Update

Update

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Use of Botulinum Toxin Type A in Children With Cerebral Palsy ўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўўў

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erebral palsy is one of the most common causes of activity limitation in children. The central nervous system (CNS) lesion causing the disorder of posture and movement is nonprogressive, but the manifestations of the lesion may change over time. Children with cerebral palsy may display a range of movement disorders, alone or in combination, including dystonia, athetosis, ataxia, and spasticity.1 Spasticity is a complex phenomenon and has been defined as “a motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerks, resulting from hyperexcitability of the stretch reflex, as one component of the upper motoneuron syndrome.”2(p485) Spasticity can be associated with co-contraction, clonus, and hyperreflexia. Children with spastic cerebral palsy generally have a typical pattern of muscle weakness, impairment in selective motor control, and sensory impairment, in addition to spasticity.1 In some centers, traditional management for children with spastic cerebral palsy has included physical therapy interventions and use of orthotic devices, with the goal of postponing orthopedic surgery until the child is older (eg, after age 6 years).3 These interventions aim to optimize function and strive to delay or treat deformity resulting from spasticity, but they do not effect any sustainable change in the amount of spasticity. Botulinum toxin, a relatively recent addition to the available medical interventions for children with cerebral palsy, has rapidly gained acceptance as a treatment that temporarily reduces focal muscle spasticity.4 The purpose of this article is to describe current evidence regarding the effectiveness of botulinum toxin A (BtA) in the treatment of children with spasticity associated with cerebral palsy. Specific attention will be devoted to aspects of BtA treatment that are likely to be pertinent to physical therapists, including basic pathophysiology, indications, procedural considerations, and evidence regarding effect on spasticity reduction, range of motion, gross motor function, and gait.

[Nolan KW, Cole LL, Liptak GS. Use of botulinum toxin type A in children with cerebral palsy. Phys Ther. 2006;86:573–584.]

Key Words: Cerebral palsy, Drugs, Spasticity.

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Karen W Nolan, Lynn L Cole, Gregory S Liptak

Physical Therapy . Volume 86 . Number 4 . April 2006

573

This update describes current evidence Pharmacology/Mechanism of Action The botulinum toxins are protein products of the gramnegative anaerobic bacterium, Clostridium botulinum. When absorbed through the gastrointestinal tract after ingestion of contaminated food, these toxins are known to cause the disorder commonly known as food-borne botulism. The toxins have been categorized into 7 serotypes with distinct antigens (types A, B, C, D, E, F, and G), of which type A is recognized as the most potent and has been the most studied in clinical use.4 Botulinum toxin type A is commercially available for therapeutic use as Botox* and Dysport.† Despite a common labeling system, these 2 preparations differ in their relative potency, with Botox being 3 to 5 times more potent, per unit, than Dysport.5,6 Both botulinum toxin types B and F have been under clinical investigation for clinical efficacy, and type B is now available as Myobloc‡ and has US Food and Drug Administration (FDA) approval for cervical dystonia.7 Studies on utilizing botulinum toxin type B in pediatric spasticity are not yet available. Botulinum toxin type A has been used medically for more than 20 years in the management of muscle spasticity. Current FDA-approved indications include use in adults with strabismus, blepharospasm, cervical dystonia, glabellar lines, and severe primary axillary hyperhidrosis.7 Common off-label uses include migraines, hemifacial spasms,8 spasmodic dysphonia,9 multiple sclerosis,10 and spasticity in cerebral palsy.11–13 Controlled studies demonstrating the efficacy of BtA in treatment of childhood cerebral palsy have led to approval for this indication in many European countries.14 Botulinum toxin type A has not been specifically approved for use in treatment in childhood cerebral palsy in the United States. Current evidence indicates that the botulinum toxins produce muscle weakness or paralysis by preventing the

regarding clinical applications, patient selection, and efficacy of botulinum toxin in the management of spasticity in children with cerebral palsy. presynaptic release of acetylcholine from the nerve terminal.15 The degree of paralysis is dependent on the dose and number of synapses affected.5 Clinical spasticity reduction typically lasts from 12 to 16 weeks in most patients,4,14 although functional benefit may last for 6 months or more in some patients.4 Recovery of the neuromuscular junction has been proposed to occur by a series of events, including formation of new axonal sprouts followed by resumption of cholinergic function by the original terminals and elimination of the thensuperfluous sprouts.4,16 Side effects reported in studies using BtA in children to manage spasticity are generally described as infrequent, mild, and transient. Side effects that are not gait-related occur in 6% to 12% of treatments.17 The most comprehensive documentation of pediatric side effects was by Bakheit et al,18 who conducted a retrospective study of the safety and efficacy of Dysport in 758 children who received a total of 1,594 treatments. In this study, adverse events were reported in 7% of treatments, with urinary incontinence in 1%, generalized muscle weakness in 0.5%, falls in 0.5%, and pain, fatigue, influenza-like symptoms, fever, and rash reported in ⬍1%. In this study, higher total doses per treatment session were correlated with increased incidence of adverse events. Unfortunately, this study did not include standardized measures of functional outcomes in the children in the study, limiting our ability to quantify functional gains. Several cases of a botulism-like syndrome have been reported in adults treated with modest-dose BtA,19,20 but this syndrome has not been reported in children.

* Allergan Inc, 2525 DuPont Dr, PO Box 19534, Irvine, CA 92623-9534. † Speywood Pharmaceuticals Ltd, 1 Bath Rd, Maidenhead, Berks, SL6 4UH United Kingdom. ‡ Elan Pharmaceuticals, 7475 Lusk Blvd, San Diego, CA 92121.

