Pallidal neurostimulation in patients with medication-refractory cervical dystonia: a randomised, sham-controlled trial
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- Randolf Sutton
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1 Pallidal neurostimulation in patients with medication-refractory cervical dystonia: a randomised, sham-controlled trial Jens Volkmann, Joerg Mueller, Günther Deuschl, Andrea A Kühn, Joachim K Krauss, Werner Poewe, Lars Timmermann, Daniela Falk, Andreas Kupsch, Anatol Kivi, Gerd-Helge Schneider, Alfons Schnitzler, Martin Südmeyer, Jürgen Voges, Alexander Wolters, Matthias Wittstock, Jan-Uwe Müller, Sascha Hering, Wilhelm Eisner, Jan Vesper, Thomas Prokop, Marcus Pinsker, Christoph Schrader, Manja Kloss, Karl Kiening, Kai Boetzel, Jan Mehrkens, Inger Marie Skogseid, Jon Ramm-Pettersen, Georg Kemmler, Kailash P Bhatia, Jerrold L Vitek, Reiner Benecke, for the DBS study group for dystonia* Summary 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 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 NCT 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. Introduction Cervical dystonia, also known as spasmodic torticollis, is a chronic neurological disorder in which the head turns or tilts in jerky movements or sustains a prolonged and awkward position due to involuntary contractions of neck muscles. Cervical dystonia is the most frequent focal dystonia, with an estimated prevalence of per million people in Europe and North America. 1 3 It has a profound effect on quality of life through a complex interaction of motor impairment, neck pain, and stigma, leading to significant restrictions in daily activities and social participation. 4 6 Although cervical dystonia is thought to arise from pathological neuronal activity within brain motor circuits, the mainstay treatment targets the periphery. Repeated injections of botulinum toxin to denervate dystonic neck muscles are the first-line treatment option for most patients. 7,8 This approach is more efficacious than oral treatment with anticholinergic agents 9 the most effective oral medications for dystonia. 10 However, Lancet Neurol 2014; 13: Published Online August 8, S (14) See Comment 856 *Members are listed in the appendix Department of Neurology (Prof J Volkmann MD, Prof G Deuschl MD), and Department of Neurosurgery (D Falk MD, M Pinsker MD), Christian Albrechts University, Kiel, Germany; Department of Neurology (J Mueller MD, Prof W Poewe MD, S Hering MD), Department of Neurosurgery (W Eisner MD), and Section of Biostatistics, Department of Psychiatry (G Kemmler PhD), Medical University Innsbruck, Innsbruck, Austria; Department of Neurology (Prof A A Kühn MD, A Kupsch MD, A Kivi MD), and Department of Neurosurgery (G-H Schneider MD), Charité Universitätsmedizin Berlin, Campus Virchow, Berlin, Germany; Department of Neurosurgery (Prof J K Krauss MD), and Department of Neurology (C Schrader MD), Medical School Hannover, Hannover, Germany; Department of Neurology and Institute of Clinical Neuroscience and Medical Psychology, Heinrich Heine University, Düsseldorf, Germany (Prof L Timmermann MD, Prof A Schnitzler MD, M Südmeyer MD); Department of Stereotactic and Functional Neurosurgery, University of Cologne, Cologne, Germany (Prof J Voges MD); Department of Neurology, University of Rostock, Rostock, Germany (A Wolters MD, M Wittstock MD, Prof R Benecke MD); Department of Neurosurgery, Ernst Moritz Arndt University, Vol 13 September
2 Greifswald, Germany (J-U Müller MD); Division of Stereotactic and Functional Neurosurgery, University of Freiburg, Freiburg, Germany (Prof J Vesper MD, T Prokop MD, M Pinsker MD); Department of Neurology (M Kloss MD), and Department of Neurosurgery (K Kiening,MD), University of Heidelberg, Heidelberg, Germany; Department of Neurology (K Boetzel MD), and Department of Neurosurgery (Jan Mehrkens MD), Ludwig Maximilians University, Munich, Germany; Department of Neurology (I M Skogseid MD), and Department of Neurosurgery (J Ramm-Pettersen MD), University of Oslo, Oslo, Norway; Institute of Neurology, University College London, London, UK (Prof K P Bhatia FRCP); and Department of Neurology, University of Minnesota, Minneapolis, MN, USA (Prof J Vitek MD) Figure 1: Trial profile chemo denervation does not work in a proportion of patients (the exact figure is not known) because the movement pattern is too complex or involves muscles that are difficult to inject, and because treatment is limited by side-effects such as dysphagia. Moreover, up to 5% of patients develop immunoresistance to botulinum toxin type A or B, 11 which is associated with unresponsiveness to chemodenervation. A clinical study in a real-word setting reported a beneficial response to one injection session of botulinum toxin A in 58% (95% CI ) of 404 patients with cervical dystonia, as defined by physician-rated dystonia severity, self-perceived improvement on a global clinical rating scale, and good tolerance. 12 The proportion dropped to 29% (95% CI ) when adding sustained benefit through out the standard 12-week treatment cycle to the response criteria, 12 which shows the need for treatment alternatives, particularly in patients who do not respond after receiving several injection cycles by an experienced therapist. Deep brain stimulation of the internal segment of the globus pallidus via electrodes implanted in the brain has proven to be an effective and relatively safe treatment for patients with severe generalised or segmental dystonia. 