DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY
ORIGINAL ARTICLE
Motor endplate-targeted botulinum toxin injections of the gracilis muscle in children with cerebral palsy ANJA VAN CAMPENHOUT 1,2*
| LYNN BAR-ON 3,4* | KAAT DESLOOVERE 3,4 | CATHERINE HUENAERTS3 |
GUY MOLENAERS 1,2 1 Department of Orthopaedics, University Hospital Leuven, Leuven; 2 KU Leuven Department of Development and Regeneration, Leuven; 3 Clinical Motion Analysis Laboratory, University Hospital Leuven, Leuven; 4 KU Leuven Department of Rehabilitation Sciences, Leuven, Belgium. Correspondence to Anja Van Campenhout at University Hospital Leuven, Weligerveld 1, 3212 Pellenberg, Belgium. E-mail: [email protected] * These authors share first authorship of the paper. This article is commented on by Smith on pages 407–408 of this issue.
PUBLICATION DATA
Accepted for publication 11th November 2014. Published online 2nd January 2015. ABBREVIATIONS
BoNT-A ISA
Botulinum toxin-A Instrumented spasticity assessment MAS Modified Ashworth Scale MEP Motor endplate MTS Modified Tardieu Scale MVC Maximum voluntary contraction RMS-EMG Root mean square electromyography sEMG Surface electromyography
AIM Intramuscular botulinum toxin-A (BoNT-A) injections reduce spasticity by blocking neurotransmission at the motor endplate (MEP). The goal of this study was to assess the reduction in spasticity achieved by injecting BoNT-A at different sites of the gracilis muscle. METHOD Thirty-four gracilis muscles, in 27 children (10 females and 17 males, mean age of 8.6y [SD 2.5y]) with spastic cerebral palsy (unilateral and bilateral, Gross Motor Function Classification System [GMFCS] levels I–IV), were randomly assigned to one of two groups. In one group BoNT-A was injected proximally (at a site 25% of the distance from the pubic tubercle and the medial epicondyle) and in the other it was injected at the MEP zones (half of the dose was administered at 30% of this distance and half at 60%). Spasticity was assessed before and after BoNT-A injection using simultaneous measurements of surface electromyography (sEMG) and angular velocity during passive muscle stretch applied at different velocities. The primary outcome measure included the velocity-dependent change in average root mean square electromyography (RMS-EMG). Secondary outcome was assessed with the Modified Ashworth Scale (MAS) and Modified Tardieu Scale (MTS). RESULTS Spasticity decreased more in MEP-targeted muscles than in proximally injected muscles, as demonstrated by a larger reduction in average RMS-EMG values (p=0.04), though this difference was not found with the MAS or MTS. INTERPRETATION The results suggest that BoNT-A injection of the gracilis at sites with a high concentration of MEPs is effective at reducing spasticity. These preliminary findings should be confirmed by larger studies. In the case of long muscles, such as the gracilis, the injection site is important.
Intramuscular botulinum toxin-A (BoNT-A) injections are used to reduce spasticity in children with cerebral palsy (CP). Clinical studies have documented this, but also indicate variability in outcomes.1 Many factors, including injection technique, are responsible for this inconsistency.2 BoNT-A blocks neurotransmission at the neuromuscular junction by inhibiting the release of acetylcholine at the motor endplate (MEP);3 therefore, the toxin should be administered not only into the correct muscle, but also close to the MEP zone. This was first demonstrated in animal studies4,5 and more recently, in adults post stroke6 and in children with CP, in whom psoas muscle injections were performed.7 Spasticity of the gracilis muscle is a common clinical symptom in children with CP. The gracilis works as a hip adductor and knee flexor, and thus spasticity of this muscle can cause hip dislocation and deterioration of gait.8 Therefore, this muscle is often treated with BoNT-A. Because the gracilis is a long muscle, running from the symphysis pubis to the proxi476 DOI: 10.1111/dmcn.12667
mal tibia, it is important to determine the optimal injection site(s). The location of the MEP zones of the gracilis muscle can be derived from several histological and dissection studies. Using cholinesterase staining, Christensson9 and Kumar et al.10 observed two dense bands corresponding to MEP zones: one oblique band between the upper and middle thirds of the muscle, and another between the middle and lower thirds of the muscle. This and other observations (such as fine collagen fibres between muscle fibres, and the absence of double innervation)9,10 suggest that at least some of the muscle fibres in the gracilis develop from two myoblasts, each with its own MEP. However, in most textbooks describing BoNT-A injection techniques, this information is not considered. Instead, current recommendations suggest injecting the gracilis in the middle third of the thigh, along a line joining the pes anserinus and the symphysis pubis,11 or to inject proximally.12 In order to understand whether or not the specific site of gracilis muscle injection influences the effects of © 2015 Mac Keith Press
BoNT-A on muscle spasticity, a double-blind, randomized controlled trial was set up to compare two injection techniques: MEP-targeted injection and the widely used proximal injection technique.12 Previous studies comparing muscle injection sites have used surface electromyography (sEMG) during maximum voluntary contractions (MVCs) to record the denervation effects of BoNT-A.6,13 However, there have been no studies reporting the effects of injection site on spasticity. Clinical spasticity assessment methods, such as the Modified Ashworth Scale (MAS)14 and the Modified Tardieu Scale (MTS),15 have been criticized for their low reliability,16 lack of validity,17 and inadequacy in assessing the effect of treatment.18 Instrumented alternatives have been shown to provide a more robust method to quantify spasticity19 and the effect of BoNT-A.18,20 Recently, an instrumented spasticity assessment (ISA) that synchronizes angular velocity and sEMG to assess spasticity was developed for use in children with CP.19 ISA has been shown to provide reliable measurements of ankle, knee, and hip muscles.21 By manipulating one joint in isolation, passive muscle stretches are applied by an examiner, similar to those applied during a clinical examination. A parameter based on sEMG is used to quantify pathological muscle activation caused by increasing stretch velocity, thus capturing the velocity-dependent neurophysiological response.22 In the current study, it was hypothesized that MEP-targeted BoNT-A injections in the gracilis would result in a greater reduction in spasticity than would proximal BoNT-A injections. To test this hypothesis, we assessed spasticity before and after injection with BoNT-A by means of ISA.
METHOD Participants Children with CP, aged between 4 years and 18 years and with indications for BoNT-A injection in the gracilis muscle, were recruited between December 2011 and April 2013 from the CP reference centre of the University Hospital Pellenberg. Individuals were excluded from the study if ataxia or dystonia was present, if they displayed severe muscle weakness (scoring 20°/s within a velocity trial), or in case of poor-quality sEMG data (low signal-tonoise ratio or obvious artefacts). Average maximum angular velocity from the high-velocity stretches was calculated to compare the consistency of the stretch performance between measurement sessions and groups. The average RMS-EMG value was calculated as the area under the RMS-EMG time curve divided by the duration of a given interval. This interval started 200ms before the time at which maximum angular velocity was reached, and ended when 90% of the full range of motion had been completed.19 This parameter was averaged over the four stretch repetitions at high velocity and low velocity. The difference between these two values (RMS-EMG ‘high– low’) represents the velocity-dependent increase in average RMS-EMG.19 RMS-EMG ‘high–low’ was expressed as a percentage of the peak RMS-EMG from the three MVCs collected during the pre-BoNT-A injection measurement. This parameter has been reported to be a reliable and valid measure of spasticity,19,21 and is responsive to BoNT-A treatment of the hamstrings.18,20 Therefore, RMS-EMG ‘high–low’ was used as the primary outcome variable. In addition to ISAs, clinical spasticity assessments were carried out by independent, trained assessors. Because the gracilis muscle crosses the knee joint, it acts as a hamstring and as an adductor. Therefore, both hamstrings and hip adductors were assessed using the MAS.14 In participants with hamstring muscles scoring ‘1+’ or above on the MAS, MTS assessment was also performed, whereby the angle at which a spastic catch was felt during a quick passive stretch was noted (R1 angle).15 MTS assessment was not carried out for the gracilis muscle or other adductors because these evaluations are difficult to execute reliably by a single assessor. The MAS scores and hamstring MTS R1 angles were considered secondary outcome variables.
