Abstract
Botulinum toxin (BT) has been used with great success to treat various muscle hyperactivity disorders. Occasionally, antibodies against BT (BT-AB) can be formed. When they are directed against the neurotoxin component of the BT drug, they are called neutralising antibodies. They can reduce the therapeutic effect partially or completely. We have measured neutralising BT-AB by use of the mouse diaphragm assay (MDA) in 42 adult patients with spasticity in the order of their appearance in the clinic. The patients had been treated for at least 2 years with BT type A (BT-A) and received on an average 14.2 ± 6.1 BT-A injection series. BT-A was applied as Botox only, Dysport only or by sequential application of both preparations. The mean cumulative doses were 4,610 ± 1,936 units Botox and 14,033 ± 7,566 units Dysport, respectively. The mean treatment time was 4.5 ± 1.8 (2–8) years. All patients were initially responsive to BT-A therapy. MDA detected BT-AB in 12% (5/42) of patients. However, in three patients the BT-AB titre was very low (<0.3 mIU/ml), in one it was intermediate (0.6 mIU/ml) and in one patient it was high (>1.0 mIU/ml). All BT-AB negative patients and also two of the patients with low BT-AB titre remained clinically responsive to BT therapy throughout the study. In conclusion, prevalence of BT-AB formation with clinical relevance (6%, 3/42) in adult patients with spasticity is not higher than that of BT-treated patients with cervical dystonia and much lower than that of BT-treated patients with infantile cerebral palsy.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Atassi MZ (2004) Basic immunological aspects of botulinum toxin therapy. Mov Disord 19(Suppl 8):S68–S84
Bakheit AM, Thilmann AF, Ward AB, Poewe W, Wissel J, Müller J, Benecke R, Collin C, Müller F, Ward CD, Neumann C (2000) A randomized, double-blind, 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 31:2402–2406
Bakheit AM, Pittock S, Moore AP, Wurker M, Otto S, Erbguth F, Coxon L (2001) A randomized, double-blind, placebo-controlled study of the efficacy and safety of botulinum toxin A in upper limb spasticity in patients with stroke. Eur J Neurol 8:559–565
Bhakta BB, Cozens JA, Bamford JM, Chamberlain MA (1996) Use of botulinum toxin in stroke patients with severe upper limb spasticity. J Neurol Neurosurg Psychiat 61:30–35
Bhakta BB, Cozens JA, Chamberlain MA, Bamford JM (2000) Impact of botulinum toxin type A on disability and carer burden due to arm spasticity after stroke: a randomised double blind placebo controlled trial. J Neurol Neurosurg Psychiat 69:217–221
Brashear A, Gordon MF, Elovic E, Kassicieh VD, Marciniak C, Do M, Lee CH, Jenkins S, Turkel C, Botox Post-Stroke Spasticity Study Group (2002) Intramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after a stroke. N Engl J Med 347:395–400
Das CP, Dressler D, Hallett M (2006) Botulinum toxin therapy of writer’s cramp. Eur J Neurol 13(Suppl 1):55–59
Dressler D, Bigalke H (2002) Botulinum toxin antibody type A titres after cessation of botulinum toxin therapy. Mov Disord 17:170–173
Dressler D, Dirnberger G (2001) Botulinum toxin antibody testing: comparison between the immunoprecipitation assay and the mouse diaphragm assay. Eur Neurol 45:257–260
Dressler D, Hallett M (2006) Immunological aspects of Botox, Dysport and Myobloc/NeuroBloc. Eur J Neurol 13(Suppl 1):11–15
Gordon MF, Brashear A, Elovic E, Kassicieh D, Marciniak C, Liu J, Turkel C, Poststroke Spasticity Study Group BOTOX (2004) Repeated dosing of botulinum toxin type A for upper limb spasticity following stroke. Neurology 63:1971–1973
Göschel H, Wohlfarth K, Frevert J, Dengler R, Bigalke H (1997) Botulinum A toxin therapy: neutralizing and nonneutralizing antibodies-therapeutic consequences. Exp Neurol 147:96–102
