PHYS THER
Vol. 86, No. 4, April 2006, pp. 573-584
Use of Botulinum Toxin Type A in Children With Cerebral Palsy
Karen W Nolan,
Lynn L Cole and
Gregory S Liptak
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)
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)
(knolan{at}ithaca.edu). Address all correspondence to Ms Nolan
Submitted March 3, 2005;
Accepted October 5, 2005
Key Words: Cerebral palsy • Drugs • Spasticity
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Introduction
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Cerebral 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.
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Pharmacology/Mechanism of Action
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The botulinum toxins are protein products of the gram-negative 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 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 then-superfluous 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.
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Procedure/Protocol
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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
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Patient Selection
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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.
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Effects/Outcomes
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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.
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Table. Overview of Selected Studies Evaluating Clinical, Motor, and Functional Outcomes in Children With Cerebral Palsy Following Botulinum Toxin A Injectionsa
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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 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 upper-extremity 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).
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 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.
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Physical Therapists’ Role in Botulinum Toxin A Therapy
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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 appropriate 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.
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Conclusions
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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.
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Appendix
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Footnotes
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* 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.
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Copyright © 2006 by the American Physical Therapy Association.
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