Q J Med 2003; 96: 183-191
© 2003 Association of Physicians
Review |
Autoimmunity and the basal ganglia: new insights into old diseases
From the Neurosciences Unit, Institute of Child Health, and the Neuroinflammation Unit, Institute of Neurology, London, UK
 |
Summary |
|---|
 Top Summary IntroductionClinical featuresPathogenesisTreatmentImplications for...ConclusionReferences |
|---|
Sydenham's chorea (SC) occurs weeks or months after Group A streptococcal infection, and is characterized by involuntary, purposeless movements of the limbs, in addition to behavioural alteration. There is a body of evidence which suggests that SC is an immune-mediated brain disorder with regional localization to the basal ganglia. Recent reports have suggested that the spectrum of post-streptococcal CNS disease is broader than chorea alone, and includes other hyperkinetic movement disorders (tics, dystonia and myoclonus). In addition, there are high rates of behavioural sequelae, particularly emotional disorders such as obsessive-compulsive disorder, anxiety and depression. These findings have lead to the hypothesis that similar immune-mediated basal ganglia processes may be operating in common neuropsychiatric disease such as tic disorders, Tourette syndrome and obsessive-compulsive disorder. This review analyses the historical aspects of post-streptococcal CNS disease, and the recent immunological studies which have addressed the hypothesis that common neuropsychiatric disorders may be secondary to basal ganglia autoimmunity.
|
Introduction |
|---|
|
TopSummaryIntroductionClinical featuresPathogenesisTreatmentImplications for...ConclusionReferences |
|---|
The term ‘basal ganglia’ refers to a collection of nuclei lying in the centre of the brain, and include the caudate and putamen (also termed the striatum), globus pallidus, subthalamus and substantia nigra. The basal ganglia nuclei contain neurones that receive and modify information from the cerebral cortex. Dysfunction of the basal ganglia results in extrapyramidal movements (chorea, hemiballismus, dystonia, tics and parkinsonism). In addition to control of movements, the basal ganglia have an important role in control of behaviour and emotion. For example, there is accumulating evidence that the pathogenesis of obsessive-compulsive disorder is linked to caudate nucleus dysfunction, resulting in functional abnormalities in cortico-striatal circuits.1
Sydenham's chorea (SC) was the first extrapyramidal movement disorder to be described. In 1686, Thomas Sydenham described a childhood syndrome characterized by sudden onset of rapid, involuntary and purposeless limb movements. In addition, he noted an alteration in behaviour and emotion. Initially, SC was thought to be a psychological response to stress or even hysteria. However by the 19th century, physicians noted a high incidence of ‘rheumatism’ in patients with chorea, and thereafter the association between rheumatic fever and SC was made.2 At the beginning of the 20th century, streptococcal organisms were being isolated from patients with rheumatic fever and chorea, and subsequent epidemiological studies confirmed the relationship between streptococcus, SC and rheumatic fever.3 However despite being recognized over 300 years ago, the disease remains enigmatic and poorly understood. During the second half of the 20th century, the incidence of SC significantly reduced in the West, although outbreaks of disease have been recorded in the US. Consequently, the majority of Western physicians would consider SC a historical disease, although it remains endemic in developing countries. In the 1980s, interest in SC was re-ignited by the re-emergence of sudden onset movement disorders and emotional disorders after streptococcal infections.4 However, unlike SC, the movement disorder phenotype was motor tics rather than chorea. As the clinical phenotype was similar to patients with ‘idiopathic’ tics and obsessive-compulsive disorder, this discovery renewed interest in Sydenham's chorea, which has become an autoimmune model for common movement and psychiatric disorders in children.5
I will review the clinical and pathological features of post-streptococcal CNS disease, and the recent studies attempting to identify whether basal ganglia autoimmunity may have a role in common movement and psychiatric conditions.
Although it would appear these syndromes occur predominantly in childhood, adult-onset disease has been described.6
|
Clinical features |
|---|
|
TopSummaryIntroductionClinical featuresPathogenesisTreatmentImplications for...ConclusionReferences |
|---|
Movement disorders (Table 1
)The best described of all movement disorders after beta haemolytic streptococcal infection remains chorea. Chorea is usually bilateral, although hemichorea does occur, albeit rarely. Perhaps it would not be surprising to learn that other movement disorders in addition to chorea may occur in post-streptococcal CNS disease. Indeed, basal ganglia disorders rarely conform to one extrapyramidal phenotype; for example in Huntington's disease, tics, dystonia and parkinsonism may occur, although chorea remains the most characteristic phenomenon.7,8 Similarly, motor tics have been well recognized in the context of ‘Sydenham's chorea’.9–11
|
In the 1980s, an outbreak of Group A streptococcal tonsillitis in Rhode Island was associated with a 10-fold increase in the incidence of motor tics (without chorea);4 the concept of post-streptococcal tics was born. Subsequent identification of further patients led to the development of a new acronym: PANDAS (paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections).12 In addition to tics, PANDAS patients had a high incidence of psychiatric disorders, particularly obsessive-compulsive disorder (OCD) (discussed later). The patients were clinically differentiated from ‘idiopathic’ tics and OCD by the temporal association with microbiologically-defined streptococcal throat infections. Furthermore, the patients often presented suddenly (rather than insidiously), and the mean age of onset of PANDAS patients was also younger than previously described tic and OCD cohorts.4,12 Given the high frequency of streptococcal infections in the community, two or more