KW Nolan, PT, MS, PCS, is Associate Professor, Department of Physical Therapy, School of Health Science and Human Performance, Ithaca College–Rochester campus, 300 East River Rd, Rochester, NY 14623 (USA) ([email protected]). Address all correspondence to Ms Nolan. LL Cole, MS, RN, PNP, is Director, Kirch Developmental Services Center, Department of Pediatrics, University of Rochester Medical Center, Rochester, NY. GS Liptak, MD, MPH, is Professor of Pediatrics, Department of Pediatrics, University of Rochester Medical Center. Ms Nolan and Dr Liptak provided concept/idea/project design. All authors provided writing. Ms Cole and Dr Liptak provided consultation (including review of manuscript before submission). This article was received March 3, 2005, and was accepted October 5, 2005.

574 . Nolan et al


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Procedure/Protocol Currently, no consensus exists among clinicians about how an optimal dose of BtA should be determined; however, a consensus statement has been published on realistic safety margins for BtA therapy.21 The consensus statement was developed by a group of clinicians and scientists who agreed on a framework of guidelines that included factors for candidate selection. Positive factors included goals for specific functional benefits and the presence of spasticity with full joint range of motion as opposed to limited joint range of motion from fixed contractures. The absence of optimal dosing standards is primarily due to lack of evidence regarding the relationship between dose and clinical benefit, or dose and adverse effects. One multicenter retrospective review in Europe by Bakheit et al18 examined records of 758 patients who had received a total of 1,594 BtA (Dysport) treatments, with total doses ranging from 50 to 2,360 IU (⬍10 to ⬎40 IU per kilogram of body weight). The authors18 concluded that best therapeutic response and fewest side effects were achieved at less than 1,000 IU. Since its first use in children, per kilogram dosages used in clinical trials have been increasing, from 8 to 12 to 24 units of BtA per kilogram maximum dose.22 Patient Selection Selecting BtA as an appropriate treatment mechanism for a child with cerebral palsy ideally includes collaboration among the spasticity evaluation and treatment center, patient, family, and community care providers. Injection sites are determined based on physical examination and identification of clear, reasonable treatment goals pertaining to function.21 Identification and prioritization of goals may dictate choice of muscles to be injected, especially in children with many involved muscle groups. Goals may include improved motor skills, such as improved ability to stand upright, more stable gait, improved self-care skills, and improved ability to use a power wheelchair. Other appropriate goals may include pain reduction and improved positioning or ease of hygiene. Finally, some literature suggests that an optimal effect from BtA may be in the younger years before development of fixed contractures.17,23 For this reason, age also may be taken into account when considering BtA as a treatment option. Effects/Outcomes Researchers have documented the effects of BtA in children with spastic cerebral palsy using measurements in several categories, including body systems/structures and activity.3,12,13,18,23–38 Some of this literature is detailed in the Table3,12,18,23,24,26 –31,33,35–38 and included in a summary form in the narrative portion of this review. The specific measurements described include


spasticity, range of motion, gross motor function, and gait. Spasticity Reduction Children with spastic and rigid types of cerebral palsy frequently exhibit functional limitations related to their spasticity. Although cerebral palsy is a nonprogressive condition, the degree of motor impairment, functional consequence, or health-related quality of life may worsen as the child grows older.1 This outcome is particularly noted in children with complex presentations of the disorder. Many long-term functional outcomes are influenced by spasticity, which may cause muscle shortening, contractures, and joint dislocations. Botulinum toxin type A has been shown to reduce spasticity in many studies.23,24,26,27,36 The Modified Ashworth Scale (MAS) is frequently used clinically to measure spasticity, and MAS scores have been shown to have good interrater reliability in adult patients with intracranial lesions,39 although other studies in children with cerebral palsy have shown poor interrater reliability40 (see Appendix for a description of the MAS). Heinen and colleagues24 used the MAS to measure outcomes in 28 pediatric patients following BtA injections, and they found that subjects with adductor spasm, spastic foot drop (or equinus), or various focal motor problems experienced spasticity reduction of 1 to 3 points on the MAS (Table). Wong25 reported significantly decreased MAS scores in 17 children with cerebral palsy following BtA injections, with average reductions of 1.19 on the gastrocnemius muscle, 1.12 in the adductor muscles, and 2.0 in the hamstring muscles (Table). Corry and colleagues3 reported significant spasticity reduction at 2 weeks (MAS reduction of 1) that was not seen at 12 weeks (return to pretreatment MAS of 2) in a study of the effects of BtA as an alternative to serial casting in 20 children with equinus, or plantar-flexed positioning, due to cerebral palsy. Spasticity reduction was not significant in the casted group (Table). Mall and colleagues26 studied the treatment effect of BtA in 18 patients with adductor spasm related to cerebral palsy, and reported decreased MAS scores of 1 in 13 of the 18 subjects, with a mean reduction of 1 on the MAS for all subjects. The studies reporting on specific measurement of spasticity reduction included diverse presentations in children, including adductor spasm and equinus. Therefore, the spasticity reduction presumably supported different functional goals in different patient groups. Temporary spasticity reduction is clinically important in habilitation programs for children with cerebral palsy. Range of Motion Patterns of spasticity with resultant muscle imbalance across the joints can, over time, cause musculotendinous shortening, joint contracture, and even bony deformity.1

