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On the Connection Between Autoimmunity, tic Disorders and Obsessive-Compulsive Disorders: A Meta-Analysis on Anti-Streptolysin O Titres

Abstract

Anti-streptolysin O (ASO) titration is useful in the context of autoimmune pathologies, including specific cases of tic and obsessive-compulsive disorders occurring after streptococcal infections. There is currently a lack of consensus on the use of ASO titres; therefore we performed a meta-analysis to systematise available data and clarify the role of ASO titres in the context of neuropsychiatric disorders. A meta-analysis was performed on ASO titration in neuropsychiatric patients, including tic disorders and obsessive-compulsive disorders. Included studies reported numbers of positive subjects, depending on a chosen threshold, or detailed ASO titrations. Three hundred and twenty nine studies were identified, of which 13 were eligible for meta-analysis. Due to limited available data, only tic disorders were evaluated. The odds ratio of finding an abnormal ASO titre in patients was 3.22 (95 % C.I. 1.51–6.88) as compared to healthy controls and 16.14 (95 % C.I. 8.11–32.11) as compared to non-psychiatric patients. Studies using different thresholds were generally concordant. ASO titres were also compared quantitatively, finding an overall difference of the means of 70.50 U/ml (95 % C.I. 25.21–115.80) in favour of patients with tic disorders. Based on current evidence, tic disorders are associated with a significant increase in ASO titres, evident both in a threshold-level perspective and on a quantitative level. These results encourage the systematisation of ASO titration in the context of tic disorders.

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References

  1. Aran A, Lin L, Nevsimalova S et al (2009) Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. Sleep 32(8):979–983

    PubMed  PubMed Central  Google Scholar 

  2. Bernstein GA, Victor AM, Pipal AJ, Williams KA (2010) Comparison of clinical characteristics of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections and childhood obsessive-compulsive disorder. J Child Adolesc Psychopharmacol 20(4):333–340

    PubMed  Article  PubMed Central  Google Scholar 

  3. Cardona F, Orefici G (2001) Group A streptococcal infections and tic disorders in an Italian pediatric population. J Pediatr 138(1):71–75

    PubMed  Article  CAS  Google Scholar 

  4. Cardona F, Romano A, Cundari G, Ventriglia F, Versacci P, Orefici G (2004) Colour doppler echocardiography in children with group a streptococcal infection related tic disorders. Indian J Med Res 119(Suppl):186–190

    PubMed  Google Scholar 

  5. Cengel-Kültür SE, Cöp E, Kara A, Cengiz AB, Uludağ AK, Unal F (2009) The relationship between group A beta hemolytic streptococcal infection and psychiatric symptoms: a pilot study. Turk J Pediatr 51(4):317–324

    PubMed  Google Scholar 

  6. Cheng YH, Zheng Y, He F et al (2012) Detection of autoantibodies and increased concentrations of interleukins in plasma from patients with Tourette’s syndrome. J Mol Neurosci 48(1):219–224

    PubMed  Article  CAS  Google Scholar 

  7. Church AJ, Dale RC, Lees AJ, Giovannoni G, Robertson MM (2003) Tourette’s syndrome: a cross sectional study to examine the PANDAS hypothesis. J Neurol Neurosurg Psychiatr 74(5):602–607

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  8. Elia J, Dell ML, Friedman DF et al (2005) PANDAS with catatonia: a case report. Therapeutic response to lorazepam and plasmapheresis. J Am Acad Child Adolesc Psychiatry 44(11):1145–1150

    PubMed  Article  Google Scholar 

  9. Fusco FR, Pompa A, Bernardi G et al (2010) A case of PANDAS treated with tetrabenazine and tonsillectomy. J Child Neurol 25(5):614–615

    PubMed  Article  Google Scholar 

  10. Gause C, Morris C, Vernekar S, Pardo-Villamizar C, Grados MA, Singer HS (2009) Antineuronal antibodies in OCD: comparisons in children with OCD-only, OCD + chronic tics and OCD + PANDAS. J Neuroimmunol 214(1–2):118–124

    PubMed  Article  CAS  Google Scholar 

  11. Hachiya Y, Miyata R, Tanuma N et al (2013) Autoimmune neurological disorders associated with group-A beta-hemolytic streptococcal infection. Brain Dev 35(7):670–674

    PubMed  Article  Google Scholar 

  12. Husby G, van de Rijn I, Zabriskie JB, Abdin ZH, Williams RC Jr (1976) Antibodies reacting with cytoplasm of subthalamic and caudate nuclei neurons in chorea and acute rheumatic fever. J Exp Med 144(4):1094–1110

    PubMed  Article  CAS  Google Scholar 

  13. Kaplan EL, Top FH Jr, Dudding BA, Wannamaker LW (1971) Diagnosis of streptococcal pharyngitis: differentiation of active infection from the carrier state in the symptomatic child. J Infect Dis 123:490–501

    PubMed  Article  CAS  Google Scholar 

  14. Kaplan EL, Rothermel CD, Johnson DR (1998) Antistreptolysin O and anti-deoxyribonuclease B titers: normal values for children ages 2 to 12 in the United States. Pediatrics 101:86–88

    PubMed  Article  CAS  Google Scholar 

  15. Kiessling LS, Marcotte AC, Culpepper L (1993) Antineuronal antibodies in movement disorders. Pediatrics 92(1):39–43

    PubMed  CAS  Google Scholar 

  16. Kurlan R, Johnson D, Kaplan EL (2008) Tourette syndrome study group. Streptococcal infection and exacerbations of childhood tics and obsessive-compulsive symptoms: a prospective blinded cohort study. Pediatrics 121(6):1188–1197

    PubMed  Article  Google Scholar 

  17. Leckman JF, King RA, Gilbert DL et al (2011) Streptococcal upper respiratory tract infections and exacerbations of tic and obsessive-compulsive symptoms: a prospective longitudinal study. J Am Acad Child Adolesc Psychiatry 50(2):108–118

    PubMed  Article  PubMed Central  Google Scholar 

  18. Lewin AB, Storch EA, Murphy TK (2011a) Pediatric autoimmune neuropsychiatric disorders associated with Streptococcus in identical siblings. J Child Adolesc Psychopharmacol 21(2):177–182

    PubMed  Article  Google Scholar 

  19. Lewin AB, Storch EA, Mutch PJ, Murphy TK (2011b) Neurocognitive functioning in youth with pediatric autoimmune neuropsychiatric disorders associated with streptococcus. J Neuropsychiatry Clin Neurosci 23(4):391–398

    PubMed  Article  Google Scholar 

  20. Lüleyap H, Onatoğlu D, Tahiroğlu A et al (2012) Association between obsessive compulsive disorder and tumor necrosis factor-α gene −308 (G > a) and −850 (C > T) polymorphisms in Turkish children. Balkan J Med Genet 15(2):61–66

    PubMed  PubMed Central  Google Scholar 

  21. Lüleyap HU, Onatoglu D, Yilmaz MB et al (2013) Association between pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections disease and tumor necrosis factor-α gene-308 g/a, −850 c/t polymorphisms in 4-12-year-old children in Adana/Turkey. Indian J Hum Genet 19(2):196–201

    PubMed  Article  PubMed Central  Google Scholar 

  22. Luo F, Leckman JF, Katsovich L et al (2004) Prospective longitudinal study of children with tic disorders and/or obsessive-compulsive disorder: relationship of symptom exacerbations to newly acquired streptococcal infections. Pediatrics 113(6):e578–585

    PubMed  Article  Google Scholar 

  23. Macerollo A, Martino D (2013) Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS): An Evolving Concept. Tremor Other Hyperkinet Mov, Sep 25,3, pii: tre-03-167-4158-7

  24. Maini B, Bathla M, Dhanjal GS, Sharma PD (2012) Pediatric autoimmune neuropsychiatric disorders after streptococcus infection. Indian J Psychiatry 54(4):375–377

    PubMed  Article  PubMed Central  Google Scholar 

  25. Martino D, Chiarotti F, Buttiglione M et al (2011) The relationship between group a streptococcal infections and Tourette syndrome: a study on a large service-based cohort. Dev Med Child Neurol 53(10):951–957

    PubMed  Article  Google Scholar 

  26. Matsuo M, Tsuchiya K, Hamasaki Y, Singer HS (2004) Restless legs syndrome: association with streptococcal or mycoplasma infection. Pediatr Neurol 31(2):119–121

    PubMed  Article  Google Scholar 

  27. Morris CM, Pardo-Villamizar C, Gause CD, Singer HS (2009) Serum autoantibodies measured by immunofluorescence confirm a failure to differentiate PANDAS and Tourette syndrome from controls. J Neurol Sci 276(1–2):45–48

    PubMed  Article  CAS  Google Scholar 

  28. Morris-Berry CM, Pollard M, Gao S, Thompson C, Tourette Syndrome Study Group, Singer HS (2013) Anti-streptococcal, tubulin, and dopamine receptor 2 antibodies in children with PANDAS and Tourette syndrome: single-point and longitudinal assessments. J Neuroimmunol 264(1–2):106–113

    PubMed  Article  CAS  Google Scholar 

  29. Morshed SA, Parveen S, Leckman JF et al (2001) Antibodies against neural, nuclear, cytoskeletal, and streptococcal epitopes in children and adults with Tourette’s syndrome, Sydenham’s chorea, and autoimmune disorders. Biol Psychiatry 50(8):566–577

    PubMed  Article  CAS  Google Scholar 

  30. Müller N, Riedel M, Straube A, Günther W, Wilske B (2000) Increased anti-streptococcal antibodies in patients with Tourette’s syndrome. Psychiatry Res 94(1):43–49

    PubMed  Article  Google Scholar 

  31. Murphy ML, Pichichero ME (2002) Prospective identification and treatment of children with pediatric autoimmune neuropsychiatric disorder associated with group a streptococcal infection (PANDAS). Arch Pediatr Adolesc Med 156(4):356–361

    PubMed  Article  Google Scholar 

  32. Murphy TK, Goodman WK, Fudge MW, Williams RC Jr, Ayoub EM, Dalal M, Lewis MH, Zabriskie JB (1997) B lymphocyte antigen D8/17: a peripheral marker for childhood-onset obsessive-compulsive disorder and Tourette’s syndrome? Am J Psychiatry 154(3):402–407

    PubMed  CAS  Google Scholar 

  33. Murphy TK, Sajid M, Soto O et al (2004) Detecting pediatric autoimmune neuropsychiatric disorders associated with streptococcus in children with obsessive-compulsive disorder and tics. Biol Psychiatry 55(1):61–68

    PubMed  Article  Google Scholar 

  34. Murphy TK, Storch EA, Lewin AB, Edge PJ, Goodman WK (2012) Clinical factors associated with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections. J Pediatr 160(2):314–319

    PubMed  Article  PubMed Central  Google Scholar 

  35. Pavone P, Bianchini R, Parano E et al (2004) Anti-brain antibodies in PANDAS versus uncomplicated streptococcal infection. Pediatr Neurol 30(2):107–110

    PubMed  Article  Google Scholar 

  36. Peterson BS, Leckman JF, Tucker D et al (2000) Preliminary findings of antistreptococcal antibody titers and basal ganglia volumes in tic, obsessive-compulsive, and attention deficit/hyperactivity disorders. Arch Gen Psychiatry 57(4):364–372

    PubMed  Article  CAS  Google Scholar 

  37. Ray PC, Tas DA, Gul Celik G, Yolga Tahiroglu A, Avci A, Erken E (2013) Periodic fever and hyperimmunoglobulin D syndrome in a boy with pediatric autoimmune neuropsychiatric disorders associated with group A β-Hemolytic streptococcus. J Child Adolesc Psychopharmacol 23(4):302–304

    PubMed  Article  Google Scholar 

  38. Rizzo R, Gulisano M, Pavone P, Fogliani F, Robertson MM (2006) Increased antistreptococcal antibody titers and anti-basal ganglia antibodies in patients with Tourette syndrome: controlled cross-sectional study. J Child Neurol 21(9):747–753

    PubMed  Article  Google Scholar 

  39. Sanchez-Carpintero R, Albesa SA, Crespo N, Villoslada P, Narbona J (2009) A preliminary study of the frequency of anti-basal ganglia antibodies and streptococcal infection in attention deficit/hyperactivity disorder. J Neurol 256(7):1103–1108

    PubMed  Article  CAS  Google Scholar 

  40. Sen ES, Ramanan, AV (2014) How to use antistreptolysin O titre. Arch Dis Child Educ Pract Ed Jan 30

  41. Singer HS, Giuliano JD, Hansen BH et al (1998) Antibodies against human putamen in children with Tourette syndrome. Neurology 50(6):1618–1624

    PubMed  Article  CAS  Google Scholar 

  42. Singer HS, Loiselle CR, Wendlandt JT, Swedo SE, Grus FH (2002) Antineuronal antibodies in Sydenham’s chorea and PANDAS: an ELISA and Western blot analysis. Neurology 58:A372

    Google Scholar 

  43. Sokol MS (2000) Infection-triggered anorexia nervosa in children: clinical description of four cases. J Child Adolesc Psychopharmacol 10(2):133–145

    PubMed  Article  CAS  Google Scholar 

  44. Steer AC, Vidmar S, Ritika R et al (2009) Normal ranges of streptococcal antibody titers are similar whether streptococci are endemic to the setting or not. Clin Vaccine Immunol 16(2):172–175

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  45. Swedo SE, Leonard HL, Schapiro MB et al (1993) Sydenham’s chorea: physical and psychological symptoms of St Vitus dance. Pediatrics 91:706–713

    PubMed  CAS  Google Scholar 

  46. Swedo SE, Leonard HL, Garvey M et al (1998) Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections: clinical description of the first 50 cases. Am J Psychiatry 155(2):264–271

    PubMed  CAS  Google Scholar 

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Acknowledgements

The financial support by Agenzia Italiana del Farmaco (AIFA) and by the Italian Ministry of Health (Ricerca Corrente 2014, to EC) is gratefully acknowledged. The authors report no conflict of interests. The funding public institutions had no role in any part of the work.

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Correspondence to Sonia Radice.

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Marco Pozzi and Paolo Pellegrino contributed equally to the manuscript.

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Pozzi, M., Pellegrino, P., Carnovale, C. et al. On the Connection Between Autoimmunity, tic Disorders and Obsessive-Compulsive Disorders: A Meta-Analysis on Anti-Streptolysin O Titres. J Neuroimmune Pharmacol 9, 606–614 (2014). https://doi.org/10.1007/s11481-014-9561-1

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Keywords

  • Anti-streptolysin O titre
  • tic disorders
  • Tourette’s syndrome
  • Obsessive-compulsive disorders
  • PANDAS
  • Group A β–haemolytic streptococci