Joint and Muscle Assessments of the Separate Effects of Botulinum NeuroToxin-A and Lower-Leg Casting in Children With Cerebral Palsy

Nicky Peeters, Anja Van Campenhout, Britta Hanssen, Francesco Cenni, Simon-Henri Schless, Christine Van den Broeck, Kaat Desloovere, Lynn Bar-On, Nicky Peeters, Anja Van Campenhout, Britta Hanssen, Francesco Cenni, Simon-Henri Schless, Christine Van den Broeck, Kaat Desloovere, Lynn Bar-On

Abstract

Botulinum NeuroToxin-A (BoNT-A) injections to the medial gastrocnemius (MG) and lower-leg casts are commonly combined to treat ankle equinus in children with spastic cerebral palsy (CP). However, the decomposed treatment effects on muscle or tendon structure, stretch reflexes, and joint are unknown. In this study, BoNT-A injections to the MG and casting of the lower legs were applied separately to gain insight into the working mechanisms of the isolated treatments on joint, muscle, and tendon levels. Thirty-one children with spastic CP (GMFCS I-III, age 7.4 ± 2.6 years) received either two weeks of lower-leg casts or MG BoNT-A injections. During full range of motion slow and fast passive ankle rotations, joint resistance and MG stretch reflexes were measured. MG muscle and tendon lengths were assessed at resting and at maximum dorsiflexion ankle angles using 3D-freehand ultrasound. Treatment effects were compared using non-parametric statistics. Associations between the effects on joint and muscle or tendon levels were performed using Spearman correlation coefficients (p < 0.05). Increased joint resistance, measured during slow ankle rotations, was not significantly reduced after either treatment. Additional joint resistance assessed during fast rotations only reduced in the BoNT-A group (-37.6%, p = 0.013, effect size = 0.47), accompanied by a reduction in MG stretch reflexes (-70.7%, p = 0.003, effect size = 0.56). BoNT-A increased the muscle length measured at the resting ankle angle (6.9%, p = 0.013, effect size = 0.53). Joint angles shifted toward greater dorsiflexion after casting (32.4%, p = 0.004, effect size = 0.56), accompanied by increases in tendon length (5.7%, p = 0.039, effect size = 0.57; r = 0.40). No associations between the changes in muscle or tendon lengths and the changes in the stretch reflexes were found. We conclude that intramuscular BoNT-A injections reduced stretch reflexes in the MG accompanied by an increase in resting muscle belly length, whereas casting resulted in increased dorsiflexion without any changes to the muscle length. This supports the need for further investigation on the effect of the combined treatments and the development of treatments that more effectively lengthen the muscle.

Keywords: Botulinum NeuroToxin; casting; cerebral palsy; hyper-resistance; muscle length; muscle stretch reflex; spasticity; tendon length.

Copyright © 2020 Peeters, Van Campenhout, Hanssen, Cenni, Schless, Van den Broeck, Desloovere and Bar-On.

Figures

Figure 1
Figure 1
Sagittal US image with landmarks for extraction of muscle and tendon length C, calcaneus; MTJ, muscle tendon junction; MFC, medial femoral condyle.
Figure 2
Figure 2
Overview of statistical analyses. 3DfUS, 3D freehand ultrasound; BoNT-A, Botulinum NeuroToxin-A.
Figure 3
Figure 3
Flowchart of the inclusion of participants with an overview of the available and missing data. 3DfUS, 3D freehand ultrasound; GMFCS, gross motor functional classification scale; BoNT-A, Botulinum NeuroToxin-A.
Figure 4
Figure 4
Results of muscle/tendon lengths, ankle joint resistance and stretch reflex assessments. (A) Change in ankle angles. (B) Muscle and tendon lengths at resting position. (C) Muscle and tendon lengths at maximum dorsiflexion. (D) Work at the ankle joint during slow and fast joint rotations. (E) Stretch reflexes of the plantar flexors during fast rotations. *significant results (p < 0.05, difference > SEM). mm, millimeter; J, Joule; rms EMG, root mean square of the electromyographic signal; μV, microvolt; MG, medial gastrocnemius muscle; LG, lateral gastrocnemius muscle; SOL, soleus muscle; BoNT-A, Botulinum NeuroToxin-A.