Nolan et al . 575

576 . Nolan et al


CP—all types, brain injury with spasticity

Mean⫽7.2 y

4–9 y

2–20 y

2–9 y

Bakheit et al,18 2001 (n⫽758)

Boyd et al,36 2000 (n⫽25)

CalderonGonzalez et al,27 1994 (n⫽15)

Corry et al,3 1998 (n⫽20)

Diplegia, hemiplegia, quadriplegia


Diplegia, hemiplegia

Diagnosis

Age

Study

Botox 6–8 U/kg, Dysport 15 U/kg Site: gastrocnemius, soleus muscles

Botox 15 U, 120 U total Site: pectineus, adductor, hamstring, rectus femoris, gastrocnemius, tibialis posterior, flexor carpi radialis, flexor carpi ulnaris muscles

Botox mean 7 U/kg Site: gastrocnemius muscle

Dysport 50–2,360 U, mean⫽22.9 U/kg Site: varied

Dose and Site

Prospective, randomized, Botox or serial casting

Open label, prospective

Prospective, intervention study with pretestposttest assessment

Multicenter, retrospective review of records

Study Design

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Significant increases in dorsiflexion at 2 wk, both groups, with further increase in Botox group at 12 wk; casted group relapsed to no difference at 12 wk; muscle tone reduction at 2 wk in Botox group with less relapse by 12 wk compared with casted group, on clinical exam Significant change in foot-contact score and total score and improvement in both groups (Botox and casted) at 2 and 12 wk; no difference between groups; relapse in foot contact score seen in casted group by 12 wk, on videotaped gait analysis (PRS) Increased dorsiflexion in stance and decreased maximal plantar flexion in Botox group at 12 wk (Viconb gait analysis) PRS—little difference between groups ROM—comparable between groups at 2 wk, with significant differences reported at 12 wk, greater in Botox group than in casted group

Spasticity significantly reduced in all patients; MAS Postural improvement during standing (eg, significantly reduced scissoring, crouching) with improved trunk and hip posture, heel contact during stance

Improved ankle movement; 3D gait analysis, including AMQ, APQ, sagittal-plane ankle kinematics Decreased spasticity

82% overall “good response” 14% minimal/low response Best response with moderate dosing Proportion of good response highest in youngest children, decreased with increase in patient age More patients who received multilevel treatment had functional improvement

Results

Overview of Selected Studies Evaluating Clinical, Motor, and Functional Outcomes in Children With Cerebral Palsy Following Botulinum Toxin A Injectionsa

Table.

Botox is safe and clinically useful for children with CP; an additional goal of Botox should be to achieve adequate muscle growth

Botox caused change in muscle function

Recommend maximum total dose of 1,000 U Dysport Youngest children show best response to Botox

(Continued)

Botox as effective as serial casts, but with longer effect

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Comments


Nolan et al . 577

2–17 y

3–13 y

2–10 y

Eames et al,30 1999 (n⫽39)

Fehlings et al,33 2000 (n⫽30)

Age

Cosgrove et al,13 1994 (n⫽26)

Corry et al3 (continued)

Study

Continued

Table.

Hemiplegia



Diagnosis

Botox 2–6 U/kg Sites: biceps, volar forearm, adductor pollicis muscles

Botox 8–10 U/kg or Dysport 20–25 U/kg Sites: gastrocnemius muscle

5–28 U/kg of body weight Sites: gastrocnemius, soleus, hamstring, tibialis posterior muscles

Dose and Site

Single blind Randomized (treatment, control)

Prospective, open-label

Prospective, open label intervention study

Study Design

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Treatment group improved QUEST score (function) at 1 mo Treatment group small positive change in self-care skills No differences in grip strength, Ashworth scale score, PROM

Correlation between dynamic component of spasticity and magnitude and duration of response, measured by gastrocnemius muscle length, at rest and while walking Hemiplegia—duration 2⫻ as long No long-term lengthening, but some continued response at 12 mo

Reduced muscle tone on clinical examination for 25/26 subjects Improved ambulatory status in 9/19 of subjects with potential for improvement; sustained improvement after 6 mo in 6/19 subjects 14/26 subjects showed marked functional improvement, 10 subjects showed moderate improvement, 1 subject showed no change, 1 subject showed moderate deterioration No change in ROM Spasticity reduction at 2 wk, maintained in some muscle groups at 3 mo

No change in ROM Spasticity reduction at 2 wk, maintained in some muscle groups at 3 mo

Results

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(Continued)

UE Botox may result in improvements in function

Botox may delay orthopedic surgery; found that amount of dynamic lengthening was independent of Botox dose

Fixed contractures developed in older children; night splints were advised as an adjunct to optimize Botox effect; some gait improvements persisted after Botox effects ended

Comments


578 . Nolan et al


4–12 y

Thompson et al,29 1998 (n⫽20)

5–21 y

Mall et al,26 2000 (n⫽18)

2–13 y

2–16 y

Koman et al,12 2000 (n⫽114)

Sutherland,35 1999 (n⫽20)

Group 1—cervical dystonia Group 2—adductor spasm of hip Group 3–spastic foot drop Group 4–various focal motor problems associated with spastic muscle hyperactivity

6 mo–8 y

Heinen et al,24 1997 (n⫽28)

Diplegia, quadriplegia


CP with adductor spasm


Diagnosis

Age

Study

Continued

Table.