Hanna PA, Jankovic J, Vincent A (1999) Comparison of mouse bioassay and immunoprecipitation assay for botulinum toxin antibodies. J Neurol Neurosurg Psychiat 66:612–616
Herrmann J, Geth K, Mall V, Bigalke H, Schulte Monting J, Linder M, Kirschner J, Berweck S, Korinthenberg R, Heinen F, Fietzek UM (2004) Clinical impact of antibody formation to botulinum toxin A in children. Ann Neurol 55:732–735
Hesse S, Werner C (2003) Poststroke motor dysfunction and spasticity: novel pharmacological and physical treatment strategies. CNS Drugs 17:1093–1107
Jankovic J, Vuong KD, Ahsan J (2003) Comparison of efficacy and immunogenicity of original versus current botulinum toxin in cervical dystonia. Neurology 60:1186–1188
Kessler KR, Benecke R (1997) The EBD test—a clinical test for the detection of antibodies to botulinum toxin type A. Mov Disord 12:95–99
Kessler KR, Skutta M, Benecke R (1999) Long-term treatment of cervical dystonia with botulinum toxin A: efficacy, safety, and antibody frequency. German Dystonia Study Group. J Neurol 246:265–274
Marion MH, Sheehy M, Sangla S, Soulayrol S (1995) Dose standardisation of botulinum toxin. J Neurol Neurosurg Psychiatry 59:102–103
Moore AP (2002) Botulinum toxin A (BoNT-A) for spasticity in adults. What is the evidence? Eur J Neurol 9(Suppl 1):42–47
Naumann M, Albanese A, Heinen F, Molenaers G, Relja M (2006) Safety and efficacy of botulinum toxin type A following long-term use. Eur J Neurol 13(Suppl 4):35–40
Pathak MS, Nguyen HT, Graham HK, Moore AP (2006) Management of spasticity in adults: practical application of botulinum toxin. Eur J Neurol 13(Suppl 1):42–50
Pittock SJ, Moore AP, Hardiman O, Ehler E, Kovac M, Bojakowski J, Al Khawaja I, Brozman M, Kanovsky P, Skorometz A, Slawek J, Reichel G, Stenner A, Timerbaeva S, Stelmasiak Z, Zifko UA, Bhakta B, Coxon E (2003) 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. Cerebrovasc Dis 15:289–300
Rosales RL, Chua-Yap AS (2008) Evidence-based systematic review on the efficacy and safety of botulinum toxin-A therapy in post-stroke spasticity. J Neural Transm 115:617–623
Rosales RL, Bigalke H, Dressler D (2006) Pharmacology of botulinum toxin: differences between type A preparations. Eur J Neurol 13(Suppl 1):2–10
Sesardic D, Jones RG, Leung T, Alsop T, Tierney R (2004) Detection of antibodies against botulinum toxins. Mov Disord 19(Suppl 8):S85–S91
Ward AB (2008) Spasticity treatment with botulinum toxins. J Neural Transm 115:607–616
Wohlfarth K, Göschel H, Frevert J, Dengler R, Bigalke H (1997) Botulinum A toxins: units versus units. Naunyn-Schmiedeberg’s Arch Pharmacol 355:335–340
Wohlfarth K, Schwandt I, Wegner F, Jürgens T, Gelbrich G, Wagner A, Bogdahn U, Schulte-Mattler W (2008) Biological activity of two botulinum toxin type A complexes (Dysport and Botox) in volunteers: a double-blind, randomized, dose-ranging study. J Neurol 255:1932–1939
Yablon SA, Brashear A, Gordon MF, Elovic EP, Turkel CC, Daggett S, Liu J, Brin MF (2007) 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 29:683–690
Acknowledgment
The authors are thankful to the nurses Christa Tiffert and Sylvia Miethe for technical assistance during patients’ treatment and blood sampling.
Conflict of interest statement
This study was not supported by third-party funds. The authors have no conflict of financial interest to declare.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Müller, K., Mix, E., Adib Saberi, F. et al. Prevalence of neutralising antibodies in patients treated with botulinum toxin type A for spasticity. J Neural Transm 116, 579–585 (2009). https://doi.org/10.1007/s00702-009-0223-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-009-0223-z