WILSTIM - DBS (WILson STIMulation - Deep Brain Stimulation) (WILSTIM DBS)

DEEP BRAIN STIMULATION FOR SEVERE DYSTONIA ASSOCIATED WITH WILSON'S DISEASE. A Prospective Multicenter Meta-analysis of Nof1 Trials

Dystonia in Wilson's disease represent a major issue. The persistence of disabling motor symptoms despite medical treatments justifies conducting a study on deep brain stimulation (DBS) in Wilson's disease (WD). For bradykinetic patients, subthalamic nucleus (STN) could be considered as a better target than the globus pallidus (GPi). For patients with hyperkinetic dystonia, the internal globus pallidus (GPi) will be chosen as the target of DBS.

The investigators hypothesize that STN DBS will improve Wilson's disease patients, who, despite copper chelators drugs, are still impaired by severe dystonia and akinesia (more or less associated with other movement disorders).

The investigators primary objective is to demonstrate the efficacy of STN/GPi DBS on dystonia associated with Wilson's disease.

Secondary objectives:

• To evaluate the impact of STN/GPi DBS on other movements disorders (tremor, Parkinsonism, chorea) observed in Wilson's disease.
• To describe cognitive status of patients and to evaluate the consequences of STN/GPi DBS on cognition and behavioral aspects of the disease.
• To evaluate the consequences of the stimulation on speech and swallowing.
• To evaluate the social impact of STN/GPi DBS in Wilson's disease.
• To evaluate the safety of STN/GPi DBS in the specific context of Wilson's disease.

Study Overview

• Status: Completed
• Conditions: Wilson's Disease; Severe Dystonia
• Intervention / Treatment: Device: Medtronic, Activa® PC "on"; Device: Medtronic, Activa® PC "off"

Detailed Description

4 periods of stimulation on and off, sequence randomized at Day 0.

• Study Type: Interventional
• Enrollment (Actual): 5
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Lyon, France
    • Hospices Civils de Lyon
  • Paris, France
    • Hôpital Lariboisière
  • Paris, France
    • Hôpital Fondation Adolphe de Rothschild Paris

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age > 18 and < 60 years.
• Severe neurological form of Wilson's disease with predominant dystonia and akinetic-rigid syndrome, despite optimized treatment stabilized for at least 6 months.
• Important disability due to abnormal movements (Rankin score=2 to 4).
• Absence of dementia (MMS > 24 and BREF > 15).
• Stable psychiatric status and absence of severe depression (BDI <28).
• Social security coverage.
• Signature of informed consent. (signature of legal guardian for subjects under protection)

Exclusion Criteria:

• Severe hepatopathy with coagulation disorders (Platelet count < 100 G / l; INR > 1.5; V factor deficit; low level of fibrinogen < 1g/dL; increased of fibrin degradation products; low level of antithrombin).
• Liver transplanted patients < 2 years
• Patients under immunosupressive drugs and corticoids regimen.
• Participation to another biomedical research involving any drugs.
• Severe and uncontrolled psychosis or depression.
• Major atrophy on brain MRI that could represent a problem for leads implantation.
• Necrosis of the STN/GPi on brain MRI.
• Female subjects who are pregnant or lactating.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Stimulation "on"; The deep brain stimulation is "on"	Device: Medtronic, Activa® PC "on"
Sham Comparator: Stimulation "off"; The deep brain stimulation is "off"	Device: Medtronic, Activa® PC "off"

