Background and Objectives The goal of this work was to investigate the association between group A streptococcal (GAS) infections and tic incidence among unaffected children with a family history of chronic tic disorders (CTDs). Methods In a prospective cohort study, children with no history for tics who were 3 to 10 years of age with a first-degree relative with a CTD were recruited from the European Multicentre Tics in Children Study (EMTICS) across 16 European centers. Presence of GAS infection was assessed with throat swabs, serum anti–streptolysin O titers, and anti-DNAse titers blinded to clinical status. GAS exposure was defined with 4 different definitions based on these parameters. Cox regression analyses with time-varying GAS exposure were conducted to examine the association of onset of tics and GAS exposure during follow-up. Sensitivity analyses were conducted with Cox regression and logistic regression analyses. Results A total of 259 children were recruited; 1 child was found to have tic onset before study entry and therefore was excluded. Sixty-one children (23.6%) developed tics over an average follow-up period of 1 (SD 0.7) year. There was a strong association of sex and onset of tics, with girls having an ≈60% lower risk of developing tics compared to boys (hazard ratio [HR] 0.4, 95% confidence interval [CI] 0.2–0.7). However, there was no statistical evidence to suggest an association of any of the 4 GAS exposure definitions with tic onset (GAS exposure definition 1: HR 0.310, 95% CI 0.037–2.590; definition 2: HR 0.561, 95% CI 0.219–1.436; definition 3: HR 0.853, 95% CI 0.466–1.561; definition 4: HR 0.725, 95% CI 0.384–1.370). Discussion These results do not suggest an association between GAS exposure and development of tics. Classification of Evidence This study provides Class I evidence that group A streptococcal exposure does not associate with the development of tics in children with first-degree relatives with chronic tic disorder.
Bibliographical noteFunding Information:
This project has received funding from the European Union’s Seventh Framework Program for research and technological development under grant agreement No. 278367.
This research was supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London (Heyman); the Guys and St. Thomas' NHS Foundation Trust (Hedderly, Turner); the Spanish Ministry of Science and Innovation (RTC2019-007150-1), the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (PI14/01823, PI16/01575, PI18/01898, PI19/01576), the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía (CVI-02526, CTS-7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI-0471-2013, PE-0210-2018, PI-0459-2018, PE-0186-2019), and the Fundación Alicia Koplowitz (Mir); the EU (FP7-HEALTH-2011 No. 278367, FP7-PEOPLE-2012-ITN No. 316978) (Fremer and Müller-Vahl), the German Research Foundation (DFG; GZ MU 1527/3-1), the German Ministry of Education and Research (BMBF; 01KG1421), the National Institute of Mental Health (NIMH), the Tourette Gesellschaft Deutschland eV, the Else-Kroner-Fresenius-Stiftung (Müller-Vahl); the Possehl-Stiftung (Lübeck, Germany), Margot und Jürgen Wessel Stiftung (Lübeck, Germany), Tourette Syndrome Association (Germany), Interessenverband Tourette Syndrom (Germany), CHDI, Damp-Stiftung (Kiel, Germany); academic research support: DFG: projects 1692/3-1, 4-1, SFB 936, and FOR 2698 (projects 396914663, 396577296, 396474989); European Reference Network–Rare Neurological Diseases (project No. 739510); royalties for the book Neurogenetics (Oxford University Press) (Münchau); and the National Institute for Health Research UCLH Biomedical Research Centre (Schrag). The authors are deeply grateful to all children and their parents who willingly participated to make this research possible. They thank all their colleagues at the various study centers who contributed to data collection or management: Julie E. Bruun, Judy Grejsen, Christine L. Ommundsen, Mette Rubæk (Capital Region Psychiatry, Copenhagen, Denmark); Stephanie Enghardt (TUD Dresden, Germany); Stefanie Bokemeyer, Christiane Driedger-Garbe, Cornelia Reichert (MHH Hanover, Germany); Thomas Duffield (LMMU München, Germany); Jenny Schmalfeld, Jennifer Tübing (Lübeck University, Germany); Franciska Gergye, Margit Kovacs, Reka Vidomusz (Vadaskert Budapest, Hungary); Miri Carmel, Silvana Fennig, Ella Gev, Nathan Keller, Elena Michaelovsky, Matan Nahon, Chen Regev, Tomer Simcha, Gill Smollan, Avi Weizman (Tel Aviv, Petah-Tikva, Israel); Giuseppe Gagliardi (Bari, Italy); Marco Pataracchia, Simona Recchia, Giovanna Alfarone (ISS Rome, Italy); Martin Woods (Evelina London Children's Hospital GSTT, United Kingdom); Marieke Messchendorp, Anne Marie Stolte, Deborah Sival, Frank Visscher, and the Stichting Gilles de la Tourette (UMCG Groningen, the Netherlands); Maria Teresa Cáceres, Fátima Carrillo, Laura Vargas, Pilar Gómez-Garre, Ángela Periañez Vasco (Seville, Spain); Anna Marotta (ASL, Bari, Italy); and Marina Redondo (FRCB, Barcelona, Spain).
