Post‑stroke Spasticity as a Manifestation of Maladaptive Plasticity and its Modulation by Botulinum Toxin Treatment

Authors: T. Veverka;  P. Hluštík;  P. Kaňovský
Authors‘ workplace: Neurologická klinika LF UP a FN Olomouc
Published in: Cesk Slov Neurol N 2014; 77/110(3): 295-301
Category: Review Article

Tato práce vznikla za grantové podpory IGA MZ ČR číslo NT13575- 4/ 2012 a MZ ČR –  RVO („Fakultní nemocnice Olomouc –  FNOl, IČ: 00098892“).


Stroke is the leading cause of disability worldwide. Even the adult brain is capable of structural and functional reorganization following stroke, the resulting neural plasticity is assumed to underlie most of the recovery of neurological deficit. Other neuroplastic changes, however, may worsen neurological functions. Development of post‑stroke spasticity can be considered an example of such maladaptive plasticity. It is estimated that 20– 40% of stroke survivors develop spasticity. Post‑stroke spasticity affects functional status and quality of life of patients and represents a significant socioeconomic burden. Therapy of post‑stroke spasticity requires team collaboration, treatment strategies consist of physiotherapy and botulinum toxin application. Botulinum toxin type A is currently considered first‑line therapy for post‑stroke spasticity. In addition to peripheral effects of botulinum toxin on the neuromuscular junction, there is growing evidence of distant effects on the CNS. The results of recent studies using functional magnetic resonance imaging in the chronic stroke patients suggest that botulinum toxin injected into the spastic muscle modulates the abnormal cortical reorganization (maladaptive plasticity).

Key words:
stroke – plasticity – spasticity – botulinum toxin – cortex

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manu­script met the ICMJE “uniform requirements” for biomedical papers.


1. The World Health Organization MONICA Project (monitoring trends and determinants in cardiovascular disease): a major international collaboration. WHO MONICA Project Principal Investigators. J Clin Epidemiol 1988; 41(2): 105– 114.

2. Lopez AD, Mathers CD, Ezzati M, Jamison DT, Murray CJ. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006; 367: 1747– 1757.

3. WHO. The global burden of disease: 2004 update. Dostupné z URL: www:http:/ / healthinfo/ global_burden_disease/ 2004_report_update/ en/ index.html>.

4. Thorvaldsen P, Asplund K, Kuulasmaa K, Rajakangas AM, Schroll M. Stroke incidence, case fatality, and mortality in the WHO MONICA project. World Health Organization Monitoring Trends and Determinants in Cardiovascular Disease. Stroke 1995; 26(3): 361– 367.

5. Lloyd‑ Jones D, Adams RJ, Brown TM, Carnethon M,Dai S, De Simone G et al. Heart disease and stroke statistics –  2010 update: a report from the American Heart Association. Circulation 2010; 121(7): e46– e215.

6. Truelsen T, Piechowski‑ Jóźwiak B, Bonita R, Mathers C, Bogousslavsky J, Boysen G. Stroke incidence and prevalence in Europe: a review of available data. Eur J Neurol 2006; 13(6): 581– 598.

7. Hendricks HT, van Limbeek J, Geurts AC, Zwarts MJ.Motor recovery after stroke: a systematic review of the literature. Arch Phys Med Rehabil 2002; 83(11): 1629– 1637.

8. Colebatch JG, Gandevia SC. The distribution of muscular weakness in upper motor neuron lesions affecting the arm. Brain 1989; 112(3): 749– 763.

9. Jørgensen HS, Nakayama H, Raaschou HO, Vive‑ Larsen J, Støier M, Olsen TS. Outcome and time course of recovery in stroke. Part I: Outcome. The Copenhagen Stroke Study. Arch Phys Med Rehabil 1995; 76(5): 399– 405.

10. Page SJ, Gater DR, Bach‑ Y‑ Rita P. Reconsidering the motor recovery plateau in stroke rehabilitation. Arch Phys Med Rehabil 2004; 85(8): 1377– 1381.

11. Miltner WH, Bauder H, Sommer M, Dettmers C,Taub E. Effects of constraint‑induced movement therapy on patients with chronic motor deficits after stroke a replication. Stroke 1999; 30(3): 586– 592.

12. Cauraugh JH, Naik SK, Lodha N, Coombes SA, Summers JJ. Long‑term rehabilitation for chronic stroke arm movements: a randomized controlled trial. Clin Rehabil 2011; 25(12): 1086– 1096.

13. Mark VW, Taub E. Constraint‑induced movement therapy for chronic stroke hemiparesis and other disabilities. Restor Neurol Neurosci 2004; 22(3– 5): 317– 336.

14. Dobkin BH, Carmichael TS. Principles of recovery after stroke. In: Barnes M, Dobkin B, Bogousslavsky J(eds). Recovery After Stroke. Cambridge: Cambridge University Press 2005.

15. Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359(13): 1317– 1329.

16. Wahlgren N, Ahmed N, Eriksson N, Aichner F, Bluhmki E, Dávalos A et al. Multivariable analysis of outcome predictors and adjustment of main outcome results to baseline data profile in randomized controlled trials: Safe Implementation of Thrombolysis in Stroke‑ MOnitoring STudy (SITS‑ MOST). Stroke 2008; 39(12): 3316– 3322.

17. Krakauer JW. Motor learning: its relevance to stroke recovery and neurorehabilitation. Curr Opin Neurol 2006; 19(1): 84– 90.

18. Nudo RJ. Retuning the misfiring brain. Proc Natl Acad Sci U.S.A. 2003; 100(13): 7425– 7427.

19. Pascual‑ Leone A, Amedi A, Fregni F, Merabet LB. The plastic human brain cortex. Annu Rev Neurosci 2005; 28: 377– 401.

20. Hebb DO. The organization of behavior. A neuropsychological theory. New York: Wiley 1949.

21. Nudo RJ, Plautz EJ, Frost SB. Role of adaptive plasticity in recovery of function after damage to motor cortex. Muscle Nerve 2001; 24(8): 1000– 1019.

22. Johansson BB. Brain plasticity in health and disease. Keio J Med 2004; 53(4): 231– 246.

23. Weiller C, Chollet F, Friston KJ, Wise RJ, Frackowiak RS. Functional reorganization of the brain in recovery from striatocapsular infarction in man. Ann Neurol 1992; 31(5): 463– 472.

24. Aguirre GK, Zarahn E, D’esposito M. The variability of human, BOLD hemodynamic responses. Neuroimage 1998; 8(4): 360– 369.

25. Hallett M. Transcranial magnetic stimulation: a primer. Neuron 2007; 55(2): 187– 199.

26. Bareš M, Kaňovský P, Dufek J (eds). Transkraniální magnetická stimulace. Brno: Národní centrum ošetřovatelství a nelékařských oborů v Brně 2003.

27. Bares M, Kanovský P, Klajblová H, Rektor I. Intracortical inhibition and facilitation are impaired in patients with early Parkinson’s disease: a paired TMS study. Eur J Neurol 2003; 10(4): 385– 389.

28. Ziemann U. Intracortical inhibition and facilitation in the conventional paired TMS paradigm. Electroencephalogr Clin Neurophysiol 1999; 51 (Suppl): 127– 136.

29. Roland PE, Zilles K. Functions and structures of the motor cortices in humans. Curr Opin Neurobio­l 1996; 6(6): 773– 781.

30. Rektor I, Bares M, Kanovský P, Kukleta M. Intracerebral recording of readiness potential induced by a complex motor task. Mov Disord 2001; 16(4): 698– 704.

31. Rektor I, Bares M, Brázdil M, Kanovský P, Rektorová I, Sochurková D et al. Cognitive‑  and movement‑related potentials recorded in the human basal ganglia. Mov Disord 2005; 20(5): 562– 568.

32. Nudo RJ. Recovery after damage to motor cortical areas. Curr Opin Neurobio­l 1999; 9(6): 740– 747.

33. Hluštík P, Mayer M. Paretic hand in stroke: from motor cortical plasticity research to rehabilitation. Cogn Behav Neurol 2006; 19(1): 34– 40.

34. Nudo RJ, Wise BM, SiFuentes F, Milliken GW. Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct. Science 1996; 272(5269): 1791– 1794.

35. Calautti C, Baron JC. Functional neuroimaging studies of motor recovery after stroke in adults: a review. Stroke 2003; 34(6): 1553– 1566.

36. Jaillard A, Martin CD, Garambois K, Lebas JF, Hommel M. Vicarious function within the human primary motor cortex? A longitudinal fMRI stroke study. Brain 2005; 128(5): 1122– 1138.

37. Schieber MH. Constraints on somatotopic organization in the primary motor cortex. J Neurophysiol 2001; 86(5): 2125– 2143.

38. He SQ, Dum RP, Strick PL. Topographic organization of corticospinal projections from the frontal lobe: motor areas on the lateral surface of the hemisphere. J Neurosci 1993; 13(3): 952– 980.

39. Ward NS, Brown MM, Thompson AJ, Frackowiak RS. Neural correlates of outcome after stroke: a cross‑ sectional fMRI study. Brain 2003; 126: 1430– 1448.

40. Ward NS, Brown MM, Thompson AJ, Frackowiak RSJ. Neural correlates of motor recovery after stroke: a longitudinal fMRI study. Brain 2003; 126: 2476– 2496.

41. Marshall RS, Perera GM, Lazar RM, Krakauer JW, Constantine RC, DeLaPaz RL. Evolution of cortical activation during recovery from corticospinal tract infraction. Stroke 2000; 31(3): 656– 661.

42. Calautti C, Leroy F, Guincestre JY, Baron JC. Dynamics of motor network overactivation after striatocapsular stroke: a longitudinal PET study using a fixed‑ performance paradigm. Stroke 2001; 32(11): 2534– 2542.

43. Small SL, Hlustik P, Noll DC, Genovese C, Solodkin A.Cerebellar hemispheric activation ipsilateral to the paretic hand correlates with functional recovery after stroke. Brain 2002; 125(7): 1544– 1557.

44. Feydy A, Carlier R, Roby‑ Brami A, Bussel B, Cazalis F,Pierot L et al. Longitudinal study of motor recovery after stroke: recruitment and focusing of brain activation. Stroke 2002; 33(6): 1610– 1617.

45. Fridman EA, Hanakawa T, Chung M, Hummel F,Leiguarda RC, Cohen LG. Reorganization of the human ipsilesional premotor cortex after stroke. Brain 2004; 127(4): 747– 758.

46. Johansen‑ Berg H, Rushworth MFS, Bogdanovic MD,Kischka U, Wimalaratna S, Matthews PM. The role of ipsilateral premotor cortex in hand movement after stroke. Proc Natl Acad Sci U S A 2002; 99(22): 14518– 14523.

47. Feeney DM, Baron JC. Diaschisis. Stroke 1986; 17(5): 817– 830.

48. Baron JC, Levasseur M, Mazoyer B, Legault‑ Demare F, Mauguière F, Pappata S et al. Thalamocortical diaschisis: positron emission tomography in humans. J Neurol Neurosurg Psychiatry 1992; 55(10): 935– 942.

49. Pujol J, Roset‑ Llobet J, Rosinés‑ Cubells D, Deus J, Narberhaus B, Valls‑ Solé J et al. Brain cortical activation during guitar‑induced hand dystonia studied by functional MRI. Neuroimage 2000; 12(3): 257– 267.

50. Flor H. Remapping somatosensory cortex after injury. Adv Neurol 2003; 93: 195– 204.

51. Maihöfner C, Handwerker HO, Birklein F. Functional imaging of allodynia in complex regional pain syndrome. Neurology 2006; 66(5): 711– 717.

52. Kamper DG, Fischer HC, Cruz EG, Rymer WZ. Weakness is the primary contributor to finger impairment in chronic stroke. Arch Phys Med Rehabil 2006; 87(6): 1262– 1269.

53. Ada L, O’Dwyer N, O’Neill E. Relation between spasticity, weakness and contracture of the elbow flexors and upper limb activity after stroke: an observational study. Disabil Rehabil 2006; 28(13– 14): 891– 897.

54. Barnes MP. Medical management of spasticity in stroke. Age Ageing 2001; 30 (Suppl 1): 13– 16.

55. Duncan PW, Zorowitz R, Bates B, Choi JY, Glasberg JJ, Graham GD et al. Management of Adult Stroke Rehabilitation Care: a clinical practice guideline. Stroke 2005; 36(9): e100– 143.

56. WEMOVE Elasticity Research Report. [on-line] Available from:

57. Lundström E, Smits A, Borg J, Terént A. Four‑ fold increase in direct costs of stroke survivors with spasticity compared with stroke survivors without spasticity: the first year after the event. Stroke 2010; 41(2): 319– 324.

58. Lance JW. Symposium synopsis. In: Spasticity: Disordered Motor Control. Chicago: Yearbook Medical Publishers 1980: 485– 495.

59. Pandyan AD, Gregoric M, Barnes MP, Wood D, Van Wijck F, Burridge J et al. Spasticity: clinical perceptions, neurological realities and meaningful measurement. Disabil Rehabil 2005; 27(1– 2): 2– 6.

60. Ward AB. A literature review of the pathophysiology and onset of post‑stroke spasticity. Eur J Neurol 2012; 19(1): 21– 27.

61. Mayer NH, Esquenazi A, Childers MK. Common patterns of clinical motor dysfunction. Muscle Nerve 1997; 6 (Suppl): S21– S35.

62. Sheean G. The pathophysiology of spasticity. Eur J Neurol 2002; 9 (Suppl 1): 3– 9.

63. Kaňovský P, Bareš M, Dufek J. Spasticita: mechanismy, dia­gnostika a léčba. Praha: Maxdorf 2004.

64. Štětkářová I. Mechanizmy spasticity a její hodnocení. Cesk Slov Neurol N 2013; 76/ 109(3): 267– 280.

65. Sherman SJ, Koshland GF, Laguna JF. Hyper‑reflexia without spasticity after unilateral infarct of the medullary pyramid. J Neurol Sci 2000; 175(2): 145– 155.

66. Mertens P. Anatomical basis of motricity for the study of spasticity. Neurochirurgie 2003; 49: 154– 162.

67. Sommerfeld DK, Eek EU, Svensson AK, Holmqvist LW, von Arbin MH. Spasticity after stroke: its occurrence and association with motor impairments and activity limitations. Stroke 2004; 35(1): 134– 139.

68. Wissel J, Schelosky LD, Scott J, Christe W, Faiss JH, Mueller J. Early development of spasticity following stroke: a prospective, observational trial. J Neurol 2010; 257(7): 1067– 1072.

69. Urban PP, Wolf T, Uebele M, Marx JJ, Vogt T, Stoeter P et al. Occurence and clinical predictors of spasticity after ischemic stroke. Stroke 2010; 41(9): 2016– 2020.

70. Watkins CL, Leathley MJ, Gregson JM, Moore AP, Smith TL, Sharma AK. Prevalence of spasticity post stroke. Clin Rehabil 2002; 16(5): 515– 522.

71. Lundström E, Terént A, Borg J. Prevalence of disabling spasticity 1 year after first‑ ever stroke. Eur J Neurol 2008; 15: 533– 539.

72. Leathley MJ, Gregson JM, Moore AP, Smith TL, Sharma AK, Watkins CL. Predicting spasticity after stroke in those surviving to 12 months. Clin Rehabil 2004; 18(4): 438– 443.

73. Ryu JS, Lee JW, Lee SI, Chun MH. Factors predictive of spasticity and their effects on motor recovery and functional outcomes in stroke patients. Top Stroke Rehabil 2010; 17(5): 380– 388.

74. Kelley RE, Borazanci AP. Stroke rehabilitation. Neurol Res 2009; 31(8): 832– 840.

75. Rosales RL, Kanovsky P, Fernandez HH. What’s the “catch” in upper‑limb post‑stroke spasticity: expanding the role of botulinum toxin applications. Parkinsonism Relat Disord 2011; 17 (Suppl 1): S3– S10.

76. Ward AB, Aguilar M, De Beyl Z, Gedin S, Kanovsky P, Molteni F et al. Use of botulinum toxin type A in management of adult spasticity –  a European consensus statement. J Rehabil Med 2003; 35(2): 98– 99.

77. Wissel J, Ward AB, Erztgaard P, Bensmail D, Hecht MJ,Lejeune TM et al. European consensus table on the use of botulinum toxin type A in adult spasticity. J Rehabil Med 2009; 41(1): 13– 25.

78. Ehler E. Použití botulotoxinu v neurologii. Cesk Slov Neurol N 2013; 76/ 109(1): 7– 21.

79. Štětkářová I, Ehler E, Jech R. Spasticita a její léčba. Praha: Maxdorf 2012.

80. Rosales RL, Chua‑ Yap AS. Evidence‑based systematic review on the efficacy and safety of botulinum toxin‑A therapy in post‑stroke spasticity. J Neural Transm 2008; 115(4): 617– 623.

81. Simpson DM, Gracies J‑ M, Graham HK, Miyasaki JM,Naumann M, Russman B et al. 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(19): 1691– 1698.

82. Elia AE, Filippini G, Calandrella D, Albanese A. Botulinum neurotoxins for post‑stroke spasticity in adults: a systematic review. Mov Disord 2009; 24(6): 801– 812.

83. Hallett M, Glocker FX, Deuschl G. Mechanism of action of botulinum toxin. Ann Neurol 1994; 36(3): 449– 450.

84. 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.

85. Rosales RL, Kong KH, Goh KJ, Kumthornthip W, Mok VCT, Delgado‑ De Los Santos MM et al. Botulinum toxin injection for hypertonicity of the upper extremity within 12 weeks after stroke: a randomized controlled trial. Neurorehabil Neural Repair 2012; 26: 812– 821.

