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β0ToxinA®- New hope to patients with post-stroke spasticity

Some spasticity is focal, affecting a small part of the body, such as a hand or an extremity, and some is more generalized. About 5% of stroke patients regain useful function of the paralysed limb but the prospects of recovery after 3 months are usually negligible. Upper limb spasticity can be particularly disruptive to patients' lives, as it interferes with mobility, comfort, and basic daily activities. If it isn't managed effectively, post-stroke spasticity can result in pain and very disabling complications such as contractures, a condition that leaves the muscles and tendons permanently shortened. In some patients, severe hypertonia (a common complication) causes pain, discomfort, and psychological disturbance with poor self-esteem and body image. Not to mention the impact on caregivers.

In spite of spasticity frequency in after-stroke patients, for decades the treatment options were limited and less than satisfactory. These included oral agents like diazepam (Valium), dantrolene, oral baclofen and benzodiazepines or, more recently, tizanidine, which are associated with a high incidence of systemic effects such as sedation, mental confusion, lethargy, dizziness, and muscle weakness, or even hallucinations, all of which can seriously hinder rehabilitation after a stroke. Another disadvantage of these medications is that they affect the entire body, even if the area to be targeted is just a specific muscle.

To treat severe spasticity, neurologists have used definitive treatment, such as chemical neurolysis with alcohol or phenol (often causing skin sensory loss and dysesthesia), or surgery. Nowadays, however, in such cases and particularly in patients that have had a spinal cord injury, the older drugs are being put aside in favour of the intrathecal baclofen (or ITB) therapy, in which minute amounts of baclofen are continuously delivered directly into the spinal fluid through a pump that is implanted under the skin and connected to the area around the spinal cord, thus maximizing the positive effects of the drug while protecting the rest of the body from exposure.

Obviously, treatment of such a severe condition has better chances of succeeding taking a multidisciplinary approach comprising neurological, physical, and psychological rehabilitation.

In recent years, several large randomised controlled trials have shown the effectiveness of botulinum toxin type A in reducing post-stroke muscle hypertonia, especially in the upper limbs, and doctors have been using it in this condition to relax muscles for the past seven years. Indeed most botulinum toxin used for medical purposes is for neurological problems and post-stroke focal spasticity is one of the main off-label uses of it. The drug works by entering nerve endings around the muscle where it is injected, and blocking the release of chemical messages that cause the muscle to contract.

Studies on average report sustained, statistically significant functional improvement (in muscle tone, motility, and pain control effect), and at least 50% of patients satisfaction with the treatment. The objective examinations usually employed are GAS score, Ashworth scale (measuring flexor tone), and Fugl-Meyer Sensorimotor Assessment Form (see the meta analysis by Eduardo Cardoso et al., 2005 analysing all double-blind, placebo-controlled, randomized clinical trials performed between 1989 and 2004).

Probably the most important long-term study to evaluate repeated treatment with BTA for post-stroke spasticity in the upper limbs was conducted by Brashear and colleagues at Indiana University School of Medicine and presented at the 2005 Annual Meeting of the American Association of Physical Medicine and Rehabilitation (AAPM&R) in Philadelphia. The study involved 35 centres and included 279 stroke patients with post-stroke wrist, hand, or elbow spasticity.

The researcher team had previously reported (New England Journal of Medicine, August 2002) that one-time injections of BTA are safe and effective in people with wrist and finger spasticity after a stroke.

In the trial, botulinum toxin was injected intramuscularly into the wrists, fingers and elbow flexors of the patients at either 2, 3, or 6 month intervals as determined by the neurologist (for up to five treatments). The total dose of each session of injection varied between 50-100 IU which, interestingly, is about one-half of the recommended dosage in the literature. Subjective and objective examinations were conducted by the physiotherapist prior to the first injection and subsequently at 1st, 2nd week and every month after each injection. All patients were asked subjectively about their satisfaction with the treatment. The objective examinations used in this study were Ashworth scale and Fugl-Meyer Sensorimotor Assessment Form. All patients were satisfied with the treatment. Marked reduction of the spasticity was found after one to two weeks of injection. Researchers found that at week six of the study, muscle tone in the wrist, fingers, thumb, and elbow was markedly improved from baseline, and was sustained throughout the study. The average improvement in Ashworth score was between 1 and 1.5 points. The Fugl-Meyer scores showed significant improvement in most patients for the motor function of upper and lower extremities, and balance. All patients demonstrated increase in passive range of joint motion, and decreased functional disability in four areas: hygiene, dressing, limb posture and pain.

Another study shows that BTA also generates synaptic plasticity in spinal alpha-motoneurons-interneurons and facilitates relearning by Hebbian and Contrastive Hebbian modes and how it can therefore be used as a neuro-relearning tool to enhance and hasten motor recovery (see Krishnan RV., 2005).

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The five muscles to be injected with BTA when treating upper limb post-stroke spasticity.

Intervention is limited by the number of muscles that can be injected during a given treatment and the amount of BTA that can be administered. For focal post-stroke spasticity a 23 to 30 gauge needle is to be used for superficial muscles, or longer needle for deeper musculature. Adult spasticity of the arm is treated with injections distributed amongst the following five muscles with EMG guidance: flexor digitorum profundus, flexor digitorum superficialis, flexor carpi ulnaris, flexor carpi radialis, and biceps brachii. Usually only one site per muscle is injected except for the biceps brachii, which was injected in two sites.

