Marie-Laure Welter1, Jean-Luc Houeto2, Stéphane Thobois3, Benoit Bataille4, Marc Guenot5, Yulia Worbe6, Andreas Hartmann6, Virginie Czernecki6, Eric Bardinet7, Jerome Yelnik7, Sophie Tezenas du Montcel8, Yves Agid7, Marie Vidailhet7, Philippe Cornu9, Audrey Tanguy10, Solène Ansquer2, Nematollah Jaafari11, Emmanuel Poulet12, Giulia Serra13, Pierre Burbaud14, Emmanuel Cuny15, Bruno Aouizerate16, Pierre Pollak17, Stephan Chabardes18, Mircea Polosan19, Michel Borg20, Denys Fontaine21, Bruno Giordana22, Sylvie Raoul23, Tiphaine Rouaud24, Anne Sauvaget25, Isabelle Jalenques26, Carine Karachi27, Luc Mallet28. 1. Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Neurology Department, Paris, France; Clinical Investigation Centre, INSERM 1127, Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, Paris, France; Unité Mixte de Recherche (UMR) S1127, Centre National de la Recherche Scientifique (CNRS), UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France. Electronic address: marie-laure.welter@psl.aphp.fr. 2. Department of Neurology, INSERM-Centre d'Investigation Clinique 1402, University of Poitiers, Centre Hospitalier Universitaire (CHU) de Poitiers, Poitiers, France. 3. Department of Neurology C, Hôpital Neurologique, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France; CNRS, Lyon Centre for Neuroscience Research, University Lyon 1, Bron, France. 4. Department of Neurosurgery, INSERM-Centre d'Investigation Clinique 1402, University of Poitiers, Centre Hospitalier Universitaire (CHU) de Poitiers, Poitiers, France. 5. Department of Neurosurgery A, Hôpital Neurologique, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France. 6. Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Neurology Department, Paris, France. 7. Unité Mixte de Recherche (UMR) S1127, Centre National de la Recherche Scientifique (CNRS), UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France. 8. AP-HP, Pitié-Salpêtrière Hospital, Biostatistics and Medical Informatics Unit and Clinical Research Unit, Paris, France; Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, UMR S1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France. 9. Neurosurgery, INSERM 1127, Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, Paris, France. 10. AP-HP, Pitié-Salpêtrière Hospital, Biostatistics and Medical Informatics Unit and Clinical Research Unit, Paris, France. 11. Department of Psychiatry, INSERM-Centre d'Investigation Clinique 1402, University of Poitiers, Centre Hospitalier Universitaire (CHU) de Poitiers, Poitiers, France. 12. PsyR2 Team, U 1028, INSERM and UMR 5292, Centre Hospitalier Le Vinatier, Bron, France. 13. Department of Neurology C, Hôpital Neurologique, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France. 14. Department of Neurophysiology, Charles Perrens Hospital, University Bordeaux 2, CNRS UMR 5543, Bordeaux, France. 15. Department of Neurosurgery, Charles Perrens Hospital, University Bordeaux 2, CNRS UMR 5543, Bordeaux, France. 16. Department of Psychiatry, Charles Perrens Hospital, University Bordeaux 2, CNRS UMR 5543, Bordeaux, France. 17. Department of Neurology, Grenoble Alpes University, CHU Grenoble, Grenoble, France. 18. Department of Neurosurgery, Grenoble Alpes University, CHU Grenoble, Grenoble, France. 19. Department of Psychiatry, Grenoble Alpes University, CHU Grenoble, Grenoble, France. 20. Department of Neurology, University Hospital, Nice, France. 21. Department of Neurosurgery, University Hospital, Nice, France. 22. Department of Psychiatry, University Hospital, Nice, France. 23. Department of Neurosurgery, Nantes University Hospital, Nantes, France. 24. Department of Neurology, Nantes University Hospital, Nantes, France. 25. Department of Psychiatry, Nantes University Hospital, Nantes, France. 26. Department of Psychiatry, CHU Clermont-Ferrand and Clermont Auvergne University, Equipe d'Accueil 7280, Clermont-Ferrand, France. 27. Neurosurgery, INSERM 1127, Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, Paris, France; Unité Mixte de Recherche (UMR) S1127, Centre National de la Recherche Scientifique (CNRS), UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France. 28. Unité Mixte de Recherche (UMR) S1127, Centre National de la Recherche Scientifique (CNRS), UMR 7225, Institut du Cerveau et de la Moelle Epinière, Paris, France; AP-HP, Personalised Neurology and Psychiatry University Department, Hôpitaux Universitaires Henri Mondor - Albert Chenevier, Université Paris Est Créteil, Créteil, France; Department of Mental Health and Psychiatry, Geneva University Hospital, University of Geneva, Geneva, Switzerland.
