Experimental animal study.
Spastic hypertonia is originally believed to cause contractures from clinical observations. Botulinum toxin is effective for the treatment of spasticity and is widely used in patients who have joints with contractures. Using an established rat model with knee contractures after spinal cord injuries, we aimed to verify whether hypertonia contributes to contracture development, and the botulinum toxin improves structural changes in muscles and joint components responsible for contractures.
University laboratory in Japan.
To evaluate the effect of hypertonia on contracture development, the rats received botulinum toxin injections after spinal cord injuries. Knee extension motion was measured with a goniometer applying a standardized torque under anesthesia, and the contribution by muscle or non-muscle structures to contractures were calculated by measuring joint motion before and after the myotomies. We quantitatively measured the muscle atrophy, muscle fibrosis, and synovial intima length.
Botulinum toxin injections significantly improved contractures, whereas did not completely prevent contracture development. Botulinum toxin was effective in improving the muscular factor, but little difference in the articular factor. Spinal cord injuries induced muscle atrophy, and botulinum toxin significantly accelerated muscle atrophy and fibrosis. The synovial intima length decreased significantly after spinal cord injuries, and botulinum toxin did not improve this shortening.
This animal study provides new evidence that hypertonia is not the sole cause rather is the partial contributor of contractures after spinal cord injuries. Furthermore, botulinum toxin has adverse effects in the muscle.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $30.08 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
All data generated or analyzed during this study are included in this published article and its supplementary information files.
Dalyan M, Sherman A, Cardenas DD. Factors associated with contractures in acute spinal cord injury. Spinal Cord. 1998;36:405–8.
Harvey LA, Herbert RD. Muscle stretching for treatment and prevention of contracture in people with spinal cord injury. Spinal Cord. 2002;40:1–9.
Botte MJ, Nickel VL, Akeson WH. Spasticity and contracture. Physiologic aspects of formation. Clin Orthop Relat Res. 1988;233:7–18.
Moriyama H, Yoshimura O, Sunahori H, Nitta H, Imakita H, Saka Y, et al. Progression and direction of contractures of knee joints following spinal cord injury in the rat. Tohoku J Exp Med. 2004;204:37–44.
Moriyama H, Yoshimura O, Sunahori H, Tobimatsu Y. Comparison of muscular and articular factors in the progression of contractures after spinal cord injury in rats. Spinal Cord. 2006;44:174–81.
Moriyama H, Nishihara K, Hosoda M, Saka Y, Kanemura N, Takayanagi K, et al. Contrasting alteration patterns of different cartilage plates in knee articular cartilage after spinal cord injury in rats. Spinal Cord. 2009;47:218–24.
Moriyama H, Yoshimura O, Kawamata S, Takayanagi K, Kurose T, Kubota A, et al. Alteration in articular cartilage of rat knee joints after spinal cord injury. Osteoarthr Cartil. 2008;16:392–8.
Moriyama H, Yoshimura O, Kawamata S, Takemoto H, Saka Y, Tobimatsu Y. Alteration of knee joint connective tissues during contracture formation in spastic rats after an experimentally induced spinal cord injury. Connect Tissue Res. 2007;48:180–7.
Huang W, Foster JA, Rogachefsky AS. Pharmacology of botulinum toxin. J Am Acad Dermatol. 2000;43:249–59.
Catz A, Barkol H, Steinberg F, Ronen J, Bluvshtein V, Keren O. Repeated botulinum toxin injections can improve mobility in patients with spinal cord lesions. Eura Med. 2007;43:319–25.
Lidman G, Nachemson A, Peny-Dahlstrand M, Himmelmann K. Botulinum toxin A injections and occupational therapy in children with unilateral spastic cerebral palsy: a randomized controlled trial. Dev Med Child Neurol. 2015;57:754–61.
Pittock SJ, Moore AP, Hardiman O, Ehler E, Kovac M, Bojakowski J, et al. A double-blind randomised placebo-controlled evaluation of three doses of botulinum toxin type A (Dysport) in the treatment of spastic equinovarus deformity after stroke. Cereb Dis. 2003;15:289–300.
Pickett A, O’Keeffe R, Judge A, Dodd S. The in vivo rat muscle force model is a reliable and clinically relevant test of consistency among botulinum toxin preparations. Toxicon. 2008;52:455–64.
Sakitani N, Iwasawa H, Nomura M, Miura Y, Kuroki H, Ozawa J, et al. Mechanical stress by spasticity accelerates fracture healing after spinal cord injury. Calcif Tissue Int. 2017;101:384–95.
Iwasawa H, Nomura M, Sakitani N, Watanabe K, Watanabe D, Moriyama H. Stretching after heat but not after cold decreases contractures after spinal cord injury in rats. Clin Orthop Relat Res. 2016;474:2692–701.
Moriyama H, Tobimatsu Y, Ozawa J, Kito N, Tanaka R. Amount of torque and duration of stretching affects correction of knee contracture in a rat model of spinal cord injury. Clin Orthop Relat Res. 2013;471:3626–36.
Trudel G, Uhthoff HK. Contractures secondary to immobility: is the restriction articular or muscular? An experimental longitudinal study in the rat knee. Arch Phys Med Rehabil. 2000;81:6–13.
Kawamoto T. Use of a new adhesive film for the preparation of multi-purpose fresh-frozen sections from hard tissues, whole-animals, insects and plants. Arch Histol Cytol. 2003;66:123–43.
Hadi AM, Mouchaers KT, Schalij I, Grunberg K, Meijer GA, Vonk-Noordegraaf A, et al. Rapid quantification of myocardial fibrosis: a new macro-based automated analysis. Cell Oncol (Dordr). 2011;34:343–54.
Ando A, Hagiwara Y, Onoda Y, Hatori K, Suda H, Chimoto E, et al. Distribution of type A and B synoviocytes in the adhesive and shortened synovial membrane during immobilization of the knee joint in rats. Tohoku J Exp Med. 2010;221:161–8.
Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transpl. 2013;48:452–8.
Hedges LV, Olkin I Statistical methods for meta-analysis. (Academic Press, Orlando, 1985).
van de Meent H, Hamers FP, Lankhorst AJ, Buise MP, Joosten EA, Gispen WH. New assessment techniques for evaluation of posttraumatic spinal cord function in the rat. J Neurotrauma. 1996;13:741–54.
Honda Y, Sakamoto J, Nakano J, Kataoka H, Sasabe R, Goto K, et al. Upregulation of interleukin-1beta/transforming growth factor-beta1 and hypoxia relate to molecular mechanisms underlying immobilization-induced muscle contracture. Muscle Nerve. 2015;52:419–27.
Fortuna R, Vaz MA, Sawatsky A, Hart DA, Herzog W. A clinically relevant BTX-A injection protocol leads to persistent weakness, contractile material loss, and an altered mRNA expression phenotype in rabbit quadriceps muscles. J Biomech. 2015;48:1700–6.
Olabisi R, Chamberlain CS, Petr S, Steiner S, Consigny D, Best TM, et al. The effects of botulinum toxin A on muscle histology during distraction osteogenesis. J Orthop Res. 2009;27:310–7.
Li J, Allende A, Martin F, Fraser CL. Histopathological changes of fibrosis in human extra-ocular muscle caused by botulinum toxin A. J Aapos. 2016;20:544–6.
Wilmet E, Ismail AA, Heilporn A, Welraeds D, Bergmann P. Longitudinal study of the bone mineral content and of soft tissue composition after spinal cord section. Paraplegia. 1995;33:674–7.
Choi WH, Song CW, Kim YB, Ha CS, Yang GH, Woo HD, et al. Skeletal muscle atrophy induced by intramuscular repeated dose of botulinum toxin type A in rats. Drug Chem Toxicol. 2007;30:217–27.
Thacker BE, Tomiya A, Hulst JB, Suzuki KP, Bremner SN, Gastwirt RF, et al. Passive mechanical properties and related proteins change with botulinum neurotoxin A injection of normal skeletal muscle. J Orthop Res. 2012;30:497–502.
We thank Naoyoshi Sakitani, Shin Ogasawara, Ryota Suzuki, Eriko Mizuno, and Masato Nomura for their skilled technical assistance.
This work was supported in part by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant no. 17K19908.
This study was approved by the Institutional Animal Care and Use Committee (Permission number: P130408) and carried out according to the Kobe University Animal Experimentation Regulations.
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.