A Pilot Study of the Effect of Botulinum Toxin Type a (Dysport®, Abobotulinum Toxin A) Injection on Changes in Musculotendinous Length and Dynamics of Hamstring Muscles During Gait in Children With Spastic Cerebral Palsy Walking With Excessive Knee Flexion
Condition: Cerebral Palsy
MeSH terms: Cerebral Palsy
Study type: Interventional

Summary: 
      This is a longitudinal, prospective, and open-label interventional study in a single center.
      We will investigate the effect of single injection in each patient. This study was designed
      to establish the clinical evidence for effect of botulinum toxin type a (Dysport,
      abobotulinum toxin A) injection on changes in musculotendinous length and dynamics of
      hamstring muscles during gait in children with spastic cerebral palsy walking with excessive
      knee flexion.

      Baseline data such as Modified Ashworth scale (MAS), Modified Tardieu scale (MTS), Gross
      Motor Function Measures (GMFM), and Gross Motor Function Classification System (GMFCS) level
      will be assessed. Gait analysis will be performed using a computerized gait analysis system
      (VICON MX-T10 System with 6 infrared cameras, Oxford Metrics Inc., Oxford, UK) to measure the
      kinematic data (angle of each joint) during the gait cycle. A trained investigator will place
      14 reflective markers on the anterior and posterior superior iliac spine, the mid points of
      the lateral femur, the lateral knee joint axis, the midpoints of the lateral tibia, the
      lateral malleolus, and the dorsal foot between metatarsal heads 2 and 3. All subjects should
      walk barefoot at a self-selected speed along an 8-meter path with the markers in place and
      the motion will be captured with a 100-Hz sampling frequency. Force-plates (AMTI OR 6-5,
      Advanced Mechanical Technology, Newton, MA, USA) under the path will record ground reaction
      forces during the walking trials with a 1000-Hz sampling frequency, and joint moments will be
      expressed as internal moments to counter the ground reaction forces. Data collection will
      continue until the subject achieved at least 3 'clean' force-plate strikes. Kinematic and
      kinetic data from successful trials will be used for statistical analysis. Video recording
      will be done simultaneously from the front, rear, and side, with the 3D gait analysis.
    

Detailed description: 
      Based on the evaluation including gait analysis, we will select the target muscles and inject
      the toxin into the selected muscles of the spastic lower limb under the guidance of
      ultrasonography or electrical stimulation. After BoNT-A injection, these children will be
      evaluated after 1 month. Clinical data obtained in the baseline measurement will be assessed
      again. Motion capture data will also be collected. Finally, clinical data of patients will be
      collected 4 months after injection to identify the clinical improvement and side effects.

      Motion capture data will be imported to OpenSim. We will generate an inverse kinematic
      analysis of each subject using following procedure:

        1. Scale the model to match the anthropometry of each subject. We will scale the dimensions
           of the torso, pelvis, thigh, shank, and foot based on the relative distances between
           pairs of markers measured experimentally and the corresponding markers in the model. The
           muscle attachments will also be scaled with the segment.

        2. Using a least-squares formulation, a set of desired joint angles for tracking,
           consistent with each scaled model, based on the marker trajectories, joint constraints,
           and joint angles from gait analysis will be computed.

        3. The musculotendinous length of each muscle will be calculated based on the "lower limb
           model 2010" by Arnold. This model adopted the wrapping surface to calculate the moment
           arm and musculotendinous unit passage at each joint. This model is intended to be used
           in research-graded kinematic analysis.

             -  Objectives <Primary objective>

      1.To determine the changes of musculotendinous length of hamstrings after a single BoNT-A
      injection during walking in children with spastic CP walking with excessive knee flexion
      <Secondary objectives>

        1. To determine the efficacy on gross motor function after BoNT-A injection

        2. To determine the benefit on gait after BoNT-A injection

        3. To determine the efficacy on spasticity after BoNT-A injection

        4. To determine the kinematic change after BoNT-A injection

        5. To determine the dynamic change after BoNT-A injection

        6. To determine the treatment emergent adverse events following BoNT-A injection

             -  Subjects : total 32 children with cerebral palsy

             -  Intervention :

      1. BoNT-A will be injected into two hamstring and/or gastrocnemius muscles under the guidance
      of ultrasonography or electrical stimulation. 2. Maximal total dose and dose regimen for each
      muscle would follow the recommendation of international consensus. A. Semitendinosus 5 to 7.5
      units/kg of body weight B. Semimembranosus 5 to 7.5 units/kg of body weight C. Gastrocnemius
      10 units/kg of body weight D. Maximal total dose per patient : unilateral injection 500
      units, bilateral injection 1,000 units E. The dosage of two hamstring muscles will depend on
      the severity of spasticity and gait abnormalities of children with CP

        -  Studies : 3D motion analysis, GMFM (gross motor function measure), GMFCS (gross motor
           function classification system), MAS (modified Ashworth scale), MTS (modified Tardieu
           scale)

        -  Evaluation plan : 1) pre-intervention, 2) post-4 weeks after intervention, 3) 16 weeks
           after intervention
    

Intervention name(s): Botulinum toxin injection
Intervention type(s): Drug
Intervention description(s): BoNT-A will be injected into two hamstring and/or gastrocnemius muscles under the guidance of ultrasonography or electrical stimulation.
Maximal total dose and dose regimen for each muscle would follow the recommendation of international consensus.
A. Semitendinosus 5 to 7.5 units/kg of body weight B. Semimembranosus 5 to 7.5 units/kg of body weight C. Gastrocnemius 10 units/kg of body weight D. Maximal total dose per patient : unilateral injection 500 units, bilateral injection 1,000 units E. The dosage of two hamstring muscles will depend on the severity of spasticity and gait abnormalities of children with CP
Intervention MeSH terms: Botulinum Toxins
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment