Skip to main content
SpringerLink
Log in

Efficacy and Safety of Long-term Botulinum Toxin Treatment in Craniocervical Dystonia: A Systematic Review

  • Review
  • Published:
Neurotoxicity Research Aims and scope Submit manuscript

Abstract

Botulinum neurotoxins have been shown to be a safe and effective therapeutic option for most forms of focal dystonia, and are now considered to provide the best symptomatic treatment in these disorders. However, only a few papers addressed the long-term efficacy and safety of repeated treatments with this drug. This article reviews the data from clinical trials that have assessed the long-term results of botulinum neurotoxin type A (BoNT-A) and type B in the treatment of the different forms of focal craniocervical dystonia, cervical dystonia (CD), blepharospasm, oromandibular, and laryngeal dystonia. Studies on the long-term effects of BoNT-A therapy have demonstrated that the majority of patients comply with this repeated treatment because they experience a positive and stable effect over time. It is still unclear whether in patients with focal dystonia the mean dose of BoNT-A changes over time. In spite of the wide spectrum of side effects reported to be associated with BoNT-A treatment, there is no evidence of specific side effects due exclusively to the long-term use of such drugs. The only exception to these positive long-term findings is the occurrence of a subgroup of patients with CD who fail to maintain a sustained response after the first or second effective treatment, partly owing to the development of neutralizing antibodies against the toxin. Longitudinal studies aimed at defining the risk factors for this abnormal pattern of response to botulinum toxin treatment are currently being conducted.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abbruzzese G, Berardelli A (2006) Neurophysiological effects of botulinum toxin type A. Neurotoxic Res 9:109–114

    Article  CAS  Google Scholar 

  • Albanese A (2009) Discussion of unique properties of botulinum toxins. Toxicon 54:702–708

    Article  PubMed  CAS  Google Scholar 

  • Albanese A, Asmus F, Bhatia KP, Elia AE, Elibol B, Filippini G, Gasser T, Krauss JK, Nardocci N, Newton A, Valls-Solé J (2011) EFNS guidelines on diagnosis and treatment of primary dystonias. Eur J Neurol 18:5–18

    Article  PubMed  CAS  Google Scholar 

  • Atassi MZ (2004) Basic immunological aspects of botulinum toxin therapy. Mov Disord 19:S68–S84

    Article  PubMed  Google Scholar 

  • Atassi MZ, Oshima M (1999) Structure, activity and immune recognition of botulinum neurotoxins. Crit Rev Immunol 19:219–260

    PubMed  CAS  Google Scholar 

  • Ben-Shlomo Y, Camfield L, Warner T, On behalf of the ESDE Collaborative Group (2002) What are the determinants of quality of life in people with cervical dystonia? J Neurol Neurosurg Psychiatry 72:608–614

    Article  PubMed  CAS  Google Scholar 

  • Bentivoglio AR, Fasano A, Ialongo T, Soleti F, Lo Fermo S, Albanese A (2009) Fifteen-year experience in treating blepharospasm with Botox or Dysport: same toxin, two drugs. Neurotoxic Res 15:224–231

    Article  CAS  Google Scholar 

  • Berman B, Seeberger L, Kumar R (2005) Long-term safety, efficacy, dosing, and development of resistance with botulinum toxin type B in cervical dystonia. Mov Disord 20:233–237

    Article  PubMed  Google Scholar 

  • Blitzer A (2010) Spasmodic dysphonia and botulinum toxin: experience from the largest treatment series. Eur J Neurol 17:28–30

    Article  PubMed  Google Scholar 

  • Blitzer A, Brin MF, Stewart CF (1998) Botulinum toxin management of spasmodic dysphonia (laryngeal dystonia): a 12-year experience in more than 900 patients. Laryngoscope 108:1435–1441

    Article  PubMed  CAS  Google Scholar 

  • Borodic G, Johnson E, Goodnough M, Schantz E (1996) Botulinum toxin therapy, immunologic resistance, and problems with available materials. Neurology 46:26–29

    Article  PubMed  CAS  Google Scholar 

  • Brainin M, Barnes M, Baron J-C, Gilhus NE, Hughes R, Selmaj K, Waldemar G (2004) Guidance for the preparation of neurological management guidelines by EFNS scientific task forces—revised recommendations 2004. Eur J Neurol 11:577–581

    Article  PubMed  CAS  Google Scholar 

  • Brans JWM, Lindeboom R, Aramideh M, Speelman JD (1998) Long-term effect of botulinum toxin on impairment and functional health in cervical dystonia. Neurology 50:1461–1463

    Article  PubMed  CAS  Google Scholar 

  • Brashear A, Hogan P, Wooten-Watts M, Marchetti A, Magar R, Martin J (2005) Longitudinal assessment of the dose consistency of botulinum toxin type A (Botox) for cervical dystonia. Adv Ther 22:49–55

    Article  PubMed  Google Scholar 

  • Brin MF (1997) Botulinum toxin: chemistry, pharmacology, toxicity, and immunology. Muscle Nerve 6:S146–S168

    Article  PubMed  CAS  Google Scholar 

  • Brin M, Lew M, Adler C et al (1999) Safety and efficacy of Neurobloc (botulinum toxin type B) in type A resistant cervical dystonia. Neurology 53(7):1431–1438

    Article  PubMed  CAS  Google Scholar 

  • Brin MF, Aoki KR, Dressler D (2004) Pharmacology of botulinum toxin therapy. In: Brin MF, Comella C (eds) Dystonia: etiology, clinical features, and treatment. Lippincott Williams & Wilkins, Philadelphia, pp 93–112

    Google Scholar 

  • Brin MF, Comella CL, Jankovic J (2008) Long-term treatment with botulinum toxin type A in cervical dystonia has low immunogenicity by mouse protection assay. Mov Disord 23:1353–1360

    Article  PubMed  Google Scholar 

  • Byrnes ML, Thickbroom GW, Wilson SA et al (1998) The corticomotor representation of upper limb muscles in writer’s cramp and changes following botulinum toxin injection. Brain 121:977–988

    Article  PubMed  Google Scholar 

  • Calace P, Cortese G, Piscopo R et al (2003) Treatment of blepharospasm with botulinum neurotoxin type A: long-term results. Eur J Ophtalmol 13:331–336

    CAS  Google Scholar 

  • Caleo M, Antonucci F, Restani L, Mazzocchio R (2009) A reappraisal of the central effects of botulinum neurotoxin type A: by what mechanism? J Neurochem 109:15–24

    Article  PubMed  CAS  Google Scholar 

  • Camargo CH, Teive HA, Becker N, Munhoz RP, Werneck LC (2011) Botulinum toxin type A and cervical dystonia: a seven-year follow-up. Arq Neuropsiquiatr 69:745–750

    Article  PubMed  Google Scholar 

  • Ceballos-Baumann AO, Sheean G, Passingham RE, Mardsen CD, Brooks DJ (1997) Botulinum toxin does not reverse the cortical dysfunction associated with writer’s cramp. A PET study. Brain 120:571–582

    Article  PubMed  Google Scholar 

  • Chan J, Brin MF, Fahn S (1991) Idiopathic cervical dystonia: clinical characteristics. Mov Disord 6:119–126

    Article  PubMed  CAS  Google Scholar 

  • Chapman MA, Barron R, Tanis DC et al (2007) Comparison of botulinum neurotoxin preparations for the treatment of cervical dystonia. Clin Ther 29(7):1325–1337

    Article  PubMed  CAS  Google Scholar 

  • Cillino S, Raimondi G, Guépratte N et al (2010) Long-term efficacy of botulinum toxin A for treatment of blepharospasm, hemifacial spasm, and spastic entropion: a multicentre study using two drug-dose escalation indexes. Eye 24:600–607

    Article  PubMed  CAS  Google Scholar 

  • Colosimo C, Berardelli A (2011) Clinical phenomenology of dystonia. In: Brotchie J, Bezard E, Jenner P (eds) International Review of Neurobiology, vol 98. pp 509–524

  • Colosimo C, Tiple D, Berardelli A (2009) Treatment of blepharospasm. In: Truong D, Hallett M, Dressler D (eds) Manual of Botulinum toxin therapy. Cambridge University Press, Cambridge, pp 49–53

    Chapter  Google Scholar 

  • Colosimo C, Suppa A, Fabbrini G, Bologna M, Berardelli A (2010) Craniocervical dystonia: clinical and pathophysiological features. Eur J Neurol 17(Suppl 1):15–21

    Article  PubMed  Google Scholar 

  • Currà A, Berardelli A (2009) Do the unintended actions of botulinum toxin at distant sites have clinical implications? Neurology 72:1095–1099

    Article  PubMed  Google Scholar 

  • Damrose FJ, Goldman NS, Groessl EJ, Orloff LA (2004) The impact of long-term botulinum toxin injections on symptom severity in patients with spasmodic dysphonia. J Voice 18:415–422

    Article  PubMed  Google Scholar 

  • Defazio G, Abbruzzese G, Girlanda P et al (2002) Botulinum toxin A treatment for primary hemifacial spasm: a 10-year multicenter study. Arch Neurol 59:418–420

    Article  PubMed  Google Scholar 

  • Dressler D, Benecke R (2003) Autonomic side effects of botulinum toxin type B treatment of cervical dystonia and hyperhidrosis. Eur Neurol 49:34–38

    Article  PubMed  CAS  Google Scholar 

  • Dressler D, Hallett M (2006) Immunological aspects of Botox, Dysport and Myobloc/Neurobloc. Eur J Neurol 13:11–15

    Article  PubMed  Google Scholar 

  • Dressler D, Munchau A, Bhatia KP, Quinn NP, Bigalke H (2002) Antibody induced botulinum-toxin therapy failure: can it be overcome by increased botulinum toxin doses? Eur Neurol 47:118–121

    Article  PubMed  CAS  Google Scholar 

  • Dressler D, Bigalke H, Beneche R (2003) Botulinum toxin type B in antibody-induced botulinum toxin type A therapy failure. J Neurol 250:967–969

    Article  PubMed  CAS  Google Scholar 

  • Dutton JJ (1996) Botulinum-A toxin in the treatment of craniocervical muscle spasms: short-and long-term, local and systemic effects. Surv Ophthalmol 41:51–65

    Article  PubMed  CAS  Google Scholar 

  • Dutton JJ, Buckley EG (1988) Long-term results and complications of botulinum toxin A in the treatment of blepharospasm. Ophtalmology 95:1529–1534

    CAS  Google Scholar 

  • Eleopra R, Tugnoli V, Quatrale R, Rossetto O, Montecucco C (2004) Different types of botulinum toxin in humans. Mov Disord 19:S53–S59

    Article  PubMed  Google Scholar 

  • Engstrom PF, Arnoult JB, Mazow ML et al (1987) Effectiveness of botulinum toxin therapy for essential blepharospasm. Ophtalmology 17:971–975

    Google Scholar 

  • Fabbrini G, Berardelli I, Moretti G et al (2010) Psychiatric disorders in adult-onset focal dystonia: a case–control study. Mov Disord 25:459–465

    Article  PubMed  Google Scholar 

  • Filippi GM, Errico P, Santarelli R et al (1993) Botulinum A toxin effects o rat jaw muscle spindles. Acta Otolaryngol 113:400–404

    Article  PubMed  CAS  Google Scholar 

  • Garcia Ruiz PJ, Martinez Castrillo JC, Burguera JA et al (2011) Evolution of dose and response to botulinum toxin A in cervical dystonia: a multicenter study. J Neurol 258:1055–1057

    Article  CAS  Google Scholar 

  • Giglio F, Curra A, Lorenzano C, Modugno N, Manfredi M, Berardelli A (2000) Effects of botulinum toxin type A on intracortical inhibition in patients with dystonia. Ann Neurol 48:20–26

    Article  Google Scholar 

  • Gill HS, Kraft SP (2010) Long-term efficacy of botulinum a toxin for blepharospasmand hemifacial spasm. Can J Neurol Sci 37:631–636

    PubMed  Google Scholar 

  • Grafe S, Hanschmann A (2010) Safety and efficacy of repeated NT 201 (botulinum neurotoxin type A free from complexing proteins) injections of patients with cervical dystonia: a first long-term safety analysis. Neurology 74(9 Suppl 2):A88

    Google Scholar 

  • Grandas F, Elston J, Quinn N, Marsden CD (1988) Blepharospasm: a review of 264 patients. J Neurol Neurosurg Psychiatry 51:767–772

    Article  PubMed  CAS  Google Scholar 

  • Greene P, Fahn S, Diamond B (1994) Development of resistance to botulinum toxin type A in patients with torticollis. Mov Disord 9:213–217

    Article  PubMed  CAS  Google Scholar 

  • Gudex CM, Hawthorne MR, Butler AG, Duffey P (1998) Effect of dystonia and botulinum toxin treatment on health-related quality of life. Mov Disord 13:941–946

    Article  PubMed  CAS  Google Scholar 

  • Hatheway CL, Dang C (1994) Immunogenicity of the neurotoxins of Clostridium botulinum. In: Jankovic J, Hallett M (eds) Therapy with botulinum toxin. Marcel Dekker, New York, pp 93–108

    Google Scholar 

  • Haussermann P, Marczoch S, Klinger C, Landgrebe M, Conrad B, Ceballos-Baumann A (2004) Long-term follow-up of cervical dystonia patients treated with botulinum toxin A. Mov Disord 19:303–308

    Article  PubMed  Google Scholar 

  • Hilker R, Schischniaschvili M, Ghaemi M, Jacobs A, Rudolf J (2001) Health related quality of life is improved by botulinum neurotoxin type A in long term treated patients with focal dystonia. J Neurol Neurosurg Psychiatry 71:193–199

    Article  PubMed  CAS  Google Scholar 

  • Holden PK, Vokes DE, Taylor MB, Till JA, Crumley RL (2007) Long-term botulinum toxin dose consistency for treatment of adductor spasmodic dysphonia. Ann Otol Rhinol Laryngol 116:891–896

    PubMed  Google Scholar 

  • Hsiung GYR, Das SK, Ranawaya R, Lafontaine AL, Suchowersky O (2002) Long-term efficacy of botulinum toxin A in treatment of various Movement Disorders over a 10-year period. Mov Disord 17:1288–1293

    Article  PubMed  Google Scholar 

  • Jankovic J (2004a) Treatment of cervical dystonia with botulinum toxin. Mov Disord 19:S109–S115

    Article  PubMed  Google Scholar 

  • Jankovic J (2004b) Botulinum toxin in clinical practice. J Neurol Neurosurg Psychiatry 75:951b–957b

    Article  Google Scholar 

  • Jankovic J, Orman J (1984) Blepharospasm: demographic and clinical survey of 250 patients. Ann Ophthalmol 16:371–376

    PubMed  CAS  Google Scholar 

  • Jankovic J, Schwartz K (1995) Resistance and immunoresistance to botulinum toxin injections. Neurology 45:1743–1746

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Kraft SP, Lang AE (1988) Cranial dystonia, blepharospasm and hemifacial spasm: clinical features and treatment, including the use of botulinum toxin. CMAJ 139:837–844

    PubMed  CAS  Google Scholar 

  • Lowenstein DH, Aminoff MJ (1988) The clinical course of spasmodic torticollis. Neurology 38:530–532

    Article  PubMed  CAS  Google Scholar 

  • Maia FM, Kanashiro AK, Chien HF, Goncalves LR, Barbosa ER (2010) Clinical changes of cervical dystonia pattern in long-term botulinum toxin treated patients. Parkinsonism Relat Disord 16:8–11

    Article  PubMed  Google Scholar 

  • Mejia NI, Young KD, Jankovic J (2005) Long-term botulinum toxin efficacy, safety and immunogenicity. Mov Disord 20:592–597

    Article  PubMed  Google Scholar 

  • Modugno N, Priori A, Berardelli A et al (1998) Botulium toxin restores presynaptic inhibition of group la afferents in patients with essential tremor. Muscle Nerve 21:1701–1705

    Article  PubMed  CAS  Google Scholar 

  • Mohammadi B, Buhr N, Bigalke H, Krampfl K, Dengler R, Kollewe K (2009) A long-term follow-up of botulinum toxin A in cervical dystonia. Neurol Res 31:463–466

    Article  PubMed  CAS  Google Scholar 

  • Müller J, Kemmler G, Wissel J et al (2002) The impact of blepharospasm and cervical dystonia on health-related quality of life and depression. J Neurol 249:842–846

    Article  PubMed  Google Scholar 

  • Naumann M, Jankovic J (2004) Safety of botulinum toxin type A: a systematic review and meta-analysis. Curr Med Res Opin 20:981–990

    Article  PubMed  CAS  Google Scholar 

  • Paniello RC, Barlow J, Serna JS (2008) Longitudinal follow-up of adductor spasmodic dysphonia patients after botulinum toxin injection: quality of life results. Laryngoscope 118:564–568

    Article  PubMed  Google Scholar 

  • Papapetropoulos S, Singer C (2007) Botulinum toxin in movement disorders. Semin Neurol 27:183–194

    Article  PubMed  Google Scholar 

  • Priori A, Berardelli A, Mercuri B, Manfredi M (1995) Physiological effects produced by botulinum toxin treatment of upper limb dystonia. Changes in reciprocal inhibition between forearm muscles. Brain 118:801–807