Botox 5–8 U/kg maximum dose Site: medial hamstring muscle

Botox 4 U/kg at 0 and 4 wk Site: gastrocnemius muscle

Botox 12 U/kg or Dysport 30 U/kg Sites: adductor and hamstring muscles

Botox 4 U/kg at 0 and 4 wk Site: gastrocnemius muscle

Dysport: 1st dose 5 U/kg, 2nd dose 5–30 U/kg Sites: group 1—splenius capitis, sternoclediomastoid, trapezius muscles; group 2—adductor muscles; group 3— triceps surae, tibialis posterior muscles; group 4—focal motor problems (eg, teres major, adductor hallucis, flexor carpi ulnaris, rectus femoris, iliopsoas muscles)

Dose and Site

Open-label, treatment, control

Prospective, randomized, double-blind placebo control

Prospective, intervention study with pretestposttest assessment

Prospective, randomized, placebo-controlled


Study Design

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Muscle excursion significantly reduced in short muscle length groups Improved knee extension in stance Semimembranosus and semitendinosus muscle length significantly increased in all injected muscles Improvement noted in 3 nonambulatory children (to exercise ambulator); 5 ambulatory children did not change

Increased peak ankle dorsiflexion in stance and swing in subjects after Botox injection, not found in controls, using gait analysis with kinematic measures

Increase in PROM in 14/18 subjects Decreased Ashworth scale score in 16/18 subjects Increased GMFM total scores more notable in patients with moderate limitation levels 3–4

Improvements in PRS score (gait pattern) lasting ⬎8 wk in Botox group Botox group increase in AROM, but not PROM

Changes in joint mobility (calculated as percentage of normal values, for comparison among 4 groups) differed among groups: significant improvement for groups 1, 2, and 4; significant improvement was not found in group 3 Significant improvement; half of group 1 showed complete and lasting remission (⬎2 y) after 3–4 treatments with Dysport Spasticity significantly reduced in groups 2, 3, and 4 Significant improvement in condition found for groups 1, 2, and 4; group 3 had 3/7 patients showing no functional benefit

Results

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(Continued)

Botox has short-term effects on gait

Improvement in gross motor function is an achievable goal in patients with moderate functional limitation GMFM not a good tool for assessing other goals in patients with severe impairments

Botox may delay orthopedic surgery

Safe and effective for varied presentations, including spasms, cervical dystonia

Comments


Nolan et al . 579

1–14 y

3–21 y

Wissel et al,23 1999 (n⫽33)

Age

Wallen et al,37 2004 (n⫽16)

Thompson et al29 (continued)

Study

Continued

Table.


Spastic CP, upperextremity involvement

Diagnosis

High-dose group total amount 200 U Botox per treated leg Low-dose group total amount 100 U per treated leg Sites: gastrocnemius, soleus, semitendinosus, gracilis, rectus femoris muscles

0.5–2 U Botox per kilogram of body weight, total dose not exceeding 12 U/kg (400 U) per visit, maximum of 50 U per injection site Sites: pronator quadratus and teres, brachioradialis, biceps, brachialis, flexor carpi radialis and ulnaris, finger flexor (FDP, FDS), thumb (adductor pollicis, opponens) muscles

Dose and Site

Randomized, double blind

Case series

Study Design

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16/33 subjects or parents reported improvement; no improvement in 16/ 33 subjects and deterioration in 1/33 subjects; no significant difference noted between “high-dose” group (n⫽9) and “low-dose“ group (n⫽7) Muscle tone decreased significantly after 6–8 wk (MAS) Improvement in passive ankle dorsiflexion, with significantly greater improvement in “high-dose” group; significant improvement in knee AROM and PROM, with no difference between treatment groups

Significant improvement on Canadian Occupational Performance Measure at 3 and 6 mo Parent questionnaires indicated positive outcomes Significant spasticity reduction at 2 wk, return to baseline by 6 mo No significant change reported for AROM or PROM

Significant decrease in spasticity Significant improvement in joint motion of hips, knees, and ankles after injections in gastrocnemius and hamstring muscles Pattern of movement improved in functional and community ambulators, when assessed by blinded, independent observers

Results

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(Continued)

More improvement found in “high-dose” treatment arm for most frequently targeted outcomes, without difference in frequency or severity of side effects; greatest functional benefit in younger children No systemic SE in either group; noted focal SE were mild and transient. Deterioration reported in 1/33 subjects in low-dose group

Sustained functional outcomes occurred after BtA despite return of spasticity

Comments


580 . Nolan et al


3–8.5 y

Zelnik et al,31 1997 (n⫽14)


Diplegia, ambulatory

Diplegia, tetraplegia Sites: adductor, gastrocnemius, hamstring muscles

Diagnosis

Botox 4–6.8 U/kg Sites: gastrocnemius, soleus muscles

Botox 1–3 U/kg per muscle group Sites: adductor, hamstring, gastrocnemius muscles

Botox 6 U/kg

Dose and Site


Comparison, Botox vs phenol block

Prospective intervention study with pretestpostest assessment

Study Design

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Significant improvement at the ankle, knee, hip abduction Improved quality of gait in 9/14 subjects (ankle dorsiflexion and foot clearance)

Improvement in gait speed and cadence in Botox group as compared with phenol

Greatest percentage of parents noted effect of Botox between 1–2 h Duration of effect reported to last 3–10 mo Improvement noted in 3 nonambulatory children, to “nonfunctional” (ie, exercise) ambulatory; 5 ambulatory children did not change Significant decrease in spasticity Significant improvement in PRS in both lower extremities of all 11 ambulatory children Significant improvement in joint motion of hips, knees, and ankles after injection to gastrocnemius and hamstring muscles Pattern of movement improved in functional and community ambulators, when assessed by blinded, independent observers

