RANDOMIZED TRIAL OF BOTULINUM TOXIN TO PREVENTPES CAVUS PROGRESSION IN PEDIATRICCHARCOT–MARIE–TOOTH DISEASE TYPE 1AJOSHUA BURNS, PhD,1,2 ADAM SCHEINBERG, MMed,3,4 MONIQUE M. RYAN, MMed,5 KRISTY J. ROSE, MHSc,2

and ROBERT A. OUVRIER, MD2

1 Faculty of Health Sciences, University of Sydney, Sydney, New South Wales, Australia2 Institute for Neuroscience and Muscle Research, Children’s Hospital at Westmead, Locked Bag 4001, Sydney,New South Wales 2145, Australia

3Department of Rehabilitation, The Children’s Hospital at Westmead, Sydney, New South Wales, Australia4 Victorian Paediatric Rehabilitation Service, Victoria, Australia5 Children’s Neuroscience Centre, Royal Children’s Hospital/Murdoch Children’s Research Institute/Department of Paediatrics,Faculty of Medicine, University of Melbourne, Victoria, Australia

Accepted 26 January 2010

ABSTRACT: Pes cavus in Charcot–Marie–Tooth disease type1A (CMT1A) is thought to be due to muscle imbalance of thelower leg. Botulinum toxin type A (BoNT-A) can modify foot de-formity in other conditions of muscle imbalance. We tested thesafety and effectiveness of BoNT-A on pes cavus progression inpediatric CMT1A. A 24-month, randomized, single-blind trial ofBoNT-A was undertaken in 10 affected children (20 legs), aged3–14 years. The treated leg received intramuscular BoNT-Ainjections at 6-month intervals in the tibialis posterior and pero-neus longus. The control leg received no injections. Primaryoutcome was radiographic alignment at 24 months. Secondaryoutcomes were foot posture, ankle flexibility, and strength,assessed every 6 months. Radiographically, BoNT-A produceda small non-significant reduction in cavus progression. Therewas no effect of BoNT-A on secondary outcomes. There wereno serious adverse events. At 24 months, the intramuscularBoNT-A injections proved safe and well-tolerated but did notaffect the progression of pes cavus in CMT1A.

Muscle Nerve 42:262–267, 2010

There are presently no effective preventive treat-ments for foot deformities in the progressive inher-ited neuropathies.1 Pes cavus is the cardinal mani-festation of Charcot–Marie–Tooth disease type 1A(CMT1A) and is associated with foot pain, weak-ness, ankle contracture, disability, and diminishedquality of life in affected children.2 CMT1A, themost common inherited neuropathy, causes demy-elination of the peripheral nerves, progressiveweakness of distal limb musculature, impairedmotor function, and sensory loss. CMT1A is mostcommonly caused by a duplication of PMP22, thegene that encodes peripheral myelin protein 22,on chromosome 17p11.2.

The pathogenesis of pes cavus in CMT1A iscontroversial.3 Across the various studies, broadlyat least, there is support for a model in whichsome weakness occurs in all muscle groups, partic-ularly in the intrinsic muscles of the foot and the

anterolateral compartment of the lower leg.3 Sev-eral investigators have hypothesized from studiesof manual muscle testing,4,5 computerized tomo-graphy,6 and magnetic resonance imaging7 thatweakness of the intrinsic foot muscles may contrib-ute to the development of pes cavus in CMT1A.Alternatively, pes cavus in CMT1A has been linkedto an imbalance of the long muscles of the leg andfoot. In this model, the weak peroneus brevis isoverpowered by a relatively strong tibialis posterior,causing adduction of the forefoot and inversion ofthe hindfoot,4,8 with a weak tibialis anterior beingoverpowered by a stronger peroneus longus, caus-ing plantar flexion of the first metatarsal and ante-rior pes cavus.9 Theoretically, addressing thisimbalance may arrest the progression of pes cavusin CMT1A.

