Long-term effects of repeated Botulinum toxin A injections on muscle volume, muscle morphology and muscle stiffness in muscles affected by stroke

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Project leader

Associate professor Arve Opheim, Physiotherapist, Head of research group for Movement and Function, Sunnaas Rehabilitation Hospital, Head of R&D, Habilitation & Health, Region Västra Götaland, Sweden, Institute for Rehabilitation Medicine, University of Gothenburg, Sweden.

Abstract

Since there are more and more people not only with stroke, but also with other neurological disorders who receive Botulinum Toxin A (BoNT-A) treatment over a long period of time, there is a great need for studies investigating the long-term effects of this. Results from this study may contribute to improved spasticity treatment, to an increased degree of self-reliance, and better quality of life in stroke patients. Disabling spasticity in these patients may lead to less independence and an increased need for personal assistance, as well as the use of special equipment and aids. Increased knowledge of BoNT-A treatment could lead to social and economic gains, not only for stroke patients, but for society as a whole.

Primary objective/hypothesis

The main objective is to build evidence on the long-term effect of repeated BoNT-A injections on muscle volume, muscle morphology and muscle rigidity, as well as on the achievement of treatment goals in stroke patients. Research questions are:

Do changes in muscle volume, muscle morphology and muscle stiffness occur after treatment and are those changes consistent with each other?
Can muscle stiffness before treatment predict the effect of the treatment?
Is there an association between the changes in muscle volume, muscle morphology and muscle stiffness after treatment and achievement of the patient's goals?

Study design and methods

The design is a prospective, longitudinal cohort study. Participants will be included from the Spasticity Clinic at Sunnaas Hospital. The changes in muscle volume and muscle morphology will be investigated with Magnetic resonance imaging (MRI). The changes in muscle stiffness will be investigated with SWE (ultrasound elastography). All measurements and examinations except MRI will be performed at the spasticity clinic at Sunnaas Hospital. MRI is performed at the Intervention Centre, Oslo University Hospital.

Inclusion criteria:

Have had a stroke (at least 6 months prior to study entry)
Have increased stiffness of plantar flexors affected side
Have disabling spasticity and reduced active mobility, in at least one of the calf muscles leading to reduced walking ability.

Exclusion criteria:

patients who have had multiple strokes
patients unable to cooperate
patients who cannot be positioned safely for measurements
patients whose body metal is incompatible with MRI

This is a 2-year study. Patients will have their own control and a comparison is made between injected muscle on the affected side with non-injected muscle on the other side. Furthermore, by comparing injected and uninjected muscle, one can distinguish changes of muscle volume and muscle morphology related to BoNT-A treatment from the changes that occur as a result of the stroke.

All participants are followed up for a 2 year period, during which time they will receive BoNT-A treatment every 3 months. All participants should have 9 consultations, 8 consultations when receiving BoNT-A treatment and 1 consultation 6 weeks after the 1st treatment when BoNT-A treatment has the maximum effect. At each consultation, muscle stiffness is measured with SWE. Furthermore, the degree of achievement of the patient's goals is mapped with the Goal Attainment Scale (GAS), joint mobility is measured with angular measurements, spasticity is assessed with a Modified Ashworth Scale (MAS) () and walking function is assessed with a 10m walk test.

All participants undergo an MRI examination at the start, after 6 weeks, after 3, 12 and 24 months. In this way, changes in muscle morphology will be mapped after both short-term and long-term treatment with BoNT-A. Quality of life is recorded with EQ-E5-EL at the start, after one year and at the end of the follow-up period.

User interaction

Petter Gundhus from the Norwegian Association of Stroke Survivors has been a member of the project group from the start. The user's perspective is included in all phases of the project, planning, implementation, and publishing results. Users will be particularly involved in identifying problems related to walking function in stroke patients and in planning the follow-up period. All participants will receive information about their project results. All participants are invited to a joint meeting to obtain information about project results. The guide for user involvement in health research in the specialist health service is used as a guide.

Ethical assessment

The study is carried out in accordance with the Declaration of Helsinki and the project has been approved by the Regional Committee for Medical and Health Research Ethics (REC South-East) and the Norwegian Centre for Research Data (NSD). Information about the study will be presented to the patient in written and oral form. Participants shall be informed of possible side effects and that they have the right to withdraw from the study at any time without necessary explanation and without consequences for further treatment.

Estimated effects of the study

The study will provide new clinically relevant evidence on long-term use of BoNT-A, which may become important information for clinicians using this method. Furthermore, we will start using SWE in the diagnosis and evaluation of muscle stiffness. The results from this study can be used in further research with SWE, to distinguish between the muscles that should be treated. The study will contribute to new knowledge about spasticity treatment, and thus contribute to improved treatment options. This will contribute to fewer ailments, better mobility, increased activity and participation, and better quality of life in stroke patients. The treatment is multidisciplinary and requires close follow-up of the patient after the medical staff from the primary and specialist health services. The results will contribute to better collaboration between the specialist and primary health services.

Dissemination and Exploitation Measures

The study will result in 3-4 scientific articles in international peer-reviewed time shifts. Results will be presented in relevant forums of experts, at national and international stroke and spasticity conferences, and in relevant research schedules and in reports. Results will also be shared with user organizations and their members through various communication channels and through social media.

Jelena Simic, MD, Spasticity Clinic, Sunnaas Rehabilitation hospital, PhD-student

Kristin Østlie, MD PhD and Chief Senior Consultant, Department of Physical Medicine and Rehabilitation and Spasticity Clinic Innlandet Hospital Trust, Main supervisor

Fin Biering-Sørensen, Professor, Department of Brain- and Spinal Cord Injury, Rigshospitalet in Copenhagen, Co- supervisor

Svein Are Vatnehol, PhD amanuensis, Interventional Centre, Rikshospitalet, University of South-eastern Norway, MRI research radiographer Co-supervisor

Frank Becker, Medical director and amanuensis PhD, Sunnaas Rehabilitation Hospital and Institute for Clinical medicine, University of Oslo, Co-supervisor

Bo Biering-Sørensen, Director of Spasticity Clinic, Department of Neurology, Rigshospitalet, Copenhagen, Lead consultant

Vegard Strøm, Head of Research group Spinal Cord Injuries, Sunnaas Rehabilitation Hospital/ Associate Professor, Norwegian School of Sports Sciences, Consultant

Anne Catrine Trægde Martinsen, professor, Research director at Sunnaas Rehabilitation Hospital, Consultant

Derek John Curtis, PT PhD, Clinical Supervisor in physiotherapy at Copenhagen Council, Copenhagen, Consultant

Ethical approvals

REK nr. 452657

SIKT nr. 906214

Funding

Sunnaas Rehabilitation Hospital

Time period

2022-2026