Pedunculopontine Nucleus Stimulation for Gait Disorders in Parkinson's Disease

Study Overview
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Brief Summary
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The appearance of postural instability and gait disorders is a major turning point in the evolution of Parkinson's disease (PD). These axial symptoms are usually unresponsive to L-Dopa and represent a severe impairment for the patients due to frequent falls and reduced outside mobility. There is no effective pharmacological treatment available for these symptoms, and their pathophysiology is not well known : it is currently assumed that non-dopaminergic brainstem lesions participate to axial symptoms in PD. Surgically, these patients cannot benefit from high frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) since this operation tends to even aggravate axial symptoms unresponsive to L-Dopa in some patients. A dysfunction of the pedunculopontine nucleus (PPN) might be at the origin of these axial symptoms, since the PPN participates in the maintenance of posture and motion in primates. In PD patients, recent reports have suggested that low frequency stimulation of the PPN may equally improve gait and posture. However, these results are debatable due to methodological limitations, insufficient clinical evaluation and uncertain anatomical targeting. Thus, our aim is to propose a low frequency PPN stimulation to six advanced PD patients according to the usual criteria for STN DBS who are, however, unsuitable for this operation due to gait and posture disorders. We will perform a randomized, double-blind and cross over design (two months periods with and without DBS randomly assigned to each patient). The targeting will be allowed by a a three-dimensional and deformable atlas of the basal ganglia fusioned with the stereotaxic magnetic resonance imaging (MRI) of each patient. Evaluations will comprise 1 month before surgery and in Off and On stimulation condition: clinical motor assessment in both Off and On drug state, including cardinal parkinsonian signs, gait and balance gait initiation physiological evaluation cognitive and behavioral testing If our hypothesis is confirmed, low frequency PPN stimulation may well represent a substantial improvement of our therapeutic options for advanced PD patients suffering from debilitating gait and posture disorders unresponsive to L-Dopa.

Official Title
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Effects of Low Frequency Deep Brain Stimulation of the Pedunculopontine Nucleus on Gait and Balance Disorders of Parkinson's Disease

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Device: Low frequency DBS of the pedunculopontine nucleus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Parkinson's disease Age < 70 and > = 18 years Improvement > or = 50 % during acute levodopa test Score > or = 2 on item 29 of UPDRS part 3 score obtained in off drug state No previous DBS No evidence of atypical parkinsonism No dementia (MATTIS > 129) No psychiatric disease Contraception if woman Informed consent Exclusion Criteria: Contra indication to surgery Contra indication to MRI Severe life threatening comorbidity

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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: OFF PPN DBS-ON PPN DBS<br>Patients randomly allocated to the order OFF Low frequency DBS of the pedunculopontine nucleus then ON Low frequency DBS of the pedunculopontine nucleus | Device: Low frequency DBS of the pedunculopontine nucleus<br> <br> |
| Other: ON PPN DBS - OFF PPN DBS<br>Patients randomly allocated to the order ON Low frequency DBS of the pedunculopontine nucleus then OFF Low frequency DBS of the pedunculopontine nucleus | Device: Low frequency DBS of the pedunculopontine nucleus<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Rating scale for gait evaluation between 'Off stim off drug and On stim off drug conditions | The primary outcome criteria will be the comparison between RSGE total score in obtained 'Off' and 'On' stimulation conditions either at 4 or 6 months after surgery according to the randomized order of the cross-over | 4 months and 6 months after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events records |  | 1 month before surgery, 1-2-3-4-5-6 months after surgery | 
| Change of UPDRS part 3 score between Off Stim Off drug and ON stim Off drug conditions |  | 4 and 6 months after surgery | 
| Change of Rating scale for gait evaluation between 'Off stim on drug and On stim on drug conditions |  | 4 and 6 months after surgery | 
| Change of UPDRS part 3 score between Off Stim On drug and ON stim On drug conditions |  | 4 and 6 months after surgery | 
| Change of UPDRS part 3 score between Off Stim Off drug and No stim Off drug conditions |  | 1 month before surgery and 4 or 6 months after surgery | 
| Change of UPDRS part 3 score between Off Stim On drug and No stim On drug conditions |  | 1 month before surgery and 4 or 6 months after surgery | 
| Change of Rating scale for gait evaluation between 'Off stim Off drug and No stim off drug conditions |  | 1 month before surgery and 4 or 6 months after surgery | 
| Change of Rating scale for gait evaluation between 'Off stim On drug and No stim on drug conditions |  | 1 month before surgery and 4 or 6 months after surgery | 
| Change of Rating scale for gait evaluation between 'On stim Off drug and No stim off drug conditions |  | 1 month before surgery and 4 or 6 months after surgery | 
| Change of Rating scale for gait evaluation between 'On stim On drug and No stim On drug conditions |  | 1 month before surgery and 4 or 6 months after surgery | 
| Change of gait physiological parameters between Off Stim Off drug and ON stim Off drug conditions |  | 4 and 6 months after surgery | 
| Change of gait physiological parameters between Off Stim On drug and ON stim On drug conditions |  | 4 and 6 months after surgery | 
| Change of gait physiological parameters between No Stim On drug and Off stim On drug conditions |  | 1 month before surgery and 4 or 6 months after surgery | 
| Change of gait physiological parameters between No Stim Off drug and On stim off drug conditions |  | 1 month before surgery and 4 or 6 months after surgery | 
| Change of gait physiological parameters between No Stim Off drug and Off stim off drug conditions |  | 1 month before surgery and 4 or 6 months after surgery |