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Essential tremor is a movement disorder that can result in profound disability affecting the quality of life. Medically refractory essential tremor can be successfully reduced by deep brain stimulation (DBS) traditionally targeting the thalamic ventral intermediate nucleus (Vim). Although this structure can be identified with magnetic resonance (MR) imaging nowadays, Vim-DBS electrodes are still implanted in the awake patient with intraoperative tremor testing to achieve satisfactory tremor control. This can be attributed to the fact that the more effective target of DBS seems to be the stimulation of fiber tracts rather than subcortical nuclei like the Vim. There is evidence that current coverage of the dentatorubrothalamic tract (DRT) results in good tremor control in Vim-DBS. Diffusion tensor MR imaging (DTI) tractography-assisted stereotactic surgery targeting the DRT would therefore not rely on multiple trajectories and intraoperative tremor testing in the awake patient, bearing the potential of more patient comfort and reduced operation-related risks. This is the first randomized controlled trial comparing DTI tractography-assisted stereotactic surgery targeting the DRT in general anesthesia with stereotactic surgery of thalamic/subthalamic region as conventionally used.
This clinical pilot trial aims at demonstrating safety of DTI tractography-assisted stereotactic surgery in general anesthesia and proving its equality compared to conventional stereotactic surgery with intraoperative testing in the awake patient.
The Deep Brain Stimulation for Tremor Tractographic Versus Traditional (DISTINCT) trial is a single-center investigator-initiated, randomized, controlled, observer-blinded trial. A total of 24 patients with medically refractory essential tremor will be randomized to either DTI tractography-assisted stereotactic surgery targeting the DRT in general anesthesia or stereotactic surgery of the thalamic/subthalamic region as conventionally used. The primary objective is to assess the tremor reduction, obtained by the Fahn-Tolosa-Marin Tremor Rating Scale in the 2 treatment groups. Secondary objectives include (among others) assessing the quality of life, optimal electrode contact positions, and safety of the intervention. The study protocol has been approved by the independent ethics committee of the University of Freiburg.
Recruitment to the DISTINCT trial opened in September 2015 and is expected to close in June 2017. At the time of manuscript submission the trial is open to recruitment.
The DISTINCT trial is the first to compare DTI tractography-assisted stereotactic surgery with target point of the DRT in general anesthesia to stereotactic surgery of the thalamic/subthalamic region as conventionally used. It can serve as a cornerstone for the evolving technique of DTI tractography-assisted stereotactic surgery.
ClinicalTrials.gov NCT02491554; https://clinicaltrials.gov/ct2/show/NCT02491554 (Archived by WebCite at http://www.webcitation.org/6mezLnB9D). German Clinical Trials Register DRKS00008913; http://drks-neu.uniklinik-freiburg.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00008913 (Archived by WebCite at http://www.webcitation.org/6mezCtxhS).
Essential tremor is a hyperkinetic movement disorder characterized by a postural and kinetic tremor commonly affecting the upper extremities, but the voice, head, and lower extremities can also be involved [
This clinical pilot trial, Deep Brain Stimulation for Tremor Tractographic Versus Traditional (DISTINCT), in patients with medically refractory essential tremor aims at demonstrating safety of DTI tractography-assisted stereotactic surgery in general anesthesia and proving its equality compared to conventional AC-PC coordinate-based stereotactic surgery with intraoperative testing in the awake patient. Accordingly, a randomized, controlled, rater-blinded, parallel group study was set up involving 2 patient groups each assigned to 1 of the aforementioned treatments. Established assessments of tremor and quality of life are used to compare the effect of treatments, which is then related to effective electrode contact positions.
This is an investigator-initiated monocentric, randomized, controlled, 2-armed, interventional, observer-blinded feasibility trial conducted at the Department of Stereotactic and Functional Neurosurgery and the Department of Neurology at the Freiburg University Medical Center.
The primary objective is to compare DBS-mediated tremor reduction for 2 different approaches—DTI tractography-assisted stereotactic surgery with target point of the DRT in general anesthesia and stereotactic surgery of the thalamic/subthalamic region as conventionally used—in patients suffering from essential tremor.
Primary outcome parameter will be the reduction of tremor as assessed with the Fahn-Tolosa-Marin Tremor Rating Scale (FTMTRS) [
To assess the effect in tremor reduction of both interventions at 6 months based on the total power in tremor analysis
To assess the quality of life
To assess the optimal electrode contact position
To assess differences in duration of neurosurgery in both groups
Psychiatric assessment
To assess safety of intervention
To show equality of both interventions in tremor reduction at 6 months based on the total power in tremor analysis
We plan to recruit 24 male or female patients (12 per treatment group). Patients who are referred to our departments due to disabling medically resistant essential tremor are informed about this study. Patients who give their informed consent are registered in the trial and undergo the screening. Patients who gave their informed consent but do not undergo stereotactic surgery are regarded as screening failures. See
A schedule of study events and assessments is provided in
Schedule of study events and assessments. Study assessments on the right are conducted at the corresponding study events on the left. BDI: Beck Depression Inventory; CT: computed tomography; FTMTRS: Fahn-Tolosa-Marin Tremor Rating Scale; MDRS: Mattis Dementia Rating Scale; QUEST: Quality of Life in Essential Tremor Questionnaire.
Inclusion criteria:
Aged 25 to 80 years, inclusive
Essential tremor according to the criteria of the consensus statement of the Movement Disorder Society [
Stable tremor medication for at least 3 months prior to inclusion
An FTMTRS completed within 42 days prior to surgery
Written informed consent
Exclusion criteria:
Major depression
Dementia (Mattis Dementia Rating Scale [MDRS]≤130)
Acute psychosis
Known or persistent abuse of medication, drugs, or alcohol
Patient incapability
Nursing care at home
Surgical contraindications or medications that are likely to cause interactions in the opinion of the investigator
Persons who are in a relationship of dependence/employment with the sponsor or the investigator
Fertile women not using adequate contraceptive methods or with current or planned pregnancy or nursing period
Screening evaluations must be performed within 42 days prior to neurosurgery. For this evaluation, inclusion and exclusion criteria are checked and validated. The complete pretherapeutic work-up includes a physical examination, medical history, demography, vital signs, body weight and height, tremor-related medications list, quality-of-life questionnaires Short Form (SF)-36 and Quality of Life in Essential Tremor Questionnaire (QUEST) [
Baseline visit will be performed on the day prior to neurosurgery and includes assessment of tremor-related medications, FTMTRS, and tremor analysis.
As part of the preoperative diagnostic work-up, DTI is performed on a clinical 3 Tesla MRI system (Magnetom Trio, Siemens, Erlangen, Germany) with the following specifications: single-shot, 2-dimensional; spin-echo echo-planar imaging; repetition time (TR), 10,000 ms; echo time (TE), 94 ms; diffusion values, b=0 s/mm2and b=1000 s/mm2; diffusion directions, 61; slice count, 69; voxel size, 2.0×2.0×2.0 mm3; acquisition time, 11:40 min. Deformation correction of the EPI sequence is performed according to Zaitsev et al [
Patients will be randomized within 7 days prior to neurosurgery; the DBS system will be implanted according to the randomized treatment group.
After administration of standard antibiotic prophylaxis, a patient in a stereotactic frame (Leksell, Elekta, Stockholm, Sweden) is placed in local anesthesia in group 1 and under general anesthesia in group 2.
A computed tomography (CT) scan is performed, and the image data are transferred to the StealthViz Planning Station (Medtronic, Minneapolis, MN, USA). The previously acquired MRI sequences are coregistered to the stereotactic CT scan, and the trajectories are planned in group 1 (local anesthesia) based on AC-PC coordinates and imaging of thalamic and subthalamic region. The deepest point of the implantation will be the posterior subthalamic region or the caudal zona incerta, respectively, as visualized with a T2-weighted MRI sequence. With this technique a DBS electrode will traverse the Vim region (with the superficial contacts) while reaching the posterior subthalamic region with the most inferior contact. In group 2 (general anesthesia), based on imaging of the DRT, the subthalamic region will also be the inferior-most level of implantation.
In group 1, the bilateral DBS electrode implantation is performed under local anesthesia with the patient in a semisitting position. Using a microtargeting drive (MicroTargeting Star Drive M/E System, FHC Inc, Bowdoin, ME, USA), a test electrode (Cosman Medical, Inc, Burlington, MA, USA) is inserted through a frontal burr hole in the cranium. Macrostimulation is performed to confirm a contralateral clinical benefit (at a low threshold) and to test for side effects (at a high threshold). The definitive DBS electrodes are then implanted under fluoroscopic control. The implantable pulse generator (ACTIVA INS, Medtronic, Minneapolis, MN, USA) in group 1 is then implanted and connected to the DBS electrodes under general anesthesia.
In group 2, the bilateral DBS electrode implantation through a frontal burr hole via the planned trajectories is performed in ongoing general anesthesia under fluoroscopic control and without any further testing followed by the implantation of an implantable pulse generator (ACTIVA INS, Medtronic, Minneapolis, MN, USA), which is then connected to the DBS electrodes.
All patients in group 1 and 2 undergo a postoperative CT scan to corroborate the final DBS electrode localization. The following items will be documented at this visit: duration of surgery (time points of mounting frame, start surgery, stop surgery (= dismounting frame) and serial numbers of implanted components.
At 6 and 12 months after neurosurgery, follow-up visits will be performed. The trial for the individual patient ends at the 12-month visit. On both visits, tremor-related medication, vital signs, quality of life (SF-36, QUEST), FTMTRS, tremor analysis (amplitude, frequency), and BDI will be assessed.
The rating of the FTMTRS will be digitally recorded by video at every visit. The videotapes will be rated during the study period by an external group of movement disorder specialists who are not otherwise involved in the trial. To maintain blinding for the external raters, patients should wear headgear which completely encloses the hair.
This is a feasibility study in 24 patients with essential tremor (12 DTI tractography-assisted implantations, 12 implantations with conventional intraoperative testing). To obtain estimates for the treatment effect and its variance and, thus, to obtain a solid basis for the sample size calculation of the subsequent confirmative trial, the FTMTRS score at 6 months after intervention and its change from baseline will be subjected to exploratory descriptive analysis. Julious [
The randomization code will be generated by the clinical trials unit using the following procedure to ensure that treatment assignment is unbiased and concealed from patients and investigator staff. Randomization will be performed in blocks of variable length in a ratio of 1:1. The block lengths will be documented separately and will not be disclosed to the center.
The primary efficacy analysis of this clinical trial will be conducted according to the intention-to-treat principle (ITT). This means that the patients will be analyzed in the treatment arms to which they were randomized, irrespective of whether they refused or discontinued the treatment or whether other protocol violations are revealed. Confidence intervals (95%) will be calculated for means and standard deviations within groups as well as for the difference between groups in the ITT population. The effects of DTI tractography-assisted versus conventional intraoperative testing with respect to the FTMTRS score at 6 months will be estimated and tested within a linear regression model including treatment and the baseline FTMTRS score as covariates. A conservative estimate of the effect size anticipated for a subsequent confirmative trial will be derived from these analyses by a combination of clinical and statistical judgement.
Effective tremor reduction (FTMTRS score reduction by 50% is regarded as “response”) at 12 months after intervention will be analyzed in an exact logistic regression model. Tremor reduction measured by tremor analysis and calculation of total power before and 6 and 12 months after intervention will be analyzed the same way as the primary endpoint.
Quality of life will be measured with the SF-36. The 8 summary scales per measurement will be evaluated based on the method implemented in the software program (SAS version 9.2 or higher, SAS Institute Inc) provided along with the questionnaire. Change from baseline will be evaluated for all summary scales after 6 and 12 months as the primary endpoint. BDI, effective contact position (with respect to DRT and AC-PC coordinates) and the volume of activated tissue will be analyzed similar to the primary endpoint using linear regression.
Rates of recruitment per month, screening failures, and drop-out from the trial will be evaluated and considered for the confirmative trial. All secondary analyses will be exploratory.
Safety analyses will be performed for all patients for whom 1 of the treatments was started. Patients will be analyzed according to treatment received. Rates of adverse events and serious adverse events will be calculated with corresponding 2-sided 95% confidence intervals.
An adequate subject insurance contract has been taken out. The study protocol has been approved by the independent ethics committee of the University of Freiburg (EK 207/15). The study will be conducted in accordance with the ethical principles of the Declaration of Helsinki and applicable regulatory requirements. The DISTINCT trial has been registered in the German Clinical Trials Register (DRKS00008913) and at ClinicalTrials.gov (NCT02491554).
Recruitment to the DISTINCT trial opened in September 2015 and is expected to close in June 2017. At the time of manuscript submission the trial is open to recruitment.
The DISTINCT trial is an investigator-initiated, randomized, controlled, observer-blinded trial comparing DTI tractography-assisted stereotactic surgery with a target point of the DRT in general anesthesia to stereotactic surgery of the thalamic/subthalamic region as conventionally used. It is hypothesized that DTI tractography-assisted stereotactic surgery in general anesthesia is safe and is equal to conventional AC-PC coordinate-based stereotactic surgery with intraoperative testing in the awake patient.
To examine the 2 discrete treatment groups, a randomized controlled parallel group study is the appropriate design. Efforts to blind patients would annihilate favorable effects in the tractography-based treatment group (single trajectory, shorter duration of surgery), so a rater-blinded design is implemented. Reliability is enhanced by double rating of video-documented tremor assessments by 2 independent raters.
Chen et al [
DTI tractography of the DRT can generally be achieved with probabilistic [
Tractography with a seed ROI in the ipsilateral dentate nucleus and target ROI in the ipsilateral precentral gyrus reliably yields the nondecussating fibers of the DRT described by Meola et al [
Although it is generally agreed on that effects of DBS are exerted on fibers, there is only limited published evidence on DTI tractography-assisted stereotactic surgery [
anterior commissure–posterior commissure
Beck Depression Inventory
computed tomography
deep brain stimulation
Deep Brain Stimulation for Tremor Tractographic Versus Traditional
dentatorubrothalamic tract
diffusion tensor imaging
echo-planar imaging
Fahn-Tolosa-Marin Tremor Rating Scale
intention to treat
Mattis Dementia Rating Scale
magnetic resonance imaging
Quality of Life in Essential Tremor Questionnaire
region of interest
spin-echo
Short Form 36
echo time
repetition time
thalamic ventral intermediate nucleus
This trial receives limited financial support by Medtronic Europe. The funder is not involved in the study design; collection, analysis, and interpretation of the data; writing of the report; or decision to submit the paper for publication.
This study was designed by BS, FA, PR, and VC. The manuscript was written by BS. VC is the principal investigator of the trial and initiated the trial. CJ performed the sample size calculation and planned the statistical analyses. BS is the medical coordinator of the trial. JK made substantial contributions to the organization of this trial. PR and TP are involved in trial implementation. CJ, JK, PR, FA, TP, HU, and VC critically revised the manuscript. All authors have read and approved the manuscript.
Dr Sajonz reports grants from Medtronic Europe during the conduct of the study. Dr Amtage reports nonfinancial support from UCB Pharma outside the submitted work. Dr Reinacher reports grants and personal fees from Medtronic Europe during the conduct of the study; grants, personal fees, and nonfinancial support from Medtronic Europe; grants and personal fees from Boston Scientific, USA; and grants and personal fees from the German Federal Ministry for Economic Affairs and Energy outside the submitted work. Dr. Reinacher received travel support and honoraria for talks from Boston Scientific (USA). Dr Piroth reports nonfinancial support from Actelion Pharmaceuticals, Allschwil, Switzerland, outside the submitted work. Dr Coenen reports grants and personal fees from Medtronic Europe during the conduct of the study; grants, personal fees, and nonfinancial support from Medtronic Europe; grants and personal fees from Boston Scientific, USA; and grants from the German Research Foundation, BrainLinks/BrainTools Cluster of excellence outside the submitted work. Dr Coenen has been a consultant for Medtronic USA and Europe and previously received travel support and honoraria for talks and consultation. Dr Coenen has additionally received travel support and honoraria for talks and consultation from Boston Scientific (USA) and St Jude Medical (USA). C Jenkner, J Kätzler, and H Urbach have nothing to disclose.