Highly significant improvement in stride length in “high-dose” group; no significant improvement in “low-dose” group; analysis of variance showed effect to be dose-dependent Highly significant improvement in gait speed in “high-dose” group; no significant improvement in “low-dose” group; analysis of variance showed effect to be dose-dependent

Results

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Botox is clinically useful only for dynamic deformities Biphasic injections more effective than monophasic injections

Botox has superior treatment effects, fewer SE than phenol blocks

Muscle balance temporarily restored; may prevent or reduce development of contracture or fixed deformity Reinforced benefits to younger children

Comments

a CP⫽cerebral palsy, PT⫽physical therapy, UE⫽upper extremity, ROM⫽range of motion, AROM⫽active range of motion, PROM⫽passive range of motion, COPM⫽Canadian Occupational Performance Measure, GAS⫽Goal Attainment Scale, CHQ⫽Child Health Questionnaire, TFL⫽tensor fasciae latae muscle, AMQ⫽ankle movement quotient, APQ⫽ankle power quotient, PRS⫽Physician Rating Scale, MAS⫽Modified Ashworth Scale, SE⫽side effects, GMFM⫽Gross Motor Function Measure, BtA⫽botulinum toxin A, QUEST⫽Quality of Upper Extremity Skills Test. b Oxford Metrics, Oxford, United Kingdom.

3–7 y

2–15 y

Age

Wong et al,38 2004 (n⫽27)

Wong et al25 1998 (n⫽17)

Wissel et al23 (continued)

Study

Continued

Table.


One of the goals of BtA injection is to increase the range of motion of the affected joint. Botulinum toxin A injections have been shown to produce improvements in passive range of motion in the joints over which injected muscles cross.11–13,23–27,31,33,35,37 Heinen and colleagues24 found significant improvement in subjects’ joint mobility adjacent to the injected site, when calculated as a percentage value. This improvement was reported in 8 subjects with adductor spasm and in 7 subjects with various focal motor problems. Wong25 found significant improvements in hip abduction (mean change⫽13.5°) and ankle dorsiflexion (mean change of 3.5°) after BtA injection into the adductor and gastrocnemius muscles, respectively. Calderon-Gonzalez et al27 also reported improved ankle dorsiflexion following BtA injection in the gastrocnemius muscle in 15 children with cerebral palsy. Corry et al3 and Zelnik et al31 reported significant improvements in ankle dorsiflexion in their subjects with dynamic contractures. Limitations of these studies3,31 include the small sample size and the absence of a control group. Even small increments of increased available range of motion, particularly in joints such as the ankle, have the capacity to alter standing posture and gait significantly. These 5 studies3,24,25,27,31 demonstrated significant changes in lower-extremity joint range of motion following BtA injections (Table). Improvements in available joint range of motion may help prevent development of contractures, potentially decreasing the severity of the joint long-term limitation. Gross Motor Function Measures of function and ability are essential to consider when evaluating the effects of BtA for all children with cerebral palsy. Several investigators26,32,33,41 have reported positive results in areas of function following BtA injections. Mall et al26 and Heinen et al41 evaluated the effect of BtA treatment on function in children with cerebral palsy and adductor muscle spasm. Mall and colleagues26 used the Gross Motor Function Measure (GMFM) to measure the treatment effect. The GMFM is a standardized, validated measurement instrument designed to assess gross motor function in children with cerebral palsy.42 Significant improvement in gross motor function was reported in GMFM total scores and GMFM goal total scores.26 It was further noted that patients with moderate impairment of gross motor function, defined as those who met the criteria for levels III and IV in the Gross Motor Functional Classification System,34 benefited most from treatment. The Gross Motor Function Classification System is an instrument that describes levels of motor function ability in children with cerebral palsy. Children who meet the criteria for level III are those who walk with an assistive device, but have some outdoor limitations. Children who meet the criteria for level IV are self-mobile in wheelchairs. Therefore, subjects in the study by Mall and colleagues26 who were


ambulatory but limited by need for assistive device, and subjects who are not ambulatory but are independently mobile in wheelchairs, were found to derive the greatest effect, or benefit, from BtA injections. Fehlings et al33 also reported an increase in upperextremity function in a sample of children with hemiplegia, measured with a standardized instrument known as the Quality of Upper Extremity Skills Test (QUEST). In addition to their findings in upper-extremity function, Denislic and Meh32 also reported improved foot posture (70%–90% improvement, measured using a modified Physician Rating Scale [PRS]). Although many studies have focused on functions of body systems or structure in outcome measures, these studies have reported on positive effects of BtA on patient activity or limitations (Table). The effects of BtA on daily life and functional abilities should be considered most fundamental and important. Gait Children with cerebral palsy often experience functional limitations in ambulation. The use of BtA to temporarily reduce the spasticity that contributes to deviations or limitations in gait has been reported in recent literature. These effects on gait have included improvements in scores on the PRS (which included evaluation of 6 functional aspects of the gait cycle),12 ambulatory status and sagittal-plane kinematics,13 longitudinal gait parameters (such as stride length),23 ambulatory state and observational gait analysis,25 peak ankle dorsiflexion in stance and swing phases,35 and sagittal-plane ankle kinematics, ankle moment quotient, and ankle power quotient.36 In a randomized, double-blind, placebo trial, Koman and colleagues12 evaluated the gait patterns of 114 subjects with cerebral palsy during active walking using a modification of the PRS. The results indicated that the PRS composite score was significantly greater in the BtA group versus the placebo group at all follow-up visits, which occurred at 2, 4, 8, and 12 weeks (Table). The range of scores in the PRS is 0 to 14, and the highest score represents the most normal gait, when considering six different functional aspects of the gait cycle. Wong25 studied the effects of BtA on gait in 17 children with spastic cerebral palsy (11 who were ambulatory and 6 who were nonambulatory) using both the PRS and video analysis. A significant improvement was noted in the PRS scores of both lower limbs of all children who were ambulatory (mean change of greater than 2 points on both lower extremities) following BtA injections. Observational analysis of videotapes of the subjects’ function also reported improvement in all of the children, with 8 children reported to demonstrate improved ambulatory category status (ie, new ambulatory ability, or improved independence) (Table).

Nolan et al . 581

Cosgrove et al13 used BtA to treat 26 children with cerebral palsy and severe spasticity of the lower-limb muscles that interfered with positioning or walking. These investigators reported improved walking, with significant improvements noted in sagittal-plane kinematics, and improvements in the ambulatory status of all subjects (Table). Sutherland et al35 used a randomized clinical trial of 20 children with cerebral palsy to investigate the effects of BtA injections on gait, using 3-dimensional gait analysis. Subjects who had received the drug demonstrated significantly improved mean peak ankle dorsiflexion in the stance and swing phases of gait. Gait analysis was conducted at week 8, 4 weeks after the subjects’ second injection. Improvement in ankle dorsiflexion was not found in controls (Table). A primary focus of a study by Wissel and colleagues23 was assessment of dose-response relationships to BtA treatment in 33 children and adolescents with spastic gait due to cerebral palsy. These investigators used “high-dose” and “low-dose” treatment groups. Results of gait analysis revealed significant increases in gait speed and stride length in subjects in both treatment groups over baseline values. Subjects in the high-dose group showed a greater gain in mean gait speed and mean improvement in stride length compared with the low-dose group (Table). Sites of injection were determined by the predominant clinical gait pattern. Those children with a “toe-walker pattern” with dynamic contractures of the gastrocnemius-soleus muscle complex received injections in those muscle bellies. Children with additional hip adduction or knee flexion also received injections in the semitendinosus or gracilis muscle, and in the rectus femoris muscle for children with a “stiff-knee pattern.” The findings indicated a dose-dependent functional improvement. Boyd et al36 prospectively studied the effects of BtA injection on the gastrocnemius-soleus muscle in 25 children with cerebral palsy (15 children with spastic diplegia, and 10 children with spastic hemiplegia) who were ambulatory, using measures of gait (ie, kinematics and kinetics). According to the authors, some children required a short period of serial casts (1–3 weeks) to achieve the full effect of BtA (which they described as “potentiation”) to achieve the functional goal of the intervention. Examples of a functional goal might include a “foot-flat” or “heel-toe” gait. Analysis of kinematic data revealed that improvements in mid-stance ankle dorsiflexion were significant at 3 weeks for all subjects,36 similar to results reported by Sutherland et al.35 At 12 and 24 weeks, the comparison was stratified by treatment subgroup (ie, subjects who received BtA only versus subjects who received BtA plus casting). The mean difference in ankle kinetic measures (ankle moment, or ankle movement quotient) was greatest in

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the subjects who received BtA plus casting at 12 and 24 weeks after BtA injection. Improvements in ankle dorsiflexion in mid-swing also were significant at all follow-up times, compared with baseline values for both treatment groups (Table). In children with cerebral palsy who were ambulatory, improvements in gait following BtA injection are considered important measurable functional outcomes. Botulinum toxin A has been shown to be effective for improved gait outcomes. The duration of effect varies; however, it is not permanent. Physical Therapists’ Role in Botulinum Toxin A Therapy Physical therapists are involved in numerous aspects of management of children who have been identified as candidates for BtA therapy. These activities span the continuum of care from patient selection to outcome assessment. Leach43 has identified 5 major areas in which physical therapists are involved with children who have spastic cerebral palsy and who receive BtA treatment: (1) patient selection, (2) assessment of baseline status, (3) goal determination, (4) physical therapy after BtA treatment, and (5) outcome assessment. First, through examination and evaluation, the physical therapist identifies the muscle or muscle group in which muscle spasticity interferes with function. Second, a complete assessment of the child’s baseline functional status will prepare for an evaluation of the effectiveness of the treatment. Third, the physical therapist assists with formulating realistic and measurable goals, in a collaborative process with team members, including the family and child. Careful consideration should be given to whether the patient’s spasticity is aiding or interfering with function.44 Fourth, physical therapists provide interventions that maximize the benefits of the BtA therapy, using methods that emphasize improvements in motor control,21 range of motion,21 muscle strength,45 and functional training.46,47 The fifth area relates to follow-up evaluation of the effectiveness of BtA, and will guide future decisions on use of BtA therapy for individual children. In many situations, a child will have more than one physical therapy provider in different practice settings, such as school or clinic. The importance of communication and coordination of care must be emphasized, and consensus on the functional goal for the child will promote optimal results and satisfaction for the child and family. Current Limitations of Literature Considerable information has been added to the body of knowledge pertaining to BtA since its initial use with pediatric patients, reported in 1993.11 Botulinum toxin A is a medical intervention with promising potential, but improved procedural standards are needed for appro-



