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Keeping Current Heading

Keeping Current #02-1

The Use of Botulinum Toxin in Children with Muscle Stiffness: An Update

This Keeping Current is one of a series of reports that discuss the effectiveness of rehabilitation interventions for children and youth with brain injury. When reading this Keeping Current, you will notice that the research reviewed is often taken from studies involving children and youth with a variety of neurological conditions and diagnoses. Be critical when deciding what information relates to your situation. The most relevant information will come from studies that specifically address the diagnosis in question. However, be aware that research findings from studies involving children with one specific diagnosis may be relevant for children with other diagnoses when their functional difficulties are similar, even if the causes are different.

©2002, D. Fehlings, K. Yeung & R. Teplicky

Support for the research to conduct this critical review comes from a grant from

Economical Insurance 

What is Botulinum Toxin?

When injected into a muscle, Clostridium botulinum toxin type A (BTA) produces a local, temporary weakness that is associated with a decrease in muscle stiffness (spasticity). Over the last 25 years, BTA has been used to treat many neuromuscular conditions including strabismus (crossed eyes) and vocal cord spasm. In the last ten years, BTA has been used in children with cerebral palsy and traumatic brain injury who have muscle stiffness. It is thought that decreasing the children's muscle stiffness will allow for better stretching of shortened muscles, increased range of motion and opportunities to strengthen muscles that work opposite to the muscle that has been injected.

These changes should allow the children to learn better control of their movement and to improve their motor function.

How does BTA work?

(The following section presents a brief overview of the technical and biological aspects of BTA. Some readers may wish to skip this section.)
Botulinum neurotoxins are produced by certain strains of Clostridium bacteria and are classified into 7 serotypes, A through G (Shantz & Johnson, 1992). Most clinical work has been done with serotype A. The biological effects of BTA are well understood. An injection of BTA into the muscle creates a localized muscle paralysis by causing a highly specific binding to presynaptic cholinergic peripheral nerve terminals. The toxin is then internalized into the nerve terminal and inhibits the release of acetylcholine at the neuromuscular junction. Neurotransmission recovers when the axon terminal sprouts new nerve endings and forms new synaptic contacts on adjacent muscle fibers (Jankovic & Brin, 1991). Over time the original neuromuscular junction starts to work again highlighting the reversible nature of the treatment (De Paiva et al., 1999). In humans within two to three days of the injection, the muscle becomes weak with a reduction in tone, reaching a maximum effect at two weeks. The reduction in muscle tone lasts an average of three months with gradual increase in tone and gain in muscle strength occurring after this time. Effects from BTA can still be noted up to 6 months after the injection.

Are there side effects?

BTA injections are well tolerated with few serious side effects. The primary side effect is weakening of nearby muscles. The impact this has on the individual depends on the muscle group that has been injected. For instance when injecting neck muscles, the most frequent side effect is difficulty swallowing which generally improves after two weeks. In children receiving leg muscle injections, BTA can lead to short-term stumbling when walking. Temporary urinary incontinence has been reported following hip muscle injections in 1% of the children (Bakheit et al., 2001). Whole body side effects have been rare, with generalized weakness and fatigue reported in less than 1% of children injected (Bakheit et al., 2001). The individual experiences some pain at the time of the injection (similar to receiving an immunization needle) and can develop mild soreness at the injection site.

The effects of BTA injections are temporary and repeated injections are often required. The individual can develop antibodies to the toxin and become resistant to its effect. Repeated BTA injections may not be as effective in these individuals (Hermann et al., 2000). Antibody formation has been observed in a small number of patients (less than 10%) who have received repeated injections of BTA. The dosage and frequency of the injection are felt to be the two important factors affecting antibody formation (Jankovic & Brin, 1991).

What do we know about the Use of BTA in Children with Muscle Stiffness?

Many research articles have been published on this topic. For this article, the studies have been grouped into four main areas:

· Management of Spastic Equinus (toe-walking)
· Multiple Lower Extremity Injections
· Upper Extremity Injections
· Use in Children with Head Injury

The research studies discussed in this article use a variety of research designs. Some of the designs provide stronger evidence than others. To help you determine which studies provide the best evidence about the effectiveness of BTA, we have rated each article according to its strength of evidence. A score of 1 represents the strongest or best evidence and a score of 5 is the weakest. Roman numerals are commonly used when rating research evidence and they will be used in the rest of this article (1 = I, 2 = II, 3=III, 4 = IV, 5 = V).

