Journal of Neural Transmission

, Volume 121, Issue 7, pp 761–767 | Cite as

Responsiveness to botulinum toxin type A in muscles of complex regional pain patients with tonic dystonia

  • Johanna C. M. Schilder
  • J. Gert van Dijk
  • Dirk Dressler
  • Johannes H. T. M. Koelman
  • Johan Marinus
  • Jacobus J. van Hilten
Neurology and Preclinical Neurological Studies - Original Article


Tonic dystonia of the limbs in complex regional pain syndrome (CRPS) is associated with considerable disability. Treatment options are scarce. Botulinum toxin (BoNT) is sometimes used, but the effect is often said to be disappointing. However, this notion stems from case reports and clinicians’ opinions but has never been formally studied. We therefore investigated responsiveness to BoNT in CRPS patients with tonic dystonia. We injected the extensor digitorum brevis (EDB) muscle with BoNT-A in 17 patients with CRPS and tonic dystonia to compare the response between affected and unaffected legs. We also investigated the right legs of 17 healthy controls. Responsiveness was defined as a decrease of the amplitude of the compound muscle action potential (CMAP) of >20 % from baseline 2 weeks after BoNT-A injection. We controlled for a temperature effect on BoNT efficacy by measuring skin temperature hourly directly above the EDB muscle in the first 2 weeks. CMAP amplitude decreased >20 % after injection on the affected side in 16 of 17 CRPS patients, similar to the response in unaffected legs (12/13) or legs of controls (17/17). The degree of CMAP reduction was significantly smaller in patients than in controls (56.0 ± 22.3 vs. 70.6 ± 14.6 %; p = 0.031). This may be due to a lower physical activity level and a greater difficulty to localize the EDB muscle properly in affected legs. The decrease in CMAP amplitude was not related to skin temperature. Contrary to the prevailing opinion, BoNT-A has a normal, although perhaps slightly lower efficacy in CRPS patients with dystonia.


Complex regional pain syndrome Tonic dystonia Botulinum toxin Non-responsiveness 



This study is part of TREND (Trauma RElated Neuronal Dysfunction), a Dutch Consortium that integrates research on epidemiology, assessment technology, pharmacotherapeutics, biomarkers, and genetics on CRPS type 1. The consortium aims to develop concepts on disease mechanisms that occur in response to tissue injury, its assessment, and treatment. TREND is supported by a grant of the Dutch Ministry of Economic Affairs (BSIK03016).

Conflict of interest

JS, JGvD, JM and JJvH have nothing to disclose. JK has received an unrestricted research grant from Ipsen Pharmaceutical and Allergan, inc. for studies and teaching workshops on dystonia and from Ipsen to finance a specialized dystonia nurse. DD has received compensation for consultancies from Allergan, Ipsen, Merz, Solstice/Eisai and is share holder of Allergan. None of the companies above had a role in study design, collection, analysis, interpretation of data, in the writing of the report and in the decision to submit the paper for publication.