exacerbations associated with streptococcal infections were required for diagnosis of PANDAS.12 However, the concept of PANDAS remained controversial,13 and a reliable biological marker has become necessary to improve diagnostic sensitivity and specificity (discussed later). Other than motor tics and chorea, other extrapyramidal movements have been described shortly after streptococcal pharyngitis, including dystonia and myoclonus.14,15 We have also described a patient with post-streptococcal paroxysmal dystonic choreoathetosis (PDC); this patient had episodes of chorea and dystonia lasting a few hours with intervening normal periods, suggesting that streptococcus is one of the causes of secondary PDC.16 An important question that arises is why some patients present with chorea, while other patients present with tics, dystonia or myoclonus. Demographics have demonstrated that cohorts of Sydenham's chorea are predominantly female, whereas post-streptococcal tic cohorts are predominantly male.12,17 This suggests a possible influence of sex on phenotypic expression. Relapses of SC during pregnancy (chorea gravidarum) further emphasize the potential importance of sex hormones on movement disorder expression.18 It is also possible that the extrapyramidal phenotype depends upon the specific basal ganglia region involved. It has been proposed that specific regions of the basal ganglia are associated with certain extrapyramidal phenotypes; for example, hemiballismus and parkinsonism are associated with the subthalamus and substantia nigra pathology, respectively, although this statement over-simplifies the pathophysiology of movement disorders.19
Psychiatric disorders
The high incidence of emotional factors in Sydenham's chorea has been recognized for over a century, and was initially referred to as a ‘choreic temperament’. However, further evaluation of the psychiatric sequelae of Sydenham's chorea demonstrated emotional and disruptive behaviours were common accompaniments. A follow-up study showed high prevalence of emotional disorders (obsessive-compulsive disorder, anxiety, depression) and disruptive behaviours in 75% of patients.20 More importantly, this study demonstrated that the behavioural consequences often remained for decades after the resolution of childhood chorea.20 More recent examination of SC cohorts revealed a high incidence of obsessive-compulsive behaviours.21 These findings have come at a time when the pathogenesis of obsessive-compulsive disorder (OCD) has been linked to the basal ganglia (specifically caudate) and the cortico-striatal circuits.1 Furthermore, the incidence of OCD appeared to be increasingly common in children who had relapses of SC.22 Subsequent analysis of cohorts of SC demonstrated that psychiatric comorbidity was not limited to OCD, but included other emotional disorders such as generalized anxiety, separation anxiety and major depression.11 In addition, attention deficit hyperactivity disorder (ADHD) was significantly more prevalent compared to controls, suggesting that the spectrum of post-streptococcal psychiatric disorders is broader than previously thought.23 There had been a number of reports of schizophrenia as an outcome of SC,24 although recent literature and our experience have not repeated this observation.
The psychiatric morbidity of PANDAS is similar to (if not identical to), Sydenham's chorea. In the acute stages, there is typically a rapid alteration in behaviours and emotional lability.12 PANDAS was defined as post-streptococcal emergence of OCD and/or tics; however, analysis of 50 patients with PANDAS demonstrated a high incidence of other emotional disorders (major depression 36%, separation anxiety 20%), conduct disorders (oppositional defiant disorder 40%) and attention deficit hyperactivity disorder (40%).12
Other neurological features and outcome
The clinical outcomes would appear to be relatively specific to extrapyramidal movement and psychiatric disorders. Dysarthria and hypotonia are common accompaniments of chorea, and would be considered characteristic of SC.17 By contrast, dementia, seizures and visual impairments would be considered atypical. We have recently described 10 patients with a disseminated autoimmune encephalitis after streptococcal infections, where the clinical features were dystonia, encephalopathy and acute behavioural alteration, in association with inflammatory lesions predominantly of the basal ganglia.25 Although the predominant features were dystonia and behavioural alteration, pyramidal tract signs were also common in these patients, suggesting dissemination of disease beyond the basal ganglia may occasionally occur in post-streptococcal CNS syndromes.
It is most physicians' impression that SC is a benign self-limiting disorder. However, persistence of chorea over 2 years has been observed in 50% of a recent Brazilian cohort.26 When present, relapses of SC occur most commonly in the first year after onset, or during pregnancy (chorea gravidarum). It should be noted that persistent psychiatric sequealae are common, even after the apparent resolution of chorea.20 By definition, PANDAS has a relapsing remitting course with temporal association with further infections.12 Although streptococcal infections appear to be the initiators of disease, other infective triggers may be responsible for relapses.27,28 Although there are few longitudinal studies examining the natural history of disease, it is likely that the outcome of both SC and PANDAS is variable, varying from monophasic self-limiting disease, to a persistent relapsing remitting course for many decades (unpublished observation).
|
Pathogenesis |
|---|
|
TopSummaryIntroductionClinical featuresPathogenesisTreatmentImplications for...ConclusionReferences |
|---|
Pathology
As post-streptococcal CNS syndromes are rarely fatal, pathological examination has been limited toa few post-mortem studies. By virtue of their fatal nature, it is possible that these post-mortem descriptions may represent the more severe end of the spectrum. It is also possible that some of the early reports may have mistakenly included cases of unrecognized genetic or neurodegenerative disorders such as Huntington's disease or metabolic disease.
