SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Method
  5. Results
  6. Discussion
  7. Conclusion
  8. References
  9. Supporting Information

Aim  Previous studies have shown the efficacy of botulinum toxin type A (BoNT-A) in the management of ambulant individuals with cerebral palsy (CP). There is little evidence on its use in non-ambulant children with CP. This review aimed to investigate indications and efficacy for BoNT-A use in managing pain, care, and comfort, and improving function in children with CP in Gross Motor Function Classification System (GMFCS) levels IV and V.

Method  Electronic databases were searched from the earliest available date to June 2012 using a combination of subject headings and free text. Inclusion criteria consisted of studies with (1) participants aged 18 or under, (2) participants with CP in GMFCS levels IV and V, (3) participants receiving BoNT-A treatment, and (4) studies published in English-language peer-reviewed journals.

Results  The search resulted in a total of 814 studies, of which 19 met the inclusion criteria. Eighteen studies provided level IV or V evidence and one level I evidence according to the American Academy for Cerebral Palsy and Developmental Medicine guidelines for the development of systematic reviews. Most of the studies were of weak to moderate methodological quality.

Interpretation  The evidence that BoNT-A is effective in reducing postoperative pain in children with CP in GMCFS levels IV and V is limited, with only one level I study identified. Remaining indications were general pain reduction, maintaining hip integrity, achieving functional changes, and goal attainment. A high percentage of participants in the studies showed positive changes in these areas. With the poor level of evidence of the included studies, no definite conclusion could be drawn on the indications for BoNT-A use in children with CP in GMCFS levels IV and V. Further investigation by rigorous studies is required.


What this paper adds

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Method
  5. Results
  6. Discussion
  7. Conclusion
  8. References
  9. Supporting Information
  •  The majority of studies on the use BoNT-A for children with severe CP in GMFCS levels IV and V were of poor methodological quality.
  •  Moderate evidence was shown to support the use of BoNT-A in reducing pain after hip adductor release surgery with one level I RCT.
  •  Clinical application of the evidence of benefits of BoNT-A is limited by the low quality of the studies.

Cerebral palsy (CP) refers to a group of non-progressive movement and posture disorders resulting from injuries to the developing fetal or infant brain.1 Owing to a diverse and multifactorial aetiology, CP is often accompanied by epilepsy, secondary musculoskeletal abnormalities, and deficits in sensation, cognition, behaviour, and communication.1 The worldwide incidence of CP is 2 to 3 per 1000 live births, making it the most common cause of physical disability in childhood.2,3 Classifications of CP are usually based on topographical distribution, functional motor abilities, and types of muscle tone.4

Topographical classification describes the distribution of affected body parts. These include hemiplegia (unilateral distribution), diplegia (bilateral involvement, usually the lower limbs more affected than the upper limbs), and quadriplegia (involvement of all four limbs, the head and trunk).5 This classification is commonly employed despite being of questionable reliability and validity.1,6

The Gross Motor Function Classification System (GMFCS) has been shown to be a reliable method of classifying children with CP according to age-specific gross motor function.7,8 It is an ordinal grading system of five levels (I–V), in which self-initiated movements, such as sitting, standing, or walking, are described in relation to different age groups. Distinctions between levels I to V are based on assessment of functional abilities or limitations and reliance on assistive technology (walking aids or wheeled mobility). Children of levels I and II can generally walk without aids while children of level III can walk with aids for short distances but usually choose wheeled mobility in community settings. Children at level IV have limited motor ability in assisted standing, stepping, and transfers. Children classified as level V are completely dependent on others for transportation in a wheelchair and lack antigravity postural control.7,8

Types of muscle tone are generally classified as spastic, dystonic/dyskinetic, ataxic, or mixed.2 Spasticity is a velocity-dependent increase in resistance of a muscle when the muscle is moved passively or stretched.9 It is the most common motor type, accounting for 70% to 80% of individuals with CP.10 Individuals with spastic CP experience stiffness in affected limbs due to focal muscular hyperactivity, resulting in limited or awkward movements. Dystonia/dyskinesia, affecting 10% to 20% of individuals with CP,10 is characterized by fluctuating muscle tone, causing slow writhing and twisting movements, repetitive movement, and/or abnormal postures.9 Ataxic CP is the least common form of CP, in which individuals have poor coordination and balance due to low muscle tone.2

Management of spasticity in CP involves multidisciplinary intervention intended to increase functionality, sustain health, and improve quality of life for individuals and their carers.11 This may include physiotherapy, occupational therapy, orthoses, surgical interventions, and pharmacological agents such as botulinum toxins.12 Botulinum toxin type A (BoNT-A) is a serotype of botulinum toxin, produced by the Gram-positive bacterium Clostridium botulinum.13 This potent neurotoxin selectively inhibits the release of acetylcholine from peripheral nerve terminals by binding to synaptic vesicles.12 Interruption of neuromuscular conduction by BoNT-A induces a temporary weakness, which reduces focal spasticity. The effects of BoNT-A last for approximately 3 months as the muscle will recover via proximal axonal sprouting, the formation of new neuromuscular junctions, and the regeneration of the original neuromuscular junctions.14,15

The efficacy of BoNT-A in the management of individuals with CP has been widely reported in the literature. Several studies have proven its effectiveness in the treatment of spastic equinus in ambulant children with CP (i.e. GMFCS levels I–III) with the aim of improving gait pattern.16,17 Use of BoNT-A to improve hand function has also been shown in children with less impairment.18,19 On the other hand, BoNT-A has been used in children with severe functional limitations (i.e. GMFCS levels IV and V), aimed at reducing pain and improving ease in care and positioning.20,21 In our clinical experience, these are the main goals for the use of BoNT-A in these more involved children. Nevertheless, the effectiveness of BoNT-A intervention in this group of children has not been thoroughly examined. The aim of this review was to investigate whether BoNT-A has been used to treat children with CP in GMCFS levels IV and V for pain, care and comfort, and motor function, and, if so, to report its efficacy.

