Factors Determining the Efficacy of Botulinum Toxin for Arm Tremor in Dystonia

Official title

Factors Determining the Efficacy of Botulinum Toxin for Arm Tremor in Dystonia: An Exploratory Study

Overview

Tremor occurs in up to 55% of dystonia patients, which is known as dystonic tremor syndrome (DTS). Tremor can be present in the body part affected by dystonia (dystonic tremor, DT), or an unaffected body part (tremor associated with dystonia, TAWD). DTS can be treated with botulinum neurotoxin (BoNT) injections, but BoNT is effective in only about 60-70% of patients. It is unknown which patients benefit most from BoNT treatment. The investigators aim to explore the associations between clinical and pathophysiological tremor characteristics and BoNT efficacy. To do so, the investigatorswill measure clinical, electrophysiological, ultrasonographic and (functional) magnetic resonance imaging ((f)MRI) characteristics before the start of BoNT treatment and measure BoNT efficacy after three three-monthly BoNT sessions.

Detailed description

Rationale: Tremor occurs in up to 55% of dystonia patients, which is known as dystonic tremor syndrome (DTS). Tremor can be present in the body part affected by dystonia (dystonic tremor, DT), or an unaffected body part (tremor associated with dystonia, TAWD). DTS can be treated with botulinum neurotoxin (BoNT) injections, but BoNT is effective in only about 60-70% of patients. It is unknown which patients benefit from BoNT treatment. This highlights the need for personalized treatment.

Objective: The primary objective is to explore the associations between clinical, electrophysiological, ultrasonographic and (functional) magnetic resonance imaging ((f)MRI) tremor characteristics and BoNT efficacy in DTS of the upper extremity. The secondary objectives are to:

* Explore the clinical, electrophysiological, ultrasonographic and (f)MRI differences between DT and TAWD of the upper extremity. * Explore the agreement between a clinical assessment, polymyography (PMG) and muscle ultrasound (MUS) on muscle selection in DTS of the upper extremity.

Study design: An uncontrolled multi-centre low-intervention clinical trial where subjects participate for ± 8 months Study population: 60 adults with DTS (± 30 DT/ 30 TAWD) of the upper extremity who start 12-weekly BoNT treatment in normal clinical practice.

Main study parameters/endpoints: the associations between clinical, electrophysiological, ultrasonographic, and (f)MRI tremor characteristics at baseline and BoNT efficacy (change in TRG Essential Tremor Rating Assessment Scale (TETRAS) from baseline to 28 weeks).

Secondary trial endpoints:

* The clinical, electrophysiological, ultrasonographic and (f)MRI differences between DT and TAWD at baseline. * The agreement between a clinical assessment, PMG and MUS on muscle selection. Intervention: Participants are treated with three consecutive BoNT sessions in normal clinical practice. Participants will undergo additional diagnostic procedures: 2 clinical assessments, 2 PMGs, 1 MUS recordings and 1 fMRI assessment and will fill in 2 questionnaires before and after the BoNT sessions.

Interventions

• Diagnostic test Polymyography
  We will measure muscle activity using surface electromyography and tremor using inertial measurement units while subjects perform rest, posturing and kinetic tasks.
• Diagnostic test Muscle ultrasound
  We will obtain B-mode images and videos of upper extremity muscles of the most affected upper extremity.
• Diagnostic test (Functional) magnetic resonance imaging
  Subjects will undergo (f)MRI scanning involving concurrent electromyography, accelerometry and functional magnetic resonance imaging.
• Diagnostic test Clinical assessment
  We will assess tremor and dystonia severity using clinical scales.
• Diagnostic test Questionnaires
  We will collect patient-reported outcomes.
• Drug botulinum toxin injection (BTX A)
  Three consequetive botulinum toxin injections of the upper extremities

Primary outcome measures

• Tremor severity assessed by the TRG Essential Tremor Rating Assessment Scale (TETRAS) [Time frame: Baseline, 28 weeks]

Secondary outcome measures (11)

• Tremor severity assessed by the Fahn-Tolosa-Marin Tremor Rating Scale (FTM-TRS) [Time frame: Baseline, 28 weeks]
• Dystonia severity assessed by the Burke-Fahn-Marsden Dystonia Rating Scale (BFM-DRS) [Time frame: Baseline, 28 weeks]
• Additional neurological signs assessed by the Standardised Tremor Elements Assessment (STEA) [Time frame: Baseline]
• Quality of life assessed by the Quality of Life Essential Tremor Questionnaire (QUEST) [Time frame: Baseline, 28 weeks]
• Psychological stress assessed by the Perceived stress scale (PSS) [Time frame: Baseline, 28 weeks]
• Pain assessed by the Numeric Pain Rating Scale (NPRS) [Time frame: Baseline, 28 weeks]
• Patient-reported change in tremor severity assessed by the Patient Global Impression of Change (PGIC) [Time frame: 28 weeks]
• Electrophysiological characteristics [Time frame: Baseline, 28 weeks]
• Ultrasonographic tremulous activity [Time frame: Baseline]
• Tremor related cerebral activity [Time frame: Baseline]
• Botulinum toxin parameters [Time frame: Baseline, 12 and 24 weeks]

Eligibility criteria

Inclusion criteria

• Clinical diagnosis of dystonic tremor or tremor associated with dystonia according to the 2018 consensus statement on the classification of tremors
• Tremor of one or both upper extremities
• Starting botulinum toxin injections as part of normal clinical practice
• Age ≥ 18 years

Exclusion criteria

• Acquired aetiology of dystonic tremor syndrome
• Previous botulinum toxin treatment of the to be treated upper extremity for ≥ 4 consecutive sessions
• In case of previous botulinum toxin treatment of the to be treated upper extremity for ≤3 consecutive sessions: the last botulinum toxin injections ≤ 6 months before study enrolment
• Unstable dose medications for dystonia and tremor ≤ 1 month before study enrolment
• Deep brain stimulation implantation ≤ 6 months before study enrolment
• Unstable deep brain stimulation variables ≤ 1 month before study enrolment
• Comorbidity interfering with study participation
• Known hypersensitivity for components of Dysport
• Infection at the upper extremity
• Pregnancy, trying to conceive and breastfeeding
• Insufficient knowledge of the Dutch or English language

Exclusion criteria for MRI scanning:

• Contraindications for MRI (e.g. previous brain surgery, claustrophobia, active implant, epilepsy, metal objects in the upper body that are incompatible with MRI)
• Moderate to severe head tremor while lying supine (to avoid artefacts caused by extensive head motion during scanning).
• Inability to provoke postural tremor while lying supine.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Netherlands · 3 centers

• Donders Centre for Cognitive Neuroimaging — Nijmegen
• Radboud University Medical Center — Nijmegen
• Canisius-Wilhelmina Ziekenhuis — Nijmegen

Publications

• Nieuwhof F, Toni I, Dirkx MF, Gallea C, Vidailhet M, Buijink AWG, van Rootselaar AF, van de Warrenburg BPC, Helmich RC. Cerebello-thalamic activity drives an abnormal motor network into dystonic tremor. Neuroimage Clin. 2022;33:102919. doi: 10.1016/j.nicl.2021.102919. Epub 2021 Dec 16. PMID 34929584
• Panyakaew P, Cho HJ, Lee SW, Wu T, Hallett M. The Pathophysiology of Dystonic Tremors and Comparison With Essential Tremor. J Neurosci. 2020 Nov 25;40(48):9317-9326. doi: 10.1523/JNEUROSCI.1181-20.2020. Epub 2020 Oct 23. PMID 33097635

Identifiers

NCT: NCT06411028 · 115083 · 2024-515970-28

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