The most consistent finding is of an encephalitis, with inflammatory changes predominantly of the basal ganglia and to a lesser extent the cortex.29,30 The caudate and putamen were usually the most severely involved basal ganglia regions.29,30 Perivascular infiltration by lymphocytes was characteristic in these descriptions. Neuronal degeneration was occasionally observed, although it was argued that neuronal death may be atypical given the excellent outcome in a proportion of patients with SC.29 As previously mentioned, some studies have found conflicting findings; one case reported diffuse neuronal degeneration as the predominant feature.31
Imaging
Neuroimaging often provides insight into the localization of CNS disease, although is unlikely to provide detailed biological insight into pathogenesis. Imaging of the brain using conventional CT and MRI is commonly normal in post-streptococcal CNS disease.32,33 Occasionally, inflammatory changes have been described which are predominantly (but not exclusively) localized to the basal ganglia (Figure 1).14,25,34–37 Only rarely has enhancement after contrast been described, suggesting that disruption of the blood-brain barrier is not typical.34 More sophisticated techniques, including volumetric studies, have shown that the caudate and putamen are specifically enlarged during the acute phase of Sydenham's chorea and PANDAS.23,32,38 Furthermore, anecdotal evidence has shown that basal ganglia size correlates with the disease course; a longitudinal case study demonstrated striatal enlargement during acute presentation with normalization during remission.39 SPECT studies have shown hypermetabolism and increased glucose consumption in the basal ganglia.40–42 Furthermore, a case report of proton spectroscopy has shown reduction of n-acetyl aspartate in the striatum, which was interpreted as indicative of neuronal dysfunction or loss.35 Although the majority of imaging findings are reversible, occasionally irreversible striatal changes have been described suggesting permanent damage is possible.14,43,44 Although the majority of imaging studies have localized disease to the basal ganglia, imaging is rarely useful as a diagnostic tool alone, and is more commonly used to exclude other causes of movement disorders. The imaging studies also suggest that there is a spectrum of immune mediated brain pathology, ranging from mild swelling to gross irreversible inflammatory damage and cell death.
|
Anti-neuronal antibodies in post-streptococcal CNS syndromes
The immunopathogenesis of post-streptococcal CNS syndromes is incompletely understood. It is hypothesized that Group A streptococcal infection induces an immune response which cross-reacts with the brain. There is no evidence to suggest that streptococcal organisms directly enter the brain. The mediators of disease would therefore need to be immune components (or bacterial toxins) that are capable of entering the central nervous system and then mediating nervous tissue dysfunction or damage. Recent experiments have shown that activated lymphocytes or antibodies are capable of entering the CNS without disruption of the blood brain barrier.45 If lymphocytes recognize antigens in the CNS, immune activation may occur with consequent neural dysfunction or damage.
Most of the investigation to date has focussed on anti-neuronal antibodies as the possible mediators of disease. A functional antibody-mediated disease is considered more likely given the fact that a significant proportion of SC patients make a full recovery (in contrast to cytotoxic T-cell-mediated disease, where permanent damage would be anticipated). Experimental support for the antibody hypothesis was first demonstrated by Husby who described anti-neuronal antibodies using an immunofluorescent technique in 46% of Sydenham's chorea patients (n=30), compared to 14% of rheumatic fever (without chorea n=50), and only 1.8–4% of control subjects (n=203).46 The antibodies demonstrated a cytoplasmic pattern of binding to caudate and subthalamus neurones, with occasional weaker staining in the cortex and medulla. Furthermore, Husby demonstrated a potential correlation between antibody reactivity and the clinical status, with antibody disappearance on chorea remission. In addition, the antibodies were removed by pre-incubating with a preparation of isolated caudate neurones, but not cerebral cortex or mouse liver, supporting antibody specificity to caudate neurones.46 Two further studies have expanded upon these findings; both demonstrated antibodies reactive against basal ganglia neurones universally in acute SC (100%), although less commonly in the chronic or persistent stage;47–49 this phenomenon may be important when considering anti-neuronal antibodies as an autoimmune marker in cohorts of established neuropsychiatric disorders (discussed later). Although antibody assays using immunofluorescence were important in establishing a putative antibody hypothesis, Western immunoblotting studies by Church (using human basal ganglia as the autoantigen) have suggested that a conserved group of autoantigens are involved in auto-antibody binding.47 The auto-antigens have a molecular weights of 40, 45 and 60 kDa, and would appear to be restricted to, or enriched in, the basal ganglia.47 A further small study also proposed that a 45 kDa was found in SC, although only during the acute stage.50 Similar investigations in a PANDAS cohort found an increased incidence of anti-neuronal antibodies and positive streptococcal serology in patients with tics or choreiform movements.4 The immunofluorescence antibody binding pattern in these PANDAS patients was similar to SC. We have found similar anti-neuronal antibody findings in post-streptococcal autoimmune dystonia, and propose that the same auto-antigens are involved in all post-streptococcal CNS syndromes (chorea, tics, dystonia and autoimmune encephalitis).14,25,47 The identity of these antigens is currently unknown. The majority of studies have not found other auto-antibodies or anti-nuclear antibodies in SC or PANDAS,46 further suggesting that the immune response is relatively specific to basal ganglia antigens.
The presence of antibodies in serum does not necessarily infer pathogenicity. For example, antibodies could be produced as part of tissue damage. In order to demonstrate that a disorder is autoimmune, five criteria must be fulfilled:51(i) presence of auto-antibodies; (ii) presence of antibodies in target tissue; (iii) induction of disease in animal model by passive transfer of antibody; (iv) induction of disease in animal model by auto-antigen immunisation; and (v) improvement of clinical symptoms after removal of antibodies with plasma exchange.