The following descriptions of Levels I to V are based on the rating system used by the American Academy for Cerebral Palsy and Developmental Medicine. For further information on the rating system, please go to their website (www.aacpdm.org, click on 'Committees', click on 'Treatment Outcomes', click on "Methodology for Developing Evidence Tables and Reviewing Treatment Outcomes Research").

A Level I study is a large trial where subjects are assigned randomly to either an intervention group or a control group (this is similar to flipping a coin). A Level II study is a study of an intervention and a control group, but assignment to the group is not done randomly. Level I and II studies are prospective - that is, interventions and assessments are done after the study begins. Level III studies involve a comparison between the outcome of an intervention group and a control group - information about one or more of these groups would have been collected in the past. Unlike the first 3 levels, Level IV and V studies do not have a control or comparison group - this makes it difficult to know whether it was the intervention or something else that caused the changes seen in the participants. In Level IV studies the outcome of interest is typically measured before and after an intervention. Level V studies are descriptions of cases or expert reports.

Within each area we have also given an overall grade for the evidence with "A" being the highest (evidence supported by one or more Level I studies) and "C" being the lowest (evidence supported at best by Level III, IV, and V studies).

Use of BTA for Management of Spastic Equinus (Toe-Walking)

Most of the research on BTA has been done in children with cerebral palsy who toe-walk (equinus gait). Several studies provide a high level of evidence and are summarized in Table 1. There is grade "A" evidence (the highest level) for improvement in walking over the short term (up to 3 months after the injection). One study has shown long-term effectiveness (greater than two years) of repeated BTA injections on walking. The impact of repeated injections to help prevent muscle contractures and decrease the need for orthopedic surgery is currently under evaluation.

Use of BTA in Other Leg Muscles

There is less evidence available for injections of other leg muscles. Table 2 outlines the studies in children with cerebral palsy that have examined multiple lower extremity injections.
Hip injections
A few studies have shown a decrease in stiffness of the hip adductor muscle and an improvement in gross motor function. These studies have lacked control groups and the current evidence is graded as "C" (the lowest level).

Hamstring injections

Two studies of BTA injections in the hamstrings have demonstrated improvements in muscle flexibility, knee extension during walking, and walking speed. However, again due to the lack of a control group, the strength of the evidence can only be graded as "C".

Multilevel injections

Multilevel injections were used to look at the effect of "high" versus "low" dose injection of BTA over a 12-week period (Wissel et al., 1999). Improvements were found for muscle tone, range of motion and quality of walking. Children who received the high dose improved the most. The evidence is graded as "B plus" (high level of evidence shown in only one study).
Continued work needs to be done to determine which muscles should be targeted in multilevel injections, what an appropriate dose of BTA would be, and whether BTA will be helpful in treating hip subluxation (partial dislocation of the hip joint).

Use of BTA in the Upper Extremity

Table 3 outlines studies that have been done in children with cerebral palsy who have arm and hand stiffness. There is evidence for improved range of motion (flexibility), function, and cosmetic appearance of the arm and hand in the majority of children receiving the BTA injections. The strength of the evidence is graded at an "A" level. Most studies followed children for up to six months. The role of repeated injections over time requires further investigation. Continued work is being done to evaluate the best dose and injection techniques for the arm and hand muscles.

Use of BTA with Individuals with Traumatic Brain Injury

Very little research on BTA has been done in children with traumatic brain injury. Use of BTA in individuals (aged 16-54 years) who were at various stages of recovery has been studied (see Table 4). There is evidence of increased range of motion, decreased stiffness, decreased pain, and increased ease of cleaning the arm and hand (likely related to increased range of motion). Overall, the evidence for the use of BTA in adults and young adults is graded at a "C" level. Although more research is needed to justify the use of BTA to treat muscle stiffness in children with brain injury, it appears that BTA will be helpful.