Method

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Method
  5. Results
  6. Discussion
  7. Conclusion
  8. References
  9. Supporting Information

Inclusion and exclusion criteria

Studies were included in this review if they met the following criteria: (1) participants were aged 18 years of age or less, (2) participants were diagnosed with CP equivalent to GMFCS levels of IV or V, (3) participants were receiving BoNT-A treatment, (4) the research design was anything other than a review or expert opinion that did not provide data for analysis, and (5) studies were published in English-language peer-reviewed journals. Studies were excluded if participants were not classified according to their GMFCS level and if it was not possible to classify the participants accurately by the authors of this review with information provided in the studies. Relevant data from studies with participants of mixed GMFCS levels would be included in this review if the results for participants in GMCFS levels IV and V could be separated. The same principle was applied to studies containing a mixed group of participants with a diagnosis of CP and other neurological disorders. All studies involving the use of BoNT-A to treat drooling were excluded, as the main focus of this review was on the impact of BoNT-A on reducing pain, improving ease of care and positioning, and improving the motor function of the individuals.

Search strategy

The literature search was begun from the earliest date available in each database to June 2012 across the following databases: MEDLINE, EMBASE, CINAHL, and PsycINFO. The terms ‘cerebral palsy’, ‘spasticity’, ‘dystonia’, ‘Botulinum toxin A’, ‘Botox’, ‘BTX’, ‘BTA’, ‘BoNT’, ‘Dysport’, and ‘Myobloc’ were searched as subject headings and free text if supported by the databases. Results were limited to studies involving humans aged 18 years or less and published in the English language. The reference lists of relevant studies and reviews were also searched for citation tracking and by hand. The titles and abstracts of articles identified in the initial search were screened against inclusion and exclusion criteria separately by the first two authors (TP and JE). When in doubt, the full text of an article was read to determine its suitability. Any disagreement between the two authors was resolved by consensus. No authors of excluded studies were approached to investigate if relevant data could be extracted.

Levels of evidence and quality assessment

The level of evidence of each included study was graded according to the American Academy for Cerebral Palsy and Developmental Medicine Treatment Outcome Committee (AACPDM TOC) guidelines for the development of systematic reviews.22 In general, the higher the level of the study, the more likely the intervention of interest was responsible for the outcomes.

Studies were also given a quality assessment score based on the scoring system of the AACPDM TOC guidelines.22 These scores were used to grade each study as ‘strong’, ‘moderate’, or ‘weak’ according to the methodological rigour of the study. The AACPDM TOC does not recommend the use of this quality assessment system for levels IV and V studies.22 However, preliminary screening of this review showed that the majority of studies conducted under the topic of interest had less rigorous research designs and hence, it was decided that included studies were critically reviewed and scored as a means of informing future studies.

Results

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Method
  5. Results
  6. Discussion
  7. Conclusion
  8. References
  9. Supporting Information

Of the 814 studies identified in our electronic database search, 68 met the inclusion criteria (Fig. 1). Full-text analysis of these 68 articles led to the exclusion of a further 49 articles for the following reasons: (1) study population was non-CP or mixed (CP and non-CP) and data for participants with CP could not be separated; (2) results for participants in GMCFS levels IV and V could not be isolated from a group analysis; or (3) participants were not classified according to GMFCS but according to topographical classification and there was inadequate information for the authors to reclassify the participants (Table SI, online supporting information). Hence, 19 studies investigating the use of BoNT-A in children with CP in GMCFS levels IV and V were included in this review.20,21,23–39

image

Figure 1.  Inclusion and exclusion of studies found in literature searches. GMFCS, Gross Motor Function Classification System.

Download figure to PowerPoint

Of the 19 studies, 18 were classified as providing level IV or V evidence: 15 non-controlled cohort studies,20,21,23,25,26,29–32,34–39 two case studies,28,33 and one single-subject design study.27 Only one study, a double-blinded randomized controlled trial (RCT), provided level I evidence.24 Quality assessment of the level IV and V studies of showed weak to moderate methodological rigour, whereas the level I RCT was a rigorous study (see Tables SII–SIV, online supporting information).

Table I summarizes the purpose, study design, and demographics of the 19 included studies. Study purposes were varied, and included investigating the effects of BoNT-A on pain reduction, maintaining hip integrity, functional changes to attainment of preset goals. Two32,34 of the 19 studies recruited participants over 18 years and their data were excluded in the statistical analysis carried out for this review. Only two studies24,31 investigated the use of BoNT-A solely in children classified as GMFCS levels IV and V. Nine studies25,27,29,30,32,35–38 consisted of participants with mixed GMFCS levels and the data for participants in levels IV and V were separated for analysis in this review. In the remaining eight studies,20,21,23,26,28,33,34,39 the study participants were classified according to the GMFCS using the information provided in the papers.

Table I. Purpose, design, and demographics of 19 included studies
StudyAimLevel of evidence/research designaPopulationCP typeTotal n/drop-outsAge range Mean (SD)/sex
  1. aGrading of evidence according to levels of evidence proposed by the American Academy for Cerebral Palsy and Developmental Medicine methodology for developing systematic reviews of treatment interventions (Revision 1.2), 2008.22bEight participants in each intervention and control group. cGross Motor Function Classification System (GMFCS) level classified by the authors according to the information provided in the paper. dInadequate information provided in the paper to allow classification according to GMFCS. eParticipants over 18 years of age were excluded from analysis in this review. CP, cerebral palsy; BoNT, botulinum toxin; RCT, randomized controlled trial; M, male; F, female; y, years; mo, months.

Arens et al.23Effect of BoNT-A on dynamic spasticity and dystonic posturingIV/non-controlled cohort study, before and after designGroup 1, spastic (n=5); group 2, dystonic (n=5), group 3, mixed spastic and dystonic (n=5)Hemiplegia (n=5), diplegia (n=5), quadriplegia (n=5)15/0Range 5–17y; mean 10y 10mo
Barwood et al.24Effect of BoNT-A on postoperative painI/double-blinded RCTSevere spastic CP with ‘hips at risk’; GMFCS IV (n=4) or V (n=12)Diplegia (n=3), quadriplegia (n=13)17/1bRange 2–10y; mean 4y 3mo (1y 3mo)/6M, 10F
Cosgrove et al.20Indications, safety procedures, and effects of BoNT-AIV/non-controlled cohort study, before and after designCommunity ambulators (n=7), i.e. GMFCS I/II;c functional ambulators (n=8), i.e. GMFCS II/III;c non-functional ambulators (n=8), i.e. GMFCS III or IV;c non-ambulators (n=3), i.e. GMFCS IV or VcHemiplegia (n=8), diplegia (n=7), quadriplegia (n=11)26/0Range 2–17y; mean 6y/19M, 7F
Coutinho dos Santos et al.25Effect of BoNT-A on quality of lifeIV/cross-sectional study, before and after designGMFCS I (n=7), II (n=18), III (n=6), IV (n=13), V (n=13)Spastic hemiplegia (n=21), spastic diplegia (n=14), spastic quadriplegia (n=10), others (n=12)57/0Mean 6y (2y 4mo)/34M, 23F
Fattal-Valeviski et al.26Markers for a favourable outcome with BoNT-AIV/non-controlled cohort study, before and after designIndependent walkers (n=12), i.e. GMFCS I or II;c walkers with aids (n= 9), i.e. GMFCS III;c non-walkers (n=5), i.e. GMFCS IV or VcHemiplegia (n=7), spastic diplegia (n=19)26/0Range 2–5y; mean 3y 7mo (1y 2mo)/16M, 10F
Fragala et al.27Effect of BoNT-A on impairment, disability, and parent satisfactionV/multiple single-participant AB designCP with lower extremity spasticity, GMFCS I (n=3), II (n=2), III (n=1), IV (n=1)Hemiplegia (n=3), diplegia (n=4)7/0Range 3–11y/6M, 1F
Gooch and Sandell28Effect of BoNT-A on spasticity and athetosisV/case study, before and after designSevere athetoid, dependent in all cares (n=1), i.e. GMFCS IV or V;c spastic quadriplegia in wheelchair (n=1), i.e. GMFCS IV or V;c spastic hemiplegia ambulant (n=1), i.e. GMFCS I–IIIcQuadriplegia (n=1), hemiplegia (n=1), athetosis (n=1)3/0Ages 17y, 11y, 3y/2M, 1F
Jung et al.29Effect of BoNT-A on hip lateralizationIV/non-controlled cohort study, before and after designBilateral spastic CP with bilateral adductor spasticity, GMFCS I (n=1), II (n=3), III (n=3), IV (n=12), V (n=8)Bilateral spastic (n=26), dyskinetic (n=1)27/0Range 2–10y; mean 5y 2mo (1y 11mo)/18M, 9F
Koman et al.21Efficacy of BoNT-A on the management of muscle imbalance in paediatric CPIV/non-controlled cohort study, before and after designGroup 1, non-ambulatory severe spastic and mixed quadriparesis (n=3), i.e. GMFCS IV or V;c group 2, severe spasticity in lower limbs affecting positioning and hygiene (n=8), i.e. GMFCS IV or V;c group 3, ambulatory (n=16), i.e. GMFCS I–IIIcHemiplegia (n=8), diplegia (n=9), quadriplegia (n=8), quadriplegia with athetosis (n=2)27/0Range 3–16y; mean 7y/14M, 13F
Linder et al.30Medium-term (1y) efficacy of BoNT-A on gross motor functionIV/non-controlled cohort study, before and after designSpastic CP, GMFCS I (n=5), II (n=5), III (n=4), IV (n=7), V (n=4)Hemiplegia (n=4), diplegia (n=12), quadriplegia (n=9)25/0Range 1y 6m–15y 6m; mean 6y 2mo; 15M, 10F
Lundy et al.31Effect of BoNT-A on pain due to hip spasmsIV/non-controlled cohort study, before and after designCP with spasticity and pain at hip level; GMFCS V (n=26)Quadriplegia (n=26)26/0Range 2–19y; mean 11y 6mo (4y 9mo); 12M, 14F
Mall et al.33Effect of BoNT-A on disability and QOLV/case study, before and after designParticipant 1 – severe spastic tetraparesis i.e. GMFCS IV or V;c participant 2 – spastic tetraparesis with hand contracture, unknown GMFCS;d participant 3 – ambulant spastic diplegia i.e. GMFCS II–IIIcDiplegia (n=1), tetraparesis (n=2)3/0Participant 1 M, 13y; participant 2 F, 16y; participant 3 M, 15y
Mall et al.32Effect of BoNT-A on gross motor functionIV/non-controlled cohort study, before and after designCP with adductor spasm, GMFCS II (n=2), III (n=5), IV (n=7), V (n=4)Diplegia (n=4), quadriplegia (n=14)18/0Range 5y 6m–21y 1mo;e mean 10y 7mo (4y 1mo)/2M, 16F
Manzano et al.34Safety and effect of BoNT-A on spastic masticatory musculatureIV/non-controlled cohort study, before and after designCP with spasticity of masticatory musculature, GMFCS IV/V (n=6)cQuadriplegia (n=6)6/0Range 5–20ye; mean 9y 9mo/1M, 5F
Meholjic and Madjar35Effect of BoNT-A on spasticity and functional progressIV/non-controlled cohort study, before and after designCP with spasticity in lower limbs, GMFCS II (n=4), III (n=3), IV (n=10), V (n=3)Diplegia (n=7), hemiplegia (n=2), quadriplegia (n=10), triplegia (n=1)20/0Range 2–15y; mean 5y 9mo (3y 7mo)/11M, 9F
Papavasiliou et al.36Effect of BoNT-A on multimodal spasticity managementIV/non-controlled cohort study, before and after designPreterm born children with spastic CP, GMFCS I (n=13), II (n=9), III (n=16), IV (n=15), V (n=4)Hemiplegia (n=4), diplegia (n=26), quadriplegia (n=27)57/0Range 2y 6m–13y 6mo; mean 4y 4mo/31M, 26F
Vles et al.37Effect of BoNT-A on visual analogue scale scoreIV/non-controlled cohort study, before and after designGMFCS I (n=16), II (n=9), III (n=15), IV (n=7), V (n=8)Unilateral (n=13), bilateral (n=42)55/0Range 3–18y; mean 8y 3mo (3y 3mo)/25M, 30F
Weigl et al.38Effect of BoNT-A on attainment of treatment goalsIV/non-controlled cohort study, before and after designSpastic CP, GMFCS I (n=13), II (n=11), III (n=3), IV (n=6), V (n=7)Diplegia (n=16), hemiplegia (n=15), quadriplegia (n=9)40/0Range 1y 6mo–16y; mean 5y/21M, 19F
Wong39Effect of BoNT-A on daily care and/or functional mobilityIV/non-controlled cohort study, before and after designSpastic CP; community ambulators (n=1), i.e. GMFCS I/II;c functional ambulators (n=4), i.e. GMFCS II/III;c non-functional ambulators (n=6), i.e. GMFCS III or IV;c non-ambulators (n=6), i.e. GMFCS IV or VcDiplegia (n=8), triplegia (n=1), quadriplegia (n=8)17/0Range 2–15y; mean 5y; 9M, 8F