There are two published positive studies describing disease induction in rats after PANDAS antibody infusion into rat striatum.52,53 Both describe stereotypical movements in the rats infused with PANDAS antibody but not with control antibody infusion. However, another study, published in abstract form, has not reproduced this finding.54
One controlled trial demonstrated benefit of plasma exchange and intravenous immunoglobulin in PANDAS compared to controls,55 although the numbers in each group were small (n=10 in each group). No similar immunomodulatory studies exist in SC, where the literature is limited to small retrospective studies suggesting the benefits of corticosteroid treatments.56 Therefore, although there is building evidence to support pathogenicity of the auto-antibodies (currently criteria 1,3 and 5 have been positively demonstrated), neither SC nor PANDAS can currently be considered as definite auto-antibody-mediated disorders.
The immune studies to date have almost completely focussed on anti-neuronal antibodies as the potential mediators of disease. However, alternative immune mechanisms are possible including cytotoxic T-lymphocyte attack, cytokine-mediated neuronal dysfunction and even superantigen-mediated immunity. A further unanswered question is why heart involvement (i.e. rheumatic carditis) seems to occur in SC, but not in PANDAS.
Streptococcus and brain epitope cross-reactivity
Although streptococcal organisms are the proposed mediators of SC and PANDAS, relatively little attention has focussed on why beta-haemolytic Streptococcus is capable of producing immune-mediated brain disease. The favoured hypothesis is that antibodies cross-react between streptococcal and brain epitopes (molecular mimicry). The surface M protein of Group A streptococci is considered the major virulence factor. Immunization of rats with M6 streptococcal proteins has been shown to induce cross-reactive anti-brain antibodies. Furthermore, synthetic epitopes of M6 protein sequences were capable of inhibiting anti-brain antibodies from a patient with SC.57 Husby's original experiments suggested that the antibodies against caudate neurones cross-reacted with epitopes of Group A streptococcal membranes.46 It would also appear that the antibody cross-reactivity is specific to certain strains of streptococcus.25,46,57 However appealing, definitive evidence for the molecular mimicry phenomenon does not yet exist.
Genetics and disease predisposition
The majority of people who suffer streptococcal pharyngitis (most of us at some stage!) suffer no apparent complications, whereas a minority incur significant CNS sequelae. Patients with SC have a higher incidence of rheumatic fever (RhF) and SC in first-degree family members, compared to the general population.58 This suggests that a genetic predisposition is important in addition to exposure to a virulent streptococcus organism. Likewise, the incidences of tics and OCD in first-degree relatives of children with PANDAS (39% and 26%, respectively) are significantly higher than in the general population, further supporting the importance of a genetic factor in disease evolution.59
The mechanism of this genetic predisposition is not certain; classical HLA class I and II profiles in SC do not appear to predict a genetic vulnerability.60 Instead, interest has focussed on a B-lymphocyte marker (D8/17) that is highly expressed in patients with rheumatic fever/SC compared to healthy controls and autoimmune controls (including post-streptococcal glomerulonephritis).61,62 This same marker is significantly more prevalent in PANDAS patients,63 supporting immunological similarity between SC, rheumatic fever and PANDAS (Table 2). Despite this intriguing finding, the function of this lymphocyte marker remains unknown.
|
|
Treatment |
|---|
|
TopSummaryIntroductionClinical featuresPathogenesisTreatmentImplications for...ConclusionReferences |
|---|
There are two potential treatment approaches to post-infectious autoimmune disorders: to prevent further exacerbating infections, or to modulate the autoimmune process. Antibiotic prophylaxis is an accepted treatment of RhF and SC, and should be continued throughout childhood.64 It should be noted that large studies were required to establish a benefit of penicillin prophylaxis in SC. Initial attempts to replicate these findings in PANDAS using a double-blind placebo-controlled trial were unsuccessful, although this may have been due to a failure to achieve acceptable levels of prophylaxis.65 A prospective study of antibiotic treatments for acute tonsillitis in PANDAS showed prompt improvements in obsessive-compulsive behaviours associated with antibiotic treatments, although this was an uncontrolled descriptive study.66
The only placebo-controlled trial examining the benefit of immunomodulation (plasma exchange and intravenous immunoglobulin) demonstrated improvements in the patients treated with active agents compared to patients treated with sham (saline) infusions. Importantly, the treatment improvements were maintained at one year.55 Interestingly, the same finding was not reproduced in OCD patients who did not have PANDAS, suggesting that the benefit of immune modulation is restricted to the PANDAS subgroup of neuropsychiatric disorders.67 Currently, immune treatments should not be given routinely to SC or PANDAS patients until further controlled trials confirm their benefit. Carbamazepine and sodium valproate have been proposed to be useful symptomatic treatments of SC, and are probably preferable to haloperidol, which can cause unacceptable side-effects.68
|
Implications for ‘idiopathic’ neuropsychiatric syndromes |
|---|
|
TopSummaryIntroductionClinical featuresPathogenesisTreatmentImplications for...ConclusionReferences |
|---|
Tic disorders, Tourette syndrome and obsessive-compulsive disorder are considered to be variable phenotypic expressions of the same brain disorder. Although pathophysiology is considered to be related to dysfunction of cortico-striatal circuits, the exact pathology is unknown.1 It is likely that a variety of processes can disrupt this circuit and result in these clinical phenotypes. The recognition of PANDAS has lead to speculation that a subgroup of ‘idiopathic’ tic disorders, Tourette syndrome (TS) and OCD have a (post-streptococcal) immune mediated pathophysiology. Using the biological markers previously described in the context of SC and PANDAS, researchers have attempted to address this important question.
