Multicenter Study

. 2019 Jan;28(1):91-109.

doi: 10.1007/s00787-018-1190-4. Epub 2018 Jul 7.

European Multicentre Tics in Children Studies (EMTICS): protocol for two cohort studies to assess risk factors for tic onset and exacerbation in children and adolescents

Anette Schrag¹, Davide Martino², Alan Apter³, Juliane Ball⁴, Erika Bartolini⁵, Noa Benaroya-Milshtein³, Maura Buttiglione⁶, Francesco Cardona⁷, Roberta Creti⁸, Androulla Efstratiou⁹, Maria Gariup^{10

11}, Marianthi Georgitsi^{12

13}, Tammy Hedderly¹⁴, Isobel Heyman¹⁵, Immaculada Margarit⁵, Pablo Mir¹⁶, Natalie Moll¹⁷, Astrid Morer^{18

19

20}, Norbert Müller^{21

22}, Kirsten Müller-Vahl²³, Alexander Münchau²⁴, Graziella Orefici⁸, Kerstin J Plessen^{25

26}, Cesare Porcelli²⁷, Peristera Paschou²⁸, Renata Rizzo²⁹, Veit Roessner³⁰, Markus J Schwarz¹⁷, Tamar Steinberg³, Friederike Tagwerker Gloor⁴, Zsanett Tarnok³¹, Susanne Walitza⁴, Andrea Dietrich³², Pieter J Hoekstra³³; EMTICS Collaborative Group

Collaborators, Affiliations

Collaborators

EMTICS Collaborative Group:
Zacharias Anastasiou, Alan Apter, Valentina Baglioni, Juliane Ball, Erika Bartolini, Noa Benaroya-Milshtein, Benjamin Bodmer, Emese Bognar, Bianka Burger, Judith Buse, Maura Buttiglione, Francesco Cardona, Marta Correa Vela, Roberta Creti, Andrea Dietrich, Nanette M Debes, Androulla Efstratiou, Maria Cristina Ferro, Carolin Fremer, Blanca Garcia-Delgar, Maria Gariup, Marianthi Georgitsi, Mariangela Gulisano, Annelieke Hagen, Julie Hagstrøm, Tammy J Hedderly, Isobel Heyman, Pieter J Hoekstra, Chaim Huyser, Monica Imperi, Iordanis Karagiannidis, Giovanni Laviola, Simone Macri, Marcos Madruga-Garrido, Immaculada Margarit, Anna Marotta, Davide Martino, Ute C Meier, Pablo Mir, Natalie Moll, Astrid Morer, Norbert Müller, Kirsten Müller-Vahl, Alexander Münchau, Peter Nagy, Valeria Neri, Thaïra J C Openneer, Graziella Orefici, Peristera Paschou, Alessandra Pellico, Onofrio Petruzzelli, Kerstin J Plessen, Cesare Porcelli, Marina Redondo, Renata Rizzo, Paolo Roazzi, Veit Roessner, Daphna Ruhrman, Jaana M L Schnell, Anette Schrag, Gregor A Schütze, Markus J Schwarz, Paola Rosaria Silvestri, Liselotte Skov, Tamar Steinberg, Sara Stöber, Friederike Tagwerker Gloor, Marco Tallon, Zsanett Tarnok, Victoria L Turner, Susanne Walitza, Elif Weidinger, Martin L Woods