Table SII shows the outcome measures and results of the included studies. In five studies with participants of mixed GMFCS levels,29,30,32,34,37 separate statistical analyses were performed in this review for participants with levels IV and V only, using a paired t-test for continuous data and Wilcoxon signed-rank test for nominal data (on those outcome measures used before and after the BoNT-A intervention). In eight studies, descriptive outcome measures were used and no statistical analysis was applied (Table SII). The main outcomes of interest in these 19 studies could be grouped under pain reduction, hip integrity, functional changes, and goal attainment. Table II regroups, under these four main outcomes of interest, participants in the included studies who were GMFCS levels IV and V and who showed a positive effect from the intervention. Reduction in muscle tone and improvements in ranges of motion were also shown in several studies (Table SII).20,25–28,30,32–34,36,39

Table II. Summary of 19 included studies showing positive results under the four main outcomes of interest for participants with GMFCS levels IV and V only
Pain reductionHip integrityFunctional changesGoal attainment
Ease of positioningImproved GMFM or GMFCS levelsEase of careImproved motor function
  1. aIn this study, improvement in Visual Analogue Scale standing score for nine participants and in Visual Analogue Scale walking score for five participants. GMFM, Gross Motor Function Measure; GMFCS, Gross Motor Function Classification System; I-S, level I evidence with strong research rigor; n, the number of participants with a positive result. In case of a fraction, n, number of participants who had a positive result as the nominator and total number of participants in that study as the denominator; SS, statistically significant difference; IV-M, level IV evidence with moderate research rigor; NS, no statistically significant difference; V-M, level V evidence with moderate research rigor; NA, not statistically analysed; IV-W, level IV evidence with weak research rigor; V-W, level V evidence with weak research rigor.

Barwood et al.24 (I-S) (n=8): SSJung et al.29 (IV-M) (n=27): NSFragala et al.27 (V-M) (n=1): NACoutinho dos Santos et al.25 (IV-W) (n=13/26): NA but SS as a groupFragala et al.27 (V-M) (n=1): NAArens et al.23 (IV-W) (n=1): NAFattal-Valevski et al.26 (IV-M) (n=5): NA
Gooch and Sandell28 (V-W) (n=1): NA Gooch and Sandell28 (V-W) (n=1): NALinder et al.30 (IV-W) (n=11): SSGooch and Sandell28 (V-W) (n=2): NACosgrove et al.20 (IV-M) (n=3): NAFragala et al.27 (V-M) (n=1): NA
Koman et al.21 (IV-M) (n=3): NA Koman et al.21 (IV-M) (n=8): NAMall et al.32 (IV-M) (n=11): SSMall et al.33 (V-W) (n=1): NAFragala et al.27 (IV-M) (n=1): NALundy et al.31 (IV-M) (n=26): NA
Lundy et al.31 (IV-M) (n=26): SS  Meholjic and Madjar35 (IV-W) (n=12/13): NAManzano et al.34 (IV-W) (n=5): SSMall et al.33 (V-W) (n=1): NAWeigl et al.38 (IV-M) (n=13): NS
Mall et al.33 (V-W) (n=1):NA  Papavasiliou et al.36 (IV-M) (n=5/15): NAVles et al.37 (IV-W) (n=13):SSVles et al.37 (IV-W) (n=14):a SS 
Vles et al.37 (IV-W) (n=2):NS    Wong39 (IV-M) (n=3/6): NA 

Pain reduction

Of the six studies21,28,33,37 investigating the effects of BoNT-A on pain reduction (Tables II and SII), two24,31 found a statistically significant improvement in the study participants (n=34 in total). Three studies21,28,33 reported positive changes in the absence of statistical analysis (n=5 in total), and one study37 found a non-significant difference (n=2).

Maintaining hip integrity

Only one study29 investigated the effect of BoNT-A on hip integrity (Tables II and SII). The results showed a non-significant difference in hip migration percentage over a 2-year period (n=27).