Elevated streptococcal serology was present in a cohort of German TS and Italian tic disorders, compared to age-matched controls.69,70 One American TS study demonstrated a similar association with streptococcal serology,49 although two American TS studies found no such correlation.71,72
Anti-neuronal antibody findings in TS have been generally supportive of the autoimmune hypothesis in TS; two studies have demonstrated the presence of anti-basal ganglia antibodies in TS compared to control groups, and have proposed that a striatal epitope of molecular weight 60 kDa is representative of TS antibody repertoires (similar to the findings by Church47).71,73 Furthermore, the antigen is likely to be specific to (or enriched in) the caudate/putamen rather than globus pallidus or muscle.73 Use of a neuron-like neuroblastoma cell line did not reproduce these findings,72,73 suggesting that human basal ganglia should be used as the antigenic substrate in future assays. However, a further study suggested that, although anti-neuronal antibodies are more prevalent in TS patients, the antibody reactivity was different to SC, and no common antibody reactivity could be recognized.49 At present, it is difficult to know the exact proportion of TS who may have an autoimmune aetiology. Furthermore, due to the natural tendency for TS to wax and wane, longitudinal studies are required.
The D8/17 marker does not fluctuate with disease status, and therefore has potential benefits over anti-neuronal antibodies as markers of disease.62 Both studies measuring D8/17 in TS/tic/OCD cohorts have shown statistically elevated prevalence of this marker compared to control groups74,75 (Table 2
).
|
Conclusion |
|---|
|
TopSummaryIntroductionClinical featuresPathogenesisTreatmentImplications for...ConclusionReferences |
|---|
The published findings strongly suggest that SC and PANDAS are immune-mediated brain disorders with selective involvement of the basal ganglia, although at present neither condition fulfils all the criteria for definite auto-antibody mediated disorders. Intriguing early data suggest a similar process may be occurring in a subgroup of tic disorders, Tourette's syndrome and obsessive-compulsive disorder. Therefore, further epidemiological and experimental studies are required to examine the extent of the relationship between streptococcus, autoimmunity and common neuropsychiatric disorders. A recent epidemiological community study of 1596 children reported 339 with a history of tics, often associated with co-morbid OCD and ADHD.76 If the association with streptococcus is correct, collectively these disorders may prove to be the commonest form of autoimmune disease.
|
Acknowledgments |
|---|
RCD has a research fellowship awarded by Action Research and the Barnwood House Trust, UK. Thank you to Andrew Church, Isobel Heyman and John Beale for proof-reading the manuscript.
|
Notes |
|---|
Address correspondence to Dr R.C. Dale, [[AUTHOR: please provide mailing address]. e-mail: R.Dale{at}ion.ucl.ac.uk
|
References |
|---|
|
TopSummaryIntroductionClinical featuresPathogenesisTreatmentImplications for...ConclusionReferences |
|---|
1. Stein DJ. Obsessive-compulsive disorder. Lancet 2002; 360:397–405.[CrossRef][ISI][Medline]
2. Bouteille EM. Traite de la Choree, ou Danse de St. Guy. Paris, Vincard, 1810.
3. Ayoub EM, Wannamaker LW. Streptococcal antibody titers in Sydenham's chorea. Pediatrics 1966; 38:946–56.
4. Kiessling LS, Marcotte AC, Culpepper L. Antineuronal antibodies in movement disorders. Pediatrics 1993; 92:39–43.
5. Swedo SE. Sydenham's chorea. A model for childhood autoimmune neuropsychiatric disorders. JAMA 1994; 272:1788–91.[CrossRef][ISI][Medline]
6. Bodner SM, Morshed SA, Peterson BS. The question of PANDAS in adults. Biol Psychiatry 2001; 49:807–10.[CrossRef][ISI][Medline]
7. Jankovic J, Ashizawa T. Tourettism associated with Huntington's disease. Mov Disord 1995; 10:103–5.[CrossRef][ISI][Medline]
8. van Dijk JG, van der Velde EA, Roos RA, Bruyn GW. Juvenile Huntington disease. Hum Genet 1986; 73:235–9.[CrossRef][ISI][Medline]
9. Creak M, Guttman E. Chorea, tics, compulsive utterances. J Med Sci 1935; 81:834.
10. Kerbeshian J, Burd L, Pettit R. A possible post-streptococcal movement disorder with chorea and tics. Dev Med Child Neurol 1990; 32:642–4.[ISI][Medline]
11. Mercadante MT, Busatto GF, Lombroso PJ, Prado L, Rosario-Campos MC, do Valle R, Marques-Dias MJ, Kiss MH, Leckman JF, Miguel EC. The psychiatric symptoms of rheumatic fever. Am J Psychiatry 2000; 157:2036–8.
12. Swedo SE, Leonard HL, Garvey M, Mittleman B, Allen AJ, Perlmutter S, Lougee L, Dow S, Zamkoff J, Dubbert BK. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry 1998; 155:264–71.
