Children with musculoskeletal conditions experience muscle weakness, difficulty walking and limitations in physical activities. Standard treatment includes physiotherapy, casting, and surgery. The use of botulinum toxins appears as a promising treatment on its own, but usually as an adjunct to other treatment modalities and as an alternative to surgery. The objectives were to establish the evidence on the effectiveness, safety and functional outcome of BTX-A in children with musculoskeletal conditions. A literature search using five electronic databases identified 24 studies that met our inclusion criteria. Two randomized clinical trials were included; most studies were case studies with small sample sizes and no control group. Improvements in gait pattern, function, range of motion, reduction of co-contractions, and avoidance of surgical procedures were found following BTX-A injections. Adverse events were not reported in 10 studies, minor adverse events were reported in 13 children and there were no severe adverse events. Additional doses appear safe. BTX-A is a promising treatment adjunct in improving functional outcomes in children with musculoskeletal conditions. Future studies including larger samples, longer follow-up periods and a comparison group are required to provide evidence on the effectiveness and safety of this drug in children with musculoskeletal conditions.
Thousands of children and adolescents across the United States suffer from musculoskeletal conditions each year [
Proper and timely treatment including standard approaches such as physiotherapy, casting, bracing, and surgery is essential to ensure the child optimal growth and development. Besides these traditional modalities, the use of botulinum toxins appears as a promising treatment on its own, as an adjunct to other treatment modalities and as an alternative to surgery. Several authors have suggested the use of BTX-A in children with musculoskeletal conditions, yet the evidence supporting its safety and effectiveness is not well established. The use of BTX-A in children with CP has been widely documented [
Botulinum toxin is an extremely potent, naturally occurring poison resulting from the fermentation of the anaerobic spore-forming bacterium
Clinical observations suggest that these neurotoxins have three mechanisms of action: paralytic, antisecretory, and analgesic (antinociceptive). A number of studies suggest that several pathways play a role in the analgesic effects of botulinum toxins, such as in conditions of pathologic muscle overactivity (dystonia and spasticity) [
There are seven different serotypes of the neurotoxin, named botulinum toxin (BTX) types A to G. Although they all inhibit acetylcholine release from nerve terminals, they differ according to their intracellular protein targets, potency, dosing, and duration of effect. BTX-A is the serotype that has been most studied in terms of therapeutic application. BTX-B and BTX-F have also been used in clinical practice, but are less potent than BTX-A, and have a shorter duration of action [
There are currently three types A and one type B brand of botulinum toxins available in the US market. In 2010, the US Food and Drug Administration (FDA) announced generic names for all of the versions of injectable botulinum toxins. This change in terminology is expected to differentiate between these different brands and provide each brand with its own identity thereby improving its clinical use and reducing errors and misinterpretation. Hence, OnabotulinumtoxinA (Botox by Allergan INC in the United States), AbobotulinumtoxinA (Dysport by Ipsen in France), IncobotulinumtoxinA (Xeomin by Merz Pharmaceuticals GmbH in Germany), and RimabotulinumtoxinB (Myobloc/Neurobloc by Solstice Neurosciences in the United States) are the new four generic names used in the USA. These new generic names have not yet been adopted by other regulatory agencies [
BTX-A was first approved by the FDA in 1989 for the treatment of strabismus and blepharospasm (two eye muscle disorders), making it the first botulinum toxin type A product approved in the world. In the USA, BTX-A is also approved to treat cervical dystonia and severe primary axillary hyperhidrosis in adults [
Although the use of BTX-A has not yet been approved for use in children, it has been used in a variety of clinical conditions both for its neuromuscular and analgesic effects due to its safe, predictable, and reversible effects on motor weakness. These off-label indications include CMT, CP, idiopathic clubfoot, ITW, LCPD, lower limb lengthening and NBPP [
Adverse events following botulinum toxin injection have been found to be mild, temporary, as well as dose and site related [
CMT is common and refers to unilateral contracture of the sternocleidomastoid muscle that restricts the infant’s range of motion at the neck. Infants with CMT display head tilt toward the shortened side, which is often combined with rotation of the head to the opposite side [
It is a progressive X-linked recessive disorder and is caused by a defective gene for dystrophin affecting approximately 1 out of every 3,600 male infants. Muscle tissue is replaced by adipose and connective tissue [
In this congenital deformity, the hindfoot is in equinovarus and the midfoot and forefoot are adducted and supinated. Approximately 50% of cases of clubfoot are bilateral. The exact etiology remains unknown, although numerous factors have been implicated. Clubfoot is one of the most common birth defects, occurring in 1–3 per 1000 live births. A child with an untreated clubfoot will walk on the outer edge of the foot instead of the sole, develop painful callosities, be unable to wear shoes, and have painful feet that often limit activity. Nonsurgical modalities include serial manipulation and casting, such as Ponseti’s technique [
This condition is present in children older than 3 years of age still walking on their toes without any neurological, orthopaedic, or psychiatric diseases. ITW has been estimated to occur in 7 to 24% of the childhood population [
LCPD is a degenerative disease of the hip joint affecting about 10.8 children of 100,000 children and is more common in boys [
Children undergoing lower limb lengthening using an external fixator exhibit excellent results in most cases, yet the postoperative pain can be significant and often requires prolonged use of analgesics and even narcotics [
NBPP is defined as a flaccid paresis of the upper extremity secondary to unwanted muscular cocontraction or inappropriate activation of antagonist muscles due to increased forces of distraction to the neck during delivery. Associated injuries may include fractures to the clavicle and humerus, facial nerve palsy, and torticollis. Incidence varies between 0.38 and 3 per 1000 live births in industrialized countries and occurs more frequently in infants born over 4 kg, breech deliveries, maternal diabetes, and vacuum/forceps extraction [
A literature search using the electronic databases MEDLINE, PubMed, Cochrane, Trip, and Web of Science for published articles in English from 1980 to September 2011 was conducted using botulinum toxin, congenital muscular torticollis, Duchenne muscular dystrophy, idiopathic clubfoot, idiopathic toe walking, Legg-Calvé-Perthes disease, lower limb lengthening, neonatal brachial plexus palsy, and relevant search terms. To be included, a study had to be written in English and to include children between 0 to 21 years of age with one of the above-mentioned musculoskeletal conditions. Review articles, editorials, commentaries, and conference proceedings were excluded. Research studies that were included in this review were classified as levels I to IV, based on the American Academy of Neurology (AAN) levels of evidence. Data was independently extracted by two reviewers (N. Dahan-Oliel and B. Kasaai).
The literature search yielded 791 hits, which were then reviewed for eligibility. Twenty-four studies met our inclusion criteria and were included in this review. A flow chart illustrates the search results in Figure
Findings of included studies.
Author, year | Study design | Population | Intervention and administration | Outcomes | Results | Adverse events | AAN level of evidence |
---|---|---|---|---|---|---|---|
Congenital Muscular Torticollis | |||||||
Bouchard et al., 2010 [ | Case report | Intervention: BTX-A (Allergan). Administration: initially, 100 U in right splenius capitis + 75 U in right trapezius (for pain), then 150 U in right splenius capitis, 50 U in right trapezius, 25 U in right SCM | Muscle tightness, pain, cervical ROM Evaluated for sustained relief and sustained treatment | (i) Total resolution of abnormal head posture and pain. (ii) Regular injections during 8 years were required for sustained response and dose had to be increased. | Not reported | IV | |
Collins and Jankovic, 2006 [ | Chart review | Intervention: BTX-A (Allergan) Administration: injected into affected neck muscle (SCM, trapezius, scalenius, and splenius). Range 25–150 U administered | Pain and ROM | (i) 1 child had a moderate increase in ROM. (ii) 1 child had poor response in pain/ROM. (iii) 1 child was lost to followup. | Not reported | IV | |
Joyce and de Chalain, 2005 [ | Retrospective study | Intervention: BTX-A (Allergan). Administration: injection into sternocleidomastoid and physiotherapy.Dosage: between 25 and 50 U, mean dose: 33.3 U | Subjective treatment satisfaction, ROM results | 14/15 patients improved neck ROM and head position and no longer needed surgery | (i) 1 child had neck bruising. (ii) 1 child had a sore neck. (iii) 1 child had a brief fever following injection. | IV | |
Oleszek et al., 2005 [ | Retrospective case series | Intervention: BTX-A (Allergan) + physical therapy for 23/25 patients Administration: injections by the same physician into sternocleidomastoid or upper trapezius muscle, or both 3 children received repeat injections. Dosage: based on age and muscle size Range 20–50 U/muscle | Qualitative comments by physician’s observation Quantitative measurement by goniometer to measure changes in cervical rotation and head tilt | 20/27 patients improved cervical rotation or head tilt | Two children had mild dysphagia and neck weakness | IV | |
Duchenne muscular dystrophy | |||||||
Von Wendt and Autti-Rämö, 1999 [ | Case study | 11 y.o. male with tightness in left knee flexors causing difficulties in standing exercises | Intervention: BTX-A (Allergan) + physical therapy twice/week + stretching of the hamstrings twice/day Administration: injection into the semitendinous muscle, semimembranous muscle, and in the biceps femoris muscle under electromyogram guidance Total dose 3 U/kg | Popliteal angle (range of motion), ability to do the standing exercises | Range of motion increased by 20 degrees after injection, but after 5 months an increase of 5 degrees compared to the initial finding was left | None | IV |
Idiopathic clubfoot | |||||||
Alvarez et al., 2009 [ | Long-term-5 year follow-up of Alvarez et al., 2005 [ | Intervention: manipulation, casting, and BTX-A,injection (Allergan) Administration: (i) 24 patients required no additional injections from previous treatment. (ii) 29 patients required ≥2 injections. | Passive ankle ROM Dorsiflexion with 90-degree flexion (DFF), with knee in full extension (DFE), plantar flexion, and heel bisector | Over the follow-up: (i) Treated clubfeet maintained a DFF ≥ 15 degrees (ii) 48% of clubfeet were successfully corrected after single dose of BTX-A | Not reported | IV | |
Cummings, 2009 [ | RCT | Intervention: the Ponseti method treatment + BTX-A (Allergan) or placebo Administration: Single injection of 7.5U BTX-A in gastrocsoleus muscle + 7.5 U in tibialis posterior muscle | Primary outcomes recorded: time required for casting and the need for Achilles tenotomy | No statistical effect found with BTX-A, as administered in this study, BTX-A did not reduce the time in cast by more than 16 days and did not reduce the need for tenotomy | Not reported | I | |
Alvarez et al., 2005 [ | Prospective clinical study | Intervention: Ponseti-type manipulations and castings, followed by BTX-A (Allergan) Administration: BTX-A (10 U/kg) injected into affected muscle Dose: total dose was divided between 2 legs for bilateral clubfeet | Pirani score and mean foot dorsiflexion scores Patients evaluated at regular intervals: ankle ROM, recurrences, and interventions for recurrences | (i) 50/51 patients had successful attenuation of triceps surae complex with major improvement in mean foot dorsiflexion score after BTX-A. (ii) Pirani scores also reduced after BTX-A by 4.45 and 3, in group 1, and 2, respectively. (iii) Mean follow-up: 12 months | None | III | |
Mitchell et al., 2004 [ | Preliminary report | Intervention: BTX-A (Allergan) + molded plaster casts. Administration: injection into muscle groups thought to be responsible for recurrence (e.g., gastrocnemius, soleus, and tibialis) | Foot assessment via the Harrold classification | All 3 patients had marked correction in deformity following injection and casts | None | IV | |
Delgado et al., 2000 [ | Case study | Intervention: BTX-A (Allergan). Administration: injection into the gastrocnemius and/or posterior tibial muscles (i) Dose: range 1.2 U–6.2 U/kg body weight, depending on severity and muscle type. (ii) Muscle was identified via electrical stimulation (tibia) or direct examination (gastrocnemius). | Quantitative measurements before and after treatment: Ankle ROM: degree of dorsiflexion and foot eversion | For 2/4 patients, BTX-A with physical therapy had a long-term positive effect 2/4 patients required surgical release after BTX-A and physical therapy | None | IV | |
Idiopathic toe walking | |||||||
Engström et al., 2010 [ | Follow-up study | Intervention: BTX-A (Allergan) After injection, children/parents were instructed to stretch the calf 5x/week and walk on heels at least 50 steps/day Administration: bilateral injection into 4 sites in each calf under electromyogram amplifier guidance Dose: 6 U/kg, maximum of 400 U | (i) 3D gait analysis (pre, 3 weeks, 3, 6, and 12 months post). (ii) Classification of toe walking severity (pre, 12 months post). (iii) Parents rated the perceived amount of toe walking (pre, 6 and 12 month post). | (i) Significant improvement on gait analysis in 11/11 children at 12 months. (ii) 9/14 children displayed improvement on severity classification. (iii) Parents reported that 3/11 children completely ceased toe walking at 12 months. | Parents of 3 children reported moderate pain in calf muscle for 2-3 weeks after injection | III | |
Brunt et al., 2004 [ | Follow-up study | Intervention: bilateral BTX-A (Allergan) injection, physical therapy 2x/week, and home program. Administration: gastrocnemius and soleus muscles under EMG guidance. Dose: 12 U/kg, maximum 400 U | Gait analysis (pre, mean 20 days post, and 12 months post) | Ankle EMG pattern during gait is normalized and a more normal foot-strike pattern is obtained Post injection improvement was maintained at 12 months | Not reported | III | |
Jacks et al., 2004 [ | Follow-up study | Intervention: bilateral BTX-A (Allergan) injection, short leg walking casts after injection for 7 days, AFO and home stretching program, and electrical stimulation Administration: gastrocnemius and soleus muscles Dose: 10 U/kg | Pre and 1-, 3-, 6- and 12 months post: (i) Observed gait. (ii) ROM at ankle, knee, and hip. (iii) Parent report of Lower Extremity Function Assessment Test. | All 10 children had resolution of toe walking at 3 months after the initial injection One child required repeat injection with physical therapy after which toe waking resolved Improvements in overall function | None | III | |
Lower limb lengthening | |||||||
Hamdy et al., 2009 [ | Multicenter RCT | Intervention: BTX-A (Allergan) or placebo. Administration: single injection into affected muscle group, during surgical procedure. Dose: 10 U/kg body weight, up to a maximum of 400 U of BTX-A, as recommended by FDA | Pain, medication use, quality of life, and functional mobility | Compared to placebo, BTX-A group had (i) lower Pain at middistraction. (ii) less parenteral pain medication aftersurgery. (iii) higher quality of life at 3 of the 5 time points. (iv) higher functional mobility scores. (v) These results were not statistically significant. | None related to BTX-A | I | |
Neonatal brachial plexus palsy | |||||||
Ezaki et al., 2010 [ | Follow-up study | 35 patients with posterior shoulder subluxation or dislocation (17 boys, 18 girls); mean age at treatment 5.7 m (3–16 m) | Intervention: BTX-A (Allergan) into the internal rotator muscles, closed reduction, and cast immobilization Administration: injections into subscapularis, teres major, and pectoralis major muscles Dose: 10 U/kg injected equally into the muscles (2-3 U/kg per muscle) | Passive external rotation of the shoulder, assessment with the Active Movement Scale or a modified Mallet scale in older children Imaging using radiography and/or ultrasonography | (i) 26/35 patients did not require early open surgical procedures to reduce the shoulders. (ii) The 11 children who experienced a redislocation even after a 2nd injection included the 3 oldest patients and the 2 infants whose parents refused further treatment. | None | III |
Price et al., 2007 [ | Retrospective review | 26 patients with reconstruction for a medial rotation deformity of the shoulder 13 had BTX-A injection (mean age: 5.8 y) 13 did not have BTX-A (mean age: 4.0 y) | Intervention: BTX-A (Allergan) in the pectoralis major muscle at the end of the operation. Administration: 100 U of BTX-A in the pectoralis major muscle at the end of the operation | Modified Gilbert scale | (i) No significant difference between both groups preoperatively. (ii) Postop, those who had the BTX-A injection had significantly better Gilbert scores ( | Not reported | IV |
Basciani and Intiso, 2006 [ | Case series | 22 patients with mild brachial plexus palsy who previously underwent serial cast treatment unsuccessfully (10 males, 12 females mean age: 5.6 y) | Intervention: BTX-A (Dysport), then treated arm was fixed with plaster cast and progressively lengthened over 14 days cast was maintained for 30 days Administration: BTX-A injected into biceps brachii, brachialis, pronator teres, and pectoralis major with 22 U/kg | Muscle strength assessed using the Medical Research Council scale (grades 0–5), Mallet scales, Nine Hole Peg Test (NHPT), goniometry, at baseline, 3, 6, and 12 months | (i) Scores on NHPT significantly decreased (denoting better outcome) at 3, 6, and 12 months after injection. (ii) Mallet scores did not change, elbow extension significantly improved in all but 4 patients. (iii) These 4 children were older, and repeat injections were unsuccessful. | 2 patients reported articular pain lasting 5 days after removal of the plaster cast (unrelated to the BTX-A injections) | IV |
DeMatteo et al., 2006 [ | Case series | 8 patients (5 females, 3 males, mean age: 12.5 m range, 5–22 m) | Intervention: BTX-A (Allergan) in conjunction with intensive OT and a home program Administration: BTX-A injected in target muscles at total dose of 4 U/Kg/muscle into multiple sites along triceps or latissimus dorsi and pectoralis major | Active Movement Scale (AMS) and parent report of change before and after BTX-A | (i) After a single injection, all parents reported improved function. (ii) AMS scores improved significantly from pre BTX-A to 1 month ( | Not reported | IV |
Heise et al., 2005 [ | Follow-up study | 8 patients with clinical or electromyographic evidence of biceps-triceps cocontraction and poor elbow function (4 triceps, 4 biceps; 1 male, 7 females, age: 16 m–5 y) | Intervention: BTX-A (Allergan) + home-based physiotherapy, some did physio outside the hospital Administration: 1 injection of 2-3 U/kg of BTX-A divided in 2 or 3 sites | Muscle strength assessed using the Medical Research Council scale (grades 0–5), ability to perform hand-mouth contact in the sitting position | (i) 3/4 patients with injection to the triceps were able to perform hand-mouth contact in sitting (10 d to 6 m after injection), lasting up to 18 m. (ii) For biceps, 3/4 had improvement of elbow extension lasting 3–6 months. (iii) One child had no improvement after biceps injection and parents refused additional injection. | Not reported | III |
Grossman et al., 2004 [ | Case study | 2 patients (10 m male, and 11 m female) with late nerve reconstruction for persistent shoulder paralysis following an upper brachial plexus birth injury | Intervention: BTX-A (Allergan) Administration: 10 U/kg into pectoralis major and latissimus dorsi | Modified Gilbert scale | Both scores advanced (from 1 to 4 and from 1 to 5) | Not reported | IV |
Grossman et al., 2003 [ | Follow-up study | 19 patients with a combined reconstruction of the upper brachial plexus and shoulder for sequelae of birth injury, (mean age: 16 m, range: 11–29 m) | Intervention: BTX-A (Allergan) into pectoralis major (70 U) and latissimus dorsi (30 U) Administration: not specified | Modified Gilbert scale | (i) At follow-up (mean 42.7 months), all advanced by a mean of 2 grades (range: 2 to 5). (ii) Three children required reoperation, and 4 had persistent mild medial rotation contracture at follow-up. | Not reported | III |
Hierner et al., 2001 [ | Follow-up of Rollnik and colleagues’ study (2000) at 18 m | 6 females (range: 2–4 y) | Intervention: BTX-A (Dysport) injected into the triceps muscle at 2 sites under EMG guidance. Dose: average of 40 MU at a concentration of 25 MU/mL | Muscle force (MRC classification) and ROM, recurrence of cocontraction using EMG | At 18 m follow-up (i) mean elbow flexion was about 100° (range: 80–120°). (ii) reduction of triceps contraction during biceps activity was observed using EMG. (iii) average treatment time was 8–12 months (iv) no recurrence of cocontraction at 18 months. | Mild to moderate discomfort at the injection site for several days after injection in 2 children. No severe adverse events | III |
Desiato and Risina, 2001 [ | Prospective clinical study | 50 patients with limited muscle compliance, impaired skilled movements, and dynamic deformities of the shoulder and elbow joints (26 males, 24 females, mean age: 4.8 y, range: 0.3–13.5 y) | Intervention: BTX-A (Dysport) and neurorehabilitation program using Reflex Locomotion Administration: BTX-A, 200 MU/mL injected in single site into selected muscles | ROM using goniometry, video recordings of spontaneous movements, Global Clinical Rating Scale (GCRS) These measurements were done before the first BTX-A injection, every 2 weeks for 3–9 months following injection, just before the next injection | (i) Additional injections in 30 children (ii) Active movements increased at a mean of 1.8 weeks after injection compared to baseline values ( | 6.8 y.o. a female experienced transient weakness of the adductor/internal rotator muscles after the 2nd injection, which lasted 10 days | III |
Rollnik et al., 2000 [ | Case study | 6 females with severe biceps-triceps cocontractions after nerve regeneration following birth-related brachial plexus lesions (age range: 2–4 y) | BTX-A (Dysport) injected into the triceps muscle at 2 sites under EMG guidance Dose: Average of 40 MU at a concentration of 25 MU/mL | Muscle force (MRC classification) and ROM | (i) Onset of response at a mean of 8.5 days after injection (range: 4−14 days). (ii) Elbow ROM and muscle force of elbow flexion increased ( | No severe adverse events | IV |
Four studies were included. Two of these studies [
One study met the inclusion criteria [
Five articles were included. The first study by Delgado and colleagues [
Three studies [
No studies were found.
One study [
Ten studies [
The objectives of this systematic review were to establish the evidence on the effectiveness of BTX-A in several musculoskeletal conditions in children and to show whether these studies reported improved functional outcome. Out of the 24 studies reviewed, only two randomized clinical trials were conducted, one in children with clubfeet [
A recent systematic review on the indications for the use of BTX-A treatment for children with NBPP was conducted by Gobets and colleagues [
Several factors specific to BTX-A injections may produce inter- and intrastudy variations. These factors include the different dosages and commercial sources of BTX-A used across the different studies. Two brands of BTX-A were used across the 24 studies (Allergan and Dysport). BTX-A brand was not always specified in the reviewed studies and this information was made available in several cases by contacting the authors. These two preparations should not be used interchangeably, either in terms of predicting outcome or in determining doses to be used. Though the units are not interchangeable, various published reports support a conversion ratio from 1 : 5 to 1 : 3. The technique used to identify which muscle groups will be injected also varied (palpation technique, electrical stimulation, etc.). Indeed, different studies have used different techniques and thus may lead to varying outcomes following BTX-A injection. There is no consensus as to the exact age at which a child with a musculoskeletal condition should be first administered BTX-A. Age of injection varied across the different studies reviewed. However, several authors [
Serious adverse events related to BTX-A injection were not reported in the studies included in this review. Minor adverse events such as transient muscular weakness and local discomfort at the injection site were reported in few studies. While this may be suggestive of the clinical safety of BTX-A, it is important to note that several studies did not actually report on the presence or absence of adverse events. Therefore, more rigor is required in reporting these events to establish the safety of BTX-A in children with musculoskeletal conditions.
BTX-A is a promising treatment adjunct in improving functional outcomes in children with musculoskeletal conditions by causing a flaccid paralysis of the affected muscles. Further studies should include a prospective methodology, longer follow-up periods, and comparison group and evaluate whether repeated injections are required to improve the outcome of children, thus providing evidence on the effectiveness and safety of this drug in children with musculoskeletal conditions.
R. Hamdy and N. Dahan-Oliel designed the review. N. Dahan-Oliel and B. Kasaai carried out the systematic review and data extraction. K. Montpetit participated in the methodology and clinical relevance and helped draft the manuscript. All authors read and approved the final paper.
The authors declare that they have no competing interests.
Thanks are extended to Guylaine Bédard from the medical illustrations department for her assistance.