priate use and optimal outcomes in children. Future investigators, we believe, should consider research that focuses on 5 areas: (1) standards for administration, (2) identifying subgroups of children who are most (or least) likely to benefit from BtA, (3) long-term functional and musculoskeletal outcome evaluation, (4) optimal rehabilitative methods and procedures (including adjunctive measures, such as serial casting or use of orthotic devices), and (5) qualitative research on perceived benefits and satisfaction of children and their families following BtA. Many factors complicate our interpretation and application of the literature described in this review. These factors include lack of consensus or consistency in administration protocols, such as length of time between series of injections, and use of electromyography versus palpation for identifying injection location. Optimal protocols for therapy and bracing after BtA injections have not been clearly established. Conclusions Evidence indicates that BtA can be safely used in children with spastic cerebral palsy, although this application has not yet been included as an FDA-approved indication. Side effects are generally minimal and short in duration, and younger children with moderate involvement appear to derive the greatest benefit from the use of BtA. It is best used when an appropriate, attainable functional goal is identified prior to the intervention, with agreement between all team members, including the family or care providers. The clinical effects of BtA have been reported to include decreased spasticity and increased range of motion. These effects may be critically important when considering the influence of spasticity, limited muscle length, and restricted range of motion on the growing bones of young children. Botulinum toxin A may offer temporary reduction of these influences as children grow. Studies12,13,23,25,31,33,35,36 have shown improvements in gross motor and upper-extremity function in children, gait patterns, and relative independence of ambulatory status.

6 Odergren T, Hjaltason H, Kaakkola S, et al. A double blind, randomized, parallel group study to investigate the dose equivalence of Dysport and Botox in the treatment of cervical dystonia. J Neurol Neurosurg Psychiatry. 1998;64:6 –12. 7 Transfer of therapeutic products to the Center for Drug Evaluation and Research. US Food and Drug Administration, Center for Biologics Evaluation and Research. Available at: www.fda.gov/cber/transfer/ transfprods.htm. Accessed August 30, 2005. 8 Savino PJ, Sergott RC, Bosley TM, et al. Hemifacial spasm treated with botulinum A toxin injection. Arch Opthalmol. 1985;103:1305–1306. 9 Miller RH, Woodson GE, Jankovic J. Botulinum toxin injection of the vocal fold for spasmodic dysphonia: a preliminary report. Arch Otolaryngol Head Neck Surg. 1987;113:603– 605. 10 Snow BJ, Tsui JKC, Bhatt M, et al. Treatment of spasticity with botulinum toxin: a double-blind study. Ann Neurol. 1990;28:512–515. 11 Koman LA, Mooney JF, Smith B, et al. Management of cerebral palsy with botulinum-A toxin: preliminary investigation. J Pediatr Orthop. 1993;13:489 – 495. 12 Koman LA, Mooney JF, Smith BP, et al. Botulinum toxin type A neuromuscular blockade in the treatment of lower extremity spasticity in cerebral palsy: a randomized, double-blind, placebo-controlled trial. J Pediatr Orthop. 2000;20:108 –115. 13 Cosgrove AP, Corry IS, Graham HK. Botulinum toxin in the management of the lower limb in cerebral palsy. Dev Med Child Neurol. 1994;36:386 –396. 14 Edgar TS. Clinical utility of botulinum toxin in the treatment of cerebral palsy: comprehensive review. J Child Neurol. 2001;16:37– 46. 15 Kita M, Goodkin DE. Drugs used to treat spasticity. Drugs. 2000;59: 487– 495. 16 DePavia A, Meiunier FA, Molgo J, et al. Functional repair of motor endplates after botulinum neurotoxin type A poisoning: biphasic switch of synaptic activity between nerve sprouts and their parent terminals. Proc Natl Acad Sci U S A. 1999;96:3200 –3205. 17 Priess RA, Condie DN, Rowley DI, Graham HK. The effects of botulinum toxin (Btx-A) on spasticity of the lower limb and on gait in cerebral palsy. J Bone Joint Surg Br. 2003;85:943–948. 18 Bakheit AMO, Severa S, Cosgrove A, et al. Safety profile and efficacy of botulinum toxin A (Dysport) in children with muscle spasticity. Dev Med Child Neurol. 2001;43:234 –238; erratum 2001;43:357. 19 Bakheit AMO, Ward CD, McLellan DL. Generalised botulism-like syndrome after the intramuscular injections of botulinum toxin type A: a report of two cases. J Neurol Neurosurg Psychiatry. 1997;62:198. 20 Bhatia JP, Munchau A, Thompson PD, et al. Generalised muscular weakness after botulinum toxin injections for dystonia: a report of three cases. J Neurol Neurosurg Psychiatry. 1999;67:90 –93.

1 Koman LA, Smith BP, Shilt JS. Cerebral palsy. Lancet. 2004;363: 1619 –1631.

21 Graham HK, Aoki KR, Autti-Ramo I, et al. Recommendations for the use of botulinum toxin type A in the management of cerebral palsy. Gait Posture. 2000;11:67–79.

2 Lance JW. Symposium synopsis. In: Feldman FG, Young RR, Koella WP, eds. Spasticity: Disorder of Motor Control. Chicago, Ill: Year Book Medical; 1980:485– 494.

22 Bell KR, Williams E. Use of botulinum toxin type A and type B for spasticity in upper and lower limbs. Phys Med Rehabil Clin N Am. 2003;14:821– 835.

3 Corry IS, Cosgrove AP, Duffy CM, et al. Botulinum toxin A compared with stretching casts in the treatment of spastic equines: a randomized prospective trial. J Pediatr Orthop. 1998;18:304 –311.