Conclusion

Overall, there is good evidence for the use of BTA in children to decrease muscle stiffness, improve motor function and improve range of motion of limb joints for up to three to six months after the injection. More information is required to evaluate the long-term effects of BTA.

Update written by:

Darcy Fehlings MD MSc FRCP(C), Physician Director Neurodevelopmental Program, Bloorview MacMillan Centre; Division of Neurology, Hospital for Sick Children; Assistant Professor, University of Toronto

Ka-Kei Yeung, PT, Physiotherapist, Bloorview MacMillan Children's Centre

Rachel Teplicky, OT Ont. (Reg.), Research Coordinator, CanChild Centre for Childhood Disability Research

Want to know more?

Contact: Darcy Fehlings
CanChild Centre for Childhood Disability Research
Institute for Applied Health Sciences, Room 408
1400 Main St. W., Hamilton, ON L8S 1C7
Tel: 905-525-9140 x 27850 Fax: 905-522-6095
canchild@mcmaster.ca

Table 1: Use of BTA for Management of Spastic Equinus (Toe-walking)

Title of Study
(Authors)
Description of StudyOutcomeLevel of Evidence
BTA neuromuscular blockade in the treatment of lower extremity spasticity.
(Koman et al., 2000)
Randomized* double-blind** trial in 114 children with CP and spastic equinus
Treatment = BTA or saline into calf
BTA group improved gait up to 12 weeks post injection
No serious side effects were noted
I
Double blind study of BTA into the gastrocnemius muscle in patients with cerebral palsy.
(Sutherland et al., 1999)
Randomized double blind trial of 20 children with cerebral palsy and equinus
Treatment = BTA or saline into the calf muscle (gastrocnemius)
Improvement in ankle movement on gait analysis
No adverse events
I
Randomized double blind placebo controlled trial of the effect of BTA on walking in CP.
(Ubhi et al., 2000)
Randomized double-blind trial in 40 children with CP, spastic diplegia or hemiplegia
Treatment = BTA or saline into calf muscle
Improvement in walking found on Gross Motor Function Measure and on gait analysis in the BTA groupI
BTA versus fixed cast stretching for dynamic calf tightness in cerebral palsy.
(Flett et al., 1999)
Randomized single blind study of 20 children with CP and equinus
Treatment = BTA into calf or serial casting
Both groups had similar improvements
Parents favoured BTA over casting
II
BTA compared with stretching casts in the treatment of spastic equines.
(Corry et al., 1998)
Randomized trial of 20 children with CP and equinus
Treatment = BTA into calf or serial casting
Both groups improved ankle motion during gait
BTA group had longer lasting effects (12 weeks) and fewer side effects
II
BTA neuromuscular blockade in the treatment of equinus foot deformity in cerebral palsy: a multi-center, open-label clinical trial.
(Koman et al., 2001)
Prospective study evaluating long term safety and efficacy of repeated BTA injections
155 of 207 children with spastic equinus completed at least one year
Improvements in gait were maintained in 41 to 58% of children at 2 years
Adverse effects related to the treatment included stumbling, leg cramps, and calf atrophy
One child had a serious adverse event with self-limited generalized weakness
IV

* Randomized = The participants in the study are assigned randomly to either the intervention group or the control group.

** Double-blind = A research design in which the participant and the person doing the assessment do not know if the participant is in the control group or the intervention group.

Table 2: Use of BTA in Other Leg Muscles

Title of Study
(Authors)
Description of StudyOutcomeLevel of Evidence
Evaluation of botulinum toxin A therapy in children with adductor spasm by Gross Motor Function Measure.
(Mall et al., 2000)
Prospective study of 18 children with CP with adductor (hip muscle) spasm
Treatment = BTA into adductor muscle (hip) and/or hamstring injection
Improvements in tone, range of motion, and GMFM scores IV
Botulinum toxin A in hamstring spasticity.
(Corry et al., 1999)
Prospective study of 10 children with CP who had dynamic hamstring spasticity likely requiring orthopaedic surgery in the future
Treatment = BTA in hamstrings muscles
Improvement in hamstring flexibility, knee extension during gait, and speed of walkingIV
Botulinum toxin in the management of the lower limb in cerebral palsy.
(Cosgrove et al., 1994)
Prospective study of 26 children with spastic CP with involvement in the lower extremity
Treatment = BTA into calf and/or hamstrings muscles
Decrease in muscle tone
Increased range of motion and flexibility at the ankle and/or knee
Improved walking
Increased knee extension during gait
IV
Treatment of cerebral palsy with botulinum toxin: evaluation with Gross Motor Function Measure.
(Yang et al., 1999)
Prospective study on 38 children with spastic CP in lower extremities
Treatment = BTA into lower extremity muscles as determined by clinical exam and goals.
Improvements in tone and walking distance
Improvements in gross motor function
No difference in quality of gait
IV
BTA in the management of spastic gait disorders in children and young adults with CP: a randomized, double-blind study of "high-dose" vs. "low-dose" treatment.
(Wissel et al., 1999)
Randomized*, double blind**, controlled study on 33 children with spastic diplegia or hemiplegia
Treatment = Multilevel = BTA into calf and a second level (hamstrings, hip adductor or hip flexor) using a high or low dose
Dose-dependent improvements in tone, active and passive range of motion at ankle, improved stride length and speed of walking
Improvements in active and passive range of motion at knee found in both the high and low dose groups
I

* Randomized = The participants in the study are assigned randomly to either the intervention group or the control group.

** Double-blind = A research design in which the participant and the person doing the assessment do not know if the participant is in the control group or the intervention group.

Table 3: Use of BTA in the Upper Extremity

Title of Study
(Authors)
Description of StudyOutcomeLevel of Evidence
Botulinum toxin A in the hemiplegic upper limb: a double-blind** trial.
(Corry et al., 1997)
Randomized*, double blind, controlled study of 14 children with hemiplegia
BTA into multiple spastic arm muscles
Improvement seen in range, tone, grasp, and cosmetic appearance
Decreased ability to pick up coins

I

(evidence for improvement in tone, range and cosmetic appearance but not function)

An evaluation of BTA to improve upper extremity function in children with hemiplegia.
(Fehlings et al., 2000)
Randomized trial of 30 children with hemiplegia
BTA into multiple spastic arm muscles
Improvement found in function in the BTA groupI
(evidence for improvement in upper extremity function)
Botulinum A chemodenervation: a new modality in cerebral palsied hands.
(Wall et al., 1993)
Prospective study of 5 children with hemiplegia
BTA into adductor pollicis muscle plus splinting
Improvement in the cosmetic appearance and function of the hand was seen in all 5 children (rated by a blinded panel)IV
Botulinum toxin in the treatment of cerebral palsy.
(Denisilc & Meh, 1995)
Prospective study of 10 children with CP
BTA into multiple muscles in the arm
9 out of 10 children improved function/toneIV
Effects of BTA on upper limb spasticity in children with cerebral palsy.
(Friedman et al., 2000)
Prospective study of 32 children with CP
BTA into multiple spastic arm muscles
Improvement seen in toneIV
(evidence for reduction in tone)
BTA as an adjunct when planning hand surgery in children with spastic hemiplegia.
(Autti-Ramo et al., 2000)
Prospective study of 8 children with hemiplegia
BTA into multiple spastic arm muscles
5 of the 8 children met treatment goals, with improvement in grasp and bimanual functionIV

* Randomized = The participants in the study are assigned randomly to either the intervention group or the control group.

** Double-blind = A research design in which the participant and the person doing the assessment do not know if the participant is in the control group or the intervention group.

Table 4: Use of BTA with Individuals with Traumatic Brain Injury

Title of Study
(Authors)
Description of StudyOutcomeLevel of Evidence
Botulinum toxin in severe upper extremity spasticity among patients with traumatic brain injury: An open labeled trial.
(Yablon et al., 1996
Prospective (before-after) study of 21 individuals with a traumatic brain injury and related upper extremity spasticity, aged 16-54 years (9 individuals were treated less than one year after the injury)
Treatment = BTA into multiple muscles in the upper extremity and therapy including casting
Both groups (acute and chronic) had increased range at the wrist and decreased spasticity
Decreased pain during range of motion, and improved positioning and hygiene
IV
Botulinum toxin type A in the treatment of upper limb spasticity among patients with traumatic brain injury.
(Pavesi et al., 1998)
Prospective (before-after) study of 6 individuals with traumatic brain injury and related upper extremity spasticity, aged 18-42 years
Spasticity had been present for 4-6 months.
Treatment = BTA into multiple muscles in the upper extremity plus casting
Increased range of motion and decreased spasticity were found
Improvements in functional arm use were reported based on clinical evaluation
Decreased pain
IV
Botulinum toxin treatment of lumbrical spasticity: A brief report.
(Palmer et al., 1998)
Prospective study of a 19-year-old male who had a traumatic brain injury and related wrist and hand spasticity. He was two years post injury.
Treatment = BTA into the lumbrical muscles of the left hand (from the index to the little finger)
Decreased spasticity in the hand (lumbrical muscles)
No change in hand function
Hygiene more easily preformed on the left hand
IV
Kinematic changes following botulinum toxin injection after traumatic brain injury.
(Wilson et al., 1997)
Prospective (single-subject) study of a 19-year-old male who had a traumatic brain injury and related lower extremity spasticity.
The individual was two years post-injury.
Treatment = BTA into calf muscle
Improvements seen in walking pattern - walking speed increased, and movement at the ankle and knee improved
No difference in range of motion
IV

References

Bakheit, A. M., Severa, S., Cosgrove, A. et al. (2001). Safety profile and efficacy of botulinum toxin A (Dys-
port a) in children with muscle spasticity. Developmental Medicine and Child Neurology, 43, 234-238.

De Paiva, A, Meunier, F. A., Molgo, J., Aoki, K. R. & Dolly, J. O. (1999). Functional repair of motor endplates after botulinum neurotoxin type A poisoning: biphasic switch of synaptic activity between nerve sprouts and their parent terminals. Proceedings of the National Academy of Science USA, 16 (96), 3200-3205.

Herrmann, J., Mall, V., Bigalke, H., Geth, K., Korinthenberg, R. & Heinen, F. (2000). Secondary non-response due to development of neutralising antibodies to Botulinum Toxin a during treatment of children with cerebral palsy. Neuropediatrics, 31, 333-334.

Jankovic, J. & Brin, M. F. (1991). Therapeutic uses of Botulinum toxin. New England Journal of Medicine, 324, 1186-1194.

Shantz, E. J. & Johnson, E. A. (1992). Properties and use of Botulinum toxin and other microbial neurotoxins in medicine. Microbiological Review, 56, 80-99.

References for Table 1: Management of Spastic Equinus (Toe-walking)

Corry, I. S., Cosgrove, A. P., Duffy, C. M. et al. (1998). Botulinum toxin a compared with stretching cats in the treatment of spastic equinus: a randomized prospective trial. Journal of Pediatric Orthopedics, 18, 304-311.

Flett, P. J., Stern, L. M., Waddy, H., Connell, T. M., Seeger, J. D. & Gibson, S. K. (1999). Botulinum toxin A versus fixed cast stretching for dynamic calf tightness in cerebral palsy. Journal of Peadiatrics and Child Health, 35, 71-77.

Koman, L. A., Mooney, J. F., Smith, B. P., et al.(2000) Botulinum toxin type A neuromuscular blockade in the treatment of lower extremity spasticity in cerebral palsy: a randomized double-blind, placebo-controlled trial. Journal of Pediatric Orthopedics, 20, 108-115.

Koman, L. A., Brashear, A., Rosenfeld, H., Chambers, H., Russman, B., Rang, M., Root, L., Ferrari, E., Garcia De Yebenes Prous, J., Smith, B. P., Turkel, C., Walcot, J. M. & Molloy, P. T. (2001). Botulinum toxin type a neuromuscular blockade in the treamtent of equinus foot deformity in cerebral palsy: a multicenter, open-label clinical trial. Pediatrics, 108, 1062-71.

