Childhood-onset obsessive-compulsive disorder and tic disorders: case report and literature review

A subgroup of childhood-onset obsessive-compulsive disorder (OCD) and tic disorders has been found to have a postinfectious autoimmune-mediated etiology. Clinical observations and systematic investigations have shown that a subgroup of children with OCD and/or tic disorders have the onset and subsequent exacerbations of their symptoms following infections with group A beta-hemolytic streptococci (GABHS). This subgroup has been designated by the acronym PANDAS: pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Five clinical characteristics define the PANDAS subgroup: presence of OCD and/or tic disorder, prepubertal symptom onset, sudden onset or abrupt exacerbations, association with neurological abnormalities during exacerbations (adventitious movements or motoric hyperactivity), and the temporal association between symptom exacerbations and GABHS infections. The proposed poststreptococcal inflammatory etiology provides a unique opportunity for treatment and prevention, including immunomodulatory therapies such as plasma exchange and intravenous immunoglobulin. A placebo-controlled trial revealed that both intravenous immunoglobulin and plasma exchange were effective in reducing neuropsychiatric symptom severity (40 and 55% reductions, respectively) for a group of severely ill children in the PANDAS subgroup. Further research is required to determine why the treatments are helpful and to ascertain whether or not antibiotic prophylaxis can help prevent poststreptococcal symptom exacerbations.     

Tic disorders and obsessive-compulsive disorder: is autoimmunity involved?

The precise cause of tic disorders and paediatric obsessive-compulsive disorder (OCD) is unknown. In addition to genetic factors, autoimmunity may play a role, possibly as a sequela of preceding streptococcal throat infections in susceptible children. Here we review the most recent findings, from July 2003 onwards, with regard to a possible relationship between tics/OCD and autoimmunity. Evidence about an intriguing correlation between streptococcal infections and tic disorders and OCD is accumulating. Specific criteria have been outlined for paediatric autoimmune disorders associated with streptococcal infections (PANDAS), but autoimmunity may also be involved in tic disorders and/or OCD in general. Anti-basal ganglia auto-antibodies are an important potential indicator of autoimmunity. Although the lack of a standardized methodology makes comparisons of findings difficult, new data has emerged pointing to the possible involvement of specific auto-antigens. Earlier findings of increased D8/17 B cell expression as a putative susceptibility marker could not be replicated, possibly due to instability of the D8/17-binding antibody. Although PANDAS patients have been reported to improve after therapeutic plasma exchange, and antibiotics may prevent symptom exacerbations, immune-based treatments should not be routinely given. In future studies, demonstrating the pathogenetic significance of anti-basal ganglia antibodies in animals is a major challenge to draw any firm conclusions about a role for autoimmunity. Future longitudinal studies should be aimed at assessing the precise relationship between symptom exacerbations, infections, and immune parameters, possibly along with gene expression profiles.     

Tic disorders and obsessive-compulsive disorder: Is autoimmunity involved?

The precise cause of tic disorders and paediatric obsessive-compulsive disorder (OCD) is unknown. In addition to genetic factors, autoimmunity may play a role, possibly as a sequela of preceding streptococcal throat infections in susceptible children. Here we review the most recent findings, from July 2003 onwards, with regard to a possible relationship between tics/OCD and autoimmunity. Evidence about an intriguing correlation between streptococcal infections and tic disorders and OCD is accumulating. Specific criteria have been outlined for paediatric autoimmune disorders associated with streptococcal infections (PANDAS), but autoimmunity may also be involved in tic disorders and/or OCD in general. Anti-basal ganglia auto-antibodies are an important potential indicator of autoimmunity. Although the lack of a standardized methodology makes comparisons of findings difficult, new data has emerged pointing to the possible involvement of specific auto-antigens. Earlier findings of increased D8/17 B cell expression as a putative susceptibility marker could not be replicated, possibly due to instability of the D8/17-binding antibody. Although PANDAS patients have been reported to improve after therapeutic plasma exchange, and antibiotics may prevent symptom exacerbations, immune-based treatments should not be routinely given. In future studies, demonstrating the pathogenetic significance of anti-basal ganglia antibodies in animals is a major challenge to draw any firm conclusions about a role for autoimmunity. Future longitudinal studies should be aimed at assessing the precise relationship between symptom exacerbations, infections, and immune parameters, possibly along with gene expression profiles.     

A pilot study of penicillin prophylaxis for neuropsychiatric exacerbations triggered by streptococcal infections.