Abstract
BACKGROUND:Deep brain stimulation (DBS) has been proposed to treat patients with severe Tourette's syndrome, and open-label trials and two small double-blind trials have tested DBS of the posterior and the anterior internal globus pallidus (aGPi). We aimed to specifically assess the efficacy of aGPi DBS for severe Tourette's syndrome. METHODS: In this randomised, double-blind, controlled trial, we recruited patients aged 18-60 years with severe and medically refractory Tourette's syndrome from eight hospitals specialised in movement disorders in France. Enrolled patients received surgery to implant bilateral electrodes for aGPi DBS; 3 months later they were randomly assigned (1:1 ratio with a block size of eight; computer-generated pairwise randomisation according to order of enrolment) to receive either active or sham stimulation for the subsequent 3 months in a double-blind fashion. All patients then received open-label active stimulation for the subsequent 6 months. Patients and clinicians assessing outcomes were masked to treatment allocation; an unmasked clinician was responsible for stimulation parameter programming, with intensity set below the side-effect threshold. The primary endpoint was difference in Yale Global Tic Severity Scale (YGTSS) score between the beginning and end of the 3 month double-blind period, as assessed with a Mann-Whitney-Wilcoxon test in all randomly allocated patients who received active or sham stimulation during the double-blind period. We assessed safety in all patients who were enrolled and received surgery for aGPi DBS. This trial is registered with ClinicalTrials.gov, number NCT00478842. FINDINGS: Between Dec 6, 2007, and Dec 13, 2012, we enrolled 19 patients. We randomly assigned 17 (89%) patients, with 16 completing blinded assessments (seven [44%] in the active stimulation group and nine [56%] in the sham stimulation group). We noted no significant difference in YGTSS score change between the beginning and the end of the 3 month double-blind period between groups (active group median YGTSS score68·5 [IQR 34·0 to 83·5] at the beginning and 62·5 [51·5 to 72·0] at the end, median change 1·1% [IQR -23·9 to 38·1]; sham group 73·0 [69·0 to 79·0] and 79·0 [59·0 to 81·5], median change 0·0% [-10·6 to 4·8]; p=0·39). 15 serious adverse events (three in patients who withdrew before stimulation and six each in the active and sham stimulation groups) occurred in 13 patients (three who withdrew before randomisation, four in the active group, and six in the sham group), with infections in DBS hardware in four patients (two who withdrew before randomisation, one in the sham stimulation group, and one in the active stimulation group). Other serious adverse events included one electrode misplacement (active stimulation group), one episode of depressive signs (active stimulation group), and three episodes of increased tic severity and anxiety (two in the sham stimulation group and one in the active stimulation group). INTERPRETATION: 3 months of aGPi DBS is insufficient to decrease tic severity for patients with Tourette's syndrome. Future research is needed to investigate the efficacy of aGPi DBS for patients over longer periods with optimal stimulation parameters and to identify potential predictors of the therapeutic response. FUNDING: French Ministry of Health.
RCT Entities:
BACKGROUND: Deep brain stimulation (DBS) has been proposed to treat patients with severe Tourette's syndrome, and open-label trials and two small double-blind trials have tested DBS of the posterior and the anterior internal globus pallidus (aGPi). We aimed to specifically assess the efficacy of aGPi DBS for severe Tourette's syndrome. METHODS: In this randomised, double-blind, controlled trial, we recruited patients aged 18-60 years with severe and medically refractory Tourette's syndrome from eight hospitals specialised in movement disorders in France. Enrolled patients received surgery to implant bilateral electrodes for aGPi DBS; 3 months later they were randomly assigned (1:1 ratio with a block size of eight; computer-generated pairwise randomisation according to order of enrolment) to receive either active or sham stimulation for the subsequent 3 months in a double-blind fashion. All patients then received open-label active stimulation for the subsequent 6 months. Patients and clinicians assessing outcomes were masked to treatment allocation; an unmasked clinician was responsible for stimulation parameter programming, with intensity set below the side-effect threshold. The primary endpoint was difference in Yale Global Tic Severity Scale (YGTSS) score between the beginning and end of the 3 month double-blind period, as assessed with a Mann-Whitney-Wilcoxon test in all randomly allocated patients who received active or sham stimulation during the double-blind period. We assessed safety in all patients who were enrolled and received surgery for aGPi DBS. This trial is registered with ClinicalTrials.gov, number NCT00478842. FINDINGS: Between Dec 6, 2007, and Dec 13, 2012, we enrolled 19 patients. We randomly assigned 17 (89%) patients, with 16 completing blinded assessments (seven [44%] in the active stimulation group and nine [56%] in the sham stimulation group). We noted no significant difference in YGTSS score change between the beginning and the end of the 3 month double-blind period between groups (active group median YGTSS score 68·5 [IQR 34·0 to 83·5] at the beginning and 62·5 [51·5 to 72·0] at the end, median change 1·1% [IQR -23·9 to 38·1]; sham group 73·0 [69·0 to 79·0] and 79·0 [59·0 to 81·5], median change 0·0% [-10·6 to 4·8]; p=0·39). 15 serious adverse events (three in patients who withdrew before stimulation and six each in the active and sham stimulation groups) occurred in 13 patients (three who withdrew before randomisation, four in the active group, and six in the sham group), with infections in DBS hardware in four patients (two who withdrew before randomisation, one in the sham stimulation group, and one in the active stimulation group). Other serious adverse events included one electrode misplacement (active stimulation group), one episode of depressive signs (active stimulation group), and three episodes of increased tic severity and anxiety (two in the sham stimulation group and one in the active stimulation group). INTERPRETATION: 3 months of aGPi DBS is insufficient to decrease tic severity for patients with Tourette's syndrome. Future research is needed to investigate the efficacy of aGPi DBS for patients over longer periods with optimal stimulation parameters and to identify potential predictors of the therapeutic response. FUNDING: French Ministry of Health.
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