Affiliations

¹ Department of Clinical Neurosciences, UCL Institute of Neurology, University College London, London, UK.
² Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.
³ Child and Adolescent Psychiatry Department, Schneider Children's Medical Center of Israel, Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Petah-Tikva, Israel.
⁴ Clinic of Child and Adolescent Psychiatry and Psychotherapy, University of Zurich, Zurich, Switzerland.
⁵ GSK, Siena, Italy.
⁶ Department of Biological Sciences and Human Oncology, Medical School, University of Bari "Aldo Moro", Bari, Italy.
⁷ Department of Human Neurosciences, University La Sapienza of Rome, Rome, Italy.
⁸ Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy.
⁹ WHO Global Collaborating Centre for Reference and Research on Diphtheria and Streptococcal Infections, Reference Microbiology, Directorate National Infection Service, Public Health England, London, UK.
¹⁰ University of Barcelona, Barcelona, Spain.
¹¹ Intensive Inpatient Unit, Copenhagen Psychiatric Center, Copenhagen, Denmark.
¹² Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupoli, Greece.
¹³ Department of Medicine, Aristotle University of Thessaloniki, Thessaloníki, Greece.
¹⁴ Evelina London Children's Hospital GSTT, Kings Health Partners AHSC, London, UK.
¹⁵ Great Ormond Street Hospital for Children, UCL Institute of Child Health, London, UK.
¹⁶ Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clinica, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Seville, Spain.
¹⁷ Institute of Laboratory Medicine, University Hospital, LMU Munich, Munich, Germany.
¹⁸ Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic Universitari, Barcelona, Spain.
¹⁹ Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
²⁰ Centro de Investigacion en Red de Salud Mental (CIBERSAM), Instituto Carlos III, Madrid, Spain.
²¹ Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany.
²² Marion von Tessin Memory-Zentrum gGmbH, Munich, Germany.
²³ Clinic of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany.
²⁴ Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
²⁵ Child and Adolescent Mental Health Center, Mental Health Services, Capital Region of Denmark and University of Copenhagen, Copenhagen, Denmark.
²⁶ Service of Child and Adolescent Psychiatry, Department of Psychiatry, University Medical Center, University of Lausanne, Lausanne, Switzerland.
²⁷ Azienda Sanitaria Locale di Bari, Mental Health Department, Child and Adolescent Neuropsychiatry Service of Bari Metropolitan Area, Bari, Italy.
²⁸ Department of Biological Sciences, Purdue University, West Lafayette, USA.
²⁹ Child Neuropsychiatry Section, Department of Clinical and Experimental Medicine, School of Medicine, Catania University, Catania, Italy.
³⁰ Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Dresden, Germany.
³¹ Vadaskert Child and Adolescent Psychiatric Hospital, Budapest, Hungary.
³² Department of Child and Adolescent Psychiatry, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
³³ Department of Child and Adolescent Psychiatry, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands. p.hoekstra@accare.nl.

PMID: 29982875
PMCID: PMC6349795
DOI: 10.1007/s00787-018-1190-4

Multicenter Study

European Multicentre Tics in Children Studies (EMTICS): protocol for two cohort studies to assess risk factors for tic onset and exacerbation in children and adolescents

Anette Schrag et al. Eur Child Adolesc Psychiatry. 2019 Jan.

. 2019 Jan;28(1):91-109.

doi: 10.1007/s00787-018-1190-4. Epub 2018 Jul 7.

Authors

Collaborators

EMTICS Collaborative Group:
Zacharias Anastasiou, Alan Apter, Valentina Baglioni, Juliane Ball, Erika Bartolini, Noa Benaroya-Milshtein, Benjamin Bodmer, Emese Bognar, Bianka Burger, Judith Buse, Maura Buttiglione, Francesco Cardona, Marta Correa Vela, Roberta Creti, Andrea Dietrich, Nanette M Debes, Androulla Efstratiou, Maria Cristina Ferro, Carolin Fremer, Blanca Garcia-Delgar, Maria Gariup, Marianthi Georgitsi, Mariangela Gulisano, Annelieke Hagen, Julie Hagstrøm, Tammy J Hedderly, Isobel Heyman, Pieter J Hoekstra, Chaim Huyser, Monica Imperi, Iordanis Karagiannidis, Giovanni Laviola, Simone Macri, Marcos Madruga-Garrido, Immaculada Margarit, Anna Marotta, Davide Martino, Ute C Meier, Pablo Mir, Natalie Moll, Astrid Morer, Norbert Müller, Kirsten Müller-Vahl, Alexander Münchau, Peter Nagy, Valeria Neri, Thaïra J C Openneer, Graziella Orefici, Peristera Paschou, Alessandra Pellico, Onofrio Petruzzelli, Kerstin J Plessen, Cesare Porcelli, Marina Redondo, Renata Rizzo, Paolo Roazzi, Veit Roessner, Daphna Ruhrman, Jaana M L Schnell, Anette Schrag, Gregor A Schütze, Markus J Schwarz, Paola Rosaria Silvestri, Liselotte Skov, Tamar Steinberg, Sara Stöber, Friederike Tagwerker Gloor, Marco Tallon, Zsanett Tarnok, Victoria L Turner, Susanne Walitza, Elif Weidinger, Martin L Woods