BACKGROUND: Some children with obsessive-compulsive disorder (OCD) and tic disorders appear to have symptom exacerbations triggered by group A beta-hemolytic streptococcal infections in a manner that is similar to rheumatic fever and its neurologic variant, Sydenham's chorea. Because penicillin prophylaxis has proven to be effective in preventing recurrences of rheumatic fever, it was postulated that it might also prevent streptococcal-triggered neuropsychiatric symptom exacerbations in children with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS). These children are identified by five clinical characteristics: presence of OCD or tic disorder, prepubertal onset, episodic symptom course, neurologic abnormalities (i.e., choreiform movements) and streptococcal-triggered symptom exacerbations. METHODS: Thirty-seven children with PANDAS were enrolled in an 8 month, double-blind, balanced cross-over study. Patients were randomized to receive either 4 months of the active compound (twice daily oral 250 mg penicillin V) followed by 4 months of placebo, or placebo followed by penicillin V. Tic, OCD, and other psychiatric symptoms were monitored monthly. Throat cultures and streptococcal antibody titers were also obtained. RESULTS: There were an equal number of infections in both the active and placebo phases of the study. There was no significant change seen in either the obsessive-compulsive or tic symptom severity between the two phases. CONCLUSIONS: Because of the failure to achieve an acceptable level of streptococcal prophylaxis, no conclusions can be drawn from this study regarding the efficacy of penicillin prophylaxis in preventing tic or OCD symptom exacerbations. Future studies should employ a more effective prophylactic agent, and include a larger sample size.     

Antibiotic prophylaxis with azithromycin or penicillin for childhood-onset neuropsychiatric disorders.

BACKGROUND: The acronym PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) describes a subgroup of children with obsessive-compulsive disorder and/or tic disorder that experience symptom exacerbations following streptococcal infections. We hypothesized that the prevention of streptococcal infections among children in the PANDAS subgroup would decrease neuropsychiatric symptom exacerbations. METHODS: Twenty-three subjects with PANDAS were enrolled in a double blind, randomized controlled trial. Antibiotic prophylaxis with penicillin or azithromycin was administered for 12 months. Rates of streptococcal infections and neuropsychiatric symptom exacerbations were compared between the study year and the baseline year prior to entry. RESULTS: Significant decreases in streptococcal infections during the study year were found with a mean of .1 (.3 SD) per subject, compared to the baseline year with 1.9 (1.2 SD) in the penicillin group and 2.4 (1.1 SD) in the azithromycin group [p<.01]. Significant decreases in neuropsychiatric exacerbations during the study year were also found with a mean of .5 (.5 SD) per subject in the penicillin group and .8 (.6 SD) in the azithromycin group, compared to the baseline year with 2.0 (.9 SD) in the penicillin group and 1.8 (.6 SD) in the azithromycin group [p<.01]. CONCLUSIONS: Penicillin and azithromycin prophylaxis were found to be effective in decreasing streptococcal infections and neuropsychiatric symptom exacerbations among children in the PANDAS subgroup.     

Antibasal ganglia antibodies and their relevance to movement disorders

PURPOSE OF REVIEW: Recently, autoaggressive immunological responses were included among the causative agents of basal ganglia dysfunction. Autoaggressive immune-mediated illnesses secondary to group A beta-haemolytic streptococcal infections present with motor and psychiatric symptoms, due to basal ganglia involvement. These disorders have been associated with serum antineuronal antibodies, relatively specific to human basal ganglia tissue. This review summarizes the most recent studies concerning antibasal ganglia antibodies, focusing on the associated phenotypes and the hypotheses concerning their pathogenicity. RECENT FINDINGS: The spectrum of post-streptococcal neuropsychiatric disorders associated with antibasal ganglia antibodies seems broader than previously recognized. Other than chorea, tics and obsessive-compulsive disorder, which constituted the bulk of previously described disorders associated with antibasal ganglia antibodies, post-streptococcal neuropsychiatric disturbances include a wider range of motor and behavioural abnormalities, in keeping with the multifunctional role of the basal ganglia. An encephalitis lethargica-like illness following streptococcal infection was reported, and unusual adult-onset movement disorders associated with antibasal ganglia antibodies were documented. Moreover, investigators provided preliminary evidence for a pathogenic role of autoantibodies in Sydenham's chorea, the prototypic post-streptococcal neuropsychiatric disorder. SUMMARY: Antibasal ganglia antibodies are relatively specific in identifying post-streptococcal neuropsychiatric disorders, which constitute a wider spectrum of movement disorders than previously recognized. Although their sensitivity in diagnosing Sydenham's chorea seems excellent, it is not yet possible to extrapolate this sensitivity to all the recently identified post-streptococcal neuropsychiatric disorders. The antigens targeted by these autoantibodies and their pathogenic importance are currently under investigation. Preliminary evidence suggests that antibasal ganglia antibodies may be pathogenic.     

Is Tourette's syndrome an autoimmune disease?

We provide a review of recent research findings which support the involvement of autoimmunity in childhood-onset tic disorders, in particular the presence of antineuronal autoantibodies, D8/17 B lymphocyte overexpression, a marker of chorea associated with streptococcal infection, and possible beneficial effects of immunomodulatory intervention. One of the most controversial areas in this field is the validity of the proposed PANDAS concept. Some researchers have delineated a putatively unique subgroup of patients, from the spectrum of illness encompassing Tourette's syndrome and obsessive-compulsive disorder (OCD), whose tics and obsessive-compulsive symptoms are shown to arise in response to beta-hemolytic streptococcal infections. They designated it by the term pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Herein we additionally present pros and cons concerning the concept of PANDAS. Finally, recommendations for future research directions are given.     

Post-streptococcal autoimmune disorders of the central nervous system

PURPOSE OF REVIEW: Autoimmune disease has long been intertwined with investigations of infectious causes. Antibodies that are formed against an infectious agent can, through the process of molecular mimicry, also recognize healthy cells. When this occurs, the immune system erroneously destroys the healthy cells causing autoimmune disease in addition to appropriately destroying the offending infectious agent and attenuating the infectious process. The first infectious agent shown to cause a post-infectious autoimmune disorder in the central nervous system was Streptococcus pyogenes in Sydenham's chorea. The present review summarizes the most recent published findings of central nervous system diseases that have evidence of a post-streptococcal autoimmune etiology. RECENT FINDINGS: Sydenham's chorea and other central nervous system illnesses that are hypothesized to have a post-streptococcal autoimmune etiology appear to arise from targeted dysfunction of the basal ganglia. PANDAS (pediatric autoimmune disorders associated with streptococcal infections) is the acronym applied to a subgroup of children with obsessive-compulsive disorder or tic disorders occurring in association with streptococcal infections. In addition, there are recent reports of dystonia, chorea encephalopathy, and dystonic choreoathetosis occurring as sequelae of streptococcal infection. Investigators have begun to isolate and describe antistreptococcal-antineuronal antibodies as well as possible genetic markers in patients who are susceptible to these illnesses. SUMMARY: Clinical and research findings in both immunology and neuropsychiatry have established the existence of post-streptococcal neuropsychiatric disorders and are beginning to shed light on possible pathobiologic processes.     

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.     

Is parental report of upper respiratory infection at the onset of obsessive-compulsive disorder suggestive of pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection?

The diagnosis of pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) requires a prospectively determined association between group A beta-hemolytic streptococcal (GABHS) infection and obsessive-compulsive disorder (OCD) or tic disorder. Screening for GABHS infection imposes a significant burden on both patient and clinician. To heighten the index of suspicion for PANDAS, it would be useful to know if parent-reported upper respiratory infection (URI) is associated with PANDAS symptoms or associated characteristics. Eighty-three consecutive, clinically referred patients aged 6 to 17 years with a primary diagnosis of OCD and their primary caregivers were asked about URI signs and symptoms at the time of OCD onset, PANDAS symptoms, OCD and tic symptoms, comorbidity, and putative PANDAS risk factors. Specific inquiry regarding URI symptoms proved more informative than general inquiry. In the URI present versus URI absent group, more patients experienced a sudden rather than insidious onset of symptoms. Additionally, more patients with a URI plus sudden onset exhibited a comorbid tic disorder. Until validated biomarkers permit retrospective diagnosis, a history that OCD began around the time of a URI should clue the clinician to look prospectively for PANDAS. Additional research is required to define the boundaries of PANDAS and to develop psychometrically reliable and valid diagnostic strategies.     

Psychiatric disorders in first-degree relatives of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS)

OBJECTIVE: To determine the rates of psychiatric disorders in the first-degree relatives of children with infection-triggered obsessive-compulsive disorder (OCD) and/or tics (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections; PANDAS). METHOD: The probands of this study were 54 children with PANDAS (n = 24 with a primary diagnosis of OCD; n = 30 with a primary diagnosis of a tic disorder). One hundred fifty-seven first-degree relatives (100 parents [93%] and 57 siblings [100%]) were evaluated for the presence of a tic disorder. One hundred thirty-nine first-degree relatives (100 parents [93%] and 39 of 41 siblings over the age of 6 [95%]) were evaluated with clinical and structured psychiatric interviews to determine the presence of subclinical OCD, OCD, and other DSM-IV Axis I disorders. RESULTS: Twenty-one probands (39%) had at least one first-degree relative with a history of a motor or vocal tic; 6 mothers (11%), 9 fathers (19%), and 8 siblings (16%) received this diagnosis. Fourteen probands (26%) had at least one first-degree relative with OCD; 10 mothers (19%), 5 fathers (11%), and 2 siblings (5%), received this diagnosis. An additional 8 parents (8%) and 3 siblings (8%) met criteria for subclinical OCD. Eleven parents (11%) had obsessive-compulsive personality disorder. CONCLUSIONS: The rates of tic disorders and OCD in first-degree relatives of pediatric probands with PANDAS are higher than those reported in the general population and are similar to those reported previously for tic disorders and OCD. Further study is warranted to determine the nature of the relationship between genetic and environmental factors in PANDAS.     

Obsessive compulsive disorder: is there an association with childhood streptococcal infections and altered immune function?

During the last few years, an increased interest in the possibility of immune mediated pathophysiology of obsessive compulsive disorder (OCD) and related disorders has been seen. In the late 1980s, the National Institute of Mental Health reported an increase of obsessive compulsive symptoms in patients with Sydenham chorea (SC). Subsequently, a precipitating streptococcal infection in children with sudden onset of OCD symptoms but no chorea led to the coining of PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus).This association has furthered interest in studying immune parameters in non-PANDAS OCD as well. This article will review the neuropsychiatric findings in OCD and Tourette syndrome (TS) with emphasis placed on PANDAS, and its association with SC, and a review of the existing studies that have assessed immunologic measures in patients with OCD and TS.     

Obsessive-compulsive disorder and immunology: a review

Interest in the possibility of an immune-mediated pathophysiology of obsessive-compulsive disorder and related disorders has increased. In the late 1980s, the National Institute of Mental Health reported an increase in obsessive-compulsive symptoms (OCS) in patients with Sydenham chorea (SC). Subsequently, a precipitating streptococcal infection in children with sudden onset of OCS but no chorea led to the coining of PANDAS (Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection). This association has furthered interest in biological measures for immune and genetic susceptibility in non-PANDAS obsessive-compulsive disorder patients (OCD). Furthermore, some studies are trying to demonstrate alterations of immune parameters in OCD patients, with few positive results. In this narrative review, our objective was to describe the immunologic findings in OCD, PANDAS, and their association with SC.     

The PANDAS subgroup of tic disorders and childhood-onset obsessive–compulsive disorder

Diagnosis and treatment of the PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) variant of Gilles de la Tourette syndrome (GTS) and childhood-onset obsessive–compulsive disorder (OCD) are still controversial issues. Most cross-sectional studies confirm a significant association between GTS and the development of an immune response against group A β-hemolytic streptococcus (GABHS). Moreover, longitudinal retrospective studies suggest that a recent exposure to GABHS might be a risk factor for the onset of tics and obsessive–compulsive symptoms. However, further evidence from longitudinal prospective research is needed to verify whether a temporal association between GABHS infections and symptom exacerbations is a useful and reliable criterion for the diagnosis of PANDAS. In addition, preliminary results suggest that the PANDAS spectrum might be enlarged to include attention deficit/hyperactivity disorder.Although a number of immunological biomarkers have been proposed as markers of the PANDAS variant, at present, none of these has been conclusively proved useful to diagnose and monitor disease course in children with a suspicion of PANDAS.Finally, despite their empirical use in community settings, we still lack conclusive, evidence-based data regarding the usefulness of antibiotic and immunomodulatory treatments in children with PANDAS. Given the relevance of this topic for general pediatric health, additional research efforts to solve all the pending issues and the hottest points of debate are warranted.     

Detecting pediatric autoimmune neuropsychiatric disorders associated with streptococcus in children with obsessive-compulsive disorder and tics.