Functional changes

Ease of positioning and care, improvements in the GMFCS level or Gross Motor Function Measure (GMFM) scores, and various motor functions were arbitrarily grouped under functional changes (Table II). Three studies21,27,28 reported positive results of BoNT-A treatment in increasing ease of positioning but with no statistical analysis of the results (n=10 in total; Tables II and SII). BoNT-A was shown to result in a statistically significant increase in ease of care in two studies34,37 (n=18 in total) and also in another three studies27,28,33 without any statistical analysis (n=4 in total; Tables II and SII). In three studies,25,35,36 participants in GMCFS levels IV and V showed an improvement in the GMFCS level (n=30/54 in total) although statistical analysis was either not performed or performed on a mixed population in these studies (Table SII). For the GMFM score, statistically significant improvement was noted in two studies30,32 (n=22 in total) (Tables II and SII). Participants of six studies20,23,27,33,37,39 showed improvement in various motor functions. The study by Vles et al.37 demonstrated statistically significant improvement in standing and walking (n=14) and the other five studies showed positive improvements, including transfers and ambulation, without conducting statistical analyses on the data20,23,27,33,39 (n=9 in total; Tables II and SII).

Goal attainment

Four studies26,27,31,38 investigated the efficacy of BoNT-A on the attainment of preset goals by the participants and/or their carers (Tables II and SII). Three studies26,27,31 noted positive results using descriptive measures (n=32 in total) and one study38 showed non-statistically significant changes using a modified goal attainment scale (n=13).

Discussion

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Method
  5. Results
  6. Discussion
  7. Conclusion
  8. References
  9. Supporting Information

BoNT-A has been closely scrutinized for its effectiveness in treating ambulant children with CP (i.e. GMFCS levels I–III) with the aim of improving their gait pattern.16,17 Clinically, this intervention has also been used for pain reduction and improvement in positioning or ease of hygiene40 in non-ambulant children with CP (i.e. GMFCS levels IV and V); however, its effectiveness has not been thoroughly reviewed. This review was carried out attempting to fill in the gap in existing knowledge. We found 19 studies that examined the use of BoNT-A in children with CP in GMFCS levels IV and V for pain reduction, better positioning, ease of hygiene, and better motor function. As almost all of these studies had low levels of evidence and low to moderate methodological quality, except the RCT by Barwood et al.,24 caution is advised when interpreting the results of this review. Over two-thirds of the included studies demonstrated that the use of BoNT-A reduced spasticity and increased range of movements in the related joints at the impairment level with or without statistical analyses (Table SII). These are believed to be known outcomes based on the mechanism of BoNT-A at neuromuscular junctions.12,14,15 Pain reduction and maintaining hip integrity are less frequently reported outcomes at this level. At the level of function and activity, it appears that after the BoNT-A injections positive results were demonstrated in terms of achieving functional changes and attaining goals. These outcomes (i.e. pain reduction, maintaining hip integrity, achieving functional changes, and attaining preset goals) are the main focus of this review.

Several studies were found to investigate if BoNT-A was effective in reducing general pain as well as specific post-orthopaedic surgery pain in children classified as GMFCS levels IV and V. Outcome measures used to assess pain varied among the studies. Descriptive measures were used in three studies,21,28,33 while Lundy et al.31 used both objective questionnaires and subjective parent description to assess the pain reduction post intervention. In these studies, the majority of participants demonstrated positive changes (Tables II and SII). In their RCT, Barwood et al.24 used three outcome measures – amount of analgesia required, pain score, and hospital admission time – and found a statistically significant reduction in all these outcome measures in the treatment group (Table SII). With its strong methodological quality, this study provided good evidence to show that BoNT-A is effective in reducing post-operative pain in children in GMCFS levels IV and V, but the clinical application of this evidence may be limited by the lack of further high-quality RCTs to support this outcome. In the study by Vles et al.,37 pain, as assessed by Visual Analogue Scale scores, was reduced non-significantly after the BoNT-A injections (Tables II and SII). This result may have been insignificant because of the very small number of participants who were assessed (2/55 participants in the study). This review has found moderate evidence to support the use of BoNT-A for pain reduction in children undergoing hip adductor release surgery and weak to moderate evidence for its use in the reduction of spasticity-related pain.

Among children with severe CP, spastic hip disease is a common problem, putting their hips at ‘high risk’ of dislocation.41,42 It has also been shown that hip lateralization occurs in as many as 90% of children in GMFCS level V.43 Only one study29 we found investigated the effects of BoNT-A on maintenance of hip integrity, using the migration percentage as an outcome measure (Tables II and SII). The authors of this study found that the mean changes in the migration percentage were of no clinical significance (<10%) over a 2-y period, indicating that the BoNT-A assisted in maintaining hip stability. Owing to the low level of evidence, moderate methodological rigour, and lack of a control group in this study (Table SII), it is not possible to conclude that BoNT-A had real impact on hip integrity for these participants. Indeed, another RCT with a high level of evidence has shown that children with hip adductor spasticity would require surgery for hip integrity in the long term.44 While it appears that hip integrity may be a possible indication for the use of BoNT-A in children in GMCFS levels IV and V, existing evidence in this area is weak. Studies with rigorous study designs are needed to verify this possible indication for the use of BoNT-A in maintaining hip status for children in GMCFS levels IV and V.

Fourteen studies found positive results of BoNT-A treatment on ease of positioning and care, improvements in GMFM scores or GMFCS levels, and motor function, such as transfer and assisted ambulation (Tables II and SII). In all studies in which statistical analyses were performed, statistical significance was achieved,25,30,32,34,37 whereas those studies using descriptive measures reported marked improvement in gross motor function, standing, walking, ambulatory status, transfer, positioning, and ease of care20,21,23,27,28,33,35,36,39 (Table SII). Three studies25,35,36 used the GMFCS level to document changes in the gross motor function of the participants. Over half of the participants in these studies showed improvement in the GMFCS level post BoNT-A injections (Tables II and SII). GMFCS levels have been shown to be stable with time in older children and adolescents with CP, but not in children under 6 years of age.45,46 The study participants in these three studies25,35,36 were relatively young (mean age 6, 5.7, and 4.4y, respectively) (Table I), which might explain the large improvement in their gross motor function after BoNT-A intervention. In fact, the GMFCS is a classification of motor abilities of individuals with CP, not a functional assessment, and hence more robust outcome measures, such as the GMFM or the Pediatric Evaluative of Disability Inventory,47 should be used to document changes in motor function after the use of BoNT-A. Despite positive results in this domain after the BoNT-A intervention, all studies investigating functional mobility provided low levels of evidence and were of weak to moderate methodological vigour. It remains unclear whether targeting functional changes is an appropriate indication for the use of BoNT-A in children in GMCFS levels IV and V who have severe functional limitations.

