Sub-thalamic Nucleus Stimulation in Parkinson Disease

Study Overview
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Brief Summary
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Deep brain stimulation (DBS) is an established procedure for the symptomatic treatment of Parkinson's disease. This procedure performed in two steps using electrophysiology. This study is a prospective, randomized and monocentric study to compare two DBS procedures with or without electrophysiology. A better control of targeting and trajectory is necessary before not using electrophysiology, which is the reference procedure. A new definition of sub thalamic nuclei with new MRI stereotactic landmarks, the use of surgical robot (Neuromata Renishaw) and the use of operative imaging (O-arm) could allow the implantation of electrode in sub-thalamic nuclei without the need of electrophysiology. Two groups of patients will be followed: a first group of patients with a procedure under general anesthesia alone without electrophysiological stimulation and a second smaller group of patients with a first step of electrode implantation under awake surgery with electrophysiological stimulation followed by a second step under general anesthesia for the implantation of stimulator. Clinical results will be assessed at 6 months after implantation.

Detailed Description
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Deep brain stimulation (DBS) is an established procedure for the symptomatic treatment of Parkinson's disease. This procedure performed in two steps using electrophysiology (Limousin et al., 1995) to register the activity of the sub-thalamic nucleus and test the efficacy of stimulation while the patient is awake. A second procedure is needed a few days later to implant the stimulation device under general anaesthesia. The duration of the first procedure is long because of a necessary time of deep stimulation to control the target before definitive implantation. Firstly, the long time of procedure causes pain for the patient. Secondly, the time of procedure, and thus of electrophysiology, is correlated with a rate of device infection of 5 % - 6 % (Hamani et al., 2006; Kenney et al., 2007; Sillay et al., 2008; Doshi et al., 2011). Thirdly, the introduction of several microelectrodes increases the risk of operative and postoperative haemorrhages, estimated at 1 % (Kenney et al., 2007; Sansur et al., 2007; Voges et al., 2007; Bhatia et al., 2008). Moreover, Foltynie et al. (2011) described 12/79 patients treated under general anaesthesia alone with the same post operative results than those who were firstly treated under local anaesthesia. A better control of targeting and trajectory is necessary before not using electrophysiology, which is the reference procedure. A new definition of sub thalamic nuclei with new MRI stereotactic landmarks, the use of surgical robot (Neuromata Renishaw) and the use of operative imaging (O-arm) could allow the implantation of electrode in sub-thalamic nuclei without the need of electrophysiology. (Caire et al. 2012, In press). This study is a prospective, randomized and monocentric study. The randomization will be made according to a ratio 2:1 in favour of the technique without electrophysiology. Two groups of patients will be followed: a first group of patients with a procedure under general anesthesia alone without electrophysiological stimulation and a second smaller group of patients with a first step of electrode implantation under awake surgery with electrophysiological stimulation followed by a second step under general anesthesia. After a preoperative assessment, a end-point evaluation at 6 months after implantation will complete the follow-up. The stimulation efficacy (UPDRS-3) and the post operative adverse effects will be noticed. This study will also evaluate the occurrence of a post-traumatic stress disorder (PTSD) in Parkinson disease patients operated under deep brain stimulation.

Official Title
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Sub-thalamic Nucleus Stimulation in Parkinson Disease: Comparison of a Two-steps Electrophysiological Approach Under Local and General Anesthesia and a One-step Approach Under General Anesthesia

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Procedure: New targeting procedure without electrophysiology
* Procedure: Classical neurosurgical procedure


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age : between 18 and 70 years old Parkinson disease in fluctuation state despite the use of an optimal medical treatment Dopa sensibility higher than 50% with the L-DOPA test Normal MRI Mattis Scale > 130 Surgical indication approved by a multidisciplinary team Patient covered by a social insurance Informed consent signed by patient and investigator Exclusion Criteria: Patients with surgical or anesthetic contraindications Cerebral atrophy or signal abnormalities on MRI Severe Depressive State : The Beck Scale score > 15 Women of childbearing potential without efficient contraceptive mean Need of long-term antithrombotic treatment

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: New targeting procedure without electrophysiology<br>Patients with the high precision procedure under general anesthesia alone without electrophysiological stimulation | Procedure: New targeting procedure without electrophysiology<br>* It is a neurosurgical procedure of electrodes implantation in the sub thalamic nuclei under general anaesthesia using a new targeting procedure without electrophysiology.<br>|
| Active Comparator: Classical neurosurgical procedure<br>patients with a first step of electrode implantation under awake surgery with electrophysiological control followed by a second step under general anesthesia | Procedure: Classical neurosurgical procedure<br>* It is a neurosurgical procedure of electrodes implantation in the sub thalamic nuclei under awake surgery with electrophysiological control. A second surgical step is performed to implant the subcutaneous stimulation device, under general anesthesia.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the ratio of preoperative and postoperative UPDRS 3 score | The primary outcome is defined after six months of sub-thalamic nucleus deep brain stimulation with the ratio of preoperative and postoperative UPDRS 3 score. The ratio is : (post operative UPDRS 3 OFF medicine and OFF stimulation- post operative UPDRS 3 OFF medicine ON stimulation)/(post operative UPDRS 3 OFF medicine OFF stimulation) | 6 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stimulation efficacy | Efficacy with the ratio : (Preoperative UPDRS 3 OFF medicine - post operative UPDRS 3 OFF medicine ON stimulation)/( preoperative UPDRS 3 OFF medicine ) | 6 month | 
| The variance of improvement mean for the high precision technique | The variance of improvement mean for the high precision technique | 6 month | 
| Percentage of patients with an improvement of UPDRS III score | Percentage of patients with an improvement of UPDRS III score of 35%, 50% et 65% | 6 month | 
| The Calculated preoperative and post operative (6 months) equivalent dose of L-DOPA and the decrease of between preoperative and post operative period (6 months). | The Calculated preoperative and post operative (6 months) equivalent dose of L-DOPA and the decrease of between preoperative and post operative period (6 months). | 6 month | 
| Percentage of patients with failure of the new surgical technique defined with an improvement of less than 35 % with the UPDRS 3 score and an electrode located more than 4 mm from the target | Percentage of patients with failure of the new surgical technique defined with an improvement of less than 35 % with the UPDRS 3 score and an electrode located more than 4 mm from the target | 6 month | 
| Quality of Life | Quality of Life scale : PDQ-39 | 6 month | 
| Non motor items of UPDRS score in the high precision technique under general anesthesia alone | Non motor items of UPDRS score in the high precision technique under general anesthesia alone | 6 month | 
| Adverse effects and complications | Adverse effects and complications : infection, haemorrhages, paresthesia, hypophonia and dyskinesia | 6 month | 
| Percentage of improvement in patients with the reference technique | Percentage of improvement in patients with the reference technique (electrophysiological approach in awake surgery) | 6 month | 
| Compare the technical feasibility for both surgeries based on the number of electrodes implanted in the target | Compare the technical feasibility for both surgeries based on the number of electrodes implanted in the target | after surgery | 
| Operative and postoperative surgical adverse effects. | Operative and postoperative surgical adverse effects. | 6 month | 
| Evaluate the influence of two operative procedures on the onset and maintenance of post-operative PTSD | Evaluate the influence of two operative procedures on the onset and maintenance of post-operative PTSD | 6 month | 
| Evaluate the influence of two operative procedures on the level of preoperative anxiety and the time course of this anxiety | Evaluate the influence of two operative procedures on the level of preoperative anxiety and the time course of this anxiety | 1, 3 and 6 month | 
| Differentiate thymic and cognitive factors potentially predictors of the occurrence of post-surgical PTSD | Differentiate thymic and cognitive factors potentially predictors of the occurrence of post-surgical PTSD | 6 month | 
| Evaluate the long-term effects of the two operating procedures on thymic and cognitive state | Evaluate the long-term effects of the two operating procedures on thymic and cognitive state | 6 month | 
| Evaluate the dose of irradiation received by patients during surgery in both procedures |  | During surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Deep Brain Stimulation (DBS), Parkinson disease, Stereotaxis Technique, Subthalamic nucleus