    Article  PubMed  Google Scholar 

  • Reimer J, Gilg K, Karow A, Esser J, Franke GH (2005) Health-related quality of life in blepharospasm or hemifacial spasm. Acta Neurol Scand 111:64–70

    Article  PubMed  CAS  Google Scholar 

  • Rosales RL, Arimura K, Takenaga S et al (1996) Extrafusal and intrafusal muscle effects in experimental botulinum toxin injection. Muscle Nerve 19:488–496

    Article  PubMed  CAS  Google Scholar 

  • Rossetto O, Seveso M, Caccin P, Schiavo G, Montecucco C (2001) Tetanus and botulinum neurotoxins: turning bad guys into good by research. Toxicon 39:27–41

    Article  PubMed  CAS  Google Scholar 

  • Sampaio C, Costa J, Ferreira JJ (2004) Clinical comparability of marketed formulations of botulinum toxin. Mov Disord 19:S129–S136

    Article  PubMed  Google Scholar 

  • Scott AB, Kennedy RA, Stubbs HHA (1985) Botulinum A toxin injection as a treatment for blepharospasm. Arch Ophthalmol 103:347–350

    Article  PubMed  CAS  Google Scholar 

  • Simpson DM, Blitzer A, Brashear A (2008) Assessment: Botulinum neurotoxin for the treatment of movement disorders (an evidence based review): report of the therapeutics and technology assessment subcommittee of the American Academy of Neurology. Neurology 70:1699–1706

    Article  PubMed  CAS  Google Scholar 

  • Skogseid IM, Kerty E (2005) The course of cervical dystonia and patient satisfaction with long-term botulinum toxin A treatment. Eur J Neurol 12:163–170

    Article  PubMed  CAS  Google Scholar 

  • Skogseid IM, Malt UF, Roislien J, Kerty E (2007) Determinants and status of quality of life after long-term botulinum toxin therapy for cervical dystonia. Eur J Neurol 14:1129–1137

    Article  PubMed  CAS  Google Scholar 

  • Tan EK, Jankovic J (1999) Botulinum toxin A in patients with oromandibular dystonia: long-term follow-up. Neurology 53:2102–2107

    Article  PubMed  CAS  Google Scholar 

  • Tiple D, Strano S, Colosimo C et al (2008) Autonomic cardiovascular function and baroreflex sensitivity in patients with cervical dystonia receiving treatment with botulinum toxin type A. J Neurol 255:843–847

    Article  PubMed  CAS  Google Scholar 

  • Trompetto C, Currà A, Buccolieri A, Suppa A, Abbruzzese G, Berardelli A (2006) Botulinum toxin changes intrafusal feedback in dystonia: a study with the tonic vibration reflex. Mov Disord 21:777–782

    Article  PubMed  Google Scholar 

  • Truong D, Brodsky M, Lew M et al (2010) Long-term efficacy and safety of botulinum toxin type A (Dysport) in cervical dystonia. Parkinsonism Relat Disord 16:316–323

    Article  PubMed  Google Scholar 

  • Van den Bergh P, Francart J, Mourin S, Kollmann P, Laterre EC (1995) Five-year experience in the treatment of focal movement disorders with low-dose Dysport botulinum toxin. Muscle Nerve 18:720–729

    Article  PubMed  CAS  Google Scholar 

  • Vitek JL (2002) Pathophysiology of dystonia: a neuronal model. Mov Disord 17:S49–S62

    Article  PubMed  Google Scholar 

Download references

Conflict of interest

CC received honoraria for Advisory Boards from Ipsen and Allergan; AB received research grants and honoraria for Advisory Boards from Merz, Ipsen and Allergan; DT had nothing to declare.

Author information

Authors and Affiliations

  1. Dipartimento di Neurologia e Psichiatria, Sapienza Università di Roma, Viale dell’Università 30, 00185, Rome, Italy

    Carlo Colosimo, Dorina Tiple & Alfredo Berardelli

  2. IRCCS Neuromed Institute, Pozzilli, IS, Italy

    Alfredo Berardelli

Authors
  1. Carlo Colosimo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dorina Tiple
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alfredo Berardelli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carlo Colosimo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Colosimo, C., Tiple, D. & Berardelli, A. Efficacy and Safety of Long-term Botulinum Toxin Treatment in Craniocervical Dystonia: A Systematic Review. Neurotox Res 22, 265–273 (2012). https://doi.org/10.1007/s12640-012-9314-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12640-012-9314-y

Keywords

Search

Navigation