References

    1. Gage JR, Schwartz MH, Koop SE, Novacheck TF. The Identification And Treatment Of Gait Problems In Cerebral Palsy. 2nd Edn. London: Mac Keith Press; John Wiley & Sons; (2009).
    1. Gough M, Shortland AP. Could muscle deformity in children with spastic cerebral palsy be related to an impairment of muscle growth and altered adaptation? Dev Med Child Neurol. (2012) 54:495–9. 10.1111/j.1469-8749.2012.04229.x
    1. Willerslev-Olsen M, Choe Lund M, Lorentzen J, Barber L, Kofoed-Hansen M, Nielsen JB. Impaired muscle growth precedes development of increased stiffness of the triceps surae musculotendinous unit in children with cerebral palsy. Dev Med Child Neurol. (2018) 60:672–9. 10.1111/dmcn.13729
    1. Domenighetti XAA, Mathewson MA, Pichika R, Sibley LA, Zhao L, Chambers HG, et al. . Loss of myogenic potential and fusion capacity of muscle stem cells isolated from contractured muscle in children with cerebral palsy. Am J Physiol Cell Physiol. (2019) 315:C247–57. 10.1152/ajpcell.00351.2017
    1. Von Walden F, Gantelius S, Liu C, Borgström H, Björk L, Gremark O, et al. . Muscle contractures in patients with cerebral palsy and acquired brain injury are associated with extracellular matrix expansion, pro-inflammatory gene expression, and reduced rRNA synthesis. Muscle Nerve. (2018) 58:277–85. 10.1002/mus.26130
    1. Dayanidhi S, Dykstra PB, Lyubasyuk V, McKay BR, Chambers HG, Lieber RL. Reduced satellite cell number in situ in muscular contractures from children with cerebral palsy. J Orthop Res. (2015) 33:1039–45. 10.1002/jor.22860
    1. Molenaers G, Schörkhuber V, Fagard K, Van Campenhout A, De Cat J, Pauwels P, et al. . Long-term use of botulinum toxin type A in children with cerebral palsy: treatment consistency. Eur J Paediatr Neurol. (2009) 13:421–9. 10.1016/j.ejpn.2008.07.008
    1. Molenaers G, Fagard K. Botulinum toxin A treatment of the lower extremities in children with cerebral palsy. J Child Orthop. (2013) 7:383–7. 10.1007/s11832-013-0511-x
    1. Martín Lorenzo T, Rocon E, Martínez Caballero I, Ramírez Barragán A, Lerma Lara S. Prolonged stretching of the ankle plantarflexors elicits muscle-tendon adaptations relevant to ankle gait kinetics in children with spastic cerebral palsy. Med Hypotheses. (2017) 109:65–9. 10.1016/j.mehy.2017.09.025
    1. Alexander C, Elliott C, Valentine J, Stannage K, Bear N, Donnelly CJ, et al. . Muscle volume alterations after first botulinum neurotoxin A treatment in children with cerebral palsy : a 6-month prospective cohort study. Dev Med Child Neurol. (2018) 60:1165–72. 10.1111/dmcn.13988
    1. Boyaci A, Tutoglu A, Boyaci N, Koca I, Calik M, Sakalar A, et al. . Changes in spastic muscle stiffness after botulinum toxin A injections as part of rehabilitation therapy in patients with spastic cerebral palsy. NeuroRehabilitation. (2014) 35:123–9. 10.3233/NRE-141107
    1. Barber L, Hastings-Ison T, Baker R, Kerr Graham H, Barrett R, Lichtwark G. The effects of botulinum toxin injection frequency on calf muscle growth in young children with spastic cerebral palsy: A 12-month prospective study. J Child Orthop. (2013) 7:425–33. 10.1007/s11832-013-0503-x
    1. Reid S, Elliott C, Shipman P, Valentine J. Muscle volume alterations in spastic muscles immediately following botulinum toxin type-A treatment in children with cerebral palsy. Dev Med Child Neurol. (2013) 55:813–20. 10.1111/dmcn.12200
    1. Williams SA, Elliott C, Valentine J, Gubbay A, Shipman P, Reid S. Combining strength training and botulinum neurotoxin intervention in children with cerebral palsy: the impact on muscle morphology and strength. Disabil Rehabil. (2013) 35:596–605. 10.3109/09638288.2012.711898
    1. Kawano A, Yanagizono T, Kadouchi I, Umezaki T, Chosa E. Ultrasonographic evaluation of changes in the muscle architecture of the gastrocnemius with botulinum toxin treatment for lower extremity spasticity in children with cerebral palsy. J Orthop Sci. (2017) 23:389–93. 10.1016/j.jos.2017.10.012
    1. Schless S-H, Cenni F, Bar-On L, Hanssen B, Kalkman BM, O'Brien TD, et al. . Medial gastrocnemius volume and echo-intensity after botulinum neurotoxin A interventions in children with spastic cerebral palsy. Dev Med Child Neurol. (2019) 61:783–90. 10.1111/dmcn.14056.
    1. Park ES, Sim E, Rha D-W, Jung S. Architectural changes of the gastrocnemius muscle after botulinum toxin type A injection in children with cerebral palsy. Yonsei Med J. (2014) 55:1406. 10.3349/ymj.2014.55.5.1406
    1. Van Campenhout A, Verhaegen A, Pans S, Molenaers G. Botulinum toxin type A injections in the psoas muscle of children with cerebral palsy: muscle atrophy after motor end plate-targeted injections. Res Dev Disabil. (2013) 34:1052–8. 10.1016/j.ridd.2012.11.016
    1. Huijing PA, Bénard MR, Harlaar J, Jaspers RT, Becher JG. Movement within foot and ankle joint in children with spastic cerebral palsy : a 3-dimensional ultrasound analysis of medial gastrocnemius length with correction for effects of foot deformation. BMC Musculoskelet Disord. (2013) 14:365. 10.1186/1471-2474-14-365
    1. Bohannon RW, Smith MB. Interrater reliability of a modified ashworth scale of muscle spasticity. Phys Ther. (1987) 67:206–7. 10.1093/ptj/67.2.206
    1. Boyd RN, Graham HK. Objective measurement of clinical findings in the use of botulinum toxin type A for the management of children with cerebral palsy. Eur J neurol. (1999). 6(suppl. 4):23–35. 10.1111/j.1468-1331.1999.tb00031.x
    1. Cenni F, Monari D, Desloovere K, Aertbeliën E, Schless S-H, Bruyninckx H. The reliability and validity of a clinical 3D freehand ultrasound system. Comput Methods Programs Biomed. (2016) 136:179–87. 10.1016/j.cmpb.2016.09.001
    1. Cenni F, Schless SH, Bar-On L, Aertbeliën E, Bruyninckx H, Hanssen B, et al. . Reliability of a clinical 3D freehand ultrasound technique: analyses on healthy and pathological muscles. Comput Methods Programs Biomed. (2018) 156:97–103. 10.1016/j.cmpb.2017.12.023
    1. Cenni F, Schless S-H, Bar-On L, Molenaers G, Van Campenhout A, Aertbeliën E, et al. . Can in vivo medial gastrocnemius muscle–tendon unit lengths be reliably estimated by two ultrasonography methods? A within-session analysis. Ultrasound Med Biol. (2018) 44:110–8. 10.1016/j.ultrasmedbio.2017.09.018
    1. Bar-On L, Aertbelien E, Wambacq H, Severijns D, Lambrecht K, Dan B, et al. . A clinical measurement to quantify spasticity in children with cerebral palsy by integration of multidimensional signals. Gait Posture. (2013) 38:141–7. 10.1016/j.gaitpost.2012.11.003
    1. Aymard C, Katz R, Lafitte C, Lo E, Penicaud A, Pradat-Diehl P, et al. . Presynaptic inhibition and homosynaptic depression: a comparison between lower and upper limbs in normal human subjects and patients with hemiplegia. Brain. (2000) 123:1688–702. 10.1093/brain/123.8.1688
    1. Weir JP. Quantifying test-retest reliability using the intraclass correlation coefficient and the SEM. J strength Cond Res. (2005) 19:231–40. 10.1519/00124278-200502000-00038
    1. Rauch HE, Tung F, Striebel C. Maximum likelihood estimates of linear dynamic systems. Am Inst Aeronaut Astronaut J. (1965) 3:1445–50. 10.2514/3.3166
    1. Altman D. Practical Statistics for Medical Research. Boca Raton, FL: Chapman and Hall/CRC; (1991).
    1. Rosenthal R. Meta-analytic procedures for social research. In: Starika MR. editor Meta-analytic Procedures for Social Research. Newbury Park, CA: Sage Publications; (1991). p. 14–20.
