Abstract
Spasticity with muscle paresis and loss of dexterity is a common feature of upper motor neuron syndrome due to injuries or the pyramidal tract in several neurological conditions. Botulinum toxin type A has been considered the gold standard treatment for spasticity and movement disorders, with efficacy, reversibility, and low prevalence of complications. During the last 30 years, thousands of studies of its use have been performed, but few guidelines are available. Therefore, there is great variability in both the doses and intervals of administration and the approaches taken by clinicians with considerable experience in spasticity and movement disorder treatment. In the present review article, we provide a short overview of the benefits and risks of non-approved injection regimens and doses for botulinum toxins, focusing on the treatment of post-stroke spasticity, where there is great interest in the potential for increasing the number of treatment/years and the dose of botulinum toxin treatment for subjects with upper and lower limb spasticity. However, many doubts exist regarding antibody development and possible adverse effects.
Similar content being viewed by others
References
Das TK, Park DM. Effect of treatment with botulinum toxin on spasticity. Postgrad Med J. 1989;65:208–10.
Kassicieh VD, Marciniak C, Do M, Lee CH, Jenkins S, Turkel C, Botox Post-Stroke Spasticity Study Group. Intramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after a stroke. N Engl J Med. 2002;347:395–400.
Simpson DM, Gracies JM, Graham HK, Miyasaki JM, Naumann M, Russman B, Simpson LL, So Y, Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Assessment: Botulinum neurotoxin for the treatment of spasticity (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2008;70:1691–8.
Esquenazi A, Albanese A, Chancellor MB, Elovic E, Segal KR, Simpson DM, Smith CP, Ward AB. Evidence-based review and assessment of botulinum neurotoxin for the treatment of adult spasticity in the upper motor neuron syndrome. Toxicon. 2013;67:115–28.
Wissel J, Ward AB, Erztgaard P, Bensmail D, Hecht MJ, Lejeune TM, Schnider P, Altavista MC, Cavazza S, Deltombe T, Duarte E, Geurts AC, Gracies JM, Haboubi NH, Juan FJ, Kasch H, Kätterer C, Kirazli Y, Manganotti P, Parman Y, Paternostro-Sluga T, Petropoulou K, Prempeh R, Rousseaux M, Slawek J. European consensus table on the use of botulinum toxin type A in adult spasticity. J Rehabil Med. 2009;41:13–25.
Jost WH, Kohl A, Brinkmann S, Comes G. Efficacy and tolerability of a botulinum toxin type A free of complexing proteins (NT 201) compared with commercially available botulinum toxin type A (BOTOX) in healthy volunteers. J Neural Transm (Vienna). 2005;112:905–13.
Dressler D, Mander G, Fink K. Measuring the potency labelling of onabotulinumtoxinA (Botox(®)) and incobotulinumtoxinA (Xeomin (®)) in an LD50 assay. J Neural Transm (Vienna). 2012;119:13–5.
Sheean G, Lannin NA, Turner-Stokes L, Rawicki B, Snow BJ. Botulinum toxin assessment, intervention and after-care for upper limb hypertonicity in adults: international consensus statement. Eur J Neurol. 2010;17(Suppl 2):74–93.
Sheean GL. Botulinum treatment of spasticity: why is it so difficult to show a functional benefit? Curr Opin Neurol. 2001;14:771–6.
Benecke R. Clinical relevance of botulinum toxin immunogenicity. BioDrugs. 2012;26:e1–9.
Bakheit AM, Thilmann AF, Ward AB, Poewe W, Wissel J, Muller J, Benecke R, Collin C, Muller F, Ward CD, Neumann C. A randomized, doubleblind, placebo-controlled, dose-ranging study to compare the efficacy and safety of three doses of botulinum toxin type A (Dysport) with placebo in upper limb spasticity after stroke. Stroke. 2000;31:2402–6.
Kanovský P, Slawek J, Denes Z, Platz T, Sassin I, Comes G, Grafe S. Efficacy and safety of botulinum neurotoxin NT 201 in poststroke upper limb spasticity. Clin Neuropharmacol. 2009;32:259–65.
Varghese-Kroll E, Elovic EP. Contralateral weakness and fatigue after high-dose botulinum toxin injection for management of poststroke spasticity. Am J Phys Med Rehabil. 2009;88:495–9.
Crowner BE, Torres-Russotto D, Carter AR, Racette BA. Systemic weakness after therapeutic injections of botulinum toxin a: a case series and review of the literature. Clin Neuropharmacol. 2010;33:243–7.
Thomas AM, Simpson DM. Contralateral weakness following botulinum toxin for poststroke spasticity. Muscle Nerve. 2012;46:443–8.
Baricich A, Grana E, Carda S, Santamato A, Cisari C, Invernizzi M. High doses of onabotulinumtoxinA in post-stroke spasticity: a retrospective analysis. J Neural Transm (Vienna). 2015;122:1283–7.
Hesse S, Jahnke MT, Luecke D, Mauritz KH. Short-term electrical stimulation enhances the effectiveness of Botulinum toxin in the treatment of lower limb spasticity in hemiparetic patients. Neurosci Lett. 1995;201:37–40.
