rTMS in Wilson Disease Dysarthria (WILSTIM2)

Wilson disease is a hereditary hepatic and neurological disease associated with copper accumulation. Neurological symptoms are of extra-pyramidal, cerebellar and dystonic origin. Dysarthria is one of the debilitating symptoms of Wilson disease poorly responsive to pharmacological treatment. The most common form is a dystonic hyperkinetic Dysarthria. Pathophysiology of dystonia is still not elucidated. Motor cortex hyperexcitability has been demonstrated in various forms of dystonia. Furthermore, rTMS inhibitory applied over motor cortex has been shown to transitory reduce dystonic symptoms in various forms of dystonia. In the present study, we investigate the effect of a single 1Hz 20-minutes inhibitory rTMS session applied over the motor laryngeal cortex on dyasarthria is the main kinetic dysarthria has been shown to be associated with inhibition of laryngeal motor cortex in Parkinson disease.

A consecutive series of Wilson disease patients with dystonic hyperkinetic dysarthria will be prospectively recruited. Patients will receive 3 days apart to two rTMS sessions. rTMS procedures will be performed with a figure of eight coiled. A single 20-minutes 1 Hz biphasic stimulation (1200 pulses) session will be applied over the laryngeal motor cortex. A brain imaging positioning device will be used during all the procedure A second stimulation session will be performed 3 days apart. Patients will be centrally randomized to receive first either the active stimulation (80% of the resting motor threshold) or the sham stimulation (using a visually identical coil to reproduce the click sound and the scalp sensation of the active coil). A TMS evaluation of cortical silent period over the left motor cortex will be performed before the first rTMS session. Before and immediately after each stimulation (active or sham) patient will received an clinical evaluation including Clinical Assessment Battery for Dysarthria intelligibility score, "A" phonation time, diadococinesia , bucco-linguo-facial motricity score and UWDRS. A standard 20-minutes EEG will be performed before the first rTMS session and immediately after the second rTMS session.

After randomization, patients are to receive blindly the first rTMS session according to the arm (placebo or active). A second stimulation session is to be performed 3 days apart to apply the reverse arm.

Patients are centrally randomized to receive first either the active stimulation (80% of the resting motor threshold) or the sham stimulation (using a visually identical coil to reproduce the click sound and the scalp sensation of the active coil). The operator is unblided. The evaluator is blinded.

Patients receive an inhibitor treatment of rTMS using activ coil (MCF B65 coil) for 30 minutes at 1Hz at 80% of the resting motor threshold (MagPro stimulator; MagVenture A / S, Farum, Denmark) onto the left laryngeal cortex located thanks to a neuronavigation device (Syneika one [SYN1], Syneika, Cesson-Sévigné, France).

Patients receive a treatment of rTMS using placebo coil (MCF P B65 coil) for 30 minutes at 1Hz (MagPro stimulator; MagVenture A / S, Farum, Denmark) onto the left laryngeal cortex located thanks to a neuronavigation device (Syneika one [SYN1], Syneika, Cesson-Sévigné, France).

Improvement of the Clinical Assessment Battery for Dysarthria intelligibility score with active stimulation in comparison to sham stimulation

Improvement of the Clinical Assessment Battery for Dysarthria intelligibility sub-scores with active stimulation in comparison to sham stimulation

Improvement of bucco-linguo-facial motricity with active stimulation in comparison to sham stimulation

Correlation between clinical Assessment Battery for Dysarthria intelligibility score and UWDRS, and MRI brain atrophy and basal ganglia lesions

Correlation of changes in the Battery for Dysarthria intelligibility score with clinical parameters (age at diagnosis, delay related to first symptoms, degree of neurological handicap and brain lesions observed on basline MRI (cortical atrophy and lesions of the basal ganglia)

Any side effect after stimulation (fatigue, neck pain, neck stiffness, dizziness, nausea, itching, mood disorders ..) will be collected following the stimulation. Side effects of rTMS are rare. Most often they are minor and transient.

Inclusion Criteria: Conseting adult patients with social insurance Wilson disease with dystonic hyperkinetic dysarthria Stable pharmacological therapy n the last 6 monts Brain MRI in the previous 6 months, without additional brain lesion Patients that did not receive botulinium toxin in the previous 4 months Exclusion Criteria: Incapacitated adult Previous mdedical history of epilepsia Pregnancy or breastfeeding Brain lesion outside basal ganglia on brain MRI Patient consider by the investigator not able to sustain an 30 minutes rTMS session without moving Vocal chord lesion Previous history of laryngeal surgery rTMS contra indication