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in movement disorder evaluated by the Canadian Occupational Performance Measure (COPM) performance and satisfaction scores	Efficacy will be assessed by the change in the COPM performance and satisfaction scores after each 4 month-period of stimulation on and off, using blinded evaluations. The COPM is a standardized outcome measure widely used in occupational therapy. This tool can facilitate the identification of functional difficulties and individualized subject-specific priorities for intervention, which may not be captured with other standardized scales.	21 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Other movement disorder will be assessed by the reduction of the Burke-Fahn-Marsden (BFM) dystonia scale score	The reduction of the Burke-Fahn-Marsden (BFM) dystonia scale score is evaluated after each 4 month-period of stimulation on and off, using blinded video evaluations. This scale is the standard of assessments on dystonia and Parkinson.	21 months
Change in other movement disorder evaluated by the Clinical global impression (CGI) scale		21 months
Change in other movement disorder evaluated by the Unified Wilson Disease Rate Scale (UWDRS)	The UWDRS consists of 3 sections, including: consciousness, a historical review based on the Barthel scale, and neurological examination.	21 months
Cognitive evaluation using the Mini Mental Status Examination (MMSE)	The MMSE is a brief 30-point questionnaire test commonly used to screen for dementia.	Screening visit (2 days)
Cognitive evaluation using the Frontal Assessment Battery (FAB)	The FAB is a brief tool used to assess dysexecutive symptoms.	Screening visit (2 days)
Cognitive evaluation using the BDI-II (Beck Depression Inventory)	The BDI-II is a self- report inventory for measuring the severity of depression.	Screening visit (2 days)
Cognitive evaluation using the similarities and matrix reasoning tests from the Wechsler Adult Intelligence Scale (WAIS-IV)	The test of similarities measures concrete, functional, and abstract concept formation. The test of matrix reasoning measures nonverbal analytical reasoning.	Pre-surgery visit (2 days)
Cognitive evaluation using the Modified Card Sorting Test (MCST)	The MCST assess problem solving and the ability to shift cognitive strategies in response to changing environmental contingencies.	Pre-surgery visit (2 days)
Cognitive evaluation using the Trail Making Test (TMT)	The TMT assess visuo-motor speed and task switching abilities.	Pre-surgery visit (2 days)
Cognitive evaluation using the phonemic verbal fluency task	The phonemic verbal fluency task assesses intrinsic response generation.	Pre-surgery visit (2 days)
Cognitive evaluation using the 16-items free and cued recall test (RL/RI 16-items)	The RL/RI 16-items test assesses episodic memory and especially abilities to retrieve information from memory.	Pre-surgery visit (2 days)
Change in cognitive outcome evaluated by the Tasks of the test of Attentional Performance (TAP)	The TAP is a normalized computerized battery to assess attentional and executive abilities.	21 months
Change in behavioral and neuropsychiatric outcome evaluated by the "Inventaire du Syndrome Dysexécutif Comportemental" (ISDC)	The ISDC assesses behavioral dysexecutive symptoms.	21 months
Change in behavioral and neuropsychiatric outcome evaluated by the Brief Psychiatric Rating Scale with anchor (BPRS-E(A))	The BPRS-E(A) is widely used to measure psychiatric symptoms and unusual behavior.	21 months
Change in dysarthria and deglutition outcome evaluated by the spontaneous speech and reading		21 months
Change in dysarthria and deglutition outcome evaluated by the the "Batterie d'Evaluation de la Dysarthrie" (BECD)	This BECD score provides a global assessment of dysarthria severity.	21 months
Change in dysarthria and deglutition outcome evaluated by the Voice Handicap Index (VHI)	The VHI is a questionnaire to quantify the functional, physical and emotional impacts of a voice disorder on a patient's quality of life.	21 months
Change in dysarthria and deglutition outcome evaluated by the maximum phonation time		21 months
Change in dysarthria and deglutition outcome evaluated by the GRBAS (Grade, Roughness, Breathiness, Asthenia, Strain) scale	Auditory-perceptual evaluation method for hoarseness is the GRBAS scale of the Japan Society of Logopedics and Phoniatrics, which rates hoarseness.	21 months
Change in dysarthria and deglutition outcome evaluated by the Deglutition Handicap Index (DHI)	The DHI questionnaire is composed of statements on deglutition related aspects in daily life. It is subdivided in three domains: physical (S) (symptoms related to swallowing), functional (F) (nutritional and respiratory consequences) and emotional (E) (psychosocial consequences).	21 months
Change in dysarthria and deglutition outcome evaluated by the timed test of swallowing capacity		21 months
Change in social outcome evaluated by the Zarit Burden Inventory (ZBI)	The ZBI is a popular caregiver self-report measure used by many aging agencies.	21 months
Tolerance of Deep Brain Stimulation: occurrence of serious adverse events	Clinical examination focusing specifically on vital signs.	23 months

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon
• Investigators: Principal Investigator: Stéphane THOBOIS, MD, Hospices Civils de Lyon

Publications and helpful links

General Publications

• Laurencin C, Poujois A, Bonjour M, Demily C, Klinger H, Roze E, Leclert V, Danaila T, Langlois-Jacques C, Couchonnal E, Woimant F, Obadia MA, Perez G, Pernon M, Blanchet L, Broussolle E, Vidailhet M, Kassai B, Moro E, Karachi C, Polo G, Grabli D, Portefaix A, Thobois S. Deep brain stimulation for severe dystonia associated with Wilson disease: A prospective multicenter meta-analysis of an N-of-1 trial. Eur J Neurol. 2025 Jan;32(1):e16524. doi: 10.1111/ene.16524. Epub 2024 Oct 29.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2016
• Primary Completion (Actual): July 20, 2022
• Study Completion (Actual): July 20, 2022

Study Registration Dates

• First Submitted: September 11, 2015
• First Submitted That Met QC Criteria: September 16, 2015
• First Posted (Estimated): September 17, 2015

Study Record Updates

• Last Update Posted (Actual): August 22, 2025
• Last Update Submitted That Met QC Criteria: August 20, 2025
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: Deep Brain Stimulation; dystonia; Wilson's Disease
• Additional Relevant MeSH Terms: Neurologic Manifestations; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Digestive System Diseases; Neurodegenerative Diseases; Liver Diseases; Movement Disorders; Heredodegenerative Disorders, Nervous System; Basal Ganglia Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Dyskinesias; Metal Metabolism, Inborn Errors; Hepatolenticular Degeneration; Dystonia; Dystonic Disorders
• Other Study ID Numbers: 69HCL14_0448; IDRCB (Other Identifier: 2025-A02589-40)