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.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

Ictal SPECT in children with partial epilepsy due to focal cortical dysplasia

We studied the usefulness of ictal single-photon emission computed tomography in the presurgical evaluation of children with partial epilepsy resulting from focal cortical dysplasia. Fifteen children, age 1-18 years, were identified with partial epilepsy caused by focal cortical dysplasia (confirmed by histology) who underwent subtraction ictal single-photon emission computed tomography during presurgical evaluation. All children later underwent surgery at the Cleveland Clinic Epilepsy Center between 1996 and 2000. The findings of ictal single-photon emission computed tomography and brain positron emission tomography were classified as localized when "localizing and concordant" with the surgical resection site, nonconcordant when "localizing but not concordant" with the surgical resection, or nonlocalized when "no well-localized region of ictal hyperperfusion was observed on the difference image". In 15 patients, age 1.5-18 years (median age 8 years), epilepsy was classified as frontal in 7, posterior temporal/occipital in 3, temporal in 2, multilobar in 2, and parietal in 1. Of 15 patients, preoperative magnetic resonance imaging revealed focal cortical dysplasia in 11, positron emission tomography was localized in 9, and ictal single-photon emission computed tomography was localized in 8 patients. In 4 patients with normal magnetic resonance imaging but scalp electroencephalographic findings of partial epilepsy, ictal single-photon emission computed tomography and positron emission tomography were localized in 3 each. Fourteen patients were monitored for 6-39 months (mean 20 months). Six of 7 patients (85%) with localized ictal single-photon emission computed tomography compared with 4 of 7 (57%) with nonconcordant/nonlocalized ictal single-photon emission computed tomography had no seizures at follow-up. In 4 patients with normal magnetic resonance imaging, 3 patients with localized ictal single-photon emission computed tomography were free of seizures compared with 1 with nonconcordant ictal single-photon emission computed tomography who continued to have seizures. Ictal single-photon emission computed tomography is a useful adjunctive test in presurgical evaluation of children with refractory partial epilepsy due to focal cortical dysplasia, especially when brain magnetic resonance imaging is normal.     

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.     

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.     

PANDAS: current status and directions for research

The recognition of the five criteria for PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) by Swedo et al established a homogenous subgroup of children with childhood onset obsessive-compulsive disorder (OCD) and/or tic disorders. The five clinical characteristics that define the PANDAS subgroup are the presence of OCD and/or tic disorder, prepubertal age of onset, abrupt onset and relapsing-remitting symptom course, association with neurological abnormalities during exacerbations (adventitious movements or motoric hyperactivity), and a temporal association between symptom exacerbations and a Group-A beta-hemolytic streptococcal (GAS) infection. These five criteria have been used for the purpose of systematic research on the phenomenology and unique therapies for the PANDAS subgroup as well as studies of the pathophysiology of post-streptococcal OCD and tic disorders. The etiology of OCD and tics in the PANDAS subgroup is unknown, but is theorized to occur as a result of post-streptococcal autoimmunity in a manner similar to that of Sydenham's chorea. The working hypothesis for the pathophysiology begins with a GAS infection in a susceptible host that incites the production of antibodies to GAS that crossreact with the cellular components of the basal ganglia, particularly in the caudate nucleus and putamen. The obsessions, compulsions, tics, and other neuropsychiatric symptoms seen in these children are postulated to arise from an interaction of these antibodies with neurons of the basal ganglia.     

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.     

Advances in in vivo imaging of serotonergic neurons in neuropsychiatric disorders

Alterations of central serotonergic neurotransmission, particularly changes in the presynaptically located serotonin transporter (SERT) availability, are thought to be one of the major pathomechanisms of neuropsychiatric symptoms. Modern neuroimaging techniques such as single-photon emission computed tomography and positron emission tomography employ radiolabeled tracers, which bind to SERT, and thus, allow detection of cerebral SERT availability in vivo. We review SERT imaging studies in patients with depression, anxiety disorders, eating disorders and patients with neurological diseases. We furthermore elucidate the potential of SERT imaging techniques in estimating the effect of selective serotonin reuptake-inhibitors.     

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.     

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.     

Soluble adhesion molecules in Gilles de la Tourette's syndrome

To investigate the immune-mediated response in TS, and its relationship with streptococcal infection, we measured serum levels of soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin in patients with TS, compared to healthy and diseased controls. Soluble VCAM-1 and sE-selectin were significantly elevated in children and adults with TS, and sVCAM-1 was higher among anti-basal ganglia antibodies (ABGA)-positive adults with TS. No correlation of adhesion molecule levels to clinical severity or anti-streptococcal antibodies was observed. Children with Sydenham's chorea and paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) showed an increased level of sICAM-1, but not sVCAM-1 and sE-selectin. These results provide initial evidence for a role of adhesion molecules and systemic inflammation in TS, and support the hypothesis of an ongoing immune-mediated process in this condition.     

Adult acute disseminated encephalomyelitis associated with poststreptococcal infection.

Acute disseminated encephalomyelitis (ADEM) is a monophasic illness that is thought to develop from antigenic mimicry with antibodies having cross-reactivity to host epitopes in the nervous system. The disorder typically follows an exanthematous or recent viral infection. In contrast, complications from bacterial poststreptococcal infections more commonly give rise to disorders in the pediatric population including Sydenham's chorea, pediatric autoimmune neuropsychiatric disorders, and ADEM. We present the novel case of documented streptococcal pharyngitis and elevated antideoxyribonuclease B (ADNB) titers in an adult giving rise to ADEM. Furthermore, the absence of basal ganglia abnormalities on MRI and the degree of leukocytosis in the CSF distinguish the adult form of ADEM from childhood ADEM and adult viral demyelinating diseases.     

Functional Caudate Imaging in Symptomatic Huntington's Disease: Positron Emission Tomography Versus SinglePhoton Emission Computed Tomography

Functional neuroimaging with positron emission tomography previously demonstrated reduced caudate glucose metabolism in virtually all symptomatic patients with Huntington's disease (HD) Single-photon emission computed tomography studies of brain blood flow also have shown caudate abnormalities in patients with HD. The present study compared these two functional imaging modalities in 6 patients with HD who had been symptomatic for fewer than 5 years. All patients had significantly impaired caudate-thalamus and caudate-whole-slice glucose metabolism ratios as measured by positron emission tomography. However, only 3 had clearly abnormal caudate-thalamus activity ratios and 2 had clearly abnormal caudate-whole-slice ratios on single-photon emission computed tomography. These findings indicate that single-photon emission computed tomography imaging of caudate blood flow is a less sensitive indicator of caudate dysfunction in early HD than is positron emission tomography imaging of caudate glucose metabol1sm.     

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.