Affiliations

¹ Department of Clinical Neurosciences, UCL Institute of Neurology, University College London, London, UK.
² Department of Clinical Neurosciences, University of Calgary, Calgary, Canada.
³ Child and Adolescent Psychiatry Department, Schneider Children's Medical Center of Israel, Affiliated to Sackler Faculty of Medicine, Tel Aviv University, Petah-Tikva, Israel.
⁴ Clinic of Child and Adolescent Psychiatry and Psychotherapy, University of Zurich, Zurich, Switzerland.
⁵ GSK, Siena, Italy.
⁶ Department of Biological Sciences and Human Oncology, Medical School, University of Bari "Aldo Moro", Bari, Italy.
⁷ Department of Human Neurosciences, University La Sapienza of Rome, Rome, Italy.
⁸ Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy.
⁹ WHO Global Collaborating Centre for Reference and Research on Diphtheria and Streptococcal Infections, Reference Microbiology, Directorate National Infection Service, Public Health England, London, UK.
¹⁰ University of Barcelona, Barcelona, Spain.
¹¹ Intensive Inpatient Unit, Copenhagen Psychiatric Center, Copenhagen, Denmark.
¹² Department of Molecular Biology and Genetics, Democritus University of Thrace, Alexandroupoli, Greece.
¹³ Department of Medicine, Aristotle University of Thessaloniki, Thessaloníki, Greece.
¹⁴ Evelina London Children's Hospital GSTT, Kings Health Partners AHSC, London, UK.
¹⁵ Great Ormond Street Hospital for Children, UCL Institute of Child Health, London, UK.
¹⁶ Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clinica, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Seville, Spain.
¹⁷ Institute of Laboratory Medicine, University Hospital, LMU Munich, Munich, Germany.
¹⁸ Department of Child and Adolescent Psychiatry and Psychology, Institute of Neurosciences, Hospital Clinic Universitari, Barcelona, Spain.
¹⁹ Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
²⁰ Centro de Investigacion en Red de Salud Mental (CIBERSAM), Instituto Carlos III, Madrid, Spain.
²¹ Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany.
²² Marion von Tessin Memory-Zentrum gGmbH, Munich, Germany.
²³ Clinic of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany.
²⁴ Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
²⁵ Child and Adolescent Mental Health Center, Mental Health Services, Capital Region of Denmark and University of Copenhagen, Copenhagen, Denmark.
²⁶ Service of Child and Adolescent Psychiatry, Department of Psychiatry, University Medical Center, University of Lausanne, Lausanne, Switzerland.
²⁷ Azienda Sanitaria Locale di Bari, Mental Health Department, Child and Adolescent Neuropsychiatry Service of Bari Metropolitan Area, Bari, Italy.
²⁸ Department of Biological Sciences, Purdue University, West Lafayette, USA.
²⁹ Child Neuropsychiatry Section, Department of Clinical and Experimental Medicine, School of Medicine, Catania University, Catania, Italy.
³⁰ Department of Child and Adolescent Psychiatry, Faculty of Medicine, TU Dresden, Dresden, Germany.
³¹ Vadaskert Child and Adolescent Psychiatric Hospital, Budapest, Hungary.
³² Department of Child and Adolescent Psychiatry, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
³³ Department of Child and Adolescent Psychiatry, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands. p.hoekstra@accare.nl.

