Tourette's syndrome (TS), or tic disorder. METHODS: This is a case-control study of children 4 to 13 years old receiving their first diagnosis of OCD, TS, or tic disorder between January 1992 and December 1999 at Group Health Cooperative outpatient facilities. Cases were matched to controls by birth date, gender, primary physician, and propensity to seek health care. RESULTS: Patients with OCD, TS, or tic disorder were more likely than controls to have had prior streptococcal infection (OR: 2.22; 95% CI: 1.05, 4.69) in the 3 months before onset date. The risk was higher among children with multiple streptococcal infections within 12 months (OR: 3.10; 95% CI: 1.77, 8.96). Having multiple infections with group A beta-hemolytic streptococcus within a 12-month period was associated with an increased risk for TS (OR: 13.6; 95% CI: 1.93, 51.0). These associations did not change appreciably when limited to cases with a clear date of onset of symptoms or with tighter matching on health care behavior. CONCLUSION: These findings lend epidemiologic evidence that PANDAS may arise as a result of a postinfectious autoimmune phenomenon induced by childhood streptococcal infection.

Striatal microinfusion of Tourette syndrome and PANDAS sera: failure to induce behavioral changes.

Rodent striatal microinfusions have been suggested as a model for assessing the behavioral effects induced by antineuronal antibodies. We used this approach to evaluate the proposed autoimmune etiology for Tourette syndrome (TS) and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). Sera were assessed from patients with TS (n = 9) preselected based on the presence of elevated enzyme-linked immunosorbent assay optical densities against putamen homogenate and sera from patients with PANDAS (n = 8), selected from a larger group assayed for antibodies against a putamen synaptosomal preparation. The effect of antibodies against the streptococcal M5 protein were also studied. A total of 44 Fischer rats received bilateral infusion of sera: 23 ventral striatum (5 PANDAS, 5 TS, 5 anti-M5 protein, and 8 control); 21 ventrolateral striatum (5 PANDAS, 5 TS, 5 anti-M5 protein, and 6 controls). Cannulas were placed bilaterally and symmetrically by stereotactic techniques. After animals were allowed to recover for 1 week, sera were microinfused for 3 days. Animal behavior was then simultaneously quantified by daily observation and monitoring using automated activity boxes for 10 days after infusion. No significant alterations in stereotypic behavior or movement were observed between the PANDAS, TS, or anti-M5 protein and control groups. Our findings are in contrast to previous reports, and suggest the need for further investigations to determine the validity of the model and of autoimmune-mediated hypotheses for pediatric movement disorders.

[Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). A report of two cases]. / Popaciorkowcowe autoimmunologiczne zaburzenia neuropsychiatryczne u dzieci (PANDAS). Opis 2 przypadków.

AIM: To critically review the past years of research on paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections in children and adolescents. METHOD: Literature on PANDAS published from 1995 onward was systematically reviewed. The review focuses on definition and diagnostic consideration aetiological and therapeutical issues. To illustrate the clinical characteristic of PANDAS authors present two cases of children with a severe course of obsessive-compulsive disorder and Tourette's syndrome. RESULTS: Post-streptococcal autoimmunity has been postulated as an aetiologic factor in the development of childhood-onset obsessive-compulsive disorder, tic disorders including Tourette's disorder. This hypothesis arose from a series of clinical observations including the documentation of obsessive-compulsive symptoms of children affected by Sydenham's chorea, a variant of rheumatic fever characterised by neurological dysfunction and also by concomitant investigations of childhood-onset OCD and Tourette's syndrome. CONCLUSION: Results of these studies led to the identification of children whose clinical course is characterised by abrupt and dramatic symptom exacerbations which are temporally related to group A beta-hemolytic streptococcal infections. The identification of such a subgroup will allow for testing of the model of pathogenesis as well as development of novel treatment and prevention strategies. Future research are needed to explore the nature of PANDAS and their relationship with different psychiatric disorders in children and adolescents.

Paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS).