Dressler D. Routine use of Xeomin® in patients previously treated with Botox®: long term results. Eur J Neurol. 2009;16(Suppl 2):2–5.
Santamato A, Panza F, Ranieri M, Frisardi V, Micello MF, Filoni S, Fortunato F, Intiso D, Basciani M, Logroscino G, Fiore P. Efficacy and safety of higher doses of botulinum toxin type A NT 201 free from complexing proteins in the upper and lower limb spasticity after stroke. J Neural Transm. 2013;120:469–76.
Intiso D, Simone V, Di Rienzo F, Iarossi A, Pazienza L, Santamato A, Maruzzi G, Basciani M. High doses of a new botulinum toxin type A (NT-201) in adult patients with severe spasticity following brain injury and cerebral palsy. NeuroRehabilitation. 2014;34:515–22.
Dressler D, Adib Saberi F, Kollewe K, Schrader C. Safety aspects of incobotulinumtoxinA high-dose therapy. J Neural Transm (Vienna). 2015;122:327–33.
Invernizzi M, Carda S, Molinari C, Stagno D, Cisari C, Baricich A. Heart Rate Variability (HRV) modifications in adult hemiplegic patients after botulinum toxin type A (nt-201) injection. Eur J Phys Rehabil Med. 2015;51:353–9.
Wissel J, Bensmail D, Ferreira JJ, Molteni F, Satkunam L, Moraleda S, Rekand T, McGuire J, Scheschonka A, Flatau-Baqué B, Simon O, Rochford ET, Dressler D, Simpson DM, TOWER study investigators. Safety and efficacy of incobotulinumtoxinA doses up to 800 U in limb spasticity: the TOWER study. Neurology. 2017;88:1321–8.
Santamato A, Panza F, Intiso D, Baricich A, Picelli A, Smania N, Fortunato F, Seripa D, Fiore P, Ranieri M. Long-term safety of repeated high doses of incobotulinumtoxinA injections for the treatment of upper and lower limb spasticity after stroke. J Neurol Sci. 2017. doi:10.1016/j.jns.2017.04.052 (Epub ahead of print).
Lance JW. Symposium synopsis. In: Feldman RG, Young RR, Koella WP, editors. Spasticity: disordered motor control. Chicago: Year Book Medical Publishers; 1980. p. 485–94.
Franceschini M, Iocco M, Molteni F, Santamato A, Smania N, Italian Spasticity Study Group. Management of stroke patients submitted to botulinum toxin type A therapy: a Delphi survey of an Italian expert panel of specialist injectors. Eur J Phys Rehabil Med. 2014;50:525–33.
Santamato A, Micello MF, Panza F, Fortunato F, Picelli A, Smania N, Logroscino G, Fiore P, Ranieri M. Adhesive taping vs. daily manual muscle stretching and splinting after botulinum toxin type A injection for wrist and fingers spastic overactivity in stroke patients: a randomized controlled trial. Clin Rehabil. 2015;29:50–8.
Hafer-Macko CE, Ryan AS, Ivey FM, Macko RF. Skeletal muscle changes after hemiparetic stroke and potential beneficial effects of exercise intervention strategies. J Rehabil Res Dev. 2008;45:261–72.
Vattanasilp W, Ada L, Crosbie J. Contribution of thixotropy, spasticity, and contracture to ankle stiffness after stroke. J Neurol Neurosurg Psychiatry. 2000;69:34–9.
de Paiva A, Meunier FA, Molgó J, Aoki KR, Dolly JO. Functional repair of motor endplates after botulinum neurotoxin type A poisoning: biphasic switch of synaptic activity between nerve sprouts and their parent terminals. Proc Natl Acad Sci USA. 1999;96:3200–5.
Fortuna R, Horisberger M, Vaz MA, Herzog W. Do skeletal muscle properties recover following repeat onabotulinum toxin A injections? J Biomech. 2013;46:2426–33.
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.
Childers MK. The importance of electromyographic guidance and electrical stimulation for injection of botulinum toxin. Phys Med Rehabil Clin N Am. 2003;14:781–92.
Walter U, Dressler D. Ultrasound-guided botulinum toxin injections in neurology: technique, indications and future perspectives. Expert Rev Neurother. 2014;14:923–36.
Picelli A, Roncari L, Baldessarelli S, Berto G, Lobba D, Santamato A, Fiore P, Smania N. Accuracy of botulinum toxin type A injection into the forearm muscles of chronic stroke patients with spastic flexed wrist and clenched fist: manual needle placement evaluated using ultrasonography. J Rehabil Med. 2014;46:1042–5.
Santamato A, Micello MF, Panza F, Fortunato F, Baricich A, Cisari C, Pilotto A, Logroscino G, Fiore P, Ranieri M. Can botulinum toxin type A injection technique influence the clinical outcome of patients with post-stroke upper limb spasticity? A randomized controlled trial comparing manual needle placement and ultrasound-guided injection techniques. J Neurol Sci. 2014;347:39–43.