Statistical analysis Primary and secondary outcome variables from all children, measured before and after BoNT-A treatment, were compared using Wilcoxon signed-rank tests. The differences in outcome variables between sessions (before BoNT-A compared with after BoNT-A) and the average maximum angular velocity during the post-BoNT-A sessions were compared between intervention groups using Mann–Whitney U tests. Statistical significance was indicated by p values of
ORIGINAL ARTICLE
Motor endplate-targeted botulinum toxin injections of the gracilis muscle in children with cerebral palsy ANJA VAN CAMPENHOUT 1,2*
| LYNN BAR-ON 3,4* | KAAT DESLOOVERE 3,4 | CATHERINE HUENAERTS3 |
GUY MOLENAERS 1,2 1 Department of Orthopaedics, University Hospital Leuven, Leuven; 2 KU Leuven Department of Development and Regeneration, Leuven; 3 Clinical Motion Analysis Laboratory, University Hospital Leuven, Leuven; 4 KU Leuven Department of Rehabilitation Sciences, Leuven, Belgium. Correspondence to Anja Van Campenhout at University Hospital Leuven, Weligerveld 1, 3212 Pellenberg, Belgium. E-mail: [email protected] * These authors share first authorship of the paper. This article is commented on by Smith on pages 407–408 of this issue.
PUBLICATION DATA
Accepted for publication 11th November 2014. Published online 2nd January 2015. ABBREVIATIONS
BoNT-A ISA
Botulinum toxin-A Instrumented spasticity assessment MAS Modified Ashworth Scale MEP Motor endplate MTS Modified Tardieu Scale MVC Maximum voluntary contraction RMS-EMG Root mean square electromyography sEMG Surface electromyography
AIM Intramuscular botulinum toxin-A (BoNT-A) injections reduce spasticity by blocking neurotransmission at the motor endplate (MEP). The goal of this study was to assess the reduction in spasticity achieved by injecting BoNT-A at different sites of the gracilis muscle. METHOD Thirty-four gracilis muscles, in 27 children (10 females and 17 males, mean age of 8.6y [SD 2.5y]) with spastic cerebral palsy (unilateral and bilateral, Gross Motor Function Classification System [GMFCS] levels I–IV), were randomly assigned to one of two groups. In one group BoNT-A was injected proximally (at a site 25% of the distance from the pubic tubercle and the medial epicondyle) and in the other it was injected at the MEP zones (half of the dose was administered at 30% of this distance and half at 60%). Spasticity was assessed before and after BoNT-A injection using simultaneous measurements of surface electromyography (sEMG) and angular velocity during passive muscle stretch applied at different velocities. The primary outcome measure included the velocity-dependent change in average root mean square electromyography (RMS-EMG). Secondary outcome was assessed with the Modified Ashworth Scale (MAS) and Modified Tardieu Scale (MTS). RESULTS Spasticity decreased more in MEP-targeted muscles than in proximally injected muscles, as demonstrated by a larger reduction in average RMS-EMG values (p=0.04), though this difference was not found with the MAS or MTS. INTERPRETATION The results suggest that BoNT-A injection of the gracilis at sites with a high concentration of MEPs is effective at reducing spasticity. These preliminary findings should be confirmed by larger studies. In the case of long muscles, such as the gracilis, the injection site is important.
Intramuscular botulinum toxin-A (BoNT-A) injections are used to reduce spasticity in children with cerebral palsy (CP). Clinical studies have documented this, but also indicate variability in outcomes.1 Many factors, including injection technique, are responsible for this inconsistency.2 BoNT-A blocks neurotransmission at the neuromuscular junction by inhibiting the release of acetylcholine at the motor endplate (MEP);3 therefore, the toxin should be administered not only into the correct muscle, but also close to the MEP zone. This was first demonstrated in animal studies4,5 and more recently, in adults post stroke6 and in children with CP, in whom psoas muscle injections were performed.7 Spasticity of the gracilis muscle is a common clinical symptom in children with CP. The gracilis works as a hip adductor and knee flexor, and thus spasticity of this muscle can cause hip dislocation and deterioration of gait.8 Therefore, this muscle is often treated with BoNT-A. Because the gracilis is a long muscle, running from the symphysis pubis to the proxi476 DOI: 10.1111/dmcn.12667
mal tibia, it is important to determine the optimal injection site(s). The location of the MEP zones of the gracilis muscle can be derived from several histological and dissection studies. Using cholinesterase staining, Christensson9 and Kumar et al.10 observed two dense bands corresponding to MEP zones: one oblique band between the upper and middle thirds of the muscle, and another between the middle and lower thirds of the muscle. This and other observations (such as fine collagen fibres between muscle fibres, and the absence of double innervation)9,10 suggest that at least some of the muscle fibres in the gracilis develop from two myoblasts, each with its own MEP. However, in most textbooks describing BoNT-A injection techniques, this information is not considered. Instead, current recommendations suggest injecting the gracilis in the middle third of the thigh, along a line joining the pes anserinus and the symphysis pubis,11 or to inject proximally.12 In order to understand whether or not the specific site of gracilis muscle injection influences the effects of © 2015 Mac Keith Press