Dosage varies widely, with mean dose for upper limb spasticity of 255 U, and range in most studies and practice, of 185–300U. However, the optimal dose of BTA for the treatment of upper limb spasticity has not been established. Even before Brashear's study, in Viriyavejakul A, et al, 1998, the total dose of each session of injection varied between 50-100 U, about one-half of the recommended dosage in the literature, with satisfactory results. Further trials are needed to evaluate dose-dependent response, and individualised, flexible range of doses should be applied, and targeted muscle groups, adjusted according to the patient's sensitivity.

The reduction of symptoms begins within 3 to 7 days and lasts an average of three months with a return of the abnormal resting muscle contractility likely due to regeneration of fusion proteins and collateral sprouting of the nerve endings. Repeated injections are often necessary, with treatment cycles usually separated by either 12 or 16 weeks.

BTA has a low side-effect profile. The most frequently reported unwanted treatment effects (reported in 24% of cases) rated as mild or moderate in intensity were: pain at the injection site (20%), muscle weakness, fatigue and tiredness (10%), and flu-like symptoms (5%). The majority of events resolved within 2 weeks. Dysphagia has been reported at extremely high doses, but no cases were reported in pivotal studies.

References:

  • Bakheit A M O. Optimising the methods of evaluation of the effectiveness of botulinum toxin treatment of post-stroke muscle spasticity2004;75;665-666 J. Neurol. Neurosurg. Psychiatry.
  • Bakheit A M O, Fedorova N V, Skoromets A A, Timerbaeva S L, Bhakta B B and Coxon L. The beneficial antispasticity effect of botulinum toxin type A is maintained after repeated treatment cycles. Journal of Neurology Neurosurgery and Psychiatry 2004;75:1558-1561.
  • Bakheit AM, Pittock S, Moore AP, Wurker M, Otto S, Erbguth F, Coxon L. A randomized, double-blind, placebo-controlled study of the efficacy and safety of botulinum toxin type A in upper limb spasticity in patients with stroke. Eur J Neurol. 2001 Nov;8(6):559-65.
  • Bakheit AM, Thilmann AF, Ward AB, Poewe W, Wissel J, Muller J, Benecke R, Collin C, Muller F, Ward CD, Neumann C. 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. 2000 Oct;31(10):2402-6.
  • Brashear A, Gordon MF, Elovic E, 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. Presented at the American Academy of Neurology (May 2001) N Engl J Med. 2002 Aug 8;347(6):395-400.
  • Brashear A., Schlifstein T. Oct. 28, 2005, presentation, American Association of Physical Medicine and Rehabilitation annual meeting, Philadelphia.
  • Cardoso E, Rodrigues B, Lucena R, Oliveira IR, Pedreira G, Melo A. Botulinum toxin type A for the treatment of the upper limb spasticity after stroke: a meta-analysis. Arq Neuropsiquiatr. 2005 Mar;63(1):30-3. Epub 2005 Apr 13.
  • Childers MK, Brashear A, Jozefczyk P, Reding M, Alexander D, Good D, Walcott JM, Jenkins SW, Turkel C, Molloy PT. Dose-dependent response to intramuscular botulinum toxin type A for upper-limb spasticity in patients after a stroke. Arch Phys Med Rehabil. 2004 vol. 85, no7Jul;85(7):1063-1069.
  • Gallichio JE. Pharmacologic Management of Spasticity Following Stroke PHYS THER Vol. 84, No. 10, October 2004, pp. 973-981.
  • Krishnan RV. Botulinum toxin: from spasticity reliever to a neuromotor re-learning tool. Int J Neurosci. 2005 Oct;115(10):1451-67.
  • Slawek J, Bogucki A, Reclawowicz D. Botulinum toxin type A for upper limb spasticity following stroke: an open-label study with individualised, flexible injection regimens. Neurol Sci. 2005 Apr;26(1):32-9.
  • Sun SF, Hsu CW, Hwang CW, Hsu PT, Wang JL, Yang CL. Application of combined botulinum toxin type A and modified constraint-induced movement therapy for an individual with chronic upper-extremity spasticity after stroke. Phys Ther. 2006 Oct;86(10):1387-97.
  • Turkel CC, Bowen B, Liu J, Brin MF. Pooled analysis of the safety of botulinum toxin type A in the treatment of poststroke spasticity. Arch Phys Med Rehabil. 2006 Jun;87(6):786-92.
  • Ward A, Roberts G, Warner J, Gillard S. Cost-effectiveness of botulinum toxin type a in the treatment of post-stroke spasticity. J Rehabil Med. 2005 Jul;37(4):252-7.
  • Viriyavejakul A, Vachalathiti R, Poungvarin N. Botulinum treatment for post-stroke spasticity: low dose regime. J Med Assoc Thai. 1998 Jun;81(6):413-22.
  • Yelnik AP. [Pharmacology and upper limb poststroke spasticity: a review. International Society of Prosthetics and Orthotics.] [Article in French] Ann Readapt Med Phys. 2004 Oct;47(8):575-89.

To learn more about this condition, you can visit the websites of American Stroke Association www.strokeassociation.org/
National Stroke Association: Information on Stroke Prevention www.stroke.org/
National Institute of Neurological Disorders and Stroke (NINDS) www.ninds.nih.gov/

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