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.     

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.     

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.     

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.     

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.     

Sydenham's chorea, and its complications affecting the nervous system

The well-known symptoms of rheumatic fever and Sydenham's chorea are briefly discussed. Then the associated psychiatric and neurological disorders are considered, especially the obsessive-compulsive and the attention deficit hyperactivity disorders; all linked to previous haemolytic streptococcal infections. Dystonic syndromes, and acute disseminated encephalopathies, also show such links; and may be part of the clinical spectrum of the post-infectious streptococcal illnesses. The causes of Sydenham's chorea are considered, especially an immune reactivity against the basal ganglia, supported by the finding of antibodies reactive against the neurons of the caudate nucleus. The resulting imbalance between dopaminergic and cholinergic systems may cause the involuntary choreiform movements, and account for the beneficial effects of certain drugs. The differential diagnosis of Sydenham's chorea is discussed, and the role of tests such as special imaging techniques. The possible treatments include prophylaxis with penicillin and the use of drugs like sodium valproate, carbamazapine and haloperidol. Immune therapy occupies a special role in selected patients, There is still a need for research into the links between these conditions.     

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.     

Cross-cutting issues and future directions for the OCD spectrum

The research planning agenda for DSM-V examined possible similarities in phenomenology, comorbidity, familial and genetic features, brain circuitry, and treatment response between obsessive-compulsive disorder (OCD) and several related disorders that are characterized by repetitive thoughts or behaviors. Such data support a re-examination of the DSM-IV-TR classification of OCD and the anxiety disorders, with possible inclusion of a group of obsessive-compulsive spectrum disorders (OCSDs) in DSM-V. Various disorders were systematically examined for inclusion in such a grouping, and later a smaller number were determined to meet threshold criteria for inclusion in the OCSDs. The disorders that were originally examined included OCD, obsessive-compulsive personality disorder (OCPD), Tourette's syndrome (TS) and other tic disorders, Sydenham's chorea, Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS), trichotillomania (TTM), body dysmorphic disorder (BDD), autism, eating disorders, Huntington's and Parkinson's disease, impulse control disorders, as well as substance and behavioral addictions. Certain disorders such as BDD, OCPD, TS, and TTM share many commonalities with OCD in phenomenology, comorbidity, familial and genetic features, brain circuitry, and treatment response. Other disorders, such as the impulse control disorders (ICDs) share some common features with OCD, but also differ in many ways as well. The articles presented in this issue of Psychiatry Research are a result of this international collaboration, which examined diagnostic and classification issues of OCSDs for DSM-V in a conference titled “The Future of Psychiatric Diagnosis: Refining the Research Agenda: Obsessive-Compulsive Behavior Spectrum” held in June 2006 at the American Psychiatric Association's headquarters in Arlington, VA.     

Cause and course in a series of patients with sporadic chorea

OBJECTIVE: To identify correlations between clinical and neuroimaging features in sporadic chorea and to explicate the evolution of choreas of differing aetiologies. METHODS: We analysed the clinical and neuroimaging data of 51 consecutive cases (17 males, 34 females; age 16-95 years) of sporadic chorea admitted to the neurology departments of two general hospitals from January 1994 to December 1999, and two neurological institutes from January 1997. Six months later the patients were reassessed clinically and those still with chorea (20 cases) were asked to undergo the genetic tests for Huntington's disease and dentatorubropallidoluysian atrophy. RESULTS: There were 9 cases of focal dyskinesias, 18 of hemichorea, and 24 of generalised chorea; onset was acute in 17, subacute in 27, and insidious in seven. Analysis permitted classification as follows: vascular-related (21 cases); vasculitis (1 case); hypoxia (2 cases); drug-induced (7 cases); AIDS-related (5 cases), borreliosis (1 case); Sydenham's chorea (1 case); hyperglycaemia (2 cases); hyponatraemia (2 cases); Huntington's disease (HD) (5 cases) and acanthocytosis (1 case). In 3 patients neither etiological factors nor neuroradiological alterations were found. CONCLUSIONS: Although a convincing concordance between choreic signs and neuroradiological findings was possible in 4 patients only, it was possible to assign an aetiology in most cases with vascular related causes the most frequent and metabolic factors often participating. Huntington's disease is not unusual as a cause of sporadic choreas. HIV infection is an emerging cause of chorea and AIDS-related disease should be considered in young patients presenting without a family history of movement disorders. We emphasize the importance of follow-up to identify persistent chorea for which genetic testing is mandatory.     

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.     

Bilateral globus pallidus lesions in a patient with Tourette syndrome and related disorders.

BACKGROUND: The neuroanatomic and pathologic basis of Tourette's syndrome or related disorders such as obsessive-compulsive disorder and attention deficit-hyperactivity disorder remains unknown. Although a substantial body of neuroimaging and other data implicate basal ganglia and some point out specifically the globus pallidus in the etiopathogenesis of these three related disorders, no clear or pathologically significant isolated lesions restricted to this region have yet been demonstrated, with the exception of obsessive-compulsive disorder. METHODS: A seventeen-year-old male case of Tourette syndrome with comorbid obsessive-compulsive disorder, attention deficit-hyperactivity disorder, stuttering and gait disturbance, who had negative family history is presented. RESULTS: The patient has failed to respond to drug treatment and his MRI scan revealed bilateral and symmetrical globus pallidus lesions with specific "tiger's eye" appearance of unknown etiology. CONCLUSIONS: Well-localized lesions in the globus pallidus support growing data suggesting the involvement of this brain region in Tourette syndrome and related disorders.     

