Effect of Botulinum Toxin on Muscles of Children With Cerebral Palsy (TOXIMUS_CP)

Transversal Monocentric Study of the Anatomophysiological Effect of Botulinum Toxin on the Spastic Muscle of Children With Cerebral Palsy

Cerebral palsy (CP) is a group of non-progressive motor dysfunction but often changing, secondary to injury or brain abnormalities that occur in early stages of development. In children with CP, the brain injury lead to a delayed motor development in the first weeks, associated with muscular spasticity. Drug treatments include oral treatments (baclofen and tizanidine) and injectable treatments like Botox (intramuscular injection) and neurolysis with alcohol or phenol (local injection into the nerve).

Regarding botulinum toxin, there is no study questioning its effectiveness. However, no publication on the pathophysiology of human muscle of the CP child after toxin injection was found. The action of the toxin on the neuromuscular junction (NMJ) and muscle structure is unknown in children with CP.

The primary objective of this study is to describe structural abnormalities of the CP child's muscle following multiple toxin injections in terms of NMJ fragmentation and axonal sprouting.

Secondary objectives:

To evaluate the relationship between:

• The severity of the motor impairment and muscle structural abnormalities.
• The clinical measure of spasticity and muscle structural abnormalities.
• To compare the structure spastic muscles with toxin injections and spastic muscle without toxin injections

For muscles with multiple toxin injections, assessing the relationship between :

• The number of toxin injections and muscle structural abnormalities.
• The date of the first injection and muscle structural abnormalities.
• The total dose of injected toxin in the muscle and its structural abnormalities.
• The nature of the product injected in the muscle and its structural abnormalities.

This innovative study will improve the knowledge on the effects of long-term botulinum toxin injections on the muscle (and therefore its safety in usual care), on the spastic muscle NMJ of CP children, on the pathophysiology of the CP child's muscle.

All the visits all acts will be performed according to usual patient follow-up. Only a biopsy will be performed in addition, taken from an injected muscle during a planned operation. A biopsy may also be performed on a muscle without toxin injection if the act is made possible by the planned surgery. No biopsy will be made on a muscle that would not require surgery.

Study Overview

• Status: Completed
• Conditions: Cerebral Palsy
• Intervention / Treatment: Procedure: Muscle biopsy

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Bron, France, 69500
    • Hôpital Femme Mère Enfant

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age Children > 7 years and <18 years
• With spastic cerebral palsy (all grades of the combined GMFCS
• Having an orthopedic surgical indication already planned on the lower limbs
• Receiving toxin injections
• With social security coverage
• Whose parents / holders of parental authority have signed the consent form

Exclusion Criteria:

• Patients with an evolutive CP
• Children with a baclofen pump
• Children who underwent neurotomy or functional dorsal rhizotomy, or alcohol or phenol injections

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Children with spastic CP receiving toxin injections; Children with spastic cerebral palsy receiving toxin injections

Procedure: Muscle biopsy; A biopsy (specifically done for the study) of a muscle that has already been injected with botulinum toxin before inclusion of the patient in the study will be performed, taken during a planned surgery (for tendon transfer or muscle lengthening). A biopsy of a muscle that has never been injected with botulinum toxin may be performed during surgery. No biopsy will be made on a member that would not require surgery. Thus sampling will be conducted on a muscle requiring a surgery: 2 to 3 millimeters will be taken on 10 mm muscle before transfer or lengthening.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence of neuromuscular junctions fragmentation (both qualitative and quantitative).	The biopsy is performed at the same time of a scheduled general anesthesia surgery (multisite surgery). The biopsy is 2 to 3 mm x 10 mm. It is a simple and quick gesture, usually practiced by surgeon	6 months maximum (time of surgery)
Presence of axonal sprouting (qualitative).		6 months maximum (time of surgery)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of muscles with neuromuscular junctions fragmentation (both qualitative and quantitative) and/or axonal sprouting (qualitative) according to patient's GMFCS grade (1 to 5).	The Gross Motor Function Classification System (GMFCS) is a 5 level clinical classification system that describes the gross motor function of people with cerebral palsy on the basis of self-initiated movement abilities.	6 months maximum (time of surgery)
Proportion of muscles with neuromuscular junctions fragmentation (both qualitative and quantitative) and/or axonal sprouting (qualitative) according to Ashworth score.	The Ashworth scale is bedside tool for assessing muscle spasticity in patients with neurological conditions. Ashworth grades as follows: 0, 1, 1+, 2, 3, 4.	6 months maximum (time of surgery)
Proportion of muscles with neuromuscular junctions fragmentation (both qualitative and quantitative) and/or axonal sprouting (qualitative) according to Tardieu score.	The Tardieu Scale is bedside tool for assessing muscle spasticity in patients with neurological conditions. Tardieu scale grades from 0 to 5.	6 months maximum (time of surgery)
Proportion of muscles with neuromuscular junctions fragmentation (both qualitative and quantitative) and/or axonal sprouting (qualitative) according to the number of toxin injections in the muscle.		6 months maximum (time of surgery)
Proportion of muscles with neuromuscular junctions fragmentation (both qualitative and quantitative) and/or axonal sprouting (qualitative) according to the delay (in months) since the first toxin injection in the muscle		6 months maximum (time of surgery)
Proportion of muscles with neuromuscular junctions fragmentation (both qualitative and quantitative) and/or axonal sprouting (qualitative) according to the total volume (IU) of injected toxin since the first injection in the muscle.		6 months maximum (time of surgery)
Proportion of muscles with neuromuscular junctions fragmentation (both qualitative and quantitative) and/or axonal sprouting (qualitative) according to the brand of the injected toxin (Botox® or Dysport®).		6 months maximum (time of surgery)

Collaborators and Investigators

• Sponsor: Hospices Civils de Lyon

Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2016
• Primary Completion (Actual): January 10, 2020
• Study Completion (Actual): January 10, 2020

Study Registration Dates

• First Submitted: July 19, 2016
• First Submitted That Met QC Criteria: August 1, 2016
• First Posted (Estimate): August 2, 2016

Study Record Updates

• Last Update Posted (Actual): January 18, 2020
• Last Update Submitted That Met QC Criteria: January 14, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: children; Cerebral palsy; muscle spasticity; botulinum toxin injection
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Brain Damage, Chronic; Cerebral Palsy; Paralysis
• Other Study ID Numbers: 69HCL15_0540; 2016-001610-24 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO