Inhibitory rTMS in Dystonic Wilson Patients (WILSTIM)

Study of Writing Improvement in Patients With Wilson Disease and Dystonia After One Session of Inhibitory Repetitive Transcranial Magnetic Stimulation

Wilson disease is a genetic disorder resulting in copper accumulation in liver, brain and eye. The neurologic complications include dystonic syndrome, which is a prolonged and excessive muscle activation responsible for abnormal postures. Hand dystonia prevents daily life activities such as writing, which is particularly disabling, since writing is the only mean of communication in these patients with significant slurred speech. Treatment is limited and only partially effective.

Low frequency (<or=1Hz) repetitive transcranial magnetic stimulation (rTMS) has shown inhibiting properties when applied over the cortex. Since dystonia has been correlated to hyperactivation of the neurons of the somatosensory cortex (SSC), we hypothesize that one single 20-minute session of 1 Hz rTMS applied on left SSC will improve writing of the right dystonic hand, assessed immediately at the end of the session.

Study Overview

• Status: Completed
• Conditions: Movement Disorders; Wilson Disease; Repetitive Transcranial Magnetic Stimulation
• Intervention / Treatment: Device: Repetitive Transcranial Magnetic Stimulation (rTMS); Other: pre and post-rTMS electroencephalogram; Other: WCRS; Other: handwriting scale DPRE; Other: visual analog scale of discomfort writing and parameters collected on touchpad

Detailed Description

This study investigates the handwriting performance of an homogeneous cohort of patients with Wilson disease and right handed dystonia, after one single inhibitory repetitive transcranial magnetic stimulation (rTMS). Fifteen patients with focal right hand dystonia will receive randomly either active or sham rTMS (1 Hz) to the left somatosensory cortex (SSC) in one single 20 minutes session. Handwriting performance will be measured immediately after this unique session (Visual analogic scale of subjective discomfort in writing, DPRE and WCRS scales, pen pressure and pen velocity measured on touchpad), compared to scores obtained 24 hours before the session. Three days later, the patient will receive the other session (sham rTMS or active rTMS) and the same parameters will be evaluated.

This is a single-center, randomized, crossover, prospective, clinical and double-blind study (the rTMS session is performed by the neurophysiologist, but the patient and the neurologist who will perform the handwriting evaluation are blind to the session).

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Ile De France
    • Paris, Ile De France, France, 75010
      • Hospital Lariboisière

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Wilson disease with focal right hand dystonia
• No modification of medical treatment for 6 months
• No botulinum toxin administration within the past four months
• Right handed
• Focal right hand dystonia
• Cerebral Magnetic Resonance performed the last 6 months with no other lesion than met in Wilson disease
• Over 18
• Insurance policy holder
• Informed consent

Exclusion Criteria:

• Pregnant woman
• Guardianship procedure
• Seizure history
• Other cerebral lesions on cerebral MRI than met in Wilson Disease
• Unable to stay quiet for 30 minutes
• Handwriting impossible
• Contra-indications to repetitive Transcranial Magnetic Stimulation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active rTMS; Repetitive Transcranial Magnetic stimulation: 1 Hz rTMS, delivered to left somatosensory cortex during rest. Intervention is delivered during 20 minutes in one single session.	Device: Repetitive Transcranial Magnetic Stimulation (rTMS); Inhibitory 1 Hz rTMS, delivered to left somatosensory cortex during rest. Intervention is delivered during 20 minutes in one single session.; Other: pre and post-rTMS electroencephalogram; to verify the absence of infraclinical seizures; Other: WCRS; Writer's cramp rating scale; Other: handwriting scale DPRE; handwriting in development and being evaluated by the NRC Wilson; Other: visual analog scale of discomfort writing and parameters collected on touchpad
Sham Comparator: Sham rTMS; Placebo Transcranial Magnetic stimulation delivered to left somatosensory cortex during rest. Intervention is delivered during 20 minutes in one single session.	Device: Repetitive Transcranial Magnetic Stimulation (rTMS); Inhibitory 1 Hz rTMS, delivered to left somatosensory cortex during rest. Intervention is delivered during 20 minutes in one single session.; Other: pre and post-rTMS electroencephalogram; to verify the absence of infraclinical seizures; Other: WCRS; Writer's cramp rating scale; Other: handwriting scale DPRE; handwriting in development and being evaluated by the NRC Wilson; Other: visual analog scale of discomfort writing and parameters collected on touchpad

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
immediate and significant improvement in writing	Improvement of handwriting performance immediately after one single 20 minutes session of inhibitory (1 Hz) repetitive transcranial magnetic stimulation over the left somatosensory cortex. quantitative test score of writing WCRS Active or sham stimulation will be randomly assigned to the patient and the other session will be performed 3 days later.	up to 1 week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
significant improvement in writing	improvement of other quantitative test scores of writing (VAS subjective discomfort writing, DPRE scales and parameters measured on touchpad) after a single session of 1 Hz rTMS inhibitory to the left CSS , compared to the scores achieved in the 24 hours before the session of rTMS. Active or sham stimulation will be randomly assigned to the patient and the other session will be performed 3 days later.	up to 1 week
improvement of dystonia on the scale WDRS	Assessing the improvement of dystonia on the scale WDRS after a single session of 1 Hz rTMS inhibitory to the left CSS, compared to the scores achieved in the 24 hours before the session of rTMS. Active or sham stimulation will be randomly assigned to the patient and the other session will be performed 3 days later.	up to 1 week
correlation between the scores and the other parameters of disease severity	Assess whether age, disease duration and the presence of cortical atrophy are inversely correlated with the evolution of scores.	up to 1 week

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Study Director: Nathalie KUBIS, MD, PhD, Physiology Department, Lariboisière Hospital; Principal Investigator: Jean-Marc TROCELLO, MD, Neurology, Lariboisière Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2014
• Primary Completion (Actual): July 1, 2015
• Study Completion (Actual): July 1, 2015

Study Registration Dates

• First Submitted: October 24, 2013
• First Submitted That Met QC Criteria: November 4, 2013
• First Posted (Estimate): November 11, 2013

Study Record Updates

• Last Update Posted (Actual): June 15, 2021
• Last Update Submitted That Met QC Criteria: June 14, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Handwriting; Movement Disorders; Wilson disease; Repetitive Transcranial Magnetic Stimulation; Dystonia
• Additional Relevant MeSH Terms: Digestive System Diseases; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Liver Diseases; Genetic Diseases, Inborn; Basal Ganglia Diseases; Neurodegenerative Diseases; Metabolism, Inborn Errors; Heredodegenerative Disorders, Nervous System; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Metal Metabolism, Inborn Errors; Movement Disorders; Hepatolenticular Degeneration
• Other Study ID Numbers: P121105