Table 1.

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 [32]	Case report	N = 3 females (age range: 15–39 y) data presented on 15 y.o. patient only	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 [33]	Chart review	N = 7 children and 3 adults (age range: 6 m–41 y) data presented on 3 children (age range: 12 m–18 y)	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 [34]	Retrospective study	N = 15 patients with idiopathic muscular torticollis unresponsive to traditional regimen (age range: 3–17 m (mean= 7.6 m))	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 [35]	Retrospective case series	N = 27 patients with CMT, (age range: 6–18 m (mean = 10.1 m))	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 [36]	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 [37]	Long-term-5 year follow-up of Alvarez et al., 2005 [38]	N = 44 patients, with 65 idiopathic club feet (from the original 55- patient cohort)	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 [39]	RCT	N = 32 newborns, aged 0–30 d, with 32 congenital clubfeet (Dimeglio grade III)	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 [38]	Prospective clinical study	N = 51 patients with 73 idiopathic clubfeet Group 1: initial visit < 30 days Group 2: initial visit between 30 days and 1 y	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 ±3 months.	None	III
Mitchell et al., 2004 [40]	Preliminary report	N = 3 patients (age range: 12-13 m) who underwent surgery but with recurrent deformity 3–6 months after index procedure	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 [41]	Case study	N = 4 patients with severe clubfoot (Dimeglio grade IV), who no longer responded to physical therapy	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 [42]	Follow-up study	N = 15 patients (age range: 5–13 y) median age (9 y)	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 [43]	Follow-up study	N = 5 patients, age range 3.3–6.3 y (mean = 4.3 y).	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 [44]	Follow-up study	N = 10 patients with previously failed treatment for toe walking, age range 2–17 y	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 [45]	Multicenter RCT	N = 52 patients who underwent distraction osteogenesis and lower limb lengthening (age range: 5–21 y) (mean = 13.7 y)	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 [46]	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 [47]	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 (P = 0.012) at mean follow-up of 3 years.	Not reported	IV
Basciani and Intiso, 2006 [48]	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 [49]	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 (P = 0.014) and from before BTX-A to 4 months (P = 0.022).	Not reported	IV
Heise et al., 2005 [50]	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 [51]	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 [52]	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 [53]	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 [54]	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 (P < 0.05-0.01). (iii) Gain of shoulder abduction was directly related to younger age (r = 0.6). (iv) Videotaped recordings showed improvement in global movements. (v) Step-like increases of function using GCRS in 70% of patients. (vi) Plateau observed in remaining 30%.	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 [55]	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 (P < 0.05). (iii) Hand-to-mouth movement improved in 5 children. (iv) EMG showed reduction of triceps cocontractions during elbow flexion. (v) No clinical recurrence of cocontractions after 1 year.	No severe adverse events	IV