86. Garner CG, Straube A, Witt TN, Gasser T, Oertel WH.Time course of distant effects of local injections of botulinum toxin. Mov Disord 1993; 8(1): 33– 37.

87. Antonucci F, Rossi C, Gianfranceschi L, Rossetto O, Caleo M. Long‑distance retrograde effects of botulinum neurotoxin A. J Neurosci 2008; 28(14): 3689– 3696.

88. Tinazzi M, Fiorio M, Fiaschi A, Rothwell JC, Bhatia KP. Sensory functions in dystonia: insights from behavioral studies. Mov Disord 2009; 24(10): 1427– 1436.

89. Kanovský P. Dystonia: a disorder of motor programming or motor execution? Mov Disord 2002; 17(6): 1143– 1147.

90. Opavsky R, Hlustik P, Kanovsky P. Cortical plasticity and its implications for focal hand dystonia. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2006; 150(2): 223– 226.

91. Kanovský P, Streitová H, Dufek J, Znojil V, Daniel P, Rektor I. Change in lateralization of the P22/ N30 cortical component of median nerve somatosensory evoked potentials in patients with cervical dystonia after successful treatment with botulinum toxin A. Mov Disord 1998; 13(1): 108– 117.

92. Gilio F, Currà A, Lorenzano C, Modugno N, Manfredi M, Berardelli A. Effects of botulinum toxin type A on intracortical inhibition in patients with dystonia. Ann Neurol 2000; 48(1): 20– 26.

93. Kanovský P, Bares M, Streitová H, Klajblová H, Daniel P, Rektor I. Abnormalities of cortical excitability and cortical inhibition in cervical dystonia Evidence from somatosensory evoked potentials and paired transcranial magnetic stimulation recordings. J Neurol 2003; 250(1): 42– 50.

94. Opavský R, Hluštík P, Otruba P, Kaňovský P. Sensorimotor network in cervical dystonia and the effect of botulinum toxin treatment: a functional MRI study. J Neurol Sci 2011; 306(1– 2): 71– 75.

95. Opavský R, Hluštík P, Otruba P, Kaňovský P. Somatosensory cortical activation in cervical dystonia and its modulation with botulinum toxin: an fMRI study. Int J Neurosci 2012; 122(1): 45– 52.

96. Kaňovský P, Rosales RL. Debunking the pathophysiological puzzle of dystonia‑ – with special reference to botulinum toxin therapy. Parkinsonism Relat Disord 2011; 17 (Suppl 1): S11– S14.

97. Kim DY, Oh B‑ M, Paik NJ. Central effect of botulinum toxin type A in humans. Int J Neurosci 2006; 116(6): 667– 680.

98. Johansen‑ Berg H, Dawes H, Guy C, Smith SM, Wade DT, Matthews PM. Correlation between motor improvements and altered fMRI activity after rehabilitative therapy. Brain 2002; 125: 2731– 2742.

99. Senkárová Z, Hlustík P, Otruba P, Herzig R, Kanovský P. Modulation of cortical activity in patients suffering from upper arm spasticity following stroke and treated with botulinum toxin A: an fMRI study. J Neuroimaging 2010; 20(1): 9– 15.

100. Tomášová Z, Hluštík P, Král M, Otruba P, Herzig R,Krobot A et al. Cortical activation changes in patients suffering from post‑stroke arm spasticity and treated with botulinum toxin A. J Neuroimaging 2013; 23(3): 337– 344.

101. Manganotti P, Acler M, Formaggio E, Avesani M,Milanese F, Baraldo A et al. Changes in cerebral activity after decreased upper‑limb hypertonus: an EMG‑ fMRI study. Magn Reson Imaging 2010; 28(5): 646– 652.

102. Diserens K, Ruegg D, Kleiser R, Hyde S, Perret N,Vuadens P et al. Effect of repetitive arm cycling following botulinum toxin injection for poststroke spasticity: evidence from FMRI. Neurorehabil Neural Repair 2010; 24(8): 753– 762.

103. Veverka T, Hluštík P, Tomášová Z, Hok P, Otruba P, Král M et al. BoNT‑ A related changes of cortical activity in patients suffering from severe hand paralysis with arm spasticity following ischemic stroke. J Neurol Sci 2012; 319(1– 2): 89– 95.

Paediatric neurology Neurosurgery Neurology

Article was published in

Czech and Slovak Neurology and Neurosurgery

Issue 3

2014 Issue 3

Most read in this issue
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account