Botulinum toxin type A (BoNT-A) is a proteinproduced by the anaerobic bacterium Clostridiumbotulinum and is a widely used treatment for mus-cle hyperactivity and spasticity.10 BoNT-A binds topresynaptic membranes of cholinergic motor neu-rons, cleaving the cell’s exocytotic machinery suchthat the discharge of acetylcholine-containingvesicles, and hence neurotransmission at the neu-romuscular junction, is prevented. IntramuscularBoNT-A injection produces a dose-dependentchemical denervation resulting in reduced muscu-lar strength. Affected muscles recover after sprout-ing of new nerve terminals and reinnervation ofthe original terminal. BoNT-A can selectivelyweaken skeletal muscles and has been shown toimprove foot deformity in conditions such asequinus in children with cerebral palsy,11,12 plan-tarflexor and inverter spasticity in hemipareticpatients,13 disabling up-going toe,14 muscle imbal-ance in hallux valgus (bunion),15 progressive equi-novarus deformity in Friedreich ataxia,16 and varusalignment in hereditary spastic paraparesis.17 Incases of muscle imbalance in CMT1A, it ishypothesized that early intramuscular injections ofBoNT-A might reverse the imbalance of strength

Abbreviations: BoNT-A, botulinum toxin type A; CMT1A, Charcot–Marie–Tooth disease type 1A; EMG, electromyography; FPI, foot posture index;ICC, intraclass correlation coefficient

Correspondence to: J. Burns; e-mail: joshuab2@chw.edu.au

VC 2010 Wiley Periodicals, Inc.Published online 18 May 2010 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mus.21685

Key words: botulinum toxin, Charcot–Marie–Tooth disease, foot and ankledeformity, hereditary motor and sensory neuropathy, muscle imbalance, pescavus

262 Botulinum Toxin for Pes Cavus in CMT MUSCLE & NERVE August 2010

between the anterolateral and posteromedial com-partments of the lower leg and reverse or prevent,at least temporarily, progression of the cavus footdeformity. Therefore, the aim of this experimentaltrial was to measure the safety, tolerability, andeffectiveness of BoNT-A injections to delay andpossibly prevent the progression of pes cavus in pe-diatric CMT1A.

METHODS

Overall Study Design. This 24-month, randomized,single-blind, experimental trial of BoNT-A was con-ducted at The Children’s Hospital at Westmead(Sydney, New South Wales, Australia) between No-vember 2004 and May 2009.

Standard Protocol Approvals, Registrations, and

Patient Consents. The protocol was approved andmonitored by the institutional ethics review board(2003/092) and the Therapeutic Goods Adminis-tration of Australia. One parent or guardian pro-vided written informed consent for each child.The trial was pre-registered with the AustralianNew Zealand Clinical Trials Registry (ANZCTR,No. 12605000115639).

Participants. Boys or girls aged 2–16 years withflexible bilateral pes cavus and proven CMT1A,that is, a 17p11.2 duplication including the PMP22gene, or a confirmed duplication test in a first- orsecond-degree relative with a consistent clinicalphenotype and confirmatory neurophysiologic test-ing in the child (median nerve motor conductionvelocity <35 m/s), were eligible for inclusion.18

Pes cavus was determined using the foot postureindex (FPI), a diagnostic clinical tool that evalu-ates the multidimensional aspects of the foot usingsix criteria that together enable the foot to bescored along a continuum of cavus to planus fea-tures (FPI score for pes cavus is �12 to �1, FPIscore for normal is 0 to þ5, and FPI score for pesplanus is þ6 to þ12).19 Participants were recruitedalong the entire spectrum of cavus severity. TheFPI has demonstrated acceptable intra- and inter-rater reliability in children and adults and hasbeen independently validated against radiographicparameters and three-dimensional gait.19–21 Studyexclusions were: acute foot injuries (e.g., anklesprain) and previous foot surgery.

Intervention. Each child had a randomly allocatedtreated and control leg. The treated leg receivedintramuscular injections at 6-month intervals ofBoNT-A (Dysport; Ipsen Pty, Ltd., Victoria, Aus-tralia) in the tibialis posterior and peroneus longusmuscles. The control leg received no injections.BoNT-A (Clostridium botulinum type A toxin–hemag-

glutinin complex) was injected with a 27-gaugemonopolar Teflon-coated electromyographic(EMG) injection needle. The BoNT-A was dilutedto 250 units/ml with normal saline. We used elec-trical stimulation for accurate localization of thetarget muscles. The tibialis posterior and peroneuslongus muscles were each injected at one or twosites with doses between 6 and 7 units/kg bodyweight. The total dose per injection episode didnot exceed 500 units (i.e., maximum dose permuscle per injection episode was 250 units). Allchildren received topical anesthetic cream (EMLA,eutectic mixture of lidocaine 2.5% and prilocaine2.5%) on the injection site 1 hour prior to injec-tion, and during the injection procedure conscioussedation with inhaled nitrous oxide was adminis-tered by a qualified nurse according to hospitalprotocol.

Outcomes. The primary outcome was change inradiographic foot alignment at 24 months in theinjected leg compared with the non-injected con-trol leg. Standardized standing lateral radiographsof the foot and ankle in the angle and base of gaitwere performed with the appropriate-sized film cas-sette placed parallel to the hindfoot and themachine tube parallel to the horizontal axis at adistance of 90 cm from the foot.22 The most reli-able method of measuring pes cavus severity wasdetermined during a preliminary study of 14 radio-graphs of children with CMT1A. The most widelyreported radiographic measures of pes cavus in theliterature were evaluated by an experienced inde-pendent radiologist and the principal investigator(J.B.) for tibial–calcaneal angle (normal value 69�,SD 8.4�),22 calcaneal–first metatarsal angle (Hibb’sangle, normal value 130�, SD 9.7�),23 and talo–firstmetatarsal angle (normal value 13�, SD 7.5�).22

Interrater reliability was excellent for calcaneal–first metatarsal angle and tibial–calcaneal angle[intraclass correlation coefficients (ICC) ¼ 0.95 to0.97], but only fair for talo–first metatarsal angle(ICC ¼ 0.44). Subsequent intrarater reliability forthe calcaneal–first metatarsal angle and the tibial–calcaneal angle by the principal investigator (J.B.)was excellent (ICC ¼ 0.93–0.94), and these weresubsequently selected to evaluate the effect ofBoNT-A on pes cavus alignment during the trial.

Secondary outcomes were objective clinicalmeasures of foot structure, ankle flexibility, andmuscle strength obtained every 6 months in allchildren by the blinded principal investigator(J.B.) using highly reliable and validated age-appropriate instruments. Foot structure of eachfoot of all children was assessed using the foot pos-ture index (FPI) as described earlier. Flexibility ofankle dorsiflexion was measured weight-bearing

Botulinum Toxin for Pes Cavus in CMT MUSCLE & NERVE August 2010 263

using the reliable and valid lunge test with a digitalinclinometer (Baseline; Fabrication Enterprises,Inc., Irvington, New York) aligned with the midlineof the Achilles tendon.24 Foot and ankle strengthwas quantified in triplicate in all children using ahand-held dynamometer (Citec, Centre for Innova-tive Technics, The Netherlands), which is a porta-ble digital device that incorporates a load cell usedto measure isometric muscle strength. Strength ofinversion, eversion, plantarflexion, and dorsiflex-ion were measured as previously described.2 Reli-ability and validity of hand-held dynamometry hasbeen shown to be excellent in healthy and affectedchildren and adults,25,26 and normative referencevalues for foot and ankle strength measures areavailable in the literature.2

Safety and Tolerance. Adverse events wererecorded and monitored in accordance with theguidelines of the Therapeutic Goods Administra-tion of Australia.

Randomization and Blinding. A simple randomiza-tion sequence was determined by coin-toss. Thephysician injecting the BoNT-A (A.S.) and eachchild/parent were aware of the leg selection fortreatment. The principal investigator (J.B.) con-ducting all outcome measures was blinded to theinjected leg.

Statistical Methods. Descriptive statistics were cal-culated to characterize the study sample by usingSPSS software, version 17.0 (SPSS, Inc., Chicago,Illinois). Normality of data distribution wasassessed, and the appropriate parametric or non-parametric test was subsequently applied. Between-leg treatment effect was determined by meanchange difference at follow-up using a paired-sam-

ples t-test. Precision of the treatment effect wasbased on the 95% confidence interval (CI) with P< 0.05 considered statistically significant.

RESULTS

Baseline Characteristics. Of the 12 childrenscreened, 10 affected individuals (20 legs), aged 3–14 years, with bilateral pes cavus from 8 familiesaffected by CMT1A, were recruited (Fig. 1). Noneof the children were on medication or had anyallergies or prior exposure to BoNT-A. Baselinephysical, demographic, and disease-related charac-teristics of the study participants are shown in Ta-ble 1. All children (100%) completed 24 monthsof BoNT-A injections.

Effectiveness. The leg injected with BoNT-A hada small non-significant reduction in the progres-sion of pes cavus compared with the control legfor calcaneal–first metatarsal angle (mean differ-ence 1.0�, 95% CI �2.0 to 4.1, P ¼ 0.471) and tib-ial–calcaneal angle (mean difference 1.1�, 95% CI�1.4 to 3.5, P ¼ 0.356). There was no measurableeffect of BoNT-A on foot structure (mean FPI dif-ference �1.5, 95% CI �3.5 to 0.5, P ¼ 0.120),ankle flexibility (mean difference �2.3�, 95% CI�5.2 to 0.7, P ¼ 0.113), or muscle strength at 24months (Table 2). Analysis of secondary outcomesat 6-month intervals revealed no significant differ-ences between legs at any time-point (Fig. 2).

Safety and Tolerance. Two children reported morefrequent trips and falls during the 24-month trial,consistent with the natural history of CMT1A.2

There were no serious adverse events.

DISCUSSION

In this study we have examined a potential preven-tive intervention for pes cavus in children withCMT1A. We found no measurable effect of 24months of intramuscular injections of BoNT-A in

FIGURE 1. Study design, enrollment, and follow-up of partici-

pants in the trial.

Table 1. Baseline physical, demographic, and disease-relatedcharacteristics of the study participants.

Characteristic All children (n ¼ 10)

Age (y) 9.8 6 4.1 (range 3�14)Male gender, n (%) 3 (30)Body weight (kg) 38.8 6 14.4 (range 14.6�55.4)Height (m) 1.36 6 0.25 (range 0.96�1.60)Body mass index* 18.3 6 3.4 (range 14.3�22.9)Clinical marker of

disease severity, n (%)Foot/leg pain 4 (40)Regular ankle sprains 3 (30)Regular trips 3 (30)Regular falls 2 (20)Trouble shoe fitting 3 (30)

Data expressed as mean 6 SD, unless otherwise stated.*Body mass index is the weight (in kilograms) divided by the square ofthe height (in meters).

264 Botulinum Toxin for Pes Cavus in CMT MUSCLE & NERVE August 2010

Table 2. Primary and secondary radiographic and clinical outcomes for BoNT-A injected and control legs at baseline and 24-monthfollow-up.

Outcome

Baseline Follow-up (24 months) Change

Difference(95% CI)* P-value*

Botulinum(n ¼ 10)

Control(n ¼ 10)

Botulinum(n ¼ 10)

Control(n ¼ 10)

Botulinum(n ¼ 10)

Control(n ¼ 10)

Primary radiographicCalcaneal–first met (�)

124.4 (8.5) 125.1 (9.0) 122.2 (7.6) 121.8 (8.7) �2.2 (3.3) �3.2 (4.2)1.0 (�2.0 to 4.1)

0.471Tibial–calcaneal (�)

64.8 (4.8) 65.6 (6.4) 63.8 (5.0) 63.5 (5.3) �1.0 (2.9) �2.1 (3.7)1.1 (�1.4 to 3.5)

0.356Secondary clinicalFoot structure (FPI)

�3.7 (2.4) �4.6 (2.5) �3.9 (3.4) �3.3 (4.1) �0.2 (2.4) 1.3 (2.5)�1.5 (�3.5 to 0.5)

0.120Ankle range (�)

18.4 (7.2) 16.8 (7.0) 21.4 (7.7) 22.1 (5.1) 3.1 (6.3) 5.3 (7.4)�2.3 (�5.2 to 0.7)

0.113Dorsiflexion (N)

49.3 (21.0) 51.6 (19.2) 69.2 (21.8) 71.2 (22.8) 19.9 (24.8) 19.5 (22.7)0.4 (�7.7 to 8.5)

0.912Plantarflexion (N)

160.5 (56.2) 172.9 (63.0) 222.0 (58.4) 223.4 (56.6) 61.5 (59.9) 50.6 (58.1)10.9 (�11.0 to 32.8)

0.284Inversion (N)

86.4 (35.6) 85.0 (39.4) 122.2 (41.6) 113.9 (41.4) 35.8 (35.2) 28.8 (40.4)6.9 (�9.2 to 23.0)

0.351Eversion (N)

60.2 (30.0) 62.4 (32.0) 85.0 (27.3) 93.5 (35.0) 24.8 (26.0) 31.0 (34.5)�6.2 (�21.5 to 9.1)

0.375

Values are expressed as mean (SD). BoNT-A, botulinum toxin type A; met, metatarsal; FPI, foot posture index.*Between-leg mean change difference at follow-up using paired-samples t-test: positive value favors leg injected with BoNT-A. Precision of treatment effectbased on 95% confidence interval (CI) and P < 0.05.

FIGURE 2. Secondary outcomes for foot structure (A), ankle flexibility (B), and muscle strength [dorsiflexion (C), plantarflexion (D),

inversion (E), and eversion (F)], obtained every 6 months in the 10 children with CMT1A.

Botulinum Toxin for Pes Cavus in CMT MUSCLE & NERVE August 2010 265

the tibialis posterior and peroneus longus muscleson radiographic alignment, clinical measures offoot structure, ankle flexibility, or muscle strengthusing highly reliable and validated age-appropriateinstruments. The leg injected with BoNT-A for 24months had a less cavoid radiographic alignmentby, on average, approximately 1�, when comparedwith the control leg. Such a small change has ques-tionable clinical significance.

Our use of BoNT-A in this primary nerve disor-der has been approached with caution as there wassome concern regarding further irreversible mus-cle weakness. However, BoNT-A injections weresafe and well-tolerated. There did not seem to beexcessive weakness of the injected muscles or asso-ciated muscles. Generally, the strength of all footand ankle muscles increased during the trial in allpatients, but remained below that of healthynorms, as expected with growth and developmentin pediatric CMT1A.2 Although injections withBoNT-A at 6-month intervals were safe, there wasno clinical improvement. The cost associatedwith this intervention renders larger studiesproblematic.

This study has some limitations. First, 24months may not have been long enough to detecta significant change in this slowly progressive disor-der, and it remains unclear whether injections ofBoNT-A over longer periods would have a deleteri-ous effect. Second, although experimental, ourtrial might have been underpowered to detect asignificant difference between groups. Third, it wassurprising that there was no significant weaknessmeasured in the injected muscle groups. In otherconditions, such as limb dystonia or spasticitytreated with BoNT-A, a significant therapeuticeffect does not usually occur without some reduc-tion in strength of the injected muscle. BoNT-A isrecognized to last from 3 to 6 months. It is possi-ble that the interval period of 6 months in thisstudy was too long to provide sufficient constantrelaxation of tibialis posterior and peroneus longusto rebalance the foot deformity. Further, otherdoses and brands of BoNT-A may have had a dif-ferent effect.27 Although we believe the dose ofBoNT-A used in this study was sufficient to weakenthe injected muscles, it is an unlikely factor in thelack of a treatment effect. Indeed, it has beenshown that a Dysport dose of 10 units/kg/muscleis optimal for larger muscles such as gastrocne-mius, hamstrings, and hip flexors, whereas thesmaller tibialis posterior and peroneus longusmuscles are generally dosed at half that of thelarger muscles.28 Fourth, given that pes cavus is anindependent predictor of poor walking ability inpediatric patients with CMT1A,2 functional out-come measures, such as balance, agility, and en-

durance, might have provided further insight intothe effect of BoNT-A. Perhaps a pediatric versionof the well-validated CMT neuropathy score,18

would provide a more functionally relevant mea-sure of treatment efficacy in clinical trials of pe-ripheral neuropathy in childhood.

In conclusion, this experimental trial has pro-vided evidence that 24 months of BoNT-A injec-tions in the posterior tibialis and peroneus longusis safe and well-tolerated in children with CMT1A.However, BoNT-A did not have any significanteffect on the progression of the disease or footdeformity.

This study was supported in part by a grant from the NationalHealth and Medical Research Council of Australia (NHMRC No.336705). Dysport was provided by Ipsen Pty, Ltd. (Victoria, Aus-tralia). The authors thank P. Joseph, K. Prelog, S. Rudge, S. Grew,M. Moharir, A. Cairns, and R. Patel for their assistance with studycoordination.

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