Three of the four studies26,27,31 examining the use of BoNT-A to attain present goals showed positive results in all study participants using subjective assessments by the parent/carer (Tables II and SII). The study by Weigl et al.38 found the changes in attaining present goals were not statistically significant (Tables II and SII). A possible explanation for this negative outcome may be that a modified goal attainment scale was used to measure how the goals were achieved post BoNT-A injections, in which the grades of the modified scale were not individualized to the study participants (Table SII). This modification may have reduced the sensitivity of this outcome measure. Positive results to achieve preset goals were demonstrated by various studies of low levels of evidence and moderate methodological quality. This highlights the need for more rigorous studies to establish the efficacy of the use of BoNT-A in achieving goals set by the individuals and their carers.

Although the main goals of using BoNT-A in this population group were to reduce pain and improve care and comfort, only one study25 formally assessed the health-related quality of life of the children and/or their carers, and another study31 reported positive comments from the parents’ questionnaires when assessing functional gains of the children post intervention (Table SII). Pain reduction and improvement in positioning and ease in caring activities do not necessarily lead to improvement in the health-related quality of life of children and/or their carers. This highlights another area of the use of the BoNT-A in children in GMCFS levels IV and V requiring further research.

The efficacy of the BoNT-A in children with CP is dose dependent and varies with time intervals between injections.48 All except two included studies35,36 explicitly stated the injection dose and total dose used in the participants (Table SII). Two studies did not state which preparation of BoNT-A was used.21,27 The injection dose varied from 2 to 15U/kg using Botox (Allergan, Irvine, CA, USA) or from 5 to 150U/kg using Dysport (Ipsen, Basking Ridge, NJ, USA); the total dose varied from 100 to 500U of Botox or 100 to 1500U of Dysport (Table SII). The dose of BoNT-A used in all except two studies32,37 was within the recommended limits suggested in the recent international consensus statement.19 The two studies that used a high dose of BoNT-A were those by Mall et al.32 and Vles et al.;37 interestingly, both studies yielded statistically significant results in participants post intervention (Table SII). The follow-up periods varied from a few days to 12 months (Table SII). Moreover, the age of the study participants ranged from 2 to 17 years at the time of injections (Table I). All these variations may have important implications when assessing the effectiveness of BoNT-A. Readers are urged to take these variations into consideration when interpreting the results in this review. Future research on the standards of administration of BoNT-A, such as optimal dosage and optimal injection intervals, and identification of which subgroup of children in GMCFS levels IV and V would be likely to benefit the most from BoNT-A, and in what way and at what age, is needed.40

One may argue that studies on children in GMFCS level III should be included in this review as these children are more vulnerable to secondary musculoskeletal abnormalities and pain because of their relatively more limited motor abilities compared with children in GMCFS levels I and II. However, the goal of the use of BoNT-A in children in GMFCS level III is predominantly to improve ambulation,48 which is very different from the goals of this intervention in non-ambulant children in GMCFS levels IV and V. Hence, this review focused on studies of children in the latter group.

It appears that, other than to reduce post-operative pain due to hip adductor release surgery, the benefits of the use of BoNT-A for this group of children remain uncertain. In our recent retrospective file audit (unpublished material), about 25% of the total number of clients who received BoNT-A in our clinic in 2010 were diagnosed with CP in GMCFS levels IV and V. Over 80% of the parents or carers reported that this intervention greatly reduced their burden of care in terms of improving ease of personal hygiene, dressing, and positioning. While rigorous research studies, as well as sensitive outcome measures, are urged to investigate the indications for the use of BoNT-A in this group of children, we believe that there is a strong clinical role for this intervention in the management of children in GMCFS levels IV and V.

Limitations of this review and future research

A large number of studies have investigated the effect of BoNT-A on a population of children with CP of mixed levels of severity. In the majority of these studies, we were unable to separate data on children in GMCFS levels IV and V, or to classify the study participants according to GMFCS level (Fig. 1 and Table SI). Since relevant information about study participants in GMCFS levels IV and V in these studies was not included, this review may not show a complete picture of clinical indications for the use of BoNT-A in this population group, which may have imposed a selection bias in this review. However, we are confident with what we believe to be a thorough literature search and careful classification of study participants according to the GMFCS levels with the information provided in the papers, and that we have included the majority of, if not all, relevant studies that examined the effect of BoNT-A in this population group. Another limitation of this review is that screening of studies in the initial literature search and quality grading of studies were not performed independently. We were unable to access one article49 found in the initial literature search owing to the rarity of the publication. However, from the information provided in the abstract of that paper, it is believed that inclusion of this study would not significantly modify the conclusions of this review.

There are several challenges in conducting high level of evidence research studies on the use of BoNT-A in children in GMCFS levels IV and V. Maintaining blinding in the intervention group is not possible as changes in spasticity are often conspicuous. Nowadays, use of BoNT-A is almost part of standardized intervention regime for children with CP.8,19,50 It appears to be unethical to have a control group without intervention because of the known benefits of BoNT-A in treating muscle spasticity. It is also difficult to justify having to subject children in the control group to an injection procedure for a sham placebo. Moreover, finding a suitable control group that is comparable in terms of co-interventions and comorbidities is a challenge in a disorder as varied as CP, especially in a population of children in GMCFS levels IV and V who usually have complex medical needs. Hence, large and expensive RCTs may not be appropriate when investigating the indications for the use of BoNT-A in this population group. Alternative research designs such as high-quality longitudinal population-based studies or multiple single-participant study designs with sensitive outcome measures may be more viable options for future research studies in this area.

