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.     

Sydenham's chorea and psychopathology

Sydenham's chorea is a movement disorder seen in rheumatic fever with basal ganglia pathology. This disorder has been associated with an increased frequency of psychopathology in both the acute choreiform stage and later in life. We conducted a prospective study of 29 subjects with Sydenham's chorea and 29 age- and sex-matched controls. The total number of psychiatric symptoms 10 years after the initial contact was much greater in the study group than in controls (p less than 0.001). Similarly, schizophrenia was more common in the study group compared to controls (p less than 0.01). Possible neuropathological associations and treatment are discussed.     

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

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

Brain magnetic resonance spectroscopy in Sydenham's chorea and ADHD

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

A possible association of recurrent streptococcal infections and acute onset of obsessive-compulsive disorder

Rheumatic fever is an immunologically mediated disease that follows infection by group A beta-hemolytic Streptococcus (GABHS). In rheumatic fever, antibodies generated against GABHS cross-react with the heart, joints, skin, and other sites, inducing an inflammatory, multisystem disease. Brain tissue-specific antibodies have been demonstrated in a subset of children with Sydenham chorea (a component of the Jones criteria for the diagnosis of rheumatic fever), and most Sydenham chorea patients manifest obsessive-compulsive symptoms very similar to those in traditional obsessive-compulsive disorder. The parallels drawn from the paradigm of Sydenham's chorea to Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) is an area of active controversy. Newly emerging information on the role of GABHS superantigens in the pathogenesis of rheumatic fever is of particular interest. In this article, we review the microbial characteristics of GABHS and the subsequent immune responses to GABHS as a possible etiology of PANDAS.     

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.     

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.     

Obsessive compulsive behavior, hyperactivity, and attention deficit disorder in Sydenham chorea

The authors investigated obsessive-compulsive behavior, obsessive-compulsive disorder (OCD), and attention deficit and hyperactivity disorder (ADHD) in 50 healthy subjects, 50 patients with rheumatic fever without chorea, and 56 patients with Sydenham chorea. Obsessive-compulsive behavior, OCD, and ADHD were more frequent in the Sydenham chorea group (19%, 23.2%, 30.4%) than in the healthy subjects (11%, 4%, 8%) and in the rheumatic fever without chorea group (14%, 6%, 8%). ADHD was more common in persistent Sydenham chorea.     

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.     

Corticosteroid treatment in patients with Sydenham's chorea

Sydenham's chorea occurs in approximately 10% of acute rheumatic fever and is one of its major manifestations. The disease may last for weeks or months, with a high risk of recurrence; usually only supportive treatment is recommended. This report describes five children diagnosed with Sydenham's chorea and treated with a short course of corticosteroids. Marked improvement of the involuntary movements was observed within 24-48 hours, with complete resolution within 7-12 days after commencement of treatment; there were no relapses. Larger, possibly comparative studies are necessary, but in the meantime treatment with corticosteroids in patients with Sydenham's chorea should be considered.     

Infection-triggered anorexia nervosa in children: clinical description of four cases

BACKGROUND: Anorexia nervosa (AN) is a serious illness with no definitive treatment. Clinical and research evidence led to the hypothesis that some children with AN may have a pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS), similar in pathogenesis to other hypothesized PANDAS disorders. METHODS: Four youngsters (ages, 11-15 years) with PANDAS AN were treated with an open trial of antibiotics, in addition to conventional treatment. They were evaluated for eating disorder and obsessive-compulsive symptoms, and for weight gain. Evidence of streptococcal infection came from clinical evaluation, throat cultures, and two serological tests: anti-deoxyribonuclease B (anti-DNase B) and anti-streptolysin O (ASO) titers. The "rheumatic" marker D8/17 was also measured. This B-cell alloantigen is associated, in several publications, with poststreptococcal autoimmunity: Rheumatic fever (RF), Sydenham's chorea (SC), and possibly PANDAS obsessive compulsive disorder (OCD) and tic disorders. RESULTS: There was clinical evidence of possible antecedent streptococcal infection in all four patients, two of whom had comorbid OCD, with possible infection-triggered AN. All four had the rheumatic marker: A percentage of D8/17-positive B cells of 28-38%, with a mean of 33% (12% or more is considered positive for the marker). The patients responded to conventional treatment plus antibiotics with weight restoration and decreased eating disorder and obsessive-compulsive symptoms. Three needed to gain weight and did so. CONCLUSIONS: There may be a link between infectious disease and some cases of AN, which raises the possibility of new treatment.     

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.     

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.     

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

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

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.     

Did Gustav Mahler have Sydenham's chorea?

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

Sydenham's chorea, and 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.     

A double-blind comparison of desipramine and placebo in children and adolescents with chronic tic disorder and comorbid attention-deficit/hyperactivity disorder

BACKGROUND: Currently, there is no consensus on the best therapeutic approach to chronic tic disorders and comorbid attention-deficit/hyperactivity disorder (ADHD). To address this issue, we evaluated the tolerability and efficacy of the noradrenergic tricyclic antidepressant desipramine hydrochloride in the treatment of children and adolescents with chronic tic disorders and comorbid ADHD. METHODS: Forty-one children and adolescents with chronic tic disorders, including Tourette disorder and comorbid ADHD, were studied in a 6-week, double-blind, placebo-controlled, parallel trial. Desipramine was titrated weekly up to 3.5 mg/kg per day. We rated ADHD and tic symptoms weekly and monitored adverse effects, laboratory findings, and cardiovascular parameters. RESULTS: Treatment with desipramine (mean total daily dose, 3.4 mg/kg per day) was well tolerated without meaningful adverse effects. Desipramine significantly reduced core symptoms of ADHD (ADHD Rating Scale; 42% decrease from baseline relative to placebo, P<.001), with equal response in inattentive symptoms and hyperactive/impulsive symptoms (P<.001 for both). The ADHD response rate was robust (71% vs 0%; desipramine vs placebo, P<.001). Likewise, desipramine significantly reduced tic symptoms (Yale Global Tic Severity Scale; 30% decrease from baseline relative to placebo, P<.001), with equal response in motor and phonic tic symptoms (P<.01 for both). The tic response rate was substantial (58% vs 5%; desipramine vs placebo, P<.001). There were small but statistically significant differences between desipramine and placebo in heart rate and blood pressure. CONCLUSIONS: Treatment with desipramine was well tolerated and was associated with robust clinically significant reductions in tic and ADHD symptoms in children and adolescents with chronic tic disorders and ADHD diagnoses.     

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.