Jens Volkmann1, Joerg Mueller2, Günther Deuschl3, Andrea A Kühn4, Joachim K Krauss5, Werner Poewe2, Lars Timmermann6, Daniela Falk7, Andreas Kupsch4, Anatol Kivi4, Gerd-Helge Schneider8, Alfons Schnitzler6, Martin Südmeyer6, Jürgen Voges9, Alexander Wolters10, Matthias Wittstock10, Jan-Uwe Müller11, Sascha Hering2, Wilhelm Eisner12, Jan Vesper13, Thomas Prokop13, Marcus Pinsker14, Christoph Schrader15, Manja Kloss16, Karl Kiening17, Kai Boetzel18, Jan Mehrkens19, Inger Marie Skogseid20, Jon Ramm-Pettersen21, Georg Kemmler22, Kailash P Bhatia23, Jerrold L Vitek24, Reiner Benecke10. 1. Department of Neurology, Christian Albrechts University, Kiel, Germany. Electronic address: volkmann_j@ukw.de. 2. Department of Neurology, Medical University Innsbruck, Innsbruck, Austria. 3. Department of Neurology, Christian Albrechts University, Kiel, Germany. 4. Department of Neurology, Charité Universitätsmedizin Berlin, Campus Virchow, Berlin, Germany. 5. Department of Neurosurgery, Medical School Hannover, Hannover, Germany. 6. Department of Neurology and Institute of Clinical Neuroscience and Medical Psychology, Heinrich Heine University, Düsseldorf, Germany. 7. Department of Neurosurgery, Christian Albrechts University, Kiel, Germany. 8. Department of Neurosurgery, Charité Universitätsmedizin Berlin, Campus Virchow, Berlin, Germany. 9. Department of Stereotactic and Functional Neurosurgery, University of Cologne, Cologne, Germany. 10. Department of Neurology, University of Rostock, Rostock, Germany. 11. Department of Neurosurgery, Ernst Moritz Arndt University, Greifswald, Germany. 12. Department of Neurosurgery, Medical University Innsbruck, Innsbruck, Austria. 13. Division of Stereotactic and Functional Neurosurgery, University of Freiburg, Freiburg, Germany. 14. Department of Neurosurgery, Christian Albrechts University, Kiel, Germany; Division of Stereotactic and Functional Neurosurgery, University of Freiburg, Freiburg, Germany. 15. Department of Neurology, Medical School Hannover, Hannover, Germany. 16. Department of Neurology, University of Heidelberg, Heidelberg, Germany. 17. Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany. 18. Department of Neurology, Ludwig Maximilians University, Munich, Germany. 19. Department of Neurosurgery, Ludwig Maximilians University, Munich, Germany. 20. Department of Neurology, University of Oslo, Oslo, Norway. 21. Department of Neurosurgery, University of Oslo, Oslo, Norway. 22. Section of Biostatistics, Department of Psychiatry, Medical University Innsbruck, Innsbruck, Austria. 23. Institute of Neurology, University College London, London, UK. 24. Department of Neurology, University of Minnesota, Minneapolis, MN, USA.