Conclusion

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Method
  5. Results
  6. Discussion
  7. Conclusion
  8. References
  9. Supporting Information

Nineteen studies were included in this review examining the efficacy of BoNT-A in terms of ease of pain, care and comfort, and improvement in motor abilities in children with CP in GMFCS levels IV and V. Almost all of the included studies provided level IV or V evidence and were of poor to moderate methodological rigour. Caution is required when drawing causal inferences from the study results. Positive changes following BoNT-A intervention were demonstrated in the majority of participants in terms of pain reduction, maintaining hip integrity, achieving functional changes, and attaining preset goals. Only one level I RCT showed statistically significant reduction in the postoperative pain for children who had received BoNT-A injections, which provided moderate evidence for this intervention in reducing pain after orthopaedic surgery. For the remaining outcomes of interest, the efficacy of BoNT-A was inconclusive. Future studies of rigorous methodological quality are required to investigate the indications for the use of BoNT-A in children in GMFCS levels IV and V.

References

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Method
  5. Results
  6. Discussion
  7. Conclusion
  8. References
  9. Supporting Information
  • 1
    Rosenbaum P, Paneth N, Leviton A, Goldstein M, Bax M. A report: the definition and classification of cerebral palsy. Dev Med Child Neurol2007; 49(Suppl. 109): 814.
  • 2
    Cans C. Surveillance of cerebral palsy in Europe: a collaboration of cerebral palsy surveys and registers. Dev Med Child Neurol2000; 42: 81624.
  • 3
    Odding E, Roebroeck ME, Stam HJ. The epidemiology of cerebral palsy: incidence, impairments and risk factors. Disabil Rehabil2006; 28: 18391.
  • 4
    Mutch L. Cerebral palsy epidemiology: where are we now and where are we going?Dev Med Child Neurol1992; 34: 547.
  • 5
    Sankar C, Mundkur N. Cerebral palsy – definition, classification, etiology and early diagnosis. Indian J Pediatr2005; 72: 8658.
  • 6
    Howard J, Soo B, Graham HK, et al.Cerebral palsy in Victoria: motor types, topography and gross motor function. J Paediatr Child Health2005; 41: 47983.
  • 7
    Palisano R, Rosenbaum P, Walter S, Russell D, Wood E, Galuppi B. Development and reliability of a system to classify gross motor function in children with cerebral palsy. Dev Med Child Neurol1997; 39: 21423.
  • 8
    Wood E, Rosenbaum P. The Gross Motor Function Classification System for cerebral palsy: a study of reliability and stability over time. Dev Med Child Neurol2000; 42: 2926.
  • 9
    Sanger TD, Delgado MR, Gaebler-Spira D, Hallett M, Mink JW, Task Force on Childhood Motor Disorders. Classification and definition of disorders causing hypertonia in childhood. Pediatrics2003; 111: e8997.
  • 10
    Watson L, Blair E, Stanley FJ. Report of the Western Australian Cerebral Palsy Register to Birth Year 1999. Perth: Telethon Institute for Child Health Research, 2006.
  • 11
    Goldstein EM. Spasticity management: an overview. J Child Neurol2001; 16: 1623.
  • 12
    Ann HT. Management of spasticity in children with cerebral palsy. Semin Pediatr Neurol2004; 11: 5865.
  • 13
    Lamanna C, Carr CJ. The botulinal, tetanal, and enterostaphylococcal toxins: a review. Clin Pharmacol Ther1967; 8: 286332.
  • 14
    de Paiva A, Meunier FA, Molgó J, Aoki KR, Dolly JO. 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 USA1999; 96: 32005.
  • 15
    Duchen LW, Strich SJ. The effects of botulinum toxin on the patterns of innervation of skeletal muscle in the mouse. Exp Physiol1968; 53: 849.
  • 16
    Koog YH, Min B-I. Effects of botulinum toxin A on calf muscles in children with cerebral palsy: a systematic review. Clin Rehabil2010; 24: 685700.
  • 17
    Ryll U, Bastiaenen C, De Bie R, Staal B. Effects of leg muscle botulinum toxin A injections on walking in children with spasticity-related cerebral palsy: a systematic review. Dev Med Child Neurol2011; 53: 2106.
  • 18
    Fehlings D, Novak I, Berweck S, Hoare B, Stott NS, Russo RN. Botulinum toxin assessment, intervention and follow-up for paediatric upper limb hypertonicity: international consensus statement. Eur J Neurol2010; 17(Suppl. 2):3856.
  • 19
    Love SC, Novak I, Kentish M, et al.Botulinum toxin assessment, intervention and after-care for lower limb spasticity in children with cerebral palsy: international consensus statement. Eur J Neurol2010; 17(Suppl. 2): 937.
  • 20
    Cosgrove AP, Corry IS, Graham HK. Botulinum toxin in the management of the lower limb in cerebral palsy. Dev Med Child Neurol1994; 36: 38696.
  • 21
    Koman LA, Mooney JF 3rd, Smith B, Goodman A, Mulvaney T. Management of cerebral palsy with botulinum-A toxin: preliminary investigation. J Pediatr Orthop1993; 13: 48995.
  • 22
    Darrah J, Hickman R, O’Donnell M, Vogtle L, Wiart L. AACPDM methodology to develop systematic reviews of treatment interventions (Revision 1.2). 2008. http://www.aacpdm.org (accessed 30 June 2012).
  • 23
    Arens LJ, Leary PM, Goldschmidt RB. Experience with botulinum toxin in the treatment of cerebral palsy. S Afr Med J1997; 87: 10013.
  • 24
    Barwood S, Baillieu C, Boyd R, et al.Analgesic effects of botulinum toxin A: a randomized, placebo-controlled clinical trial. Dev Med Child Neurol2000; 42: 11621.