Picelli A, Tamburin S, Bonetti P, Fontana C, Barausse M, Dambruoso F, Gajofatto F, Santilli V, Smania N. Botulinum toxin type A injection into the gastrocnemius muscle for spastic equinus in adults with stroke: a randomized controlled trial comparing manual needle placement, electrical stimulation and ultrasonography-guided injection techniques. Am J Phys Med Rehabil. 2012;91:957–64.
Kwon JY, Hwang JH, Kim JS. Botulinum toxin A injection into calf muscles for treatment of spastic equinus in cerebral palsy: a controlled trial comparing sonography and electric stimulation-guided injection techniques: a preliminary report. Am J Phys Med Rehabil. 2010;89:279–86.
US Food and Drug Administration.FDA gives update on botulinum toxin safety warnings; established names of drugs changed. https://wayback.archive-it.org/7993/20170112032330/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2009/ucm175013.htm. Accessed 24 May 2017.
Allergan Pharmaceuticals. BOTOX® (OnabotulinumtoxinA). Package insert. ©2009. Allergan Pharmaceuticals, Inc., Irvine.
Merz Pharmaceuticals GmbH. Xeomin® US Prescribing Information [updated July 2011]. http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125360s045lbl.pdf. Accessed 24 May 2017.
Royal College of Physicians. Guidance to good practice. Guidelines for the use of botulinum toxin (BTX) in the management of spasticity in adults. London: Royal College of Physicians; 2002.
Santamato A, Micello MF, Ranieri M, et al. Employment of higher doses of botulinum toxin type A to reduce spasticity after stroke. J Neurol Sci. 2015;350:1–6.
Dressler D, Saberi FA. Safety of botulinum toxin short interval therapy using incobotulinumtoxin A. J Neural Transm (Vienna). 2017;124:437–40.
Naumann M, Jankovic J. Safety of botulinum toxin type A: a systematic review and meta-analysis. Curr Med Res Opin. 2004;20:981–90.
Bakheit AM, Ward CD, McLellan DL. Generalised botulism-like syndrome after intramuscular injections of botulinum toxin type A: a report of two cases. J Neurol Neurosurg Psychiatry. 1997;62:198.
Dressler D, Dirnberger G. Botulinum toxin therapy: risk factors for therapy failure. Mov Disord. 2000;15(suppl 2):51.
Greene P, Fahn S, Diamond B. Development of resistance to botulinum toxin type A in patients with torticollis. Mov Disord. 1994;9:213–7.
Frevert J, Dressler D. Complexing proteins in botulinum toxin type A drugs: a help or a hindrance? Biologics. 2010;4:325–32.
Dressler D, Hallett M. Immunological aspects of Botox, Dysport and Myobloc/NeuroBloc. Eur J Neurol. 2006;13(Suppl 1):11–5.
Fabbri M, Leodori G, Fernandes RM, Bhidayasiri R, Marti MJ, Colosimo C, Ferreira JJ. Neutralizing antibody and botulinum toxin therapy: a systematic review and meta-analysis. Neurotox Res. 2016;29:105–17.
Yablon SA, Brashear A, Gordon MF, Elovic EP, Turkel CC, Daggett S, Liu J, Brin MF. Formation of neutralizing antibodies in patients receiving botulinum toxin type A for treatment of poststroke spasticity: a pooled-data analysis of three clinical trials. Clin Ther. 2007;29:683–90.
Dressler D, Bigalke H, Benecke R. Botulinum toxin type B in antibody-induced botulinum toxin type A therapy failure. J Neurol. 2003;250:1263–5.
Trompetto C, Marinelli L, Mori L, Puce L, Pelosin E, Serrati C, Fattapposta F, Rinalduzzi S, Abbruzzese G, Currà A. Do flexible inter-injection intervals improve the effects of botulinum toxin A treatment in reducing impairment and disability in patients with spasticity? Med Hypotheses. 2017;102:28–32.
Gracies JM, Brashear A, Jech R, McAllister P, Banach M, Valkovic P, Walker H, Marciniak C, Deltombe T, Skoromets A, Khatkova S, Edgley S, Gul F, Catus F, De Fer BB, Vilain C, Picaut P, International AbobotulinumtoxinA Adult Upper Limb Spasticity Study Group. Safety and efficacy of abobotulinumtoxinA for hemiparesis in adults with upper limb spasticity after stroke or traumatic brain injury: a double-blind randomised controlled trial. Lancet Neurol. 2015;14:992–1001.
Acknowledgements
We wish to thank Professor Anthony B. Ward for translation and preparation of the English text.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
Dr. Santamato and Dr. Panza reported no funding for the present paper.
Conflicts of interest
Dr. Santamato and Dr. Panza reported no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Rights and permissions
About this article
Cite this article
Santamato, A., Panza, F. Benefits and Risks of Non-Approved Injection Regimens for Botulinum Toxins in Spasticity. Drugs 77, 1413–1422 (2017). https://doi.org/10.1007/s40265-017-0786-1
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40265-017-0786-1