13. Kurlan R. Tourette's syndrome and ‘PANDAS’: will the relation bear out? Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection. Neurology 1998; 50:1530–4.[Abstract]
14. Dale RC, Church AJ, Benton S, Surtees RA, Lees A, Thompson EJ, Giovannoni G, Neville BG. Post-streptococcal autoimmune dystonia with isolated bilateral striatal necrosis. Dev Med Child Neurol 2002; 44:485–9.[CrossRef][ISI][Medline]
15. DiFazio MP, Morales J, Davis R. Acute myoclonus secondary to group A beta-hemolytic streptococcus infection: a PANDAS variant. J Child Neurol 1998; 13:516–18.[ISI][Medline]
16. Dale RC, Church AJ, Surtees RA, Thompson EJ, Giovannoni G, Neville BG. Post-Streptococcal autoimmune neuropsychiatric disease presenting as paroxysmal dystonic choreoathetosis. Mov Disord 2002; 17:817–20.[CrossRef][ISI][Medline]
17. Cardoso F, Eduardo C, Silva AP, Mota CC. Chorea in fifty consecutive patients with rheumatic fever. Mov Disord 1997; 12:701–3.[CrossRef][ISI][Medline]
18. Cardoso F. Chorea gravidarum. Arch Neurol 2002; 59:868–70.
19. Albin RL, Young AB, Penney JB. The functional anatomy of basal ganglia disorders. Trends Neurosci 1989; 12:366–75.[CrossRef][ISI][Medline]
20. Freeman JM, Aron AM, Collard JE, MacKay MC. The emotional correlates of Sydenham's chorea. Pediatrics 1965; 35:42–9.
21. Swedo SE, Rapoport JL, Cheslow DL, Leonard HL, Ayoub EM, Hosier DM, Wald ER. High prevalence of obsessive-compulsive symptoms in patients with Sydenham's chorea. Am J Psychiatry 1989; 146:246–9.
22. Asbahr FR, Ramos RT, Negrao AB, Gentil V. Case series: increased vulnerability to obsessive-compulsive symptoms with repeated episodes of Sydenham chorea. J Am Acad Child Adolesc Psychiatry 1999; 38:1522–5.[CrossRef][ISI][Medline]
23. Peterson BS, Leckman JF, Tucker D, Scahill L, Staib L, Zhang H, King R, Cohen DJ, Gore JC, Lombroso P. Preliminary findings of antistreptococcal antibody titers and basal ganglia volumes in tic, obsessive-compulsive, and attention deficit/hyperactivity disorders. Arch Gen Psychiatry 2000; 57:364–72.
24. Moore DP. Neuropsychiatric aspects of Sydenham's chorea: a comprehensive review. J Clin Psychiatry 1996; 57:407–14.[ISI][Medline]
25. Dale RC, Church AJ, Cardoso F, Goddard E, Cox TC, Chong WK, Williams A, Klein NJ, Neville BG, Thompson EJ, Giovannoni G. Poststreptococcal acute disseminated encephalomyelitis with basal ganglia involvement and auto-reactive antibasal ganglia antibodies. Ann Neurol 2001; 50:588–95.[CrossRef][ISI][Medline]
26. Cardoso F, Vargas AP, Oliveira LD, Guerra AA, Amaral SV. Persistent Sydenham's chorea. Mov Disord 1999; 14:805–7.[CrossRef][ISI][Medline]
27. Allen AJ, Leonard HL, Swedo SE. Case study: a new infection-triggered, autoimmune subtype of pediatric OCD and Tourette's syndrome. J Am Acad Child Adolesc Psychiatry 1995; 34:307–11.[CrossRef][ISI][Medline]
28. Berrios X, Quesney F, Morales A, Blazquez J, Bisno AL. Are all recurrences of ‘pure’ Sydenham chorea true recurrences of acute rheumatic fever? J Pediatr 1985; 107:867–72.[CrossRef][ISI][Medline]
29. Greenfield JG, Wolfsohn JM. The pathology of Sydenham's chorea. Lancet 1922; 2:603–6.
30. Marie P, Tretiakoff C. Examen histologique des centres nerveux dans un cas de choree aigue de Sydenham. Rev Neurol 1920; 36:428–38.
31. Colony HS, Malamud N. Sydenham's chorea. A clinicopathologic study. Neurology 1956; 6:672–6.
32. Giedd JN, Rapoport JL, Kruesi MJ, Parker C, Schapiro MB, Allen AJ, Leonard HL, Kaysen D, Dickstein DP, Marsh WL, et al. Sydenham's chorea: magnetic resonance imaging of the basal ganglia. Neurology 1995; 45:2199–202.
33. Swedo SE, Leonard HL, Schapiro MB, Casey BJ, Mannheim GB, Lenane MC, Rettew DC. Sydenham's chorea: physical and psychological symptoms of St Vitus dance. Pediatrics 1993; 91:706–13.
34. Kienzle GD, Breger RK, Chun RW, Zupanc ML, Sackett JF. Sydenham chorea: MR manifestations in two cases. Am J Neuroradiol 1991; 12:73–6.[ISI][Medline]
35. Castillo M, Kwock L, Arbelaez A. Sydenham's chorea: MRI and proton spectroscopy. Neuroradiology 1999; 41:943–5.[CrossRef][ISI][Medline]
36. Traill Z, Pike M, Byrne J. Sydenham's chorea: a case showing reversible striatal abnormalities on CT and MRI. Dev Med Child Neurol 1995; 37:270–3.[ISI][Medline]
37. Robertson W, Smith C. Sydenham's chorea in the age of MRI: a case report and review. Pediatr Neurol 2002; 27:65.[CrossRef][ISI][Medline]
38. Giedd JN, Rapoport JL, Garvey MA, Perlmutter S, Swedo SE. MRI assessment of children with obsessive-compulsive disorder or tics associated with streptococcal infection. Am J Psychiatry 2000; 157:281–3.
39. Giedd JN, Rapoport JL, Leonard HL, Richter D, Swedo SE. Case study: acute basal ganglia enlargement and obsessive-compulsive symptoms in an adolescent boy. J Am Acad Child Adolesc Psychiatry 1996; 35:913–15.[CrossRef][ISI][Medline]
40. Weindl A, Kuwert T, Leenders KL, Poremba M, Grafin von Einsiedel H, Antonini A, Herzog H, Scholz D, Feinendegen LE, Conrad B. Increased striatal glucose consumption in Sydenham's chorea. Mov Disord 1993; 8:437–44.[CrossRef][ISI][Medline]
41. Goldman S, Amrom D, Szliwowski HB, Detemmerman D, Goldman S, Bidaut LM, Stanus E, Luxen A. Reversible striatal hypermetabolism in a case of Sydenham's chorea. Mov Disord 1993; 8:355–8.[CrossRef][ISI][Medline]
42. Lee PH, Nam HS, Lee KY, Lee BI, Lee JD. Serial brain SPECT images in a case of Sydenham chorea. Arch Neurol 1999; 56:237–40.
43. Emery ES, Vieco PT. Sydenham Chorea: magnetic resonance imaging reveals permanent basal ganglia injury. Neurology 1997; 48:531–3.
44. Ikuta N, Hirata M, Sasabe F, Negoro K, Morimatsu M. High-signal basal ganglia on T1-weighted images in a patient with Sydenham's chorea. Neuroradiology 1998; 40:659–61.[CrossRef][ISI][Medline]
45. Knopf PM, Harling-Berg CJ, Cserr HF, Basu D, Sirulnick EJ, Nolan SC, Park JT, Keir G, Thompson EJ, Hickey WF. Antigen-dependent intrathecal antibody synthesis in the normal rat brain: tissue entry and local retention of antigen-specific B cells. J Immunol 1998; 161:692–701.
46. Husby G, van de Rijn I, Zabriskie JB, Abdin ZH, Williams RC Jr. Antibodies reacting with cytoplasm of subthalamic and caudate nuclei neurons in chorea and acute rheumatic fever. J Exp Med 1976; 144:1094–110.
47. Church AJ, Cardoso F, Dale RC, Lees AJ, Thompson EJ, Giovannoni G. Anti-basal ganglia antibodies in acute and persistent Sydenham's chorea. Neurology 2002; 59:227–31.
48. Kotby AA, El Badawy N, El Sokkary S, Moawad H, El Shawarby M. Antineuronal antibodies in rheumatic chorea. Clin Diagn Lab Immunol 1998; 5:836–9.
49. Morshed SA, Parveen S, Leckman JF, Mercadante MT, Bittencourt Kiss MH, Miguel EC, Arman A, Yazgan Y, Fujii T, Paul S, Peterson BS, Zhang H, King RA, Scahill L, Lombroso PJ. Antibodies against neural, nuclear, cytoskeletal, and streptococcal epitopes in children and adults with Tourette's syndrome, Sydenham's chorea, and autoimmune disorders. Biol Psychiatry 2001; 50:566–77.[CrossRef][ISI][Medline]
50. Frucht S, Zabriskie J, Trifiletti RR. Immunoblot characterization of antineuronal antibody targets in Sydenham's chorea. Ann Neurol 1997; 42:533 (abstract).
51. Archelos JJ, Hartung HP. Pathogenetic role of autoantibodies in neurological diseases. Trends Neurosci 2000; 23:317–27.[CrossRef][ISI][Medline]
52. Taylor JR, Morshed SA, Parveen S, Mercadante MT, Scahill L, Peterson BS, King RA, Leckman JF, Lombroso PJ. An animal model of Tourette's syndrome. Am J Psychiatry 2002; 159:657–60.
53. Hallett JJ, Harling-Berg CJ, Knopf PM, Stopa EG, Kiessling LS. Anti-striatal antibodies in Tourette syndrome cause neuronal dysfunction. J Neuroimmunol 2000; 111:195–202.[CrossRef][ISI][Medline]
54. Loiselle CR, Moran TH, Swedo SE, Singer HS. Investigations of immune mechanisms in children with PANDAS and Tourette syndrome: microinfusion of sera into rodent striatum. Neurology 2002; 58(Suppl.3): A371 (abstract).
55. Perlmutter SJ, Leitman SF, Garvey MA, Hamburger S, Feldman E, Leonard HL, Swedo SE. Therapeutic plasma exchange and intravenous immunoglobulin for obsessive-compulsive disorder and tic disorders in childhood. Lancet 1999; 354:1153–8.[CrossRef][ISI][Medline]
56. Green LN. Corticosteroids in the treatment of Sydenham's chorea. Arch Neurol 1978; 35:53–4.[Abstract]
57. Bronze MS, Dale JB. Epitopes of streptococcal M proteins that evoke antibodies that cross-react with human brain. J Immunol 1993; 151:2820–8.[Abstract]
58. Nausieda PA, Grossman BJ, Koller WC, Weiner WJ, Klawans HL. Sydenham chorea: an update. Neurology 1980; 30:331–4.
59. Lougee L, Perlmutter SJ, Nicolson R, Garvey MA, Swedo SE. Psychiatric disorders in first-degree relatives of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). J Am Acad Child Adolesc Psychiatry 2000; 39:1120–6.[CrossRef][ISI][Medline]
60. Donadi EA, Smith AG, Louzada-Junior P, Voltarelli JC, Nepom GT. HLA class I and class II profiles of patients presenting with Sydenham's chorea. J Neurol 2000; 247:122–8.[ISI][Medline]
61. Gibofsky A, Khanna A, Suh E, Zabriskie JB. The genetics of rheumatic fever: relationship to streptococcal infection and autoimmune disease. J Rheumatol 1991; 30(Suppl.):1–5.