  • 25
    Coutinho dos Santos LH, Bufara Rodrigues DC, Simoes de Assis TR, Bruck I. Effective results with botulinum toxin in cerebral palsy. Pediatr Neurol2011; 44: 35763.
  • 26
    Fattal-Valevski A, Giladi N, Domanievitz D, et al.Parameters for predicting favorable responses to botulinum toxin in children with cerebral palsy. J Child Neurol2002; 17: 2727.
  • 27
    Fragala MA, O’Neil ME, Russo KJ, Dumas HM. Impairment, disability, and satisfaction outcomes after lower-extremity botulinum toxin A injections for children with cerebral palsy. Pediatrics2002; 14: 13244.
  • 28
    Gooch JL, Sandell TV. Botulinum toxin for spasticity and athetosis in children with cerebral palsy. Arch Phys Med Rehabil1996; 77: 50811.
  • 29
    Jung NH, Heinen F, Westhoff B, et al.Hip lateralisation in children with bilateral spastic cerebral palsy treated with botulinum toxin type A: a 2-year follow-up. Neuropediatrics2011; 42: 1823.
  • 30
    Linder M, Schindler G, Michaelis U, et al.Medium-term functional benefits in children with cerebral palsy treated with botulinum toxin type A: 1-year follow-up using gross motor function measure. Eur J Neurol2001; 8(Suppl. 5): 1206.
  • 31
    Lundy CT, Doherty GM, Fairhurst CB. Botulinum toxin type A injections can be an effective treatment for pain in children with hip spasms and cerebral palsy. Dev Med Child Neurol2009; 51: 70510.
  • 32
    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 Pediatr Neurol2000; 15: 21417.
  • 33
    Mall V, Heinen F, Linder M, Philipsen A, Korinthenberg R. Treatment of cerebral palsy with botulinum toxin A: functional benefit and reduction of disability. Three case reports. Pediatr Rehabil1997; 1: 2357.
  • 34
    Manzano FS, Granero LM, Masiero D, dos Maria TBR. Treatment of muscle spasticity in patients with cerebral palsy using BTX-A: a pilot study. Spec Care Dentist2004; 24: 2359.
  • 35
    Meholjic A, Madjar D. Application of botulinum toxin in treatment of spasticity and functional improvements for children suffering from cerebral palsy. Med Arch2010; 64: 35961.
  • 36
    Papavasiliou AS, Rapidi C-A, Filiopoulos C, Rizou C, Skouteli HN. Evaluation of a multimodal management of prematurity-related spasticity. Pediatr Neurol2006; 35: 4007.
  • 37
    Vles GF, de Louw AJA, Speth LA, et al.Visual analogue scale to score the effects of botulinum toxin A treatment in children with cerebral palsy in daily clinical practice. Eur J Paediatr Neurol2008; 12: 2318.
  • 38
    Weigl DM, Arbel N, Katz K, Becker T, Bar-On E. Botulinum toxin for the treatment of spasticity in children: attainment of treatment goals. J Pediatr Orthop B2007; 16: 2936.
  • 39
    Wong V. Use of botulinum toxin injection in 17 children with spastic cerebral palsy. Pediatr Neurol1998; 18: 12431.
  • 40
    Nolan KW, Cole LL, Liptak GS. Use of botulinum toxin type A in children with cerebral palsy. Phys Ther2006; 86: 57384.
  • 41
    Scrutton D, Baird G. Surveillance measures of the hips of children with bilateral cerebral palsy. Arch Dis Child1997; 76: 3814.
  • 42
    Dobson F, Boyd RN, Parrott J, Nattrass GR, Graham HK. Hip surveillance in children with cerebral palsy: impact on the surgical management of spastic hip disease. J Bone Joint Surg Br2002; 84: 7206.
  • 43
    Soo B, Howard JJ, Boyd RN, et al.Hip displacement in cerebral palsy. J Bone Joint Surg Am2006; 88: 1219.
  • 44
    Graham HK, Boyd R, Carlin JB, et al.Does botulinum toxin A combined with bracing prevent hip displacement in children with cerebral palsy and ‘hips at risk’? A randomized, controlled trial. J Bone Joint Surg Am2008; 90: 2333.
  • 45
    Hanna SE, Rosenbaum PL, Bartlett DJ, et al.Stability and decline in gross motor function among children and youth with cerebral palsy aged 2 to 21 years. Dev Med Child Neurol2009; 51: 295302.
  • 46
    Palisano RJ, Cameron D, Rosenbaum PL, Walter SD, Russell D. Stability of the gross motor function classification system. Dev Med Child Neurol2006; 48: 4248.
  • 47
    Haley SM, Coster WJ, Ludlow LH, Haltiwanger JT, Andrellos PJ. Pediatric Evaluation of Disability Inventory (PEDI). Development, Standardisation and Administration Manual. Boston, MA: Department of Rehabilitation Medicine, New England Medical Center Hospital, 1992.
  • 48
    Molenaers G, Desloovere K. Pharmacologic treatment with botulinum toxin. In: Gage JR, Schwartz MH, Koop SE, Novacheck TF, editors. The Identification and Treatment of Gait Problems in Cerebral Palsy, 2nd edn. London: Mac Keith Press, 2009: 36380.
  • 49
    Runu R, Agrawal V, Swaroop A, Dave D. Botulinum toxin as treatment modality for spastic diplegic cerebral palsy child: our experience in 21 patients. Indian J Physiother Occup Ther2011; 5: 69.
  • 50
    Esquenazi A, Novak I, Sheean G, Singer B, Ward A. International consensus statement for the use of botulinum toxin treatment in adults and children with neurological impairments – introduction. Eur J Neurol2010; 17(Suppl. 2): 18.

Supporting Information

  1. Top of page
  2. Abstract
  3. What this paper adds
  4. Method
  5. Results
  6. Discussion
  7. Conclusion
  8. References
  9. Supporting Information
FilenameFormatSizeDescription
dmcn4438_sm_Appendix-S1.docx17KSupporting info item
dmcn4438_sm_TableS1-S4.docx38KSupporting info item

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.