Autoimmune mechanisms in movement disorders

A number of disorders, including childhood-onset obsessive compulsive disorder (OCD) and Gilles de la Tourette's syndrome (TS), are known to be neurobiological in nature. Both TS and OCD are neuropsychiatric diagnoses that involve congitive and perceptual dysfunction in addition to motor and psychiatric manifestations. The association of the B-cell marker with both Sydenham's chorea and a group of neuropsychiatric disorders, such as OCD, tics, and TS, has been useful as a marker in these diseases. This evidence, coupled with the recent finding of anti-brain antibodies in the sera of these patients, raises a number of interesting questions concerning the pathological mechanisms involved in these diseases. Thus, further molecular characterization of the brain and streptococcal antigens will be crucial to our understanding of the neurophysiological processes involved in these disorders.     

Sporadic choreas: analysis of a general hospital series

The incidence of sporadic chorea among general hospital admissions is unknown, and the relation of clinical manifestations and etiological factors to neuroimaging findings has been little investigated in this condition. We reviewed the 7,829 cases admitted to the neurology departments of two general hospitals over 3.25 years and identified 23 (8 male and 15 female) cases of apparently sporadic chorea. Analysis of the records of these patients permitted etiological classification as follows: drug-induced chorea (5 patients), vascular chorea (6 patients), chorea-vasculitis (1 patient), Sydenham's chorea (1 patient), AIDS-related chorea (5 patients) and in 4 patients neither etiological factors nor neuroradiological alterations were found. Finally in 1 patient, the genetic test for Huntington's disease was positive. Thirteen patients had pathological neuroimaging findings; however, in only 3 were basal ganglia lesions considered to be the cause of the chorea. We conclude that sporadic chorea is not rare among neurological department admissions (we found 2.94 cases per 1,000 admissions) and only in a minority of cases is the symptomatology attributable to gross basal ganglia lesions; HIV infection is an emerging cause of 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.     

Obsessive-compulsive disorder in Huntington's disease.

Two patients with Huntington's disease (HD) and obsessive-compulsive disorder (OCD) are reported. The OCD was manifested by repetitive, stereotyped, complex, egodystonic behaviors that were disabling. These cases and other neurological syndromes with OCD (Gilles de la Tourette syndrome, neuroacanthocytosis, postencephalitic parkinsonism, caudate infarction, carbon monoxide poisoning, manganese intoxication, anoxia, progressive supranuclear palsy, Sydenham's chorea, and frontal lobe lesions) indicate that the frontal lobe, caudate nucleus, and globus pallidus are members of a complex circuit that plays a key role in mediating the symptoms of OCD. Evidence of excitatory subcortical output to cortex is shared by many neurological disorders manifesting OCD.     

Huntington’s disease and other choreas

Chorea can have many causes, some hereditary and many sporadic in nature. The archetypal hereditary cause of chorea is Huntington’s disease (HD). However, this condition often manifests as a mixed movement disorder, and some individuals with the Westphal variant may not display chorea at all. Moreover, since gene-specific testing has become available, we now know that in many cases of HD, particularly those with late onset, a positive family history may be lacking. In addition, dentatorubro-pallidoluysian atrophy (DRPLA), another dominantly inherited CAG repeat disease, can produce a similar clinical picture. In both conditions, the phenotype may vary according to repeat length, and anticipation and excess of paternal inheritance in younger-onset cases with longer repeat lengths are seen. Neuroacanthocytosis is probably genetically heterogenous, and many instances of “benign hereditary chorea” have been caused by other conditions. If it exists at all, this disorder is exceedingly rare. The principal causes of sporadic chorea include drugs, pregnancy, vascular disease, thyrotoxicosis, systemic lupus erythematosus (SLE) and the lupus anticoagulant syndrome, polycythaemia rubra vera, AIDS and both initial and recurrent Sydenham’s chorea. The symptomatic treatment of chorea is unsatisfactory and, at least in HD, neuropsychiatric disturbance may be much more important for the family. Potential disease-modifying treatments such as anti-excitotoxins, antioxidants, free radical scavengers and neuronal grafting are now being explored in this condition. Received: 27 February 1998 Accepted: 28 March 1998     

Obsessive-compulsive disorder due to neuroacanthocytosis treated with citalopram. A case report

Neuroacanthocytois is a rare hereditary disease, which causes a degeneration of the striatum. Patients develop a choreatic movement disorder and also complex psychiatric symptoms, such as psychosis or Tourette's syndrome. We report a case of obsessive-compulsive disorder due to neuroacanthocytosis. The striatum plays an important role in the pathophysiology of obsessive-compulsive disorder. In Huntington's disease we also find obsessive-compulsive disorders, due to impairment of the fronto-striatal loop. Encouraged by similar pathophysiology and promising reports of selective serotonin reuptake inhibitors in this disease, we started a treatment with citalopram to which the patient responded very well.     

The question of PANDAS in adults.

BACKGROUND: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are a well-defined cause of obsessive-compulsive disorder in children. However, they have not been described or fully investigated in adults newly diagnosed with obsessive-compulsive disorder. METHODS: We describe an adult with onset of obsessive-compulsive disorder at 25 years of age after a severe antibiotic-responsive pharyngitis. He was evaluated with multiple psychiatric rating scales for obsessive-compulsive disorder and Tourette's syndrome, as well as with serologic assays and radiologic studies. RESULTS: In all respects except age our patient fulfilled established criteria for PANDAS. Assays for antibodies to group A beta-hematolytic streptococci, serum D8,17 lymphocytes, antistriatal (neuronal) antibodies, and anticytoskeletal antibodies all supported the hypothesis that a poststreptococcal process was active. Magnetic resonance imaging was abnormal and is described. CONCLUSIONS: The findings suggest that this patient's illness is similar to PANDAS in presentation and that poststreptococcal disease may result in adult-onset obsessive-compulsive disorder.     

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.