23 Wissel J, Heinen F, Schenkel A, et al. 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. 1999;30:120 –124.

References

4 Jefferson RJ. Botulinum toxin in the management of cerebral palsy. Dev Med Child Neurol. 2004;46:491– 499. 5 Kessler KR, Benecke R. Botulinum toxin: from poison to remedy. Neurotoxicol. 1997;18:761.


24 Heinen F, Wissell J, Philipsen A, et al. Interventional neuropediatrics: treatment of dystonic and spastic muscular hyperactivity with botulinum toxin A. Neuropediatrics. 1997;28:307–313.

Nolan et al . 583

25 Wong V. Use of botulinum toxin injection in 17 children with spastic cerebral palsy. Pediatr Neurol. 1998;18:124 –130. 26 Mall V, Heinen F, Kirschner J, et al. Evaluation of botulinum toxin A therapy in children with adductor spasm by gross motor function measure. J Child Neurol. 2000;15:214 –217. 27 Calderon-Gonzalez R, Calderon-Sepulveda R, Rincon-Reyes M, et al. Botulinum toxin A in management of cerebral palsy. Pediatr Neurol. 1994;10:284 –288. 28 Cosgrove AP, Graham HK. Botulinum toxin A prevents the development of contractures in the hereditary spastic mouse. Dev Med Child Neurol. 1994;36:379 –385. 29 Thompson NS, Baker RJ, Cosgrove AP, et al. Musculoskeletal modeling in determining the effect of botulinum toxin on the hamstrings of patients with crouch gait. Dev Med Child Neurol. 1998;40:622– 625. 30 Eames NW, Baker RJ, Hill N, et al. The effect of botulinum toxin A on gastrocnemuis length: magnitude and duration of response. Dev Med Child Neurol. 1999;41:226 –232. 31 Zelnik N, Giladi N, Goikhman I, et al. The role of botulinum toxin in the treatment of lower limb spasticity in children with cerebral palsy-a pilot study. Isr J Med Sci. 1997;33:129 –133. 32 Denislic M, Meh D. Botulinum toxin in the treatment of cerebral palsy. Neuropediatrics. 1995;26:249 –252. 33 Fehlings D, Rang M, Glazier J, Steele C. An evaluation of botulinum-A toxin injections to improve upper extremity function in hemiplegic cerebral palsy. J Pediatr. 2000;137:331–337. 34 Palisano R, Rosenbaum P, Walter S, et al. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol. 1997;39:214 –223. 35 Sutherland DH, Kaufman KR, Wyatt MP, et al. Double-blind study of botulinum A toxin injections into the gastrocnemius muscle in patients with cerebral palsy. Gait Posture. 1999;10:1–9.

37 Wallen MA, O’Flaherty SJ, Waugh MCA. Functional outcomes of intramuscular botulinum toxin type A in the upper limbs of children with cerebral palsy: a phase II trial. Arch Phys Med Rehabil. 2004;85: 192–200. 38 Wong AM, Chen CL, Chen CP, et al. Clinical effects of botulinum toxin A and phenol block on gait in children with cerebral palsy. Am J Phys Med Rehabil. 2004;83:284 –291. 39 Bohannon RW, Smith MB. Interrater reliability of a modified Ashworth scale of muscle spasticity. Phys Ther. 1987;67:206 –207. 40 Fosang AL, Galea MP, McCoy AT, et al. Measures of muscle and joint performance in the lower limb of children with cerebral palsy. Dev Med Child Neurol. 2003;45:664 – 670. 41 Heinen F, Linder M, Mall V, et al. Adductor spasticity in children with cerebral palsy and treatment with botulinum toxin type A: the parents view of functional outcome. Eur J Neurol. 1999;6(suppl 4):S47–S50. 42 Russell DJ, Rosenbaum PL, Avery LM, Lane M. Gross Motor Function Measure (GMFM-66 and GMFM-88) User’s Manual. London, United Kingdom: Mac Keith Press; 2002. 43 Leach J. Children undergoing treatment with botulinum toxin: the role of the physical therapist. Muscle Nerve Suppl. 1997;6:S194 –S207. 44 Tilton AH. Management of spasticity in children with cerebral palsy. Semin Pediatr Neurol. March 2004:58 – 65. 45 Damiano DL, Kelly LE, Vaughan C. Effects of quadriceps femoris muscle strengthening on crouch gait in children with spastic diplegia. Phys Ther. 1995;75:658 – 671. 46 Damiano DL, Dodd K, Taylor NF. Should we be testing and training muscle strength in cerebral palsy? Dev Med Child Neurol. 2002;44:68 –72. 47 Ketelaar M, Vermeer A, Hart H, et al. Effects of a functional therapy program on motor abilities of children with cerebral palsy. Phys Ther. 2001;81:1534 –1545.

36 Boyd RN, Pliatsios V, Starr R, et al. Biomechanical transformation of the gastroc-soleus muscle with botulinum toxin A in children with cerebral palsy. Dev Med Child Neurol. 2000;42:32– 41.

Appendix. Modified Ashworth Scale Criteria Grade

Description

0 1

No increase in muscle tone Slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the range of motion (ROM) when the affected part(s) is moved in flexion or extension Slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the ROM More marked increase in muscle tone throughout most of the ROM, but affected part(s) easily moved Considerable increase in muscle tone, passive movement difficult Affected part(s) rigid in flexion or extension

1⫹ 2 3 4

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