Group A streptococcus and children's behavior

Case study: a new infection-triggered, autoimmune subtype of pediatric OCD and Tourette's syndrome. AJ Allen, HL Leonard, SE Swedo. J Am Acad Child Adolesc Psychiatry 1995 Mar;34(3):307-311. 2 of 4 cases with abrupt, severe onset or worsening of OCD or tics had evidence of recent group A beta-hemolytic streptococci infections, and the others had histories of recent viral illnesses.

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. SE Swedo, HL Leonard, M Garvey, B Mittleman, AJ Allen, S Perlmutter, L Lougee, S Dow, J Zamkoff, BK Dubbert. Am J Psychiatry 1998 Feb;155(2):264-271. Among 50 children with OCD and/or tic, "The children's symptom onset was acute and dramatic, typically triggered by GABHS infections at a very early age (mean=6.3 years, SD=2.7, for tics; mean=7.4 years, SD=2.7, for OCD). The PANDAS clinical course was characterized by a relapsing-remitting symptom pattern with significant psychiatric comorbidity accompanying the exacerbations; emotional lability, separation anxiety, nighttime fears and bedtime rituals, cognitive deficits, oppositional behaviors, and motoric hyperactivity were particularly common. Symptom onset was triggered by GABHS infection for 22 (44%) of the children and by pharyngitis (no throat culture obtained) for 14 others (28%). Among the 50 children, there were 144 separate episodes of symptom exacerbation; 45 (31%) were associated with documented GABHS infection, 60 (42%) with symptoms of pharyngitis or upper respiratory infection (no throat culture obtained), and six (4%) with GABHS exposure.... The symptoms of the comorbid diagnoses (particularly ADHD) were also reported to be exacerbated following streptococcal infections, although this was not assessed systematically."

Preliminary findings of antistreptococcal antibody titers and basal ganglia volumes in tic, obsessive-compulsive, and attention deficit/hyperactivity disorders. BS Peterson, JL Leckman, D Tucker, L Scahill, L Staib, H Zhang, R King, DJ Cohen, JC Gore, P Lombroso. Arch Gen Psychiatry 2000 Apr;57(4):364-372. Antibodies to streptococcus were associated with ADHD in 105 patients vs 37 controls.

Infection: a stimulus for tic disorders. HS Singer, JD Giuliano, AM Zimmerman, JT Walkup. Pediatr Neurol 2000 May;22(5):380-383. "A structured clinical interview was used to evaluate 80 consecutive children, 5-17 years of age, with a diagnosis of tic disorder. Forty-two patients (53%) described a sudden, explosive onset or worsening of tic symptoms; 15 of these 42 had their exacerbation historically associated with an infection, nine of the 15 specifically with a streptococcal infection."

The psychiatric symptoms of rheumatic fever. MT Mercadante, GF Busatto, PJ Lombroso, L Prado, MC Rosário-Campos, R do Valle, MJ Marques-Dias, MH Kiss, JF Leckman, EC Miguel. Am J Psychiatry 2000 Dec;157(12):2036-2038. Twenty children with rheumatic fever, 22 with Sydenham's chorea, and 20 comparison children. "Obsessive-compulsive symptoms were more frequent in both the Sydenham's chorea and rheumatic fever groups than in the comparison group. The Sydenham's chorea group had a higher frequency of major depressive disorder, tic disorders, and attention deficit hyperactivity disorder (ADHD) than both the comparison and rheumatic fever groups. ADHD symptoms were associated with a higher risk of developing Sydenham's chorea."

Prospective identification and treatment of children with pediatric autoimmune neuropsychiatric disorder associated with group A streptococcal infection (PANDAS). ML Murphy, ME Pichichero. Arch Pediatr Adolesc Med 2002 Apr;156(4):356-361. And: Behavioral syndrome linked to strep pharyngitis, responds to antibiotics. Reuters Health 2002 Apr 15 / Medscape. "Drs. Murphy and Pichichero speculate that a streptococcal toxin, rather than an autoimmune antibody-mediated process, is the mediator of PANDAS... They suggest that 'perhaps the PANDAS syndrome should be expanded to include primary diagnosis of late-onset ADHD and age-inappropriate separation anxiety disorders." And: PANDAS confirmed: Antibiotics for group-A strep relieve OCD Synptoms. By Laurie Barclay. MedscapeWire 2002 Apr 19.