  1. Bank PJ, Peper CL, Marinus J, Beek PJ, van Hilten JJ (2013) Deficient muscle activation in patients with complex regional pain syndrome and abnormal hand postures: an electromyographic evaluation. Clin Neurophysiol 124:2025–2035PubMedCrossRefGoogle Scholar
  2. Birklein F, Riedl B, Sieweke N, Weber M, Neundörfer B (2000) Neurological findings in complex regional pain syndromes-analysis of 145 cases. Acta Neurol Scand 101:262–269PubMedCrossRefGoogle Scholar
  3. Black JD, Dolly JO (1986) Interaction of 125I-labeled botulinum neurotoxins with nerve terminals. II. Autoradiographic evidence for its uptake into motor nerves by acceptor-mediated endocytosis. J Cell Biol 103:535–544PubMedCrossRefGoogle Scholar
  4. Chen R, Karp BI, Goldstein SR, Bara-Jimenez W, Yaseen Z, Hallett M (1999) Effect of muscle activity immediately after botulinum toxin injection for writer’s cramp. Mov Disord 14:307–312PubMedCrossRefGoogle Scholar
  5. Coderre TJ, Bennett GJ (2010) A hypothesis for the cause of complex regional pain syndrome-type I (reflex sympathetic dystrophy): pain due to deep-tissue microvascular pathology. Pain Med 11:1224–1238PubMedCrossRefGoogle Scholar
  6. Cordivari C, Misra VP, Catania S, Lees AJ (2001) Treatment of dystonic clenched fist with botulinum toxin. Mov Disord 16:907–913PubMedCrossRefGoogle Scholar
  7. Crammond DJ (2011) Neurophysiological mapping of muscle endplate location: precise targeting improves the efficacy of Botulinum neurotoxin injections. Clin Neurophysiol 122:1487–1489PubMedCrossRefGoogle Scholar
  8. De Boer RDH, Marinus J, Van Hilten JJ, Huygen FJ, Van Eijs F, Van Kleef M, Bauer MCR, Van Gestel M, Zuurmond WWA, Perez RSGM (2011) Distribution of signs and symptoms of complex regional pain syndrome type I in patients meeting the diagnostic criteria of the International Association for the Study of Pain. Eur J Pain 15(8):830e1–830e8Google Scholar
  9. De Mos M, Huygen FJPM, Van der Hoeven-Borgman M, Dieleman JP, Ch Stricker BH, Sturkenboom MCJM (2009) Outcome of the complex regional pain syndrome. Clin J Pain 25:590–597PubMedCrossRefGoogle Scholar
  10. Dreyer F, Schmitt A (1983) Transmitter release in tetanus and botulinum A toxin-poisoned mammalian motor endplates and its dependence on nerve stimulation and temperature. Eur J Physiol 399:228–234CrossRefGoogle Scholar
  11. Eberle T, Doganci B, Krämer HH, Geber C, Fechir M, Magerl W, Birklein F (2009) Warm and cold complex regional pain syndromes: differences beyond skin temperature? Neurology 72:505–512PubMedCrossRefGoogle Scholar
  12. Eleopra R, Tugnoli V, De Grandis D (1997) The variability in the clinical effect induced by botulinum toxin type A: the role of muscle activity in humans. Mov Disord 12:89–94PubMedCrossRefGoogle Scholar
  13. Esquenazi A, Albanese A, Chancellor MB, Elovic E, Segal KR, Simpson DM, Smith CP, Ward AB (2012) Evidence-based review and assessment of botulinum neurotoxin for the treatment of adult spasticity in the upper motor neuron syndrome. Toxicon 67:115–128PubMedCrossRefGoogle Scholar
  14. Gordon PH, Gooch CL, Greene PE (2002) Extensor digitorum brevis test and resistance to botulinum toxin type A. Muscle Nerve 26:828–831PubMedCrossRefGoogle Scholar
  15. Groeneweg G, Huygen FJPM, Coderre TJ, Zijlstra FJ (2009) Regulation of peripheral blood flow in complex regional pain syndrome: clinical implication for symptomatic relief and pain management. BMC Musculoskelet Disord 10:116–128PubMedCentralPubMedCrossRefGoogle Scholar
  16. Hamjian JA, Walker FO (1994) Serial neurophysiological studies of intramuscular botulinum-A toxin in humans. Muscle Nerve 17:1385–1392PubMedCrossRefGoogle Scholar
  17. Hesse S, Jahnke MT, Luecke D, Mauritz KH (1995) Short-term electrical stimulation enhances the effectiveness of botulinum toxin in the treatment of lower limb spasticity in hemiparetic patients. Neurosci Lett 201:37–40PubMedCrossRefGoogle Scholar
  18. Jankovic J, Van der Linden C (1988) Dystonia and tremor induced by peripheral trauma: predisposing factors. J Neurol Neurosurg Psychiatry 51:1512–1519PubMedCentralPubMedCrossRefGoogle Scholar
  19. Jeynes LC, Gauci CA (2008) Evidence for the use of botulinum toxin in the chronic pain setting–a review of the literature. Pain Pract 8:269–276PubMedCrossRefGoogle Scholar
  20. Kessler KR, Benecke R (1997) The EBD test––a clinical test for the detection of antibodies to botulinum toxin type A. Mov Disord 12:95–99PubMedCrossRefGoogle Scholar
  21. Lapatki BG, Van Dijk JP, Van de Warrenburg BPC, Zwarts MJ (2011) Botulinum toxin has an increased effect when targeted toward the muscle’s endplate zone: a high-density surface EMG guided study. Clin Neurophysiol 122:1611–1616PubMedCrossRefGoogle Scholar
  22. Lundh H (1983) Antagonism of botulinum toxin paralysis by low temperature. Muscle Nerve 6:56–60PubMedCrossRefGoogle Scholar
  23. Marinus J, Moseley GL, Birklein F, Baron R, Maihöfner C, Kingery WS, Van Hilten JJ (2011) Clinical features and pathophysiology of complex regional pain syndrome. Lancet Neurol 10:637–648PubMedCrossRefGoogle Scholar
  24. Merskey H, Bogduk N (1994) Relatively generalized syndromes. In: Merskey H, Bogduk N (eds) Classification of chronic pain, 2nd edn. IASP Press, Seattle, pp 40–43Google Scholar
  25. Perez RS, Zollinger PE, Dijkstra PU, Thomassen-Hilgersom IL, Zuurmond WW, Rosenbrand KC, Geertzen JH (2010) Evidence based guidelines for complex regional pain syndrome type 1. BMC Neurol 10:20PubMedCentralPubMedCrossRefGoogle Scholar
  26. Poulain B, De Paiva A, Deloye F, Doussau F, Tauc L, Weller U, Dolly J (1996) Difference in the multiple step process of inhibition of neurotransmitter release induced by tetanus toxin and botulinum neurotoxins type A and B at aplysia synapses. Neuroscience 25:567–576CrossRefGoogle Scholar
  27. Schilder JCM, Sigtermans MJ, Schouten AC, Putter H, Dahan A, Noldus LPJJ, Marinus J, Van Hilten JJ (2013) Pain relief is associated with improvement in motor function in complex regional pain syndrome type 1: secondary analysis of a placebo-controlled study on the effects of ketamine. J Pain 14:1514–1521PubMedCrossRefGoogle Scholar
  28. Schwartzman RJ, Kerrigan J (1990) The movement disorder of reflex sympathetic dystrophy. Neurology 40:57–61PubMedCrossRefGoogle Scholar
  29. Simpson L (1980) Kinetic studies on the interaction between type A and the cholinergic neuromuscular botulinum junction. J Pharmacol Exp Ther 212:16–21PubMedGoogle Scholar
  30. Sloop RR, Escutin RO, Matus JA, Cole BA, Peterson GW (1996) Dose-response curve of human extensor digitorum brevis muscle function to intramuscularly injected botulinum toxin type A. Neurology 46:1382–1386PubMedCrossRefGoogle Scholar
  31. Thenganatt MA, Fahn S (2012) Botulinum toxin for the treatment of movement disorders. Curr Neurol Neurosci Rep 12:399–409PubMedCrossRefGoogle Scholar
  32. Tjon-A-Tsien AM, Lemkes HH, Van der Kamp-Huyts AJ, Van Dijk JG (1996) Large electrodes improve nerve conduction repeatability in controls as well as in patients with diabetic neuropathy. Muscle Nerve 19:689–695PubMedCrossRefGoogle Scholar
  33. Van de Beek WJT, Vein A, Hilgevoord AAJ, Van Dijk JG, Van Hilten BJ (2002) Neurophysiologic aspects of patients with generalized or multifocal tonic dystonia of reflex sympathetic dystrophy. J Clin Neurophysiol 9:77–83CrossRefGoogle Scholar
  34. Van Dijk JG, Tjon-a-Tsien A, Van der Kamp W (1995) CMAP variability as a function of electrode site and size. Muscle Nerve 18:68–73PubMedCrossRefGoogle Scholar
  35. Van Dijk JG, Van Benten I, Kramer CG, Stegeman DF (1999) CMAP amplitude cartography of muscles innervated by the median, ulnar, peroneal, and tibial nerves. Muscle Nerve 22:378–389PubMedCrossRefGoogle Scholar
  36. Van Hilten JJ, Van de Beek WJT, Vein AA, Van Dijk J, Middelkoop HAM (2001) Clinical aspects of multifocal or generalized tonic dystonia in reflex sympathetic dystrophy. Neurology 56:1762–1765PubMedCrossRefGoogle Scholar
  37. Van Rijn MA, Munts AG, Marinus J, Voormolen JHC, De Boer KS, Teepe-Twiss IM, Van Dasselaar NT, Delhaas EM, Van Hilten JJ (2009) Intrathecal baclofen for dystonia of complex regional pain syndrome. Pain 143:41–47PubMedCrossRefGoogle Scholar
  38. Van Rooijen DE, Geraedts EJ, Marinus J, Jankovic J, Van Hilten JJ (2011) Peripheral trauma and movement disorders: a systematic review of reported cases. J Neurol Neurosurg Psychiatry 82:892–898PubMedCrossRefGoogle Scholar
  39. Wasner G (2010) Vasomotor disturbances in complex regional pain syndrome–a review. Pain Med 11:1267–1273PubMedCrossRefGoogle Scholar
  40. Wasner G, Schattschneider J, Heckmann K, Maier C, Baron R (2001) Vascular abnormalities in reflex sympathetic dystrophy (CRPS I): mechanisms and diagnostic value. Brain 124:587–599PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2014

Authors and Affiliations

  • Johanna C. M. Schilder
    • 1
  • J. Gert van Dijk
    • 1
  • Dirk Dressler
    • 2
  • Johannes H. T. M. Koelman
    • 3
  • Johan Marinus
    • 1
  • Jacobus J. van Hilten
    • 1
  1. 1.Department of Neurology and Clinical NeurophysiologyLeiden University Medical CenterLeidenThe Netherlands
  2. 2.Department of NeurologyHannover Medical SchoolHannoverGermany
  3. 3.Department of Neurology and Clinical NeurophysiologyAcademic Medical CenterAmsterdamThe Netherlands

Personalised recommendations