13,14 Results of small retrospective cohort studies and one controlled trial with ten patients 21 also suggest a beneficial effect in cervical dystonia. The risk benefit ratio of this surgical therapy for patients with cervical dystonia, however, should be scrutinised because focal dystonia is 85 patients screened for eligibility 32 assigned to receive neurostimulation (intention-to-treat population) 1 withdrew consent after failed implantation 31 completed randomised phase (baseline to month 3) 1 incomplete 3-month visit (no primary outcome) 31 entered extension phase 31 completed extension phase (6 months active neurostimulation) 62 patients enrolled, randomly assigned to a treatment group, and operated upon 30 assigned to receive sham stimulation (intention-to-treat population) 30 completed randomised phase (baseline to month 3) 30 entered extension phase (neurostimulation activated) 23 excluded 15 did not give consent 7 did not meet inclusion criteria 1 death before inclusion 30 completed extension phase (6 months active neurostimulation) 2 missed 6-month visit not a life-threatening disease and botulinum toxin treatment provides some symptomatic relief for most patients. In this study, we aimed to assess the clinical efficacy and safety of bilateral pallidal neurostimulation for patients with medication-refractory cervical dystonia. Methods Study design and patients This study was a multicentre, randomised, patient-blind and observer-blind, sham-controlled, parallel-group trial done at ten academic centres in Germany, Norway, and Austria. Patients with idiopathic or inherited isolated cervical dystonia 22 were eligible if they met the following inclusion criteria: age years; disease duration 3 years or longer; severity score for motor symptoms 15 points or higher on the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS); previous botulinum toxin treatment received at least 6 months ago; documented unsatisfactory response to oral treatment with trihexyphenidyl at the maximally tolerated dose; and documented unsatisfactory response to previous botulinum toxin treatment (appendix). Exclusion criteria were previous brain surgery; cognitive impairment (Mattis Dementia Rating Scale score <120); moderate-tosevere depression (Beck Depression Inventory score >25); hemidystonia or generalised dystonia; marked brain atrophy (detected by MRI or CT); pregnancy; increased bleeding risk; immune deficiency; and relevant cerebrovascular disease or other medical or psychiatric comorbidities that could increase surgical risk or interfere with successful trial completion. The study was investigator-initiated (JM, RB) in collaboration with the Section of Biostatistics, Department of Psychiatry, Medical University Innsbruck, Innsbruck, Austria (GK). The trial conformed to the Helsinki Declaration, and Good Clinical Practice Guidelines, and was approved by the ethics committees at participating centres. All patients provided written informed consent before randomisation. Full source data verification was done by monitors of the KKS Marburg (clinical trials coordination centre), Marburg, Germany. Randomisation and masking Participants were randomly assigned in a 1:1 ratio to either neurostimulation or sham stimulation by computer-generated randomisation lists with randomly permuted block lengths stratified by centre. The randomisation sequence was known only to the clinical trials coordination centre (KKS Marburg), which was contacted by the local principal investigator or coinvestigator at the participating centre after enrolment of a patient. The coordination centre then communicated the treatment assignment by return fax. Patients, but not treating physicians, were masked to group assignment, the success of which was assessed at 3 months by asking patients to guess their treatment allocation. Treatment Vol 13 September 2014
3 outcomes were assessed by two independent dystonia experts (KB and JLV) who were unaware of the treatmentgroup assignment and order of the examinations, by rating the severity of cervical dystonia on standardised videos recorded at baseline and 3 months, and after 6 months of active neurostimulation. Procedures Patients were screened for eligibility and after inclusion completed a baseline assessment within 12 weeks of screening. Within 6 weeks of their baseline assessment, they underwent simultaneous bilateral stereotactic implantation of electrodes (model 3387 or 3389, Medtronic, Minneapolis, MN, USA) into the posteroventrolateral internal globus pallidus, which were connected to an implantable pulse generator (Kinetra, Medtronic) during the same or a subsequent surgery. Within 1 week after surgery, patients underwent a review session to screen for the chronic monopolar stimulation contact (appendix). Thereafter, patients assigned to the stimulation group were programmed with neurostimulation parameters (180 Hz, 120 μs pulse width) by setting the amplitude to 0 5 V below the threshold of acute adverse effects, and those assigned to sham stimulation received 0 V output. A follow-up assessment was scheduled at 3 months. At the end of this visit, neurostimulation was activated in the sham-stimulation group with the settings defined by the previous monopolar review, and was adjusted in the neurostimulation group if needed. Patients were reassessed after 6 months of active neurostimulation (ie, 6 months after randomisation for the neurostimulation group and 9 months for the sham-stimulation group). Clinical follow-up and programming sessions could be scheduled at any time on the request of the treating physician or the patient. Adverse events in all patients (intention-to-treat population) were reported by the local investigators, and full source data verification was obtained through the KKS Marburg. Serious adverse events were defined as any events that led to death, disability, required hospital admission, or lengthened a hospital stay, with serious health impairment. Outcomes The primary endpoint was the change in TWSTRS severity score at 3 months. Prespecified secondary outcomes were change in TWSTRS disability and pain scores, Bain tremor score, and Craniocervical Dystonia Questionnaire-24 score. All other outcomes were analysed post hoc. Neurostimulation (n=32) Sham stimulation (n=30) Age, years 57 1 (9 82) 56 6 (11 33) Duration of disease, years 14 9 (7 95) 14 8 (6 41) Sex Men 12 (38%) 15 (50%) Women 20 (63%) 15 (50%) Type of cervical dystonia Simple 3 (9%) 6 (20%) TC 3 (9%) 6 (20%) Combined 13 (41%) 12 (40%) TC+AC 4 (13%) 5 (17%) TC+LC 8 (25%) 7 (23%) TC+RC 1 (3%) 0 Complex 16 (50%) 12 (40%) TC+LC+AC 10 (31%) 6 (20%) TC+LC+RC 6 (19%) 6 (20%) Dystonia classification* Isolated cervical 32 (100%) 30 (100%) Facial involvement 8 (25%) 3 (10%) Upper limb involvement 0 1 (3%) Truncal involvement 0 1 (3%) Previous botulinum toxin treatment Onabotulinum toxin 14 (44%) 10 (33%) Last dosage (MU) 160 ( ) 180 ( ) Abobotulinum toxin 10 (31%) 10 (33%) Last dosage (MU) 775 ( ) 800 ( ) Rimabotulinum toxin B 8 (25%) 9 (30%) Last dosage (MU) ( ) ( ) Number of botulinum toxin injection sessions 24 (15 33) 22 (10 39) Reason for discontinuation of botulinum toxin treatment Primary non-response 3 (9%) 3 (10%) Secondary non-response 29 (91%) 26 (87%) Unknown 0 1 (3%) Confirmation of botulinum therapy non-response Clinically documented 28 (88%) 22 (73%) Botulinum A antibodies positive 9 (28%) 8 (27%) EDB test negative 5 (16%) 6 (20%) On-site reinjection failed 1 (3%) 4 (13%) Previous surgical therapy Peripheral denervation surgery 0 2 (7%) Data are mean (SD), number (%), or median (IQR). TC=torticollis. AC=anterocollis. LC=laterocollis. RC=retrocollis. MU=mouse units. EDB=extensor digitorum brevis test. *According to a 2013 consensus statement. 22 Data missing for six patients in the neurostimulation group and eight patients in the sham stimulation group. Clinical documentation of at least three subsequent injection cycles of botulinum A and one of botulinum B with less than 30% symptom improvement. Table 1: Baseline characteristics of the study population Statistical analysis The primary null hypothesis was an outcome of no difference in the change of the TWSTRS severity score (mean of the two observer-blinded scores) from baseline to 3 months between patients receiving active neurostimulation and those receiving sham stimulation. We estimated that a sample size of 60 patients ie, 30 per group would power the study at 80% with a 5% probability of a type I error (two-sided Mann-Whitney U test of the primary null hypothesis). This design allows detection of a 20% difference between treatment groups with respect to the primary outcome criterion (percentage change in TWSTRS severity score) assuming an SD of 25%, 23,24 while making provision for an overall dropout Correspondence to: Prof Jens Volkmann, Department of Neurology, Julius- Maximilians-University, D Würzburg, Germany volkmann_j@ukw.de See Online for appendix Vol 13 September
4 A B C p= Active stimulation 30 5 No stimulation Active stimulation 0 Change in TWSTRS severity score TWSTRS severity score TWSTRS severity score Sham stimulation Neurostimulation 0 0 Baseline 3 months 6 months Baseline 3 months 6 months Time since randomisation Time since randomisation 9 months Figure 2: Effect of neurostimulation and sham stimulation on dystonia severity in the per-protocol population (A) Change in TWSTRS severity score from baseline to 3 months; each dot or triangle denotes each individual patient s TWSTRS severity score change (the centre line of the boxplots shows the median score change, the upper and lower boundaries show the IQRs, and the whiskers show the 5% to 95% CI). (B and C) Individual courses of the TWSTRS severity score throughout the trial for patients initially randomised to neurostimulation (B) or to sham stimulation (C). TWSTR=Toronto Western Spasmodic Torticollis Rating Scale. rate of 10%. 23,24 We analysed the primary endpoint on an intention-to-treat basis, which meant that we included all randomly assigned patients and imputed missing values using the method of last observation carried forward. We analysed all other outcomes per protocol (ie, in only those patients for whom we had data for that particular outcome) without imputation of missing values. We compared outcomes after 6 months of active neurostimulation with baseline using the Wilcoxon signed-rank test for matched pairs. We used the χ² test for categorical data. All statistical tests were two-tailed and were not adjusted for multiple testing. We did statistical analyses with the JMP statistical package, version (SAS Institute). This trial is registered with ClinicalTrials.gov, number NCT Role of the funding source The funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors had full access to the statistical report (and source data on request) and vouch for the completeness and veracity of the data and data analyses. The writing committee (appendix) had final responsibility for the decision to submit the paper for publication. Results Between Jan 19, 2006, and May 29, 2008, 85 patients with cervical dystonia were referred to the participating centres for deep brain stimulation and screened for eligibility. 62 patients entered the trial and were randomly assigned to the two treatment groups after surgery (figure 1). The intention-to-treat population consisted of 32 patients assigned to neurostimulation and 30 assigned to sham stimulation for the first 3 months after deep brain stimulation surgery. In the neurostimulation group, one patient withdrew his consent for study participation after undergoing surgery during which electrodes were misplaced, and had the system explanted, and one patient had an incomplete 3-month visit without video documentation of the primary endpoint, leaving 30 patients in this group at 3 months for analysis of the primary endpoint. The mean age of patients in the neurostimulation group was 57 1 years (SD 9 82) compared with 56 6 years (11 33) in the sham-stimulation group, and the mean duration of cervical dystonia was also simi lar between groups (table 1). Two patients with isolated cervical dystonia had a proven TOR1A mutation both of whom were in the sham stimulation group but we did not screen systematically for inherited dystonia. Three patients in each treatment group were primary non-responders to botulinum toxin treatment. These patients had a combined or complex, biaxial, or triaxial head deviation, often dominated by phasic movements. The remaining patients had become unresponsive secondarily after a median of 28 injection cycles (IQR 19 34) in patients assigned to the neurostimulation group and 22 injection cycles (10 39) in those assigned to sham stimulation (table 1). The primary outcome (TWSTRS severity score), measured in the intention-to-treat population, improved by 5 1 points (95% CI ), a 26% improvement, in the neurostimulation group compared with 1 3 points (95% CI ), a 6% improvement, in the shamstimulation group (p=0 0024). The between-group difference in the mean change from baseline was Vol 13 September 2014
5 Score scale Baseline 3 months Change from baseline to 3 months Neurostimulation Sham stimulation Neurostimulation Sham stimulation Neurostimulation Sham stimulation p value n Mean (SD) n Mean (SD) n Mean (SD) n Mean (SD) n Mean (SD) n Mean (SD) Primary outcome* TWSTRS severity score Intention to treat (3 7) (3 3) (5 0) (3 9) (5 1) (2 4) Per protocol (3 7) (3 3) (5 2) (3 9) (5 1) (2 4) Secondary outcomes TWSTRS disability score (5 3) (5 1) (5 7) (6 1) (5 6) (3 8) TWSTRS pain score** (5 3) (3 6) (5 6) (5 6) (4 7) (4 7) 0 47 Bain tremor scale (3 0) (2 8) (1 7) (1 9) (2 3) (2 1) 0 02 CDQ (14 7) (16 0) (18 1) (18 2) (13 8) (13 1) 0 27 Exploratory outcomes TWSTRS total score (9 9) (8 9) (14 5) (14 5) (14 3) (10 0) TWSTRS severity score (3 4) (3 5) (7 2) (5 9) (6 5) (4 4) A: maximal excursion (1 8) (1 7) (2 1) (2 1) (2 0) (1 5) Torticollis (0 9) (1 1) (0 9) (1 1) (1 1) (1 0) 0 08 Laterocollis (0 8) (0 9) (0 8) (1 0) (0 8) (0 8) 0 15 Antero-/retrocollis (1 1) (0 9) (0 7) (0 9) (0 9) (0 7) Shift (lateral/sagittal) (0 8) (0 6) (0 4) (0 4) (0 5) (0 5) 0 19 B: duration factor (1 0) (0 6) (1 5) (1 3) (1 7) (1 2) C: effect of sensory tricks (0 7) (0 4) (0 7) (0 5) (0 5) (0 6) 0 29 D: shoulder elevation/ (0 7) (0 9) (0 8) (0 8) (0 6) (0 7) 0 50 displacement E: range of motion (1 1) (1 2) (1 0) (1 1) (1 0) (0 9) 0 97 F: time (0 8) (0 8) (1 6) (1 5) (1 9) (1 3) 0 01 Tsui score (4 0) (4 5) (4 2) (5 0) (4 1) (4 0) Clinical Global Impression score Dystonia severity (1 7) (1 9) (2 2) (1 7) (2 7) (1 8) (patient rating) Dystonia severity (1 5) (1 5) (2 1) (1 6) (2 2) (1 3) < (physician rating) Beck Depression Inventory (6 2) (5 8) (6 1) (6 4) (5 6) (3 7) 0 02 Brief Psychiatric Rating Scale (9 4) (5 8) (5 8) (5 9) (9 0) (3 8) 0 79 SF-36 score Physical function (26 0) (28 9) (24 7) (25 4) (21 9) (19 2) 0 97 Role physical (44 1) (39 5) (42 0) (41 6) (48 6) (35 3) 0 20 Bodily pain (27 5) (24 9) (26 4) (27 3) (21 9) (21 1) 0 33 General health (18 1) (18 4) (17 4) (22 3) (15 1) (15 1) 0 10 Vitality (17 3) (23 5) (16 6) (19 2) (17 2) (14 4) 0 49 Social function (25 3) (29 6) ( 27 3) (29 4) (33 2) (29 1) 0 38 Role emotional (45 2) (47 7) (48 5) (45 5) (52 1) (35 1) 0 11 Mental health (18 2) (19 8) (17 3) (17 0) (18 2) (14 4) 0 71 TWSTRS=Toronto Western Spasmodic Torticollis Rating Scale. CDQ=Craniocervical Dystonia Questionnaire. SF-36=Short-Form-36. *Video-based, blinded assessment. The TWSTRS severity score (a measure of symptom severity) is the sum of individual scores for the maximal dystonic head deviation along the three spatial axes (item A), the duration (item B; multiplied by a factor of 2), the effect of sensory tricks (item C), the level of shoulder displacement (item D), the active range of head motion (item E), and the time that the head can be held in a neutral position (item F). Mean score of the video-based rating of two masked examiners for each patient. Primary analysis; all randomly assigned patients were included in the analysis (Mann-Whitney U test, unadjusted two-sided) with missing value replacement by the last observation carried forward method. Open, unblinded assessment. The TWSTRS disability score represents the sum of individual ratings for six activities ability to work, undertake activities of daily living, drive, read, watch television, and do leisure activities with a higher score indicating a more impaired ability. **The TWSTRS pain score (a measure of the duration of and the disability from neck pain) contains a visual analogue scale (0 10) for pain severity, with a higher score indicating more frequent and severe pain. Sum of the severity, disability, and pain scores. Global rating of dystonia severity on a 10-point Likert scale (physician and patient rated). Table 2: Primary, secondary, and exploratory outcomes from baseline to 3 months, in each treatment group 3 8 points (95% CI ); a similar result was noted in the per-protocol population (4 1 points [ ]; figure 2A; video). Of the secondary outcomes, patients in the neurostimulation group had a substantially greater percentage improvement than those in the sham-stimulation group See Online for video Vol 13 September
6 Score scale Baseline 6 months of neurostimulation Change from baseline to 6 months N Mean (SD) n Mean (SD) n Mean (SD) TWSTRS severity score* Intention to treat (3 53) (5 18) (5 31) < Per protocol (3 53) (5 20) (5 35) < TWSTRS disability score (5 22) (6 28) (7 26) < TWSTRS pain score (4 70) (5 81) (5 51) < Bain tremor scale score (2 92) (1 77) (3 01) < CDQ (15 43) (16 41) (12 50) < TWSTRS total score** (9 80) (13 92) (15 21) < TWSTRS severity score (3 49) (6 95) (5 93) < A: maximal excursion (1 72) (1 81) (2 12) < Torticollis (1 04) (0 97) (1 17) < Laterocollis (0 83) (0 75) (1 17) < Antero-/retrocollis (1 03) (0 66) (1 01) < Shift (lateral/sagittal) (0 69) (0 47) (0 69) B: duration factor (0 82) (1 45) (1 46) < C: effect of sensory tricks (0 56) (0 68) (0 64) < D: shoulder elevation/displacement (0 79) (0 77) (0 82) < E: range of motion (1 16) (0 88) (0 92) < F: time (0 76) (1 77) (1 74) < Tsui score (4 21) (4 16) (4 60) < Clinical Global Impression score Dystonia severity (patient rating) (1 82) (2 16) (2 84) < Dystonia severity (physician rating) (1 49) (1 91) (2 01) < Beck Depression Inventory (6 00) (6 81) (6 29) Brief Psychiatric Rating Scale (7 83) (5 06) (7 84) Mattis Dementia Rating Scale (3 60) (3 78) (6 08) 0 94 Significance was tested with the Wilcoxon test (unadjusted two-sided p-values) unless otherwise stated. TWSTRS=Toronto Western Spasmodic Torticollis Rating Scale. CDQ=Craniocervical Dystonia Questionnaire. SF-36=Short-Form-36. *Video-based, blinded assessment; all other outcomes were unblinded assessments. The TWSTRS severity score (a measure of symptom severity) is the sum of individual scores for the maximal dystonic head deviation along the three spatial axes (item A), the duration (item B; multiplied by a factor of 2), the effect of sensory tricks (item C), the level of shoulder displacement (item D), the active range of head motion (item E), and the time that the head can be held in a neutral position (item F). Mean score of the video-based rating of two blinded examiners for each patient. All randomly assigned patients were included in the analysis (Mann-Whitney U test, unadjusted two-sided) with missing value replacement by the Restricted Maximum Likelihood estimation method in a multivariate model; all other analyses were descriptive. The TWSTRS disability score represents the sum of individual ratings for six activities ability to work, undertake activities of daily living, drive, read, watch television, and do leisure activities with a higher score indicating a more impaired ability. The TWSTR pain score (a measure of the duration of and the disability from neck pain) contains a visual analogue scale (0 10) for pain severity, with a higher score indicating more frequent and severe pain. **Sum of the severity, disability, and pain scores. Global rating of dystonia severity on a 10-point Likert scale (physician and patient rated). Table 3: Post-hoc analysis of outcomes at baseline and after 6 months of neurostimulation p value in TWSTRS disability score at 3 months (41% in the neurostimulation group vs 11% in the sham-stimulation group) and Bain tremor score (61% vs 16%, respectively; table 2). Pain (TWSTRS pain score) and health-related quality of life (Craniocervical Dystonia Questionnaire-24 score) improved at 3 months, but not to a significantly different extent in the two treatment groups (table 2). Of the subitems of the TWSTRS severity score, which we analysed post hoc, the change in the magnitude of dystonic head deviation (item A, maximal excursion) from baseline to 3 months differed significantly between groups; the duration of dystonic postures (item B, duration factor) and the ability to hold the head in a neutral position (item F, time) also differed significantly. The changes between baseline and 3 months in the other subitems did not differ significantly between groups (table 2). The beneficial effect of neurostimulation on dystonia severity compared with sham stimulation was supported by significantly greater changes in the Tsui score (63% vs 7%) and the physicianrated (43% vs 6%) and patient-rated (47% vs 16%) Clinical Global Impression (table 2). For a summary of other exploratory outcomes at 3 months, see table 2. 6 months after activation of the neurostimulation device, patients initially assigned to sham stimulation had improved by 5 0 points (SD 4 8), a 26% improvement, on the TWSTRS severity score since the 3-month visit, whereas patients assigned to neurostimulation had only minor additional benefit from an extra 3 months of treatment ( 0 4 points [SD 3 3]; 3% improvement; figure 2B and 2C) Vol 13 September 2014
7 Neurostimulation (n=32) Sham stimulation (n=30) All (n=62) Events Resolved events* Events Resolved events* Events Resolved events* Serious adverse events Related to surgery or device Device infection Surgical exchange of device components 0 NA Tethering of extension cable 0 NA Electrode dislocation 0 NA Electrode misplacement NA 1 0 IPG dislocation NA 1 1 Hemiparesis or stroke NA 1 1 Seizure 0 NA Related to medication or stimulation Depression NA 1 0 Related to dystonia or another disorder Gastrointestinal infection 0 NA Anal abscess 0 NA De-novo parkinsonism 0 NA Neck pain 0 NA Total 5 (16% ) 3 (60% ) 11 (37% ) 8 (73% ) 16 (26% ) 11 (69% ) Adverse events Related to surgery or device Pain at extension cable 0 NA Pain at IPG pocket NA 1 1 IPG infection 0 NA Related to medication or stimulation Depression Dysarthria Dysequilibrium 0 NA Facial numbness NA 1 1 Hand tremor 0 NA Impaired fine motor hand function NA 2 1 Paraesthesia NA 1 1 Worsening of dystonia Dyskinesia NA 3 3 Double vision 0 NA Hand tremor 0 NA Muscle stiffness NA 1 0 Shortness of breath NA 1 1 Related to dystonia or other disorder Menstrual disturbance NA 1 1 Headache 0 NA Nausea Syncope 0 NA Neck pain NA 2 1 Total 21 (66% ) 13 (62% ) 20 (67% ) 7 (35% ) 41 (66% ) 20 (49% ) Events were recorded from randomisation to 6 months in patients initially assigned to neurostimulation and from randomisation to 9 months in patients initially assigned to sham stimulation. NA=not applicable. IPG=implantable pulse generator. *Events that resolved within the study period. A life-threatening event or an event that requires hospital admission or lengthens a hospital stay. Percentage of patients. Percentage of events. Table 4: Adverse events in the intention-to-treat population during the entire study period A post-hoc comparison of the outcome measures at baseline and after 6 months of active neurostimulation was used to assess the magnitude of the treatment effect in the entire study population (table 3). All scores assessing the motor severity of cervical dystonia significantly improved after 6 months of neuro stimulation compared Vol 13 September
8 Panel: Research in context with baseline scores, including the TWSTRS severity score (28%), Tsui score (57%), Bain tremor score (66%), and global dystonia ratings by patients (49%) or physicians (53%). Disability (TWSTRS disability score) was reduced by 46% and pain (TWSTRS pain score) by 51%. Depressive mood (Beck Depression Inventory), a frequent non-motor symptom of dystonia, was signifi cantly reduced by 20%. The symptomatic improve ments had a significant bearing on quality of life as assessed by the Craniocervical Dystonia Questionnaire-24 (28% score reduction). Only the Mattis Dementia Rating Scale showed no improvement after 6 months (table 3). Medication changes and stimulation parameters are outlined in the appendix. During the first 3 months after randomisation, 20 (63%) of 32 patients in the neurostimulation group had 22 adverse events, and 12 (40%) of 30 patients in the sham-stimulation group had 13 adverse events. 11 (31%) of these 35 adverse events were rated as serious (five [16%] in the neurostimulation group and six [20%] in the sham stimulation group) and were mostly well known complications related to surgery or the implanted hardware. An additional 22 adverse events (none serious) in the neurostimulation group and 18 adverse events (five serious) in the sham stimulation group occurred during the extension phase of the study (months 3 9 after randomisation; table 4). Systematic review We searched PubMed (Dec 30, 2013, updated May 28, 2014) with the terms cervical dystonia or torticollis for meta-analyses, randomised controlled trials, or multicentre studies. The search was further refined to include articles containing reference to DBS or deep brain stimulation or botulinum toxin. Our search was restricted to reports published in English. We also manually searched the reference lists of included reports and national or international guidelines for the diagnosis and treatment of dystonia. We identified 225 publications, screened them for content, and assessed them for trial design and methodological quality. Seven articles were related to the application of deep brain stimulation in cervical dystonia: one prospective multicentre trial, 21 three singlecentre studies with masked outcome assessment, 26,27,28 and three retrospective multicentre studies, 17,20,29 including a total of 51 patients. One additional single-centre study assessed the efficacy and safety of the subthalamic nucleus as an alternative target in nine patients. 30 Another study used a crossover design to compare subthalamic and pallidal stimulation in various types of idiopathic dystonia including six patients with cervical dystonia. 31 The studies reported a median improvement of 55% (range 42 70%) of dystonia severity with pallidal neurostimulation as assessed by the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) at the last available follow-up (median 30 months). No previous trial used a control group or a staggered-onset design, as used in our study. Interpretation Our prospective, patient-blind and observer-blind, randomised trial assessed the safety and efficacy of pallidal neurostimulation in a large sample of patients with cervical dystonia. Our results add to the scientific literature by showing benefit and an acceptable safety profile of deep brain stimulation in this focal form of dystonia for patients who are not responding to conventional medical therapy. However, longer follow-up to establish the magnitude and stability of chronic neurostimulation effects is needed before this therapy can be recommended as a routine treatment. Over the whole study period, 11 of the 16 serious adverse events resolved without sequelae. Ongoing events that arose throughout the course of the study included neck pain, an electrode dislocation, and a misplaced electrode not yet resolved at the end of the study period, a depressive episode requiring psychiatric treatment, and a de-novo diagnosis of parkinsonism. Dysarthria, followed by involuntary movements (ie, dyskinesia or worsening of dystonia), pain at the extension cable, and depression were the most common non-serious adverse events. Dysarthria, manifesting as a slightly slurred speech, was related to neurostimulation and, in principle, is reversible with reprogramming. However, six of seven patients had to accept dysarthria as a permanent adverse effect. Two of three non-serious depressive episodes resolved, but the other required ongoing outpatient counselling. Stimulation-induced involuntary movements were mostly transient (in four of six patients) and improved spontaneously or with reprogramming. Discussion In this prospective, randomised, multicentre study of neurostimulation in patients with cervical dystonia, 3 months of bilateral pallidal deep brain stimulation reduced dystonia severity and related disability, as shown by the TWSTRS score. These improvements were significantly better than those associated with sham stimulation. A strength of this study was the sham-controlled design and the fact that it assessed the largest sample of patients recruited into a neurostimulation study for dystonia so far. A limitation was the short observational period, which precluded optimisation of stimulation parameters. Therefore, treatment effects might not be representative of those achieved by best clinical practice and their duration needs to be ascertained, as has been done for generalised and segmental dystonia. 25 Moreover, we did not withdraw medication before surgery, such that acute drug effects (eg, drowsiness after benzodiazepines) might have affected some outcome measures. Finally, the TWSTRS overrated mild but permanent dystonic postures and did not adequately capture treatment effects on dystonic movements, which might explain discrepancies with the blinded video rating and global clinical impression of change rated by patients and physicians. Patients initially assigned to sham-stimulation were switched to effective neurostimulation at the end of the 3-month randomised study period and all patients were reassessed after 6 months of continuous neuro stimulation. Compared with presurgical baseline scores, we noted reductions in dystonia severity, disability, and pain, which translated into significantly improved quality of life. A previous controlled, but single-blind, study of neurostimulation in ten patients with cervical dystonia also reported 28% improvement of head and neck posture in the TWSTRS severity score at 6 months Vol 13 September 2014
9 Uncontrolled and single-centre case series had suggested an even larger symptomatic benefit 6 12 months after bilateral pallidal neurostimulation (panel). 17,18,26 Nevertheless, the 5 2 point (26%) reduction of the TWSTRS severity score and the 18 3 point (40%) reduction of the TWSTRS total score in this study at 3 months are clinically meaningful as shown by a patient-rated global clinical improvement of 46%, and compare favorably to the average point severity score and point TWSTRS total score change reported as peak effect after the injection of botulinum toxin A or B in two randomised controlled trials. 32,33 Of note, our patients were more severely affected at baseline than those in any previous randomised controlled trial for cervical dystonia; some patients had very complex multiaxial types of dystonic movements and postures, and some had not responded to any conventional treatments at inclusion. The clinical relevance of the neurostimulation effect was further supported by a reduction in the number of patients taking comedication for pain and muscle spasms at 6 months. A previous study of pallidal neurostimulation in patients with severe segmental or generalised dystonia reported a 39% reduction of dystonia severity after 3 months. 13 The seemingly smaller symptomatic effect in this study might be largely attributed to differences between the Burke-Fahn-Marsden dystonia rating scale, used in this previous study, and the TWSTRS, used in our study. The TWSTRS combines severity ratings of abnormal head, neck, and shoulder posture with categories such as the duration of abnormal posturing, presence or absence of geste antagoniste effects (ie, sensory tricks that can diminish dystonic movements), and the range of voluntary head movements. 34 The total motor score is strongly affected by the duration factor; improving severe, permanent head rotation from a maximum baseline of 14 points to a mild rotation would still yield 11 points (a 21% score reduction), despite a 75% reduction in head-position abnormality. In our study, we noted a 38% reduction in postural abnormality (TWSTRS item A), but only a 20% reduction in duration (TWSTRS item B) in the neurostimulation group at 3 months, with an overall severity score reduction of 26%. Our study design did not allow comparison of the safety aspects of the surgical treatment to the conservative standard of care, because we did not include a medically managed control group. Generally, however, the surgery was well tolerated and we did not encounter any unexpected adverse events compared with previous studies of pallidal neurostimulation for dystonia. 13,14,21 In particular, we neither observed changes in cognitive status nor encountered de-novo behavioural abnormalities. Depressive mood, a well recognised non-motor symptom and determinant of quality of life in patients with cervical dystonia, 4 improved in the neurostimulation group compared with the sham-stimulation group at 3 months and in the entire group of patients after 6 months of active neurostimulation compared with baseline. Mild dysarthria, transient dyskinesia, and mild impairment of fine hand motor skills were adverse effects related to neurostimulation, which were amenable to programming changes, but were deliberately accepted by some patients in return for control of cervical dystonia. We did not encounter gait freezing or bradykinesia, previously reported as potentially serious adverse effects of pallidal neurostimulation in patients with cervical dystonia 35,36 that have led to the consideration of the subthalamic nucleus as an alternative target for electrode implantation. 30 In conclusion, results of this randomised, controlled trial showed that bilateral pallidal neurostimulation reduced motor impairment and associated disability in patients with medication-refractory cervical dystonia, when compared with sham stimulation. Contributors RB and JMu were the principal investigators and were responsible for the study design. GK was the statistical advisor. KPB and JLV did the external video rating. JVol and JMu analysed the data. JVol was responsible for the figures. RB, GD, AAK, JKK, JM, WP, LT, and JVol reviewed the data and drafted the report. JVol, JMu, GD, DF, AAK, AKu, Aki, G-HS, AS, MS, JVog, AW, MW, J-UM, WP, SH, WE, JVe, TP, MP, JKK, CS, MK, KK, KB, JMe, IMS, JR-P, LT, and RB collected the data and critically reviewed the report. Declaration of interests 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 ( ). 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 Vol 13 September
10 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. Acknowledgments 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. References 1 Epidemiological Study of Dystonia in Europe (ESDE) Collaborative Group. A prevalence study of primary dystonia in eight European countries. J Neurol 2000; 247: Jankovic J, Tsui J, Bergeron C. Prevalence of cervical dystonia and spasmodic torticollis in the United States general population. Parkinsonism Relat Disord 2007; 13: Nutt JG, Muenter MD, Aronson A, Kurland LT, Melton LJ 3rd. Epidemiology of focal and generalized dystonia in Rochester, Minnesota. Mov Disord 1988; 3: Ben-Shlomo Y, Camfield L, Warner T. What are the determinants of quality of life in people with cervical dystonia? J Neurol Neurosurg Psychiatry 2002; 72: Camfield L, Ben-Shlomo Y, Warner TT. Impact of cervical dystonia on quality of life. Mov Disord 2002; 17: Muller J, Kemmler G, Wissel J, et al. The impact of blepharospasm and cervical dystonia on health-related quality of life and depression. J Neurol 2002; 249: Albanese A, Asmus F, Bhatia KP, et al. EFNS guidelines on diagnosis and treatment of primary dystonias. Eur J Neurol 2011; 18: Simpson DM, Blitzer A, Brashear A, et al. Assessment: botulinum neurotoxin for the treatment of movement disorders (an evidencebased review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2008; 70: Brans JW, Lindeboom R, Snoek JW, et al. Botulinum toxin versus trihexyphenidyl in cervical dystonia: a prospective, randomized, double-blind controlled trial. Neurology 1996; 46: Balash Y, Giladi N. Efficacy of pharmacological treatment of dystonia: evidence-based review including meta-analysis of the effect of botulinum toxin and other cure options. Eur J Neurol 2004; 11: Kessler KR, Skutta M, Benecke R. Long-term treatment of cervical dystonia with botulinum toxin A: efficacy, safety, and antibody frequency. German Dystonia Study Group. J Neurol 1999; 246: Misra VP, Ehler E, Zakine B, Maisonobe P, Simonetta-Moreau M. Factors influencing response to botulinum toxin type A in patients with idiopathic cervical dystonia: results from an international observational study. BMJ Open 2012; 2: e Kupsch A, Benecke R, Muller J, et al. Pallidal deep-brain stimulation in primary generalized or segmental dystonia. N Engl J Med 2006; 355: Vidailhet M, Vercueil L, Houeto JL, et al. Bilateral deep-brain stimulation of the globus pallidus in primary generalized dystonia. N Engl J Med 2005; 352: Krauss JK. Deep brain stimulation for cervical dystonia. J Neurol Neurosurg Psychiatry 2003; 74: Eltahawy HA, Saint-Cyr J, Poon YY, Moro E, Lang AE, Lozano AM. Pallidal deep brain stimulation in cervical dystonia: clinical outcome in four cases. Can J Neurol Sci 2004; 31: Hung SW, Hamani C, Lozano AM, et al. Long-term outcome of bilateral pallidal deep brain stimulation for primary cervical dystonia. Neurology 2007; 68: Cacciola F, Farah JO, Eldridge PR, Byrne P, Varma TK. Bilateral deep brain stimulation for cervical dystonia: long-term outcome in a series of 10 patients. Neurosurgery 2010; 67: Contarino MF, Van Den Munckhof P, Tijssen MA, et al. Selective peripheral denervation: comparison with pallidal stimulation and literature review. J Neurol 2014; 261: Krauss JK, Pohle T, Weber S, Ozdoba C, Burgunder J-M. Bilateral stimulation of globus pallidus internus for treatment of cervical dystonia. Lancet 1999; 354: Kiss ZH, Doig-Beyaert K, Eliasziw M, Tsui J, Haffenden A, Suchowersky O. The Canadian multicentre study of deep brain stimulation for cervical dystonia. Brain 2007; 130: Albanese A, Bhatia K, Bressman SB, et al. Phenomenology and classification of dystonia: a consensus update. Mov Disord 2013; 28: Brashear A, Lew MF, Dykstra DD, et al. Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-responsive cervical dystonia. Neurology 1999; 53: Brin MF, Lew MF, Adler CH, et al. Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-resistant cervical dystonia. Neurology 1999; 53: Volkmann J, Wolters A, Kupsch A, et al, for the DBS study group for dystonia. Pallidal deep brain stimulation in patients with primary generalised or segmental dystonia: 5-year follow-up of a randomised trial. Lancet Neurol 2012; 11: Skogseid IM, Ramm-Pettersen J, Volkmann J, Kerty E, Dietrichs E, Roste GK. Good long-term efficacy of pallidal stimulation in cervical dystonia: a prospective, observer-blinded study. Eur J Neurol 2012; 19: Pretto TE, Dalvi A, Kang UJ, Penn RD. A prospective blinded evaluation of deep brain stimulation for the treatment of secondary dystonia and primary torticollis syndromes. J Neurosurg 2008; 109: Walsh RA, Sidiropoulos C, Lozano AM, et al. Bilateral pallidal stimulation in cervical dystonia: blinded evidence of benefit beyond 5 years. Brain 2013; 136: Bittar RG, Yianni J, Wang S, et al. Deep brain stimulation for generalised dystonia and spasmodic torticollis. J Clin Neurosci 2005; 12: Ostrem JL, Racine CA, Glass GA, et al. Subthalamic nucleus deep brain stimulation in primary cervical dystonia. Neurology 2011; 76: Schjerling L, Hjermind LE, Jespersen B, et al. A randomized double-blind crossover trial comparing subthalamic and pallidal deep brain stimulation for dystonia. J Neurosurg 2013; 119: Comella CL, Jankovic J, Shannon KM, et al. Comparison of botulinum toxin serotypes A and B for the treatment of cervical dystonia. Neurology 2005; 65: Benecke R, Jost WH, Kanovsky P, Ruzicka E, Comes G, Grafe S. A new botulinum toxin type A free of complexing proteins for treatment of cervical dystonia. Neurology 2005; 64: Albanese A, Sorbo FD, Comella C, et al. Dystonia rating scales: critique and recommendations. Mov Disord 2013; 28: Berman BD, Starr PA, Marks WJ Jr, Ostrem JL. Induction of bradykinesia with pallidal deep brain stimulation in patients with cranial-cervical dystonia. Stereotact Funct Neurosurg 2009; 87: Schrader C, Capelle HH, Kinfe TM, et al. GPi-DBS may induce a hypokinetic gait disorder with freezing of gait in patients with dystonia. Neurology 2011; 77: Vol 13 September 2014
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