Whither PANDAS?
Whither PANDAS?
Abstract & Commentary
By Hal B. Jenson, MD, FAAP, Chief Academic Officer, Baystate Health Professor of Pediatrics and Dean of the Western Campus of Tufts University School of Medicine, Baystate Medical Center Springfield, MA, is Associate Editor for Infectious Disease Alert.
Synopsis: Two prospective studies of a cohort of children with pediatric autoimmune neuropsychiatric disorders associated with group A streptococcal infections (PANDAS) suggest that the role of streptococcus as a precipitant of neuropsychiatric symptom exacerbations is minor. Laboratory studies including ELISA and Western immunoblotting for antibodies to brain proteins and for inflammatory cytokines failed to identify a basis for the purported autoimmune mechanism of PANDAS.
Source: Kurlan R, et al. Streptococcal infection and exacerbations of childhood tics and obsessive-compulsive symptoms: A prospective blinded cohort study. Pediatrics. 2008;121:1188-1197; Singer HS, et al. Serial immune markers do not correlate with clinical exacerbations in pediatric autoimmune neuropsychiatric disorders associate with streptococcal infections. Pediatrics. 2008;121:1198-1205.
A blinded, prospective, case-control study of 40 children meeting all of the DSM-IV criteria for PANDAS matched with 40 children with obsessive-compulsive disorder and/or a chronic tic disorder was conducted with periodic intensive laboratory testing for group A streptococcus for 2 years, especially with clinical exacerbations or acute illness. There were 10 cases and 6 controls subjects who withdrew before completing the two-year study; 4 cases and 3 controls were replaced.
PANDAS subjects were more likely than controls to have a family history of rheumatic fever (P = 0.03). Over the two years of the study, PANDAS subjects and control subjects had an average of 24.3 ± 6.8 and 24.3 ± 5.4 throat cultures and 13.9 ± 5.3 and 12.7 ± 4.0 serum samples, respectively. Some subjects illustrated chronic carriage of group A streptococcus, with 23 positive of 25 throat cultures (all type M/emm-77) in one subject and 24 positive of 24 throat cultures (all type M/emm-2) in a second subject.
There were 65 clinical exacerbations, including 40 cases in 21 PANDAS subjects, and 25 cases in 14 control subjects. The exacerbation rate was 0.56 per person per year for PANDAS subjects and 0.28 per person per year for control subjects. There were 43 definite or probable group A streptococcal infections, with 31 infections in 31 PANDAS subjects and 12 infections in 9 control subjects. The group A streptococcal infection rate (definite or probable) was 0.43 per person per year for PANDAS subjects and 0.13 per person per year for control subjects.
Only 5 of 64 clinical exacerbations were temporally associated (within 4 weeks) with streptococcal infection, all occurring among cases. Over 75% of clinical exacerbations in such cases had no definable temporal association with group A streptococcal infections.
Another prospective, blinded, controlled study was conducted among 12 children participating in an intensive clinical and laboratory cohort of children diagnosed with PANDAS. The mean age was 11.4 years and included 8 boys and 4 girls. Serial serum samples were obtained before (2 samples), within 2 weeks (1 sample), and after (2 samples) a well-defined clinical exacerbation. Of the 12 children, 6 had an exacerbation associated with a well-documented streptococcal infection, and 6 children had an exacerbation without streptococcal infection. Assays of antineuronal antibodies included: ELISA of antineuronal antibodies using tissue proteins from human caudate, putamen, and Brodmann's area 10 (BA10); Western immunoblotting using the same tissue proteins with emphasis on brain proteins of 40, 45, and 60 kDa; ELISA for IgM and IgG lysoganglioside GM1 antibodies; competitive inhibition assay for IgG lysoganglioside GM1; and measures of inflammatory cytokines including: T-helper (Th1) cytokines IFN-a and IL-12; CD8 releasing cytokines IFN-a and tumor necrosis factor (TNF)-α; Th2 cytokines (IL-4, IL-5, IL-6, IL-10, and IL-13); the immunomodulatory cytokine IL-1; and the chemokines macrophage chemoattractant protein (MCP)-1 and RANTES (CCL5).
There was no association of clinical worsening or streptococcal infection with quantitative measures of autoantibodies. Antineuronal antibodies did not correlate with the phenotype, phenomenology, severity, or duration.
Commentary
PANDAS was first described in 1998 with 5 diagnostic criteria: 1) presence of an obsessive-compulsive disorder and/or a chronic tic disorder (Tourette disorder, chronic motor or vocal tic disorder); 2) onset at 3 years to beginning of puberty; 3) abrupt onset of symptoms or pattern of dramatic, recurrent symptom exacerbations and remissions; 4) temporal relationship between group A streptococcal infection and clinical onset of symptoms, as reported by the subject or parent; and 5) neurologic abnormalities such as motoric hyperactivity, tics, or choreiform movements duringan exacerbation. PANDAS was hypothesized to be a continuation of a spectrum of autoimmune-mediated responses to group A streptococcal infections that included Sydenham chorea, the neurologic sequela of rheumatic fever, and, furthermore, that neurological exacerbations resulted from repeated group A streptococcal infections.
This is the first prospective cohort of patients diagnosed with PANDAS that has been studied with comprehensive clinical and immunologic testing. In this study, the PANDAS subjects showed an increased rate of exacerbations and also of streptococcal infections, though most of the clinical exacerbations could not be associated with streptococcal infections. This suggests that children with PANDAS may represent a subgroup of patients with Tourette syndrome or obsessive-compulsive disorder who are susceptible to group A streptococcal infections. Those clinical exacerbations that were temporally associated with group A streptococcus were not clinically distinct from exacerbations not associated with group A streptococcus. These studies have small study groups and so the lack of statistical significance must be interpreted cautiously.
The causal link of group A streptococcal infections to clinical exacerbations remains uncertain. These new results, which include serial antibody testing, combined with lack of specificity of previous studies of PANDAS patients at a single time point (many of which have methodologic concerns) and the failure of serum microinfused into rodent ventral and ventrolateral rodent striatum to produce changes of animal behavior, suggest that there is not a role of autoimmunity in PANDAS.
A blinded, prospective, case-control study of 40 children meeting all of the DSM-IV criteria for PANDAS matched with 40 children with obsessive-compulsive disorder and/or a chronic tic disorder was conducted with periodic intensive laboratory testing for group A streptococcus for 2 years, especially with clinical exacerbations or acute illness.Subscribe Now for Access
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