Sutherland, D. H., Kaufman, K. R., Wyatt, M. P., Chambers, H. G. & Mubarak, S. J. (1999). Double-blind study of botulinum A toxin injections into the gastrocnemius muscle in patients with cerebral palsy. Gait and Posture, 10, 1-9.

Ubhi, T., Bhakta, B. B., Ives, H. L., Allgar, V. & Roussounis, S. H. (2000). Randomized double blind placebo controlled trial of the effect of botulinum toxin on walking in cerebral palsy. Archives of Diseases in Childhood, 83, 481-487.

References for Table 2: Use of BTA in Other Leg Muscles

Corry, I. S., Cosgrove, A. P., Duffy, C. M., Taylor, T. C. & Graham, H. K. (1999). Botulinum toxin A in hamstring spasticity. Gait and Posture, 10, 206-210.

Cosgrove, A. P., Corry, I. S. & Graham, H. K. (1994). Botulinum toxin in the management of the lower limb in cerebral palsy. Developmental Medicine and Child Neurology, 36, 386-396.

Mall, V., Heinen, F., Kirschner, J., Linder, M., Stein, S., Michaelis, U., Bernius, P., Lane, M. & Korinthenberg, R. (2000). Evaluation of botulinum toxin A therapy in children with adductor spasm by Gross Motor Function Measure. Journal of Child Neurology, 15, 214-217.

Wissel, J., Heinen, F., Schenkel, A., Doll, B., Ebersbach, G., Müller, J. & Poewe, W. (1999). Botulinum toxin A in the management of spastic gait disorders in children and young adults with cerebral palsy: a randomized, double-blind study of "high-dose" versus "low-dose" treatment. Neuropediatrics, 30, 120-124.

Yang, T. F., Chan, R. C., Chuang, T. Y., Liu, T. J. & Chiu, J. W. (1999). Treatment of cerebral palsy with botulinum toxin: evaluation with Gross Motor Function Measure. Journal of the Florida Medical Association, 98, 832-836.

References for Table 3: Use of BTA in the Upper Extremity

Autti-Rämö, I., Larsen, A., Peltonem, J., Taimo, A. & von Wendt, L. (2000). Botulinum toxin injection as an adjunct when planning hand surgery in children with spastic hemiplegia. Neuropediatrics, 31, 4-8.
Corry, I. S., Cosgrove, A. P., Walsh, E. G., McClean, D. & Graham, H K. (1997). Botulinum toxin A in the hemiplegic upper limb: a double-blind trial. Developmental Medicine and Child Neurology, 39, 185-93.

Denislic, M. & Meh, D. (1995). Botulinum toxin in the treatment of cerebral palsy. Neuropediatrics, 26, 249-52.

Fehlings, D., Rang, M., Glazier, J. & Steel, C. (2000). An evaluation of botulinum A toxin injections to improve upper extremity function in children with hemiplegia cerebral palsy. Journal of Pediatrics, 137, 331-337.

Wall, S. A., Chait, L. A., Temlett, J. A., Perkins, B., Hillen, G. & Becker, P. (1993). Botulinum A chemodenervation: a new modality in cerebral palsied hands. British Journal of Plastic Surgery, 46, 703-6.

References for Table 4: Use in Individuals with Traumatic Brain Injury

Palmer, D. T., Horn, L. J. & Harmon, R. L. (1998). Botulinum toxin treatment of lumbrical spasticity: A brief report. American Journal of Physical Medical Rehabilitation, 77, 348-350.

Pavesi, G., Brianti, R., Medici, D., Mammi, P., Mazzucchi, A. & Mancia, D. (1998). Botulinum toxin type A in the treatment of upper limb spasticity among patients with traumatic brain injury. Journal of Neurology, Neurosurgery and Psychiatry, 64, 419-420.

Wilson, D. J., Childers, M. K., Cooke, D. L. & Smith, B. K. (1997). Kinematic changes following botulinum toxin injection after traumatic brain injury. Brain Injury, 11, 157-167.

Yablon, S. A., Agana, B. T., Ivanhoe, C. B. & Boake, C. (1996) Botulinum toxin in severe upper extremity spasticity among patients with traumatic brain injury: An open-labeled trial. Neurology, 47, 939-944.