PMID: 29982875
PMCID: PMC6349795
DOI: 10.1007/s00787-018-1190-4

Abstract

Genetic predisposition, autoimmunity and environmental factors [e.g. pre- and perinatal difficulties, Group A Streptococcal (GAS) and other infections, stress-inducing events] might interact to create a neurobiological vulnerability to the development of tics and associated behaviours. However, the existing evidence for this relies primarily on small prospective or larger retrospective population-based studies, and is therefore still inconclusive. This article describes the design and methodology of the EMTICS study, a longitudinal observational European multicentre study involving 16 clinical centres, with the following objectives: (1) to investigate the association of environmental factors (GAS exposure and psychosocial stress, primarily) with the onset and course of tics and/or obsessive-compulsive symptoms through the prospective observation of at-risk individuals (ONSET cohort: 260 children aged 3-10 years who are tic-free at study entry and have a first-degree relative with a chronic tic disorder) and affected individuals (COURSE cohort: 715 youth aged 3-16 years with a tic disorder); (2) to characterise the immune response to microbial antigens and the host's immune response regulation in association with onset and exacerbations of tics; (3) to increase knowledge of the human gene pathways influencing the pathogenesis of tic disorders; and (4) to develop prediction models for the risk of onset and exacerbations of tic disorders. The EMTICS study is, to our knowledge, the largest prospective cohort assessment of the contribution of different genetic and environmental factors to the risk of developing tics in putatively predisposed individuals and to the risk of exacerbating tics in young individuals with chronic tic disorders.

Keywords: Genetics; Longitudinal; Obsessive–compulsive disorder; Streptococcal infection; Stress; Tourette syndrome.

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Conflict of interest statement

Conflict of interest

Bartolini and Margarit report that they were employee of Novartis Vaccines at the start of the study. Following the acquisition of Novartis Vaccines by the GSK group of companies in March, 2015, Bartolini and Margarit are now employees of the GSK group of companies. Müller-Vahl received funding for research from the EU (FP7-PEOPLE-2012-ITN No. 316978), the German Research Society (DFG: GZ MU 1527/3-1), the German Ministry of Education and Research (BMBF: 01KG1421), the National Institute of Mental Health (NIMH), GW, Almirall, Abide Therapeutics, and Therapix Biosiences, and consultant’s honoraria from Abide Therapeutics, Fundacion Canna, and Therapix Biosiences. Walitza has received lecture honoraria from Eli-Lilly, Opopharma in the last 5 years. On behalf of all other authors, the corresponding author declares that the other authors have no conflict of interest.

Ethical standards

This study was approved by the institutional review boards at all participating clinical centres in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All parents (or the legal guardian) provided written informed consent and the participating child written or oral assent before entering the study.

Figures

**Fig. 1**
ONSET study flow chart. *Tele* telephone interview. If no tic onset was detected and confirmed then the original assessment schedule (left side) was retained. After an onset of tics visit, all assessments were discarded, except for a 1-year follow-up visit. The minimum study period was 1 year, tic onset at the final visit increased the maximum study period to 4 years

**Fig. 2**
COURSE study flow chart. *Tele* telephone interview, *YGTSS* Yale Global Tic Severity Scale. If no tic exacerbation was detected and confirmed then the original 16 month assessment schedule (left side) was retained. The maximum study period was 18 months if a tic exacerbation was detected at the final visit. A maximum of two pairs of expedited and post-exacerbation visits was possible. Expedited visits shortened the study period accordingly

See this image and copyright information in PMC

References

1. Arlington VA. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5. Washington, DC: American Psychiatric Publication; 2013.
1. Knight T, Steeves T, Day L, Lowerison M, Jette N, Pringsheim T. Prevalence of tic disorders: a systematic review and meta-analysis. Pediatr Neurol. 2012;47(2):77–90. - PubMed
1. Robertson MM. The prevalence and epidemiology of Gilles de la Tourette syndrome. Part 2: tentative explanations for differing prevalence figures in GTS, including the possible effects of psychopathology, aetiology, cultural differences, and differing phenotypes. J Psychosom Res. 2008;65(5):473–486. - PubMed
1. Robertson MM. A personal 35 year perspective on Gilles de la Tourette syndrome: assessment, investigations, and management. Lancet Psychiatry. 2015;2(1):88–104. - PubMed
1. Altman G, Staley JD, Wener P. Children with Tourette disorder: a follow-up study in adulthood. J Nerv Ment Dis. 2009;197(5):305–310. - PubMed

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European Multicentre Tics in Children Studies (EMTICS): protocol for two cohort studies to assess risk factors for tic onset and exacerbation in children and adolescents

Collaborators

Affiliations

European Multicentre Tics in Children Studies (EMTICS): protocol for two cohort studies to assess risk factors for tic onset and exacerbation in children and adolescents

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Conflict of interest

Ethical standards

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources