Deep Brain Stimulation for Tremor Tractographic Versus Traditional (DISTINCT): Study Protocol of a Randomized Controlled Feasibility Trial

Abstract

Background: 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.

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Clinicaltrial: ClinicalTrials.gov NCT02491554; https://ichgcp.net/clinical-trials-registry/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).

Keywords: deep brain stimulation; essential tremor; magnetic resonance tractographic-assisted implantation.

Conflict of interest statement

Conflicts of Interest: 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.

©Bastian Elmar Alexander Sajonz, Florian Amtage, Peter Christoph Reinacher, Carolin Jenkner, Tobias Piroth, Jürgen Kätzler, Horst Urbach, Volker Arnd Coenen. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 22.12.2016.

Figures

Figure 1

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.