BACKGROUND: A subgroup of children with obsessive-compulsive and tic disorders are proposed to have an infectious trigger. The purpose of this study was to investigate the relationship between group A streptococcal titers and symptom fluctuations in children with a clinical course resembling that described for pediatric autoimmune neuropsychiatric disorders associated with streptococcus. METHODS: Twenty-five children with obsessive-compulsive disorder and/or tic disorder were evaluated for neuropsychiatric severity and group A streptococcal antibody titers (streptolysin O, deoxyribonuclease B, and carbohydrate A) at 6-week intervals for > or = six consecutive evaluations (total visits=277). RESULTS: Children with large symptom fluctuations (n=15) were compared with children without dramatic fluctuations (n=10). Co-movements of obsessive-compulsive/tic severity and group A streptococcal antibodies were assessed. In subjects with large symptom changes, positive correlations were found between streptococcal titers and obsessive-compulsive severity rating changes (p=.0130). These subjects were also more likely to have elevated group A streptococcal titers during the majority of observations (p=.001). Tic symptom exacerbations occurred more often in the fall/winter months than spring/summer months (p=.03). CONCLUSIONS: Patients with marked obsessive-compulsive/tic symptom changes may be characterized by streptococcal titer elevations and exhibit evidence of seasonal tic exacerbations.     

Tic disorders: neural circuits, neurochemistry, and neuroimmunology

The neuroanatomy and neurochemistry underlying tic disorders are thought to involve corticostriatothalamocortical circuits and dysregulation of their component neurotransmitter systems. Tourette syndrome is a tic disorder that begins in childhood and follows a waxing and waning course of tic severity. Although it is generally believed to have a genetic component, its etiology has not been fully elucidated. The clinical entity pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) has led some to suggest that the pathophysiology of tics in some individuals might involve a postinfectious autoimmune component. We review the neural circuits and neurochemistry of Tourette syndrome and evaluate the evidence for and against a role for autoimmunity in the expression of tics.     

The PANDAS subgroup of tic disorders and childhood-onset obsessive–compulsive disorder

Diagnosis and treatment of the PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) variant of Gilles de la Tourette syndrome (GTS) and childhood-onset obsessive–compulsive disorder (OCD) are still controversial issues. Most cross-sectional studies confirm a significant association between GTS and the development of an immune response against group A β-hemolytic streptococcus (GABHS). Moreover, longitudinal retrospective studies suggest that a recent exposure to GABHS might be a risk factor for the onset of tics and obsessive–compulsive symptoms. However, further evidence from longitudinal prospective research is needed to verify whether a temporal association between GABHS infections and symptom exacerbations is a useful and reliable criterion for the diagnosis of PANDAS. In addition, preliminary results suggest that the PANDAS spectrum might be enlarged to include attention deficit/hyperactivity disorder.Although a number of immunological biomarkers have been proposed as markers of the PANDAS variant, at present, none of these has been conclusively proved useful to diagnose and monitor disease course in children with a suspicion of PANDAS.Finally, despite their empirical use in community settings, we still lack conclusive, evidence-based data regarding the usefulness of antibiotic and immunomodulatory treatments in children with PANDAS. Given the relevance of this topic for general pediatric health, additional research efforts to solve all the pending issues and the hottest points of debate are warranted.     

Tourette's syndrome: clinical features, pathophysiology, and therapeutic approaches

Tourette's syndrome (TS) is a disorder characterized by simple and complex motor tics, vocal tics, and frequently obsessive-compulsive symptoms. Its onset occurs before the age of 21. Typically, TS shows a waxing and waning course, but a chronification of the tics, even during later life, is often observed. TS mainly occurs in boys, and shows genetic heritability with differing penetrance. The pathological mechanism is still unclear Neuroanatomical and neuroimaging studies, as well as effective treatment using antipsychotics, suggest that a disturbance of the dopaminergic system in the basal ganglia plays an important role in the pathogenesis of TS. Several possibly causative mechanisms of the disturbed dopaminergic neurotransmission are discussed, with the main emphasis on the-infection-triggered-inflammatory immune process. Extrapyramidal movement disorders are known to occur as a symptom of poststreptococcal disease, such as in Sydenham's chorea. Cases of childhood TS are proposed to be caused by such a poststreptococcal mechanism, being part of a spectrum of childhood neurobehavioral disorders termed pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS). The overlap between TS and PANDAS is discussed, and a critical view of the PANDAS concept is presented. The therapeutic implications of the different pathological mechanisms are described, taking into consideration not only the acute or chronic natures of different infections, but also an autoimmune process. Moreover, therapeutic strategies using typical and atypical antipsychotics, and also experimental therapies such as repetitive transcranial magnetic stimulation and deep brain stimulation, are critically discussed.     

