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.
Bibliographical noteFunding Information:
RB has received consultancy fees from Merz Pharmaceuticals and payment to his institution from Merz Pharmaceuticals in relation to a single, pending patent (botulinum toxin application pumps, intracerebral botulinum injections). KB has received speaker's fees and travel expenses from Medtronic. GD has received a grant and personal fees from Medtronic, and speakers fees and travel expenses from Sapiens, Boston Scientific, Britannica, Desitin, and UCB. WE has received speaker's fees from Medtronic. DF has received speaker's fees from Medtronic. JKK has received consultancy fees and speaker's fees from Medtronic. AAK has received a grant from Medtronic; speaker's fees from Novartis, Bayer, Medtronic, St Jude Medical, and Boston Scientific; and travel expenses from Ipsen Pharma. AKu has served as an advisory board member for Medtronic, USA, and Allergan, USA; and received speaker's fees from Allergan, Boehringer Ingelheim, Ipsen Pharma, Lundbeck, Medtronic, Merck, Merz Pharmaceuticals, Orion, St Jude Medical, and UCB. JMe has received speaker's fees from Medtronic. JMu has received a grant to his institution from Merz Pharmaceuticals, and speaker's fees from Merz Pharmaceuticals and UCB. MP has received travel or meeting expenses from Medtronic. WP has received consultancy and lecture fees from AbbVie, Astra Zeneca, Teva-Lundbeck, Novartis, GlaxoSmithKline, Boehringer-Ingelheim, UCB, Orion Pharma, Merck Serono, and Merz Pharmaceuticals in relation to clinical drug development programmes for Parkinson's disease; and has received a grant from Astra Zeneca (2009–2012). G-HS has received consultancy fees from St Jude Medical and Boston Scientific. AS has received speaker's fees and payment for development of educational presentations, consultancy fees, and travel expenses from Medtronic. CS has received consultancy fees from AbbVie and speaker's fees from AbbVie and Merz Pharmaceuticals. IMS has received meeting expenses from Medtronic. MS has received speaker's fees and fees for educational presentations from Medtronic. LT has received grant, consultancy fees, and travel expenses from Medtronic; consultancy fees from Medtronic, Boston Scientific, Sapiens, St Jude Medical, Bayer Healthcare, UCB, Archimedes Pharma; board membership fees from Medtronic, Boston Scientific, TEVA, UCB, and Archimedes; grants or grants pending from Medtronic, TEVA, UCB, Boston Scientific, Archimedes, Bayer, Zur Rose Pharma; and speaker's fees from TEVA, Lundbeck, Bracco, Gianni PR, Medas, UCB, Desitin, Boehringer, GlaxoSmithKline, Eumecom, Orion Pharma, Cephalon, Abbott/AbbVie, Archimedes, Bayer. JV has received consultancy fees and travel expenses from Medtronic. JLV has received grants from Boston Scientific, Medtronic, and St Jude Medical; consultancy fees and travel expenses from Boston Scientific, Medtronic, St Jude Medical, and InSightec; fees for review activities from St Jude Medical; and speaker's fees from Boston Scientific and Medtronic. JVog has received consultancy fees from Medtronic and Sapiens, and speaker's fees from Medtronic. JVol has received grants from Medtronic, Boston Scientific, and AbbVie; consultancy fees from Medtronic, Boston Scientific, and Novartis; and speaker's fees from Medtronic, Boston Scientific, AbbVie, St. Jude Medical, TEVA, UCB, and Novartis. MW has received speaker's fees from Bristol-Myers Squibb, Medtronic, AbbVie, and Ipsen Pharma; and travel expenses from Merz Pharma, Ipsen Pharma, and Bristol-Myers Squibb. All other authors declare no competing interests.
The study was supported by an unrestricted research grant from Medtronic to JMu and RB. Additional funding was obtained from the universities involved. We thank Deborah Nock (Medical WriteAway, UK) for proofreading and editing of the manuscript, funded by the Julius Maximilians University, Würzburg, Germany.
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