BoNT-A on muscle spasticity, a double-blind, randomized controlled trial was set up to compare two injection techniques: MEP-targeted injection and the widely used proximal injection technique.12 Previous studies comparing muscle injection sites have used surface electromyography (sEMG) during maximum voluntary contractions (MVCs) to record the denervation effects of BoNT-A.6,13 However, there have been no studies reporting the effects of injection site on spasticity. Clinical spasticity assessment methods, such as the Modified Ashworth Scale (MAS)14 and the Modified Tardieu Scale (MTS),15 have been criticized for their low reliability,16 lack of validity,17 and inadequacy in assessing the effect of treatment.18 Instrumented alternatives have been shown to provide a more robust method to quantify spasticity19 and the effect of BoNT-A.18,20 Recently, an instrumented spasticity assessment (ISA) that synchronizes angular velocity and sEMG to assess spasticity was developed for use in children with CP.19 ISA has been shown to provide reliable measurements of ankle, knee, and hip muscles.21 By manipulating one joint in isolation, passive muscle stretches are applied by an examiner, similar to those applied during a clinical examination. A parameter based on sEMG is used to quantify pathological muscle activation caused by increasing stretch velocity, thus capturing the velocity-dependent neurophysiological response.22 In the current study, it was hypothesized that MEP-targeted BoNT-A injections in the gracilis would result in a greater reduction in spasticity than would proximal BoNT-A injections. To test this hypothesis, we assessed spasticity before and after injection with BoNT-A by means of ISA.
METHOD Participants Children with CP, aged between 4 years and 18 years and with indications for BoNT-A injection in the gracilis muscle, were recruited between December 2011 and April 2013 from the CP reference centre of the University Hospital Pellenberg. Individuals were excluded from the study if ataxia or dystonia was present, if they displayed severe muscle weakness (scoring 20°/s within a velocity trial), or in case of poor-quality sEMG data (low signal-tonoise ratio or obvious artefacts). Average maximum angular velocity from the high-velocity stretches was calculated to compare the consistency of the stretch performance between measurement sessions and groups. The average RMS-EMG value was calculated as the area under the RMS-EMG time curve divided by the duration of a given interval. This interval started 200ms before the time at which maximum angular velocity was reached, and ended when 90% of the full range of motion had been completed.19 This parameter was averaged over the four stretch repetitions at high velocity and low velocity. The difference between these two values (RMS-EMG ‘high– low’) represents the velocity-dependent increase in average RMS-EMG.19 RMS-EMG ‘high–low’ was expressed as a percentage of the peak RMS-EMG from the three MVCs collected during the pre-BoNT-A injection measurement. This parameter has been reported to be a reliable and valid measure of spasticity,19,21 and is responsive to BoNT-A treatment of the hamstrings.18,20 Therefore, RMS-EMG ‘high–low’ was used as the primary outcome variable. In addition to ISAs, clinical spasticity assessments were carried out by independent, trained assessors. Because the gracilis muscle crosses the knee joint, it acts as a hamstring and as an adductor. Therefore, both hamstrings and hip adductors were assessed using the MAS.14 In participants with hamstring muscles scoring ‘1+’ or above on the MAS, MTS assessment was also performed, whereby the angle at which a spastic catch was felt during a quick passive stretch was noted (R1 angle).15 MTS assessment was not carried out for the gracilis muscle or other adductors because these evaluations are difficult to execute reliably by a single assessor. The MAS scores and hamstring MTS R1 angles were considered secondary outcome variables.
Statistical analysis Primary and secondary outcome variables from all children, measured before and after BoNT-A treatment, were compared using Wilcoxon signed-rank tests. The differences in outcome variables between sessions (before BoNT-A compared with after BoNT-A) and the average maximum angular velocity during the post-BoNT-A sessions were compared between intervention groups using Mann–Whitney U tests. Statistical significance was indicated by p values of
