Pedunculopontine Nucleus Stimulation for Gait Disorders in Parkinson's Disease

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

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.

Patients randomly allocated to the order OFF Low frequency DBS of the pedunculopontine nucleus then ON Low frequency DBS of the pedunculopontine nucleus

Patients randomly allocated to the order ON Low frequency DBS of the pedunculopontine nucleus then OFF Low frequency DBS of the pedunculopontine nucleus

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

Change of Rating scale for gait evaluation between 'Off stim on drug" and "On stim on drug" conditions

Change of Rating scale for gait evaluation between 'Off stim Off drug" and "No stim off drug" conditions

Change of Rating scale for gait evaluation between 'Off stim On drug" and "No stim on drug" conditions

Change of Rating scale for gait evaluation between 'On stim Off drug" and "No stim off drug" conditions

Change of Rating scale for gait evaluation between 'On stim On drug" and "No stim On drug" conditions

Change of gait physiological parameters between "Off Stim Off drug" and "ON stim Off drug" conditions

Change of gait physiological parameters between "No Stim Off drug" and "Off stim off drug" conditions

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