62. Khanna AK, Buskirk DR, Williams RC Jr, Gibofsky A, Crow MK, Menon A, Fotino M, Reid HM, Poon-King T, Rubinstein P, et al. Presence of a non-HLA B cell antigen in rheumatic fever patients and their families as defined by a monoclonal antibody. J Clin Invest 1989; 83:1710–16.[ISI][Medline]
63. Swedo SE, Leonard HL, Mittleman BB, Allen AJ, Rapoport JL, Dow SP, Kanter ME, Chapman F, Zabriskie J. Identification of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections by a marker associated with rheumatic fever. Am J Psychiatry 1997; 154:110–12.[Abstract]
64. Dajani AS, Bisno AL, Chung KJ, Durack DT, Gerber MA, Kaplan EL, Millard HD, Randolph MF, Shulman ST, Watanakunakorn C. Prevention of rheumatic fever: a statement for health professionals by the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease of the Council on Cardiovascular Disease in the young, the American Heart Association. Pediatr Infect Dis J 1989; 8:263–6.[ISI][Medline]
65. Garvey MA, Perlmutter SJ, Allen AJ, Hamburger S, Lougee L, Leonard HL, Witowski ME, Dubbert B, Swedo SE. A pilot study of penicillin prophylaxis for neuropsychiatric exacerbations triggered by streptococcal infections. Biol Psychiatry 1999; 45:1564–71.[CrossRef][ISI][Medline]
66. Murphy ML, Pichichero ME. Prospective identification and treatment of children with pediatric autoimmune neuropsychiatric disorder associated with group A streptococcal infection (PANDAS). Arch Pediatr Adolesc Med 2002; 156:356–61.
67. Nicolson R, Swedo SE, Lenane M, Bedwell J, Wudarsky M, Gochman P, Hamburger SD, Rapoport JL. An open trial of plasma exchange in childhood-onset obsessive-compulsive disorder without poststreptococcal exacerbations. J Am Acad Child Adolesc Psychiatry 2000; 39:1313–15.[CrossRef][ISI][Medline]
68. Pena J, Mora E, Cardozo J, Molina O, Montiel C. Comparison of the efficacy of carbamazepine, haloperidol and valproic acid in the treatment of children with Sydenham's chorea: clinical follow-up of 18 patients. Arq Neuropsiquiatr 2002; 60(2-B):374–7.[Medline]
69. Muller N, Riedel M, Straube A, Gunther W, Wilske B. Increased anti-streptococcal antibodies in patients with Tourette's syndrome. Psychiatry Res 2000; 94:43–9.[CrossRef][ISI][Medline]
70. Cardona F, Orefici G. Group A streptococcal infections and tic disorders in an Italian pediatric population. J Pediatr 2001; 138:71–5.[CrossRef][ISI][Medline]
71. Singer HS, Giuliano JD, Hansen BH, Hallett JJ, Laurino JP, Benson M, Kiessling LS. Antibodies against human putamen in children with Tourette syndrome. Neurology 1998; 50:1618–24.[Abstract]
72. Singer HS, Giuliano JD, Hansen BH, Hallett JJ, Laurino JP, Benson M, Kiessling LS. Antibodies against a neuron-like (HTB-10 neuroblastoma) cell in children with Tourette syndrome. Biol Psychiatry 1999; 46:775–80.[CrossRef][ISI][Medline]
73. Wendlandt JT, Grus FH, Hansen BH, Singer HS. Striatal antibodies in children with Tourette's syndrome: multivariate discriminant analysis of IgG repertoires. J Neuroimmunol 2001; 119:106–13.[CrossRef][ISI][Medline]
74. Murphy TK, Goodman WK, Fudge MW, Williams RC Jr, Ayoub EM, Dalal M, Lewis MH, Zabriskie JB. B lymphocyte antigen D8/17: a peripheral marker for childhood-onset obsessive-compulsive disorder and Tourette's syndrome? Am J Psychiatry 1997; 154:402–7.[Abstract]
75. Hoekstra PJ, Bijzet J, Limburg PC, Steenhuis MP, Troost PW, Oosterhoff MD, Korf J, Kallenberg CG, Minderaa RB. Elevated D8/17 expression on B lymphocytes, a marker of rheumatic fever, measured with flow cytometry in tic disorder patients. Am J Psychiatry 2001; 158:605–10.
76. Kurlan R, Como PG, Miller B, Palumbo D, Deeley C, Andresen EM, Eapen S, McDermott MP. The behavioral spectrum of tic disorders: a community-based study. Neurology 2002; 59:414–20.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D Martino, A Tanner, G Defazio, A J Church, K P Bhatia, G Giovannoni, and R C Dale Tracing Sydenham's chorea: historical documents from a British paediatric hospital Arch. Dis. Child., May 1, 2005; 90(5): 507 - 511. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||