Tourette's syndrome: a cross sectional study to examine the PANDAS hypothesis. AJ Church, RC Dale, AJ Lees, G Giovannoni, MM Robertson. J Neurol Neurosurg Psychiatry 2003 May;74(5):602-607. 100 children with Tourette's compared with healthy controls and controls with other diseases. "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."

A possible association of recurrent streptococcal infections and acute onset of obsessive-compulsive disorder. SW Kim, JE Grant, SI Kim, TA Swanson, GA Bernstein, WA Jaszcz, KA Williams, PM Schlievert. J Neuropsychiatry Clin Neurosci 2004 Summer;16(3):252-260. Review of microbial characteristics of and and immune responses to group A β-hemolytic Streptococcus (GABHS) as a possible cause of PANDAS.

Does group A beta-hemolytic streptococcal infection increase risk for behavioral and neuropsychiatric symptoms in children? EM Perrin, ML Murphy, JR Casey, ME Pichichero, DK Runyan, WC Miller, LA Snider, SE. Swedo. Arch Pediatr Adolesc Med 2004 Sep;158(9):848-856. "By parent report, ill children more frequently manifested several PANDAS symptoms at baseline than well children." The ill children were treated with antibiotics at baseline, and did not have an increased risk of PANDAS afterwards.

Association between streptococcal infection and obsessive-compulsive disorder, Tourette's Syndrome, and Tic Disorder. LK Mell, RL Davis, D Owens. Pediatrics 2005 Jul;116(1):55-60. Odds ratio for Tourette's with multiple infections with group A beta-hemolytic streptococcus within a year was 13.6 (95% CI 1.93, 51.0).

Incidence of anti-brain antibodies in children with obsessive-compulsive disorder. RC Dale, I Heyman, G Giovannoni, AW Church. Br J Psychiatry 2005 Oct;187:314-319. In 50 children with OCD, "The mean ABGA binding on ABGA binding on ELISA was elevated in the patient cohort compared with all control groups (P<0.005 in all comparisons). Western immunoblotting revealed positive antibody binding (as seen in Sydenham's chorea) in 42% of the patient cohort compared with 2-10% of control groups (P<0.001 in all comparisons)."

Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). DL Miller, RM Laxer. Pediatric Rheumatology Online Journal 2006 April. Review. "ADHD is a frequent comorbid feature of TS and OCD, but recent literature postulates ADHD without tics or OCD as part of the PANDAS spectrum."

Mycoplasma pneumoniae infection and obsessive-compulsive disease: a case report. TE Ercan, G Ercan, B Severge, M Arpaozu, G Karasu. J Child Neurol 2008 Mar;23(3):338-340. "Other infectious agents such as viruses and bacteria have also been reported to be associated with the acute onset or dramatic exacerbation of obsessive-compulsive disease or Tourette syndrome, and another acronym, PITAND (pediatric infection-triggered autoimmune neuropsychiatric disorder) has appeared in the literature. The involvement of other infectious agents such as Mycoplasma pneumoniae has been described in single case reports. We describe a case of a 5.5-year-old boy who suddenly developed obsessive-compulsive disease symptoms during a M. pneumoniae pneumonia. After treatment with oral clarithromycin, all his obsessive-compulsive disease symptoms disappeared."

Streptococcal infection and exacerbations of childhood tics and obsessive-compulsive symptoms: a prospective blinded cohort study. R Kurlan, D Johnson, EL Kaplan; and the Tourette Syndrome Study Group. Pediatrics 2008 Jun;121(6):1188-1197. 40 matched PANDAS case-control pairs. "The cases had a higher clinical exacerbation rate and a higher bona fide group A beta-hemolytic streptococcus infection rate than the control group. Only 5 of 64 exacerbations were temporally associated (within 4 weeks) with a group A beta-hemolytic streptococcus infection, and all occurred in cases. The number (5.0) was significantly higher than the number that would be expected by chance alone (1.6). Yet, >/=75% of the clinical exacerbations in cases had no observable temporal relationship to group A beta-hemolytic streptococcus infection."

Serial immune markers do not correlate with clinical exacerbations in pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. HS Singer, C Gause, C Morris, P Lopez; Tourette Syndrome Study Group. Pediatrics 2008 Jun;121(6):1198-1205. 12 children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections participating in a prospective blinded study. "No correlation was identified between clinical exacerbations and autoimmune markers, including: enzyme-linked immunosorbent assay measures of antineuronal antibodies; Western immunoblotting with emphasis on brain region proteins located at 40, 45, and 60 kDa or their corresponding identified antigens; competitive inhibition enzyme-linked immunosorbent assay to evaluate lysoganglioside G(M1) antibodies; and measures of inflammatory cytokines. No differences were identified between individuals with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections with or without exacerbations triggered by streptococcal infections."

Serum autoantibodies measured by immunofluorescence confirm a failure to differentiate PANDAS and Tourette syndrome from controls. CM Morris, C Pardo-Villamizar, CD Gause, HS Singer. J Neurol Sci 2009 Jan 15;276(1-2):45-48. "No significant differences in immunofluorescence or localization were identified in patients with PANDAS (n=30) and TS (n=30) as compared to controls (n=30). IF reactivity did not correlate with tic severity or elevated titers of antistreptococcal antibodies. Further comparisons showed no correlation between autoreactivity determined by immunofluorescence and the presence of previously measured immunoblot reactivity against human caudate or putative antigens (pyruvate kinase M1 and aldolase C). These results confirm an inability to distinguish patient populations by antibody measurements and raise further concerns about the presence of an autoimmune mechanism in PANDAS and TS."

A preliminary study of the frequency of anti-basal ganglia antibodies and streptococcal infection in attention deficit/hyperactivity disorder. R Sanchez-Carpintero, SA Albesa, N Crespo, P Villoslada, J Narbona. J Neurol 2009 Jul;256(7):1103-1108. "Eleven out of 22 children (51%) with nc-ADHD showed evidence of GABHS infection compared to three out of 22 (14%) controls (P = 0.007). We found positive ABGA in one ADHD subject (4%) and in one control (4%)."

Association Between Neuropsychiatric Morbidity and Streptococcal Infections in Children. S Viswanathan, PD Moses, S Varkki, PS Russell, KN Brahmadathan. Indian Pediatr 2010 Feb;47(2):168-170. "Fourteen (63.6 %) of the 22 cases were positive for ASO and/or ADNB while 21 of the 64 controls (32.8 %) were positive for either or both antibodies. (OR = 3.428; CI: 1.15- 10.18; P=0.026)."

Streptococcal upper respiratory tract infections and exacerbations of tic and obsessive-compulsive symptoms: a prospective longitudinal study. JF Leckman, RA King, DL Gilbert, BJ Coffey, HS Singer, LS Dure 4th, H Grantz, L Katsovich, H Lin, PJ Lombroso, I Kawikova, DR Johnson, RM Kurlan, EL Kaplan. J Am Acad Child Adolesc Psychiatry 2011 Feb;50(2):108-118.e3. 31 PANDAS subjects and 53 non-PANDAS subjects (children with Tourette syndrome and/or OC disorder without a PANDAS history). "No group differences were observed in the number of clinical exacerbations or the number of newly diagnosed GABHS infections. On only six occasions of a total of 51 (12%), a newly diagnosed GABHS infection was followed, within 2 months, by an exacerbation of tic and/or OC symptoms. In every instance, this association occurred in the non-PANDAS group."

Reviews of Group A Streptococcal disease

Pathogenesis of Group A Streptococcal Infections. MW Cunningham. Clinical Microbiology Reviews 2000 Jul;13(3):470-511. "Group A streptococci are extracellular bacterial pathogens which produce a variety of pyogenic infections involving the mucous membranes, tonsils, skin, and deeper tissues, including pharyngitis, impetigo/pyoderma, erysipelas, cellulitis, necrotizing fasciitis, toxic streptococcal syndrome, scarlet fever, septicemia, pneumonia, and meningitis. Infections may be mild to extremely severe. Complications such as sepsis, pneumonia, and meningitis can occur, which may lead to a fatal outcome. Several specific clinical syndromes, such as toxic streptococcal syndrome and necrotizing fasciitis, have reemerged and perhaps become more prevalent in the past 10 years due to infections with S. pyogenes." Different strains of the bacteria cause the different illnesses: "The strong resistance of the group A streptococcus to phagocytosis is related to factor H and fibrinogen binding by M protein and to disarming complement component C5a by the C5a peptidase. Molecular mimicry appears to play a role in autoimmune mechanisms involved in rheumatic fever, while nephritis strain-associated proteins may lead to immune-mediated acute glomerulonephritis." "Although group A streptococci are exquisitely sensitive to penicillin, an unexplained resurgence of group A streptococcal infections has been observed since the mid-1980s.... A decline in rheumatic fever with a milder disease pattern had been observed in the previous decade. Therefore, the increased severity and the attack on middle-class families deviated from the past epidemiological patterns."

Director of the National Institute of Mental Health endorses the infectious hypothesis of PANDAS: From Paresis to PANDAS & PANS. By Thomas R. Insel, M.D. Director's Posts about Obsessive-Compulsive Disorder (OCD), Mar. 26, 2012. "This proved more complicated than syphilis or helicobacter. Part of the problem has been that strep is very common in childhood, making it methodologically difficult to prove a causal connection between the microbe and the OCD symptoms. The onset has not always been linked precisely with a strep infection and the critical increase in antibodies to strep has not been evident consistently. Nevertheless, immune-based treatments have proven successful, leading to the growing acceptance of the concept of Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcus (PANDAS)." With summaries of current research.

Phages Effect Virulence

Genome sequence of a serotype M3 strain of group A Streptococcus: phage-encoded toxins, the high-virulence phenotype, and clone emergence. SB Beres, GL Sylva, KD Barbian, B Lei, JS Hoff, ND Mammarella, MY Liu, JC Smoot, SF Porcella, LD Parkins, DS Campbell, TM Smith, JK McCormick, DY Leung, PM Schlievert, JM Musser. Proc Natl Acad Sci USA 2002 Jul 23;99(15):10078-10083. "Serotype M3 strains with the phage-encoded speK and sla genes increased dramatically in frequency late in the 20th century, commensurate with the rise in invasive disease caused by M3 organisms. Taken together, the results show that phage-mediated recombination has played a critical role in the emergence of a new, unusually virulent clone of serotype M3 GAS." "Our results demonstrate that among bacterial species with multiple strains sequenced, GAS is unique in the magnitude to which phages account for genome diversification. Inasmuch as virtually all of the GAS phages have genes encoding proven and putative virulence factors, it is likely that they contribute to the differences in phenotypic characteristics observed among GAS strains."

The fundamental contribution of phages to GAS evolution, genome diversification and strain emergence. DJ Banks, SB Beres, JM Musser. Trends Microbiol 2002 Nov;10(11):515-521. "The frequency and severity of GAS infections increased in the 1980s and 1990s, but the cause of this increase is unknown. Recently, genome sequencing of serotype M1, M3 and M18 strains revealed many new proven or putative virulence factors that are encoded by phages or phage-like elements. Importantly, these genetic elements account for an unexpectedly large proportion of the difference in gene content between the three strains. These new genome-sequencing studies have provided evidence that temporally and geographically distinct epidemics, and the complex array of GAS clinical presentations, might be related in part to the acquisition or evolution of phage-encoded virulence factors."

cast 04-08-12