This project has received funding from the European Union's Seventh Framework Program for research and technological development under grant agreement No. 278367.
D. Martino has received honoraria for lecturing from the Movement Disorders Society, Tourette Syndrome Association of America, and Dystonia Medical Research Foundation Canada; honoraria for advisory board attendance from Sunovion Pharmaceuticals Canada Inc; research and education funding support from Dystonia Medical Research Foundation Canada, the University of Calgary, the Michael P. Smith Family, the Owerko Foundation, Ipsen Corporate, the Parkinson Association of Alberta, and the Canadian Institutes for Health Research; and royalties from Springer-Verlag. K. Müller-Vahl has received financial or material research support from EU (FP7-HEALTH-2011 No. 278367, FP7-PEOPLE-2012-ITN No. 316978) DFG: GZ MU 1527/3-1 and GZ MU 1527/3-2, BMBF: 01KG1421, NIMH, Tourette Gesellschaft Deutschland eV Else-Kröner-Fresenius-Stiftung, GW pharmaceuticals, Almirall Hermal GmbH, Abide Therapeutics, and Therapix Biosiences. She has received consultant's honoraria from Abide Therapeutics, Boehringer Ingelheim International GmbH, Bionorica Ethics GmbH, CannaMedical Pharma GmbH, Canopy Grouth, Columbia Care, CTC Communications Corp, Demecan, Eurox Deutschland GmbH, Global Praxis Group Ltd, IMC Germany, Lundbeck, Sanity Group, Stadapharm GmbH, Synendos Therapeutics AG, and Tilray. She is an advisory/scientific board member for CannaMedical Pharma GmbH, Bionorica Ethics GmbH, CannaXan GmbH, Canopy Growth, Columbia Care, IMC Germany, Leafly Deutschland GmbH, Sanity Group, Syqe Medical Ltd, Therapix Biosciences Ltd, and Wayland Group. She has received speaker's fees from Aphria Deutschland GmbH, Almirall, Cogitando GmbH, Emalex, Eurox Deutschland GmbH, Ever Pharma GmbH, Meinhardt Congress GmbH, PR Berater, Spectrum Therapeutics GmbH, Takeda GmbH, Tilray, and Wayland Group. She has received royalties from Deutsches Ärzteblatt, Der Neurologie und Psychiater, Elsevier, Medizinisch Wissenschaftliche Verlagsgesellschaft Berlin, and Kohlhammer. She served as a guest editor for Frontiers in Neurology on the research topic “The Neurobiology and Genetics of Gilles de la Tourette Syndrome: New Avenues Through Large-Scale Collaborative Projects” and is an associate editor for Cannabis and Cannabinoid Research, an Editorial Board member of Medical Cannabis and Cannabinoids and MDPI-Reports, and a Scientific Board member for Zeitschrift für Allgemeinmedizin. A. Münchau is supported by the DFG (FOR 2698). V. Roessner has received payment for consulting and writing activities from Lilly, Novartis, and Shire Pharmaceuticals; lecture honoraria from Lilly, Novartis, Shire Pharmaceuticals, and Medice Pharma; and support for research from Shire and Novartis. He has carried out (and is currently carrying out) clinical trials in cooperation with Novartis, Shire, and Otsuka . A. Schrag has received consultancy or advisory board honoraria from Biogen, Abbvie, Bial, and Neurotechnology; research support from the National Institute of Health Research, Parkinson's UK, and the Economic and Social Research Council and the European Commission; and royalties from Oxford University Press. S. Walitza has received in the last 5 years royalties from Thieme Hogrefe, Kohlhammer, Springer, and Beltz. Her work was supported in the last 5 years by the Swiss National Science Foundation, diff. EU FP7s, HSM Hochspezialisierte Medizin of the Kanton Zurich, Switzerland, Bfarm Germany, ZInEP, Hartmann Müller Stiftung, Olga Mayenfisch, Gertrud Thalmann, Vontobel, Unicentia, and Erika Schwarz Fonds. Outside professional activities and interests are declared under the link of the University of Zurich ( uzh.ch/prof/ssl-dir/interessenbindungen/client/web/ ). On behalf of all other authors, the corresponding author declares that the other authors have no conflicts of interest. Go to Neurology.org/N for full disclosures.
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