The evidence to date, both published and unpublished, which addresses the validity of the proposed unique subgroup of children with early and abrupt onset of obsessive--compulsive disorder (OCD) and/or tic disorders subsequent to streptococcal infections was reviewed. The aetiology of OCD and tic disorders is unknown, although it appears that both disorders may arise from a variety of genetic and environmental factors. Post-streptococcal autoimmunity has been postulated as one possible mechanism for some. The acronym PANDAS (for paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) has been given to a subgroup of paediatric patients who meet five inclusionary criteria: presence of OCD and/or tic disorder, pre-pubertal symptom onset, sudden onset or episodic course of symptoms, temporal association between streptococcal infections and neuropsychiatric symptom exacerbations, and associated neurological abnormalities. The proposed model of pathophysiology provides for several unique treatment strategies, including the use of antibiotic prophylaxis to prevent streptococcal-triggered exacerbations, and the use of immunomodulatory interventions (such as intravenous immunoglobulin or therapeutic plasma exchange) in the treatment severe neuropsychiatric symptoms. For the latter study group, long-term (2--5 yr) follow-up revealed continued symptom improvement for the majority of patients, particularly when antibiotic prophylaxis had been effective in preventing recurrent streptococcal infections. In addition, the episodic nature of the subgroup's illness provides for opportunities to study brain structure and function during health and disease, as well as allowing for investigations of the aetiologic role of anti-neuronal antibodies and neuroimmune dysfunction in both OCD and tic disorders. Although much research remains to be done, an increasing body of evidence provides support for the postulate that OCD and tic disorders may arise from post-streptococcal autoimmunity. The unique clinical characteristics of the PANDAS subgroup, the presence of volumetric changes in the basal ganglia, and the dramatic response to immunomodulatory treatments, suggest that symptoms arise from a combination of local, regional and systemic dysfunction. Ongoing research is directed at understanding the nature of the abnormal immune response, as well as identifying at-risk children, in order to provide for novel strategies of prevention and treatment.

Increased titers of antibodies against streptococcal M12 and M19 proteins in patients with Tourette's syndrome.

It has been suggested that a post-streptococcal autoimmune process may be involved in the pathogenesis of a subgroup of children with tics and obsessive-compulsive symptoms (PANDAS). Elevated antibody titers against streptococcal antigens have also been described in adult patients suffering from Tourette's syndrome (TS). In order to characterise further streptococcal antigens, we focussed on M proteins. M proteins are a major virulence factor of group A streptococci and known to evoke an immunologic cross-reaction with diverse epitopes of human tissue including brain tissue. Therefore, antibodies against M proteins may play a role in the pathophysiology of at least a subgroup of TS patients. Antibodies against M proteins were studied in 25 adult patients suffering from TS and 25 healthy controls after careful medical examination. The antibody titers against the peptides M1, M4, M6, M12 and M19 were estimated by ELISA. Our results show increased titers of antibodies against the streptococcal M12 and M19 proteins in TS patients as compared with controls, while antibody titers against M1, M4 and M6 did not differ between the TS and control groups. Elevated serum titers of antibodies against M12 and M19 proteins support the view that a streptococcus-induced autoimmune process may be involved in TS. The finding of a possible autoimmune origin of TS has implications for both pathophysiology and future therapeutic strategies.

Tourette's syndrome and 'PANDAS': will the relation bear out? Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection.

Despite strong evidence of the importance of hereditary factors in the etiology of Tourette's syndrome (TS), research findings have consistently pointed to a role of environmental influences. A recent line of research has suggested that tic disorders and associated behavioral disturbances, such as obsessive-compulsive disorder, might develop following streptococcal infection by the process of molecular mimicry, whereby antibodies directed against bacterial antigens cross-react with brain targets. Such investigations have given rise to the notion that there is a spectrum of childhood neurobehavioral disorders (termed pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection [PANDAS]) that arise by postinfectious autoimmune mechanisms. This article reviews research results supporting the concept of PANDAS and discusses their limitations. Well-designed and adequately controlled studies are needed to determine whether there is a true etiologic relation between streptococcal infection and the onset or exacerbation of childhood neuropsychiatric disorders and whether the use of immune-modifying therapies for these conditions is rational.