Abstract
BACKGROUND: Cervical dystonia is managed mainly by repeated botulinum toxin injections. We aimed to establish whether pallidal neurostimulation could improve symptoms in patients not adequately responding to chemodenervation or oral drug treatment. METHODS: In this randomised, sham-controlled trial, we recruited patients with cervical dystonia from centres in Germany, Norway, and Austria. Eligible patients (ie, those aged 18-75 years, disease duration≥3 years, Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] severity score ≥15 points) were randomly assigned (1:1) to receive active neurostimulation (frequency 180 Hz; pulse width 120 μs; amplitude 0·5 V below adverse event threshold) or sham stimulation (amplitude 0 V) by computer-generated randomisation lists with randomly permuted block lengths stratified by centre. All patients, masked to treatment assignment, were implanted with a deep brain stimulation device and received their assigned treatment for 3 months. Neurostimulation was activated in the sham group at 3 months and outcomes were reassessed in all patients after 6 months of active treatment. Treating physicians were not masked. The primary endpoint was the change in the TWSTRS severity score from baseline to 3 months, assessed by two masked dystonia experts using standardised videos, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00148889. FINDINGS:Between Jan 19, 2006, and May 29, 2008, we recruited 62 patients, of whom 32 were randomly assigned to neurostimulation and 30 to sham stimulation. Outcome data were recorded in 60 (97%) patients at 3 months and 56 (90%) patients at 6 months. At 3 months, the reduction in dystonia severity was significantly greater with neurostimulation (-5·1 points [SD 5·1], 95% CI -7·0 to -3·5) than with sham stimulation (-1·3 [2·4], -2·2 to -0·4, p=0·0024; mean between-group difference 3·8 points, 1·8 to 5·8) in the intention-to-treat population. Over the course of the study, 21 adverse events (five serious) were reported in 11 (34%) of 32 patients in the neurostimulation group compared with 20 (11 serious) in nine (30%) of 30 patients in the sham-stimulation group. Serious adverse events were typically related to the implant procedure or the implanted device, and 11 of 16 resolved without sequelae. Dysarthria (in four patients assigned to neurostimulation vs three patients assigned to sham stimulation), involuntary movements (ie, dyskinesia or worsening of dystonia; five vs one), and depression (one vs two) were the most common non-serious adverse events reported during the course of the study. INTERPRETATION: Pallidal neurostimulation for 3 months is more effective than sham stimulation at reducing symptoms of cervical dystonia. Extended follow-up is needed to ascertain the magnitude and stability of chronic neurostimulation effects before this treatment can be recommended as routine for patients who are not responding to conventional medical therapy. FUNDING: Medtronic.
RCT Entities:
BACKGROUND:Cervical dystonia is managed mainly by repeated botulinum toxin injections. We aimed to establish whether pallidal neurostimulation could improve symptoms in patients not adequately responding to chemodenervation or oral drug treatment. METHODS: In this randomised, sham-controlled trial, we recruited patients with cervical dystonia from centres in Germany, Norway, and Austria. Eligible patients (ie, those aged 18-75 years, disease duration ≥3 years, Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] severity score ≥15 points) were randomly assigned (1:1) to receive active neurostimulation (frequency 180 Hz; pulse width 120 μs; amplitude 0·5 V below adverse event threshold) or sham stimulation (amplitude 0 V) by computer-generated randomisation lists with randomly permuted block lengths stratified by centre. All patients, masked to treatment assignment, were implanted with a deep brain stimulation device and received their assigned treatment for 3 months. Neurostimulation was activated in the sham group at 3 months and outcomes were reassessed in all patients after 6 months of active treatment. Treating physicians were not masked. The primary endpoint was the change in the TWSTRS severity score from baseline to 3 months, assessed by two masked dystonia experts using standardised videos, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00148889. FINDINGS: Between Jan 19, 2006, and May 29, 2008, we recruited 62 patients, of whom 32 were randomly assigned to neurostimulation and 30 to sham stimulation. Outcome data were recorded in 60 (97%) patients at 3 months and 56 (90%) patients at 6 months. At 3 months, the reduction in dystonia severity was significantly greater with neurostimulation (-5·1 points [SD 5·1], 95% CI -7·0 to -3·5) than with sham stimulation (-1·3 [2·4], -2·2 to -0·4, p=0·0024; mean between-group difference 3·8 points, 1·8 to 5·8) in the intention-to-treat population. Over the course of the study, 21 adverse events (five serious) were reported in 11 (34%) of 32 patients in the neurostimulation group compared with 20 (11 serious) in nine (30%) of 30 patients in the sham-stimulation group. Serious adverse events were typically related to the implant procedure or the implanted device, and 11 of 16 resolved without sequelae. Dysarthria (in four patients assigned to neurostimulation vs three patients assigned to sham stimulation), involuntary movements (ie, dyskinesia or worsening of dystonia; five vs one), and depression (one vs two) were the most common non-serious adverse events reported during the course of the study. INTERPRETATION: Pallidal neurostimulation for 3 months is more effective than sham stimulation at reducing symptoms of cervical dystonia. Extended follow-up is needed to ascertain the magnitude and stability of chronic neurostimulation effects before this treatment can be recommended as routine for patients who are not responding to conventional medical therapy. FUNDING: Medtronic.
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