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.     

The psychiatric symptoms of rheumatic fever

OBJECTIVE: This study examined the frequency and age at onset of psychiatric disorders among children with rheumatic fever, Sydenham's chorea, or both and a comparison group. METHOD: Twenty children with rheumatic fever, 22 with Sydenham's chorea, and 20 comparison children were assessed by means of a semistructured interview and rating scales for tic disorders and obsessive-compulsive disorder. RESULTS: Obsessive-compulsive symptoms were more frequent in both the Sydenham's chorea and rheumatic fever groups than in the comparison group. The Sydenham's chorea group had a higher frequency of major depressive disorder, tic disorders, and attention deficit hyperactivity disorder (ADHD) than both the comparison and rheumatic fever groups. ADHD symptoms were associated with a higher risk of developing Sydenham's chorea. CONCLUSIONS: Both the rheumatic fever and Sydenham's chorea groups were associated with a higher risk of developing neuropsychiatric disorders than the comparison group. ADHD appears to be a risk factor for Sydenham's chorea in children with rheumatic fever.     

Treatment of Sydenham's chorea with intravenous immunoglobulin, plasma exchange, or prednisone

Sydenham's chorea has been established as a postinfectious autoimmune neuropsychiatric disorder. Corticosteroids have been used to treat patients with severe disease but are not always effective, and relapses are frequent after cessation. Eighteen subjects were entered into this randomized-entry controlled trial designed to determine if intravenous immunoglobulin or plasma exchange would be superior to prednisone in decreasing the severity of chorea. Mean chorea severity for the entire group was significantly lower at the 1-month follow-up evaluation (overall 48% improvement). Although the between-group differences were not statistically significant, clinical improvements appeared to be more rapid and robust in the intravenous immunoglobulin and plasma exchange groups than in the prednisone group (mean chorea severity scores decreased by 72% in the intravenous immunoglobulin group, 50% in the plasma exchange group, and 29% in the prednisone group). Larger studies are required to confirm these clinical observations and to determine if these treatments are cost-effective for this disorder.     

Functional brain imaging in Sydenham's chorea and streptococcal tic disorders

Group A streptococcal infections cause a wide range of neuropsychiatric disorders, such as Sydenham's chorea, tics, obsessive-compulsive disorders, and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). Structural (computed tomography and magnetic resonance imaging) and functional (positron emission tomography, single-photon emission computed tomography) imaging studies in patients with Sydenham's chorea have suggested reversible striatal abnormalities. The objective of this study was to investigate the cerebral perfusion patterns of the subcortical structures by using hexamethylpropylenamine oxime single-photon emission computed tomography (HMPAO-SPECT) in seven cases of Sydenham's chorea and two cases of streptococcal tic disorder. HMPAO-SPECT studies revealed a hyperperfusion pattern in two and a hypoperfusion pattern in five of the chorea patients and in two patients with tic disorder. The results are discussed in relation to the duration and severity of the symptoms and the response to therapy. Functional imaging findings can be variable in Sydenham's chorea, and hyperperfusion of the striatum and thalamus could be an indicator of the response to therapy and the severity of symptoms. However, the number of cases so far investigated by either SPECT or positron emission tomography is still too limited to draw any firm conclusions.     

High prevalence of obsessive-compulsive symptoms in patients with Sydenham's chorea

The 20-item Leyton Obsessional Inventory--Child Version was completed by children and adolescents who had had Sydenham's chorea (N = 23) or rheumatic fever without chorea (N = 14). The Sydenham's chorea subjects had significantly more obsessive thoughts and compulsive behaviors and significantly greater interference from these behaviors. Three Sydenham's chorea patients but no rheumatic fever patients had substantial obsessional interference and met criteria for obsessive-compulsive disorder when interviewed by telephone. This suggests that obsessive-compulsive disorder, at least in some patients, may be due to basal ganglia dysfunction.     

On defining Sydenham's chorea: where do we draw the line?

Sydenham's chorea (SC) is a major manifestation of rheumatic fever characterized by an array of neuropsychiatric symptoms that vary in severity, timing, and character. Some of the same symptoms are seen in Tourette's syndrome and childhood-onset obsessive-compulsive disorder. Genetic vulnerability appears to play a role in all three conditions. The term PANDAS (pediatric autoimmune neuropsychiatric disorder associated with streptococcus) has been introduced to describe a putative subset of obsessive-compulsive disorder and Tourette's syndrome that bears some resemblance to Sydenham's chorea. This article discusses whether PANDAS should be subsumed under Sydenham's chorea, thus expanding the diagnostic boundaries of Sydenham's chorea to include primarily neuropsychiatric presentations now classified as cases of obsessive-compulsive disorder or Tourette's syndrome. We conclude that PANDAS is a useful construct, but that it would be premature to view it as a subset of Sydenham's chorea-whether defined narrowly or broadly.     

Brain magnetic resonance spectroscopy in Sydenham's chorea and ADHD

This report presents clinical, laboratory, and neuroimaging findings in a 7-year-old male with Sydenham's chorea associated with attention-deficit hyperactivity disorder. Western immunoblotting revealed serum anti-human basal ganglia tissue antibodies. Magnetic resonance imaging results were normal. Proton magnetic resonance spectroscopic imaging disclosed increased choline/creatine ratio in basal ganglia, frontal, and parieto-occipital areas, and decreased N-acetyl aspartate/creatine ratio in both basal ganglia and frontal areas. Moreover magnetic resonance spectroscopy revealed a peak between 3.6-4.2 ppm of unclear significance. The findings of this study are compared with the previous magnetic resonance spectroscopic studies reported on Sydenham's chorea and attention-deficit hyperactivity disorder. Magnetic spectroscopic imaging suggests an autoimmune basal ganglia damage in the pathogenesis of Sydenham's chorea and fronto-striatal impairment in attention-deficit hyperactivity disorder. In the present case, the previous history of an attention-deficit hyperactivity disorder suggests that this neurobehavioral disorder could be a risk factor for Sydenham's chorea in children with rheumatic fever.     

Obsessive-compulsive symptoms in adults with history of rheumatic fever, Sydenham's chorea and type I diabetes mellitus: preliminary results

OBJECTIVE: Rheumatic fever (RF) associated with Sydenham's chorea (a neurological variant of RF), but not RF without chorea, has been acutely related to obsessive-compulsive symptomatology/disorder (OCS/OCD). This study investigated the presence of OCS in adults who had RF with or without chorea in childhood. METHOD: The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) was used to evaluate OCS in 38 adults with history of RF (13 with chorea; 25 without chorea) or diabetes (controls; n = 19). RESULTS: The OCS was similar in both groups, although the intensity of symptoms was not clinically relevant. Moreover, subjects with RF with or without chorea did not score differently in the Y-BOCS. CONCLUSION: The similar occurrence of OCS in patients with history of RF and diabetes suggests that the development of this symptomatology, triggered by group A beta-haemolytic streptococcus infections, is restricted to the RF acute phase, occurred during infancy, and did not seem to predispose the appearance of OCS in adulthood.     

Neuropsychiatric movement disorders following streptococcal infection

The aim of this study was to describe post-streptococcal movement disorders that form part of the acute rheumatic fever complex. The clinical records of patients diagnosed with Sydenham's chorea were analyzed retrospectively to investigate epidemiology, the significance of socioeconomic deprivation, clinical manifestations, treatments, outcomes, long-term morbidity, and disease evolution. Forty-two patients (21 males, 21 females) were diagnosed with Sydenham's chorea. The median presentation age was 9 years 8 months (range 3y 5mo to 13y 2mo). Nineteen patients were of indigenous African ancestry; 23 were of mixed ancestry. All patients lived in poverty and had poor access to medical care. Twelve of the total group had disabling symptoms for longer than 2 years; six of these patients developed paediatric autoimmune neuropsychiatric disorder associated with Streptococcus (Paediatric autoimmune neuropsychiatric disorder associated with Streptococcus [PANDAS]), five Tourette syndrome (TS), and one learning difficulties. Poor outcome was significantly more prevalent in patients of mixed ancestry, in those with a positive family history, previous behavioural problems, or a failure to complete 10 days of penicillin and 'bed-rest'/hospitalization. Sydenham's chorea is one manifestation of post-streptococcal neuropsychiatric movement disorders. This study demonstrates that patients can present with one diagnosis and evolve other neuropsychiatric conditions such as TS and PANDAS. In the South African context, it is important to delineate neuropsychiatric movement disorders associated with streptococcal infections. The potential genetic susceptibility should be explored.     

Chorea: non-genetic causes

PURPOSE OF REVIEW: The aim of this article is to review the literature on the non-genetic causes of chorea. The differential diagnosis of the large number of causes of sporadic chorea is often a challenging task. Interest has also been growing in the possibility that the mechanism responsible for Sydenham's chorea plays a role in the pathogeneis of other neuropsychiatric disorders. RECENT FINDINGS: Stroke is the main cause of sporadic chorea. Sydenham's chorea shares clinical features with tic disorders, such as obsessive-compulsive disorder and attention deficit hyperactivity disorder. However, there are unequivocal differences between Sydenham's chorea and Tourette's syndrome. There is initial evidence suggesting the beneficial effect of immunosuppression in Sydenham's chorea. Other autoimmune causes of chorea include systemic lupus erythematosus as well as paraneoplastic syndromes. The growing list of drugs associated with chorea include lamotrigine, methadone and lithium. Among infectious agents, HIV is the leading reported cause of chorea. SUMMARY: Patients with sporadic chorea require a thorough work up because numerous causes can lead to this condition. It remains unconfirmed whether the pathogenic mechanisms of Sydenham's chorea are responsible for other conditions such as isolated obsessive-compulsive disorder or Tourette's syndrome. Drugs and infectious agents, especially HIV, are often implicated in the causes of chorea.     

Sydenham's chorea: a clinical follow-up of 65 patients

Sydenham's chorea, the neurological manifestation of rheumatic fever, is the most common acquired chorea of childhood. In this retrospective study, the authors aim to present the clinical and laboratory findings of 65 Sydenham's chorea patients, followed up in a clinic over less than 7 years. The mean age at the onset of the symptoms was 11.7 +/- 2.6 years (range, 6-17 years). Of the patients, 63% were female and 37% were male (male/female: 1.7/1). Chorea was generalized in 78.5% of the patients, right hemichorea in 12.3%, and left hemichorea 9.2%. There was a history of rheumatic fever in 30.8% of the patients. Echocardiographic study showed cardiac valve involvement in 70.5% of 61 patients. Brain magnetic resonance imaging, which was performed on only 18 patients, was evaluated as normal in all. Electroencephalography was also performed on only 18 patients and showed abnormal waves in 50% of them. Pimozide was mostly the first choice of drug therapy. Nevertheless, drug therapy was not needed in 18.5% of the patients. The recovery period of the first attack of the chorea was 1 to 6 months in 51.7% of the patients. The recurrence rate was 37.9%. In conclusion, Sydenham's chorea is still an important health problem in Turkey with respect to its morbidity.     

Sydenham's chorea: not gone and not forgotten

Sydenham's chorea is an ancient disease that continues to afflict large numbers of children throughout the world. A major manifestation of rheumatic fever, Sydenham's chorea is commonly manifested by movement disorder and psychiatric problems, and also may be a marker for a life-threatening carditis. Because Sydenham's chorea is triggered by streptococcal pharyngitis, the most important component of its therapy is antibiotic prophylaxis against further streptococcal infections. Because the pathogenesis of Sydenham's chorea includes the production of anti-basal ganglia antibodies, therapies that modulate immune function or that restore neurotransmitter balance within the basal ganglia may be effective for Sydenham's chorea. Recent reports have suggested that Sydenham's chorea may be part of a spectrum of neuropsychiatric syndromes induced by streptococcal infection.     

Homovanilic acid in Huntington's disease and Sydenham's chorea.

Homovanilic acid (HVA) was determined in the lumbar CSF of 12 patients with Huntington's disease and 12 with Sydenham's chorea before and after probenecid administration. The means of HVA concentration (basal and after probenecid) were lower in those with Huntington's disease than in controls, and were even lower in a sub-group characterised by increased tone and slowness of voluntary movement. There was no correlation between CSF HVA values and the severity of abnormal movements, nor with length of the illness and age of the patients with Huntington's disease. The mean basal HVA concentration did not differ from controls in those with Sydenham's chorea but the accumulation with probenecid was significantly lower. These results suggest a decrease in cerebral dopamine release in both forms of chorea.     

Sydenham's chorea is associated with decreased verbal fluency

BACKGROUND: Sydenham's chorea (SC) is a disorder associated with rheumatic fever and related to Streptococcus-induced immune reaction cross-reactive with basal ganglia antigens. Obsessive-compulsive disorder and other behavioral abnormalities have been described in SC. There are scarce data of cognitive function in this condition. OBJECTIVE: To assess verbal fluency in patients with SC. PATIENTS AND METHODS: We have compared the semantic (SVF) and phonemic verbal fluency (PVF) of 20 subjects with SC and 40 controls matched by age, gender and years of school. RESULTS: The scores of the control group on the SVF and PVF tests were 26.3 +/- 5.7 and 18.0 +/- 6.4 whereas the SC patients scored 25.1 +/- 6.9 and 12.5 +/- 8.2. PVF was significantly decreased in the SC group (p < 0.01). CONCLUSION: SC is associated with reduction of PVF. This finding may reflect disruption of the dorsolateral prefrontal-striatal circuit caused by the auto-immune process characteristic of SC.     

Poststreptococcal acute disseminated encephalomyelitis with basal ganglia involvement and auto-reactive antibasal ganglia antibodies.

Antibasal ganglia antibodies (ABGA) are associated with Sydenham's chorea and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. We present 10 patients with acute disseminated encephalomyelitis (ADEM) associated with Group A beta hemolytic streptococcal infection. The clinical phenotype was novel, with 50% having a dystonic extrapyramidal movement disorder, and 70% a behavioral syndrome. None of the patients had rheumatic fever or Sydenham's chorea. Enzyme-linked immunosorbent assay, Western immunoblotting, and immunohistochemistry were used to detect ABGA. Neurological (n = 40) and streptococcal (n = 40) controls were used for comparison. Enzyme-linked immunosorbent assay results showed significantly elevated ABGA in the patients with poststreptococcal ADEM. Western immunoblotting demonstrated ABGA reactivity to three dominant protein bands of 60, 67, or 80 kDa; a finding not reproduced in controls. Fluorescent immunohistochemistry demonstrated specific binding to large striatal neurones, which was not seen in controls. Streptococcal serology was also significantly elevated in the poststreptococcal ADEM group compared with neurological controls. Magnetic resonance imaging studies showed hyperintense basal ganglia in 80% of patients with poststreptococcal ADEM, compared to 18% of patients with nonstreptococcal ADEM. These findings support a new subgroup of postinfectious autoimmune inflammatory disorders associated with Group A beta hemolytic streptococcus, abnormal basal ganglia imaging, and elevated ABGA.     

Sydenham's chorea: clinical findings and comparison of the efficacies of sodium valproate and carbamazepine regimens

BACKGROUND: Sydenham's chorea is still the most frequently seen form of acquired chorea in childhood in developing world despite the use of antibiotics. It is a debilitating illness lasting for weeks or months and requires drug therapy. OBJECTIVE: To evaluate and compare the efficacies of sodium valproate and carbamazepine in the treatment of the choreiform movements in Sydenham's chorea. DESIGN: A prospective trial carried out with 24 children with Sydenham's chorea. Patients: Twenty-four patients were divided into two groups having similar demographic and clinical properties. One group (n = 17) was given carbamazepine (15 mg/kg per day) and the other (n = 7) was given sodium valproate (20-25 mg/kg per day). As soon as the symptoms were taken under control, doses of the drugs were tapered slowly. The duration of the drug use was recorded. The time of response to therapy was compared between the groups and the patients were monitored for the adverse effects. RESULTS: There was no significant difference between the groups with respect to the time of clinical improvement and time of complete remission, duration of the therapy and the recurrence rates. Clinical improvement began by 8.0 +/- 4.0 days in sodium valproate and 7.4 +/- 8.2 days in carbamazepine group (P = 0.88). In the whole group no adverse effect was seen due to the drugs. CONCLUSION: Carbamazepine and valproic acid are equally effective and safe drugs in the treatment of choreiform movements in Sydenham chorea.     

Did Gustav Mahler have Sydenham's chorea?

Sydenham's chorea (SC), a major manifestation of acute rheumatic fever (RF), is characterized by chorea and other motor and non-motor features. Among the latter are behavioral symptoms, including obsessive-compulsive disorder. Although SC is typically a self-limited condition, up to 50% of patients may evolve with persistent chorea. There is evidence that Gustav Mahler had a movement disorder, but its nature remains undetermined. There are witnesses describing him as having facial dyskinesia and a gait disorder consistent with chorea. His conducting performance was notorious for obsessive attention to details of the staging and musical production. Mahler was diagnosed with a valvulopathy in 1907 and died of subacute bacterial endocarditis in 1911. It is possible that the composer suffered from RF in childhood with carditis and SC, which may left him with valvulopathy, obsessive-compulsive disorder, and persistent chorea.     

Sydenham's chorea and seizures. Clinical and electroencephalographic studies

The hospital records of 28 children (mean age, 9.4 years) with typical Sydenham's chorea were reviewed. Nineteen of 28 patients had antistreptolysin O titers of greater than or equal to 200 Todd units. Other causes of chorea were excluded by appropriate laboratory and clinical follow-up studies. At the onset of the movement disorder, 17 of 28 patients had abnormal EEGs consisting of irregular posterior slowing in 15, sharp epileptic spikes in 5, and high-voltage sharp waves in 2. Two patients with spikes predominantly in the temporal lobe regions developed complex partial seizures. On follow-up evaluation, the EEGs returned to normal within one to four weeks. Seizures did not recur after therapy with anticonvulsants. Seizures have been reported only rarely in association with Sydenham's chorea. Our observation suggests that seizures may occur during chorea but may often be masked by frequent choreic movements and thus not recognized. The EEG changes and seizures were transient in our patients studied so far.     

Restricted unilateral Sydenham's chorea: reversible contralateral striatal hypermetabolism demonstrated on single photon emission computed tomographic scanning.

Sydenham's chorea results from group A streptococcus infection and subsequent generation of antineuronal antibodies directed at the caudate nucleus and putamen. Predominantly bilateral, in up to 30% of cases the chorea can be unilaterally restricted. Imaging studies, both structural (magnetic resonance imaging) and functional (positron emission tomography), in patients with bilateral Sydenham's chorea have suggested reversible striatal abnormalities. Two patients with unilateral Sydenham's chorea are presented. Computed tomographic and magnetic resonance imaging were normal in both. However, hexamethylpropylenamine oxime single photon emission tomographic (HMPAO SPECT) studies demonstrated hypermetabolism in the contralateral basal ganglia. Resolution of symptoms in one of the patients coincided with normalization of the SPECT scan. Thus, unilateral striatal hypermetabolism appears to underlie the contralateral chorea observed. A SPECT scan probably should be included in the work-up of new-onset chorea.     

Pediatric movement disorders: an update

PURPOSE OF REVIEW: Pediatric movement disorders the represent a broad range of disorders, the majority of which are intermittent and hyperkinetic. The goal of this review is to discuss recent findings in several under-recognized conditions (motor stereotypy disorder, restless legs syndrome, and infantile masturbation) as well as the area of autoimmune movement disorders [Sydenham's chorea and PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection)]. RECENT FINDINGS: Advances to be discussed include clarification of symptoms, diagnostic clues, epidemiology, pathogenesis, and treatment. SUMMARY: Significant progress has been made in the study of several paroxysmal movement disorders. Motor stereotypies can occur in typical children and persist over time. Infantile masturbation is often misdiagnosed for seizures or dystonia. Restless leg syndrome is a relatively common problem in children and established criteria are available. Advances have been made in the hallmark autoimmune disorder Sydenham's chorea, but PANDAS remains controversial.