Tourette's syndrome: a cross sectional study to examine the PANDAS hypothesis

BACKGROUND: The classical neurological disorder after group A beta haemolytic streptococcal infection is Sydenham's chorea. Recently a tic disorder occurring after group A streptococcal infection has been described and termed PANDAS (paediatric autoimmune neuropsychiatric disorders associated with streptococcal infection). It is proposed that antibodies induced after group A streptococcal infection react with basal ganglia neurones in Sydenham's chorea and PANDAS. Anti-basal ganglia antibodies (ABGA) are present in most cases of acute Sydenham's chorea, but rarely in controls. OBJECTIVE: To investigate the hypothesis that Tourette's syndrome may be associated with group A streptococcal infection and ABGA. METHODS: 100 patients with Tourette's syndrome (DSM-IV-TR) were enrolled in a cross sectional study. Children with neurological disease (n = 50) and recent uncomplicated streptococcal infection (n = 40), adults with neurological disease (n = 50), and healthy adults (n = 50) were studied as controls. Recent group A streptococcal infection was defined using antistreptolysin O titre (ASOT). ABGA were detected using western immunoblotting and indirect immunofluorescence. RESULTS: ASOT was raised in 64% of children with Tourette's syndrome compared with 15% of paediatric neurological disease controls (p < 0.0001), and in 68% of adults with Tourette's syndrome compared with 12% of adult neurological controls and 8% of adult healthy controls (p < 0.05). Western immunoblotting showed positive binding in 20% of children and 27% of adults with Tourette's syndrome, compared with 2-4% of control groups (p < 0.05). The most common basal ganglia binding was to a 60 kDa antigen, similar to the proposed antigen in Sydenham's chorea. Indirect immunofluorescence revealed autoantibody binding to basal ganglia neurones. Serological evidence of recent group A streptococcal infection, assessed by a raised ASOT, was detected in 91% (21/23) of Tourette's syndrome patients with positive ABGA compared with 57% (44/77) with negative ABGA (p < 0.01). CONCLUSIONS: The results support a role of group A streptococcal infection and basal ganglia autoimmunity in a subgroup of patients with Tourette's syndrome and suggest a pathogenic similarity between Sydenham's chorea and some patients with Tourette's syndrome.     

Preliminary findings of antistreptococcal antibody titers and basal ganglia volumes in tic, obsessive-compulsive, and attention deficit/hyperactivity disorders

BACKGROUND: Previous studies have provided preliminary serological evidence supporting the theory that symptoms of tic disorders or obsessive-compulsive disorder (OCD) may be sequelae of prior streptococcal infection. It is unclear, however, whether previously reported associations with streptococcal infection were obscured by the presence of diagnostic comorbidities. It is also unknown whether streptococcal infection is associated in vivo with anatomical alterations of the brain structures that have been implicated in the pathophysiology of these disorders. METHODS: Antistreptococcal antibody titers were measured in 105 people diagnosed as having CTD, OCD, or attention-deficit/hyperactivity disorder (ADHD) and in 37 community controls without a disorder. Subjects were unselected with regard to their history of streptococcal exposure. Basal ganglia volumes were measured in 113 of these subjects (79 patients and 34 controls). RESULTS: A DSM-IV diagnosis of ADHD was associated significantly with titers of 2 distinct antistreptococcal antibodies, antistreptolysin O and anti-deoxyribonuclease B. These associations remained significant after controlling for the effects of CTD and OCD comorbidity. No significant association was seen between antibody titers and a diagnosis of either CTD or OCD. When basal ganglia volumes were included in these analyses, the relationships between antibody titers and basal ganglia volumes were significantly different in OCD and ADHD subjects compared with other diagnostic groups. Higher antibody titers in these subjects were associated with larger volumes of the putamen and globus pallidus nuclei. CONCLUSIONS: These findings suggest that the prior reports of an association between antistreptococcal antibodies and either CTD or OCD may have been confounded by the presence of ADHD. They also support the hypothesis that in susceptible persons who have ADHD or OCD, chronic or recurrent streptococcal infections are associated with structural alterations in basal ganglia nuclei.