Lisa A. Snider

Regarding “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.

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.

Treatment of Sydenham's Chorea with Intravenous Immunoglobulin, Plasma Exchange, or Prednisone

Sydenhams 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. (J Child Neurol 2005;20:424—429).

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.

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.

Echocardiographic Findings in the PANDAS Subgroup

Background. Sydenhams 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 Sydenhams chorea also have rheumatic carditis (pathologic mitral valve regurgitation). Although there are similar neuropsychiatric symptoms and preceding group A β-hemolytic streptococcal infection associated with both Sydenhams 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 Sydenhams chorea.

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.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS)

A series of studies conducted at the National Institute of Mental Health (NIMH) demonstrated that obsessive-compulsive symptoms were more problematic for children with SC, than for those with rheumatic carditis. The obsessive-compulsive symptoms in SC are indistinguishable from those of children with primary obsessive–compulsive disorder (OCD), and include contamination fears, fear of harm coming to self or others, doubting, symmetry concerns, and other obsessional worries, as well as compulsive washing, checking, ordering, arranging, and hoarding rituals. These clinical similarities as well as observations that the OCD in SC begins several weeks prior to the manifestation of the adventitious movements led to the speculation that post-streptococcal obsessive-compulsive symptoms might occur in the absence of frank chorea. Longitudinal observations of a large cohort of pediatric patients with OCD provided support for this postulate because a subgroup of patients had an acute symptom onset—an episodic course characterized by periods of complete symptom remission interrupted by abrupt, dramatic symptom exacerbations, and a close temporal relationship between these relapses and preceding Group A beta-hemolytic streptococcal (GAS) infections. The subgroup was labeled with the acronym, “PANDAS”, to indicate the shared clinical and presumed etiopathogenic features: Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections. This chapter reviews the clinical features of the PANDAS subgroup and explores the factors postulated to participate in etiopathogenesis.