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February 10, 2021Null Hypothesis

Association of Group A Streptococcus Exposure and Exacerbations of Chronic Tic Disorders: A Multinational Prospective Cohort Study

Davide Martino, Anette Schrag, Zacharias Anastasiou, Alan Apter, Noa Benaroya-Milstein, Maura Buttiglione, Francesco Cardona, Roberta Creti, Androulla Efstratiou, Tammy Hedderly, Isobel Heyman, Chaim Huyser, Marcos Madruga, View ORCID ProfilePablo Mir, Astrid Morer, Nanette Mol Debes, Natalie Moll, View ORCID ProfileNorbert Müller, Kirsten Müller-Vahl, Alexander Munchau, Peter Nagy, Kerstin Jessica Plessen, Cesare Porcelli, Renata Rizzo, Veit Roessner, Jaana Schnell, Markus Schwarz, Liselotte Skov, Tamar Steinberg, Zsanett Tarnok, View ORCID ProfileSusanne Walitza, Andrea Dietrich, Pieter J. Hoekstra, on behalf of the EMTICS Collaborative Group
First published February 10, 2021, DOI: https://doi.org/10.1212/WNL.0000000000011610
Davide Martino
1Department of Clinical Neurosciences, Cumming School of Medicine & Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada;
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Anette Schrag
2Department of Clinical Neuroscience, UCL Institute of Neurology, University College London, London, UK;
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Zacharias Anastasiou
2Department of Clinical Neuroscience, UCL Institute of Neurology, University College London, London, UK;
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Alan Apter
3Child and Adolescent Psychiatry Department, Schneider Children’s Medical Center of Israel, Petah-Tikva. Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Israel;
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Noa Benaroya-Milstein
3Child and Adolescent Psychiatry Department, Schneider Children’s Medical Center of Israel, Petah-Tikva. Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Israel;
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Maura Buttiglione
4Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, Bari, Italy.
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Francesco Cardona
5Department of Human Neurosciences, University La Sapienza of Rome, Rome, Italy;
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Roberta Creti
6Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy;
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Androulla Efstratiou
7WHO Global Collaborating Centre for Reference and Research on Diphtheria and Streptococcal Infections, Reference Microbiology, Directorate National Infection Service, Public Health England, London, UK;
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Tammy Hedderly
8Evelina London Children’s Hospital GSTT, Kings Health Partners AHSC, London, UK;
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Isobel Heyman
9Psychological Medicine, Great Ormond Street Hospital NHS Foundation Trust, Great Ormond Street, London, WC1N 3JH, UK;
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Chaim Huyser
10Department of Child and adolescent psychiatry, De Bascule, Amsterdam UMC, Amsterdam, The Netherlands;
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Marcos Madruga
11Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Seville, Spain;
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Pablo Mir
12 Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain;
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Astrid Morer
13Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clínic, Barcelona.Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación en Red de Salud Mental (CIBERSAM), Instituto Carlos III, Madrid, Spain; Department of Medicine, University of Barcelona, Barcelona, Spain;
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Nanette Mol Debes
14Child and Adolescent Mental Health Center, Mental Health Services, Capital Region of Denmark and University of Copenhagen, Copenhagen, Denmark;
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Natalie Moll
15Institute of Laboratory Medicine, University Hospital LMU Munich, Munich, Germany;
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Norbert Müller
16Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany;
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Kirsten Müller-Vahl
17Department of Psychiatry, Social psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany;
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Alexander Munchau
18Institute of Neurogenetics, University of Lübeck, Lübeck, Germany;
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Peter Nagy
19Vadaskert Child and Adolescent Psychiatric Hospital, Budapest, Hungary;
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Kerstin Jessica Plessen
14Child and Adolescent Mental Health Center, Mental Health Services, Capital Region of Denmark and University of Copenhagen, Copenhagen, Denmark;
20Division of Child and Adolescent Psychiatry, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland;
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Cesare Porcelli
21ASL BA, Mental Health Department; Adolescence and Childhood Neuropsychiatry Unit; Bari, Italy;
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Renata Rizzo
22Child and Adolescent Neurology and Psychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy;
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Veit Roessner
23Department of Child and Adolescent Psychiatry, Medical Faculty Carl Gustav Carus, TU Dresden, Fetscherstrasse 74, 01307, Dresden, Germany;
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Jaana Schnell
16Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany;
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Markus Schwarz
15Institute of Laboratory Medicine, University Hospital LMU Munich, Munich, Germany;
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Liselotte Skov
14Child and Adolescent Mental Health Center, Mental Health Services, Capital Region of Denmark and University of Copenhagen, Copenhagen, Denmark;
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Tamar Steinberg
3Child and Adolescent Psychiatry Department, Schneider Children’s Medical Center of Israel, Petah-Tikva. Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Israel;
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Zsanett Tarnok
19Vadaskert Child and Adolescent Psychiatric Hospital, Budapest, Hungary;
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Susanne Walitza
24Clinic of Child and Adolescent Psychiatry and Psychotherapy, University of Zurich, Zurich, Switzerland;
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Andrea Dietrich
25University of Groningen, University Medical Center Groningen, Department of Child and Adolescent Psychiatry, 9713 GZ Groningen, the Netherlands.
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Pieter J. Hoekstra
25University of Groningen, University Medical Center Groningen, Department of Child and Adolescent Psychiatry, 9713 GZ Groningen, the Netherlands.
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Citation
Association of Group A Streptococcus Exposure and Exacerbations of Chronic Tic Disorders: A Multinational Prospective Cohort Study
Davide Martino, Anette Schrag, Zacharias Anastasiou, Alan Apter, Noa Benaroya-Milstein, Maura Buttiglione, Francesco Cardona, Roberta Creti, Androulla Efstratiou, Tammy Hedderly, Isobel Heyman, Chaim Huyser, Marcos Madruga, Pablo Mir, Astrid Morer, Nanette Mol Debes, Natalie Moll, Norbert Müller, Kirsten Müller-Vahl, Alexander Munchau, Peter Nagy, Kerstin Jessica Plessen, Cesare Porcelli, Renata Rizzo, Veit Roessner, Jaana Schnell, Markus Schwarz, Liselotte Skov, Tamar Steinberg, Zsanett Tarnok, Susanne Walitza, Andrea Dietrich, Pieter J. Hoekstra, on behalf of the EMTICS Collaborative Group
Neurology Feb 2021, 10.1212/WNL.0000000000011610; DOI: 10.1212/WNL.0000000000011610

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Abstract

Objective. To examine prospectively the association between Group A Streptococcus (GAS) pharyngeal exposures and exacerbations of tics in a large multicenter population of youth with chronic tic disorders (CTD) across Europe.

Methods. We followed up 715 children with CTD (age 10.7±2.8 years, 76.8% boys), recruited by 16 specialist clinics from 9 countries, and followed up for 16 months on average. Tic, obsessive-compulsive symptom (OCS) and attention deficit/hyperactivity (ADHD) severity was assessed during 4-monthly study visits and telephone interviews. GAS exposures were analyzed using four possible combinations of measures based on pharyngeal swab and serological testing. The associations between GAS exposures and tic exacerbations or changes of tic, OC and ADHD symptom severity were measured, respectively, using multivariate logistic regression plus multiple failure time analyses, and mixed effects linear regression.

Results. Four-hundred-and-five exacerbations occurred in 308 of 715 (43%) participants. The proportion of exacerbations temporally associated with GAS exposure ranged from 5.5% to 12.9%, depending on GAS exposure definition. We did not detect any significant association of any of the four GAS exposure definitions with tic exacerbations (odds ratios ranging between 1.006 and 1.235, all p values >0.3). GAS exposures were associated with longitudinal changes of hyperactivity-impulsivity symptom severity ranging from 17% to 21%, depending on GAS exposure definition.

Conclusions. This study does not support GAS exposures as contributing factors for tic exacerbations in children with CTD. Specific work-up or active management of GAS infections is unlikely to help modifying the course of tics in CTD and is therefore not recommended.

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  • Received August 4, 2020.
  • Accepted in final form December 14, 2020.
  • © 2021 American Academy of Neurology

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