    1. Harvey LA, Katalinic OM, Herbert RD, Moseley AM, Lannin NA, Schurr K. Stretch for the treatment and prevention of contracture: an abridged republication of a Cochrane Systematic Review. J Physiother. (2017) 63:67–75. 10.1016/j.jphys.2017.02.014.
    1. Guissard N, Duchateau J. Neural aspects of muscle stretching. Exerc Sport Sci Rev. (2006) 34:154–8. 10.1249/01.jes.0000240023.30373.eb
    1. Graham HK, Rosenbaum P, Paneth N, Dan B, Lin J-P, Damiano DL, et al. Cerebral palsy. Nat Rev Dis Prim. (2016) 2:15082 10.1038/nrdp.2016.5
    1. Hösl M, Böhm H, Arampatzis A, Döderlein L. Effects of ankle–foot braces on medial gastrocnemius morphometrics and gait in children with cerebral palsy. J Child Orthop. (2015) 9:209–19. 10.1007/s11832-015-0664-x
    1. Theis N, Korff T, Kairon H, Mohagheghi AA. Does acute passive stretching increase muscle length in children with cerebral palsy? Clin Biomech. (2013) 28:1061–7. 10.1016/j.clinbiomech.2013.10.001
    1. Zhao H, Wu Y, Liu J, Ren Y, Gaebler-spira DJ, Zhang L. Changes of calf muscle-tendon properties due to stretching and active movement of children with cerebral palsy a pilot study. Annu Int Conf IEEE Eng Med Biol Soc. (2009) 2009:5287–90. 10.1109/IEMBS.2009.5333518
    1. Theis N, Mohagheghi AA, Korff T. Mechanical and material properties of the plantarflexor muscles and achilles tendon in children with spastic cerebral palsy and typically developing children. J Biomech. (2016) 49:3004–8. 10.1016/j.jbiomech.2016.07.020
    1. Kalkman BM, Holmes G, Bar-on L, Maganaris CN, Barton GJ, Bass A, et al. . Resistance training combined with stretching increases tendon stiffness and is more effective than stretching alone in children with cerebral palsy : a randomized controlled trial. Front Pediatr. (2019). 7:333. 10.3389/fped.2019.00333
    1. Zhao H, Wu Y, Hwang M, Ren Y, Gaebler-Spira DJ, Zhang L. Changes of calf muscle-tendon biomechanical properties induced by passive stretching and active movement training in children with cerebral palsy. Dev Med Child Neurol. (2010) 52:40–2. 10.1152/japplphysiol.01361.2010.
    1. Meinders M, Price R, Lehmann JF, Questad KA. The stretch reflex response in the normal and spastic ankle effect of ankle position. Arch Phys Med Rehabil. (1996) 77:487–92. 10.1016/S0003-9993(96)90038-6
    1. El-Etribi MA, Salem ME, El-Shakankiry HM, El-Kahky AM, El-Mahboub SM. The effect of botulinum toxin type-A injection on spasticity, range of motion and gait patterns in children with spastic diplegic cerebral palsy: an Egyptian study. Int J Rehabil Res Int Zeitschrift fur Rehabil Rev Int Rech Readapt. (2004) 27:275–81. 10.1097/00004356-200412000-00004
    1. Sloot LH, van der Krogt MM, de Gooijer-van de Groep KL, van Eesbeek S, de Groot J, Buizer AI, et al. . The validity and reliability of modelled neural and tissue properties of the ankle muscles in children with cerebral palsy. Gait Posture. (2015) 42:7–15. 10.1016/j.gaitpost.2015.04.006
    1. Multani I, Manji J, Ison TH, Khot A, Graham K. Botulinum toxin in the management of children with cerebral palsy. Pediatr Drugs. (2019) 21:261–81. 10.1007/s40272-019-00344-8
    1. Desloovere K. Motor function following multilevel botulinum toxin type A treatment in children with cerebral palsy. Dev Med Child Neuro. (2007) 49:56–61. 10.1017/S001216220700014X.x
    1. Bar-On L, Aertbeliën E, Molenaers G, Van Campenhout A, Vandendoorent B, Nieuwenhuys A, et al. . Instrumented assessment of the effect of botulinum toxin-A in the medial hamstrings in children with cerebral palsy. Gait Posture. (2014) 39:17–22. 10.1016/j.gaitpost.2013.05.018

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe