Relationship of movements and behaviors to Group A Streptococcus infections in elementary school children.

BACKGROUND: Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS) research is based on the hypothesis that infections trigger changes in behavior and movement in children. METHODS: We enrolled 693 children (ages 3 to 12 years) into a systematic, longitudinal study. Data were collected monthly for 8 months (October-May) to determine point prevalence of Group A Streptococcal (GAS) infections, tics, behavior, and choreiform movements. Simultaneous throat cultures were obtained, and relational analyses were made between GAS and movement/observation ratings. RESULTS: Combined behavior/GAS associations (concurrent with or 3 subsequent months to GAS) revealed a strong relationship, relative risk (RR) of 1.71 (p < .0001). Detailed analysis revealed that balance/swaying and non-tic grimacing were responsible for a significant proportion of this association (RR = 2.92, p < .0001). A strong seasonal pattern was found, with fall being more significant for GAS infections and observation ratings (p < .0001) compared with winter/spring. Children with repeated streptococcus (n = 64) showed higher rates of behavior and distal choreiform observations (p = .005). CONCLUSIONS: Motor/behavior changes were noted to occur in relationship to positive GAS culture with support that repeated GAS increases risk.

Antibody-mediated neuronal cell signaling in behavior and movement disorders.

Behavioral and movement disorders may have antibody responses where mimicry and signal transduction may lead to neuropsychiatric abnormalities. In our study, antibodies in pediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS) reacted with the neuronal cell surface and caudate-putamen and induced calcium-calmodulin dependent protein (CaM) kinase II activity in neuronal cells. Depletion of serum IgG abrogated CaM kinase II cell signaling and reactivity of CSF was blocked by streptococcal antigen N-acetyl-beta-d-glucosamine (GlcNAc). Antibodies against GlcNAc in PANDAS sera were inhibited by lysoganglioside G(M1). Results suggest that antibodies from an infection may signal neuronal cells in some behavioral and movement disorders.

Antibiotic prophylaxis with azithromycin or penicillin for childhood-onset neuropsychiatric disorders.

BACKGROUND: The acronym PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) describes a subgroup of children with obsessive-compulsive disorder and/or tic disorder that experience symptom exacerbations following streptococcal infections. We hypothesized that the prevention of streptococcal infections among children in the PANDAS subgroup would decrease neuropsychiatric symptom exacerbations. METHODS: Twenty-three subjects with PANDAS were enrolled in a double blind, randomized controlled trial. Antibiotic prophylaxis with penicillin or azithromycin was administered for 12 months. Rates of streptococcal infections and neuropsychiatric symptom exacerbations were compared between the study year and the baseline year prior to entry. RESULTS: Significant decreases in streptococcal infections during the study year were found with a mean of .1 (.3 SD) per subject, compared to the baseline year with 1.9 (1.2 SD) in the penicillin group and 2.4 (1.1 SD) in the azithromycin group [p<.01]. Significant decreases in neuropsychiatric exacerbations during the study year were also found with a mean of .5 (.5 SD) per subject in the penicillin group and .8 (.6 SD) in the azithromycin group, compared to the baseline year with 2.0 (.9 SD) in the penicillin group and 1.8 (.6 SD) in the azithromycin group [p<.01]. CONCLUSIONS: Penicillin and azithromycin prophylaxis were found to be effective in decreasing streptococcal infections and neuropsychiatric symptom exacerbations among children in the PANDAS subgroup.

Obsessive-compulsive symptoms among patients with Sydenham chorea.

BACKGROUND: Among patients with tic disorders, a distinctive clinical profile of obsessive-compulsive symptomatology has been described. The present investigation was designed to document the phenomenology of obsessive-compulsive symptoms (OCS) among patients with Sydenham chorea (SC), the neurologic variant of rheumatic fever. We hypothesized that OCS occurring in association with SC would be similar to those among patients with tic disorders. METHODS: The authors studied the presence of OCS in 73 patients with SC by using the Yale-Brown Obsessive-Compulsive Scale at the Pediatric Clinics of the University of Sao Paulo Medical Center in Sao Paulo, Brazil (n = 45) and at the National Institute of Mental Health in Bethesda, Maryland (n = 28). RESULTS: The most frequent symptoms observed among subjects with comorbid SC and OCS were aggressive, contamination, and somatic obsessions and checking, cleaning, and repeating compulsions. A principal component factor analysis yielded a five-factor solution (accounting for 64.5% of the total variance), with contamination and symmetry obsessions and cleaning compulsions loading highly. CONCLUSIONS: The symptoms observed among the SC patients were different from those reported by patients with tic disorders but were similar to those previously noted among samples of pediatric patients with primary obsessive-compulsive disorder.

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

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

Does group A beta-hemolytic streptococcal infection increase risk for behavioral and neuropsychiatric symptoms in children?

OBJECTIVE: To determine whether group A beta-hemolytic streptococcal infections increase the risk of developing symptoms characteristic of the diagnosis pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). DESIGN: Prospective cohort study. METHODS: Children (N = 814) aged 4 to 11 years seen for sore throat or well-child care in a large pediatric practice in Rochester, NY, were enrolled from October 2001 to June 2002 (group A beta-hemolytic streptococcal [GAS] infected, n = 411; GAS uninfected, n = 403, of whom 207 had a sore throat of presumed viral etiology and 196 were well children). Symptomatic children with GAS infection (n = 399) were treated with antibiotics. At baseline and 2 and 12 weeks following baseline, all parents completed a 20-item questionnaire about the presence/absence of recent PANDAS symptoms in their children, and capable children answered 10 items about worries, obsessions, and compulsions. The relative risk of developing a "mild PANDAS variant" (> or = 2 new PANDAS symptoms) by illness type (GAS positive, presumed viral, or well child) and by parent and child report was determined and adjusted for potential covariates. RESULTS: By parent report, ill children more frequently manifested several PANDAS symptoms at baseline than well children. However, neither new symptoms nor the risk of developing a mild PANDAS variant developed during the subsequent 12 weeks more commonly in children with GAS infection than in those with presumed viral illness or in well children by parent or child report. CONCLUSIONS: Ill children with GAS infection, treated for their GAS infection, were not at increased risk for developing PANDAS symptoms or a mild PANDAS variant compared with children with presumed viral illness or well children. The role of antibiotics in the prevention or treatment of PANDAS as well as the investigation of PANDAS in the asymptomatic, infectious host deserves future research.

Childhood-onset obsessive-compulsive disorder and tic disorders: case report and literature review.

A subgroup of childhood-onset obsessive-compulsive disorder (OCD) and tic disorders has been found to have a postinfectious autoimmune-mediated etiology. Clinical observations and systematic investigations have shown that a subgroup of children with OCD and/or tic disorders have the onset and subsequent exacerbations of their symptoms following infections with group A beta-hemolytic streptococci (GABHS). This subgroup has been designated by the acronym PANDAS: pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. Five clinical characteristics define the PANDAS subgroup: presence of OCD and/or tic disorder, prepubertal symptom onset, sudden onset or abrupt exacerbations, association with neurological abnormalities during exacerbations (adventitious movements or motoric hyperactivity), and the temporal association between symptom exacerbations and GABHS infections. The proposed poststreptococcal inflammatory etiology provides a unique opportunity for treatment and prevention, including immunomodulatory therapies such as plasma exchange and intravenous immunoglobulin. A placebo-controlled trial revealed that both intravenous immunoglobulin and plasma exchange were effective in reducing neuropsychiatric symptom severity (40 and 55% reductions, respectively) for a group of severely ill children in the PANDAS subgroup. Further research is required to determine why the treatments are helpful and to ascertain whether or not antibiotic prophylaxis can help prevent poststreptococcal symptom exacerbations.

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.

Echocardiographic findings in the PANDAS subgroup.

BACKGROUND: Sydenham's chorea is the neurologic manifestation of rheumatic fever and is a diagnosis of exclusion requiring only the presence of frank chorea in the absence of another neurologic disorder. Two thirds of children with Sydenham's chorea also have rheumatic carditis (pathologic mitral valve regurgitation). Although there are similar neuropsychiatric symptoms and preceding group A beta-hemolytic streptococcal infection associated with both Sydenham's chorea and the PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) subgroup, it is unknown whether patients in the PANDAS subgroup have any cardiac involvement. METHODS: Sixty children meeting the criteria for PANDAS were entered into protocols at National Institute of Mental Health between 1993 and 2002. Doppler and 2-dimensional echocardiograms were performed on these subjects to assess valvular heart disease. RESULTS: Of these 60 children, no echocardiographic evidence of significant mitral or aortic valve regurgitation was found. One patient was found to have mild mitral regurgitation, and all patients had normal left atrial size and normal left ventricular size and function. Follow-up echocardiograms on 20 children showed no significant valvular regurgitation. CONCLUSION: The evidence of a clear lack of rheumatic carditis in these children supports the hypothesis that PANDAS is a distinct neuropsychiatric diagnosis separate from Sydenham's chorea.

Tics and problem behaviors in schoolchildren: prevalence, characterization, and associations.

OBJECTIVE: Tic disorders are the most common movement disorder diagnosed in children and have symptoms that fluctuate in frequency and intensity over time. We conducted an 8-month longitudinal observational study to determine the variations in frequency of motor tics and associated problem behaviors. METHODS: A total of 553 children, kindergarten through sixth grade, were observed monthly from November 1999 to June 2000 by 3 raters. Motor tics were recorded by location and rated for severity as none (0), mild (1), moderate (2), or severe (3). Problem behaviors were rated as absent (0), subclinical (1), or clinical (2) in each of 6 categories: disruptive, hyperactive, impulsive, aggressive, anxious, and distracted. RESULTS: The monthly point prevalence of motor tics ranged from 3.2% to 9.6%, with an overall frequency of 24.4%. The monthly point prevalence of problem behaviors ranged from 2.6% to 11.0%, with an overall frequency of 25.7%. The incidence of motor tics and problem behaviors was significantly higher during the winter months of November through February, compared with the spring months of March through June (motor tics: z = 4.97; problem behaviors: z = 3.79). Motor tics were observed in 2 distinct patterns (isolated and persistent), which varied by the number of months present, gender ratio of affected children, severity of tic symptoms, and association with problem behaviors. CONCLUSIONS: Motor tics and problem behaviors are frequent occurrences among schoolchildren and seem to occur more frequently during the winter months. For most children, the tics were mild, observed on only 1 occasion, and were not accompanied by problem behaviors.