Gait and Posture 11 (2000) 67–79

Review

Recommendations for the use of botulinum toxin type A in themanagement of cerebral palsy

H. Kerr Graham g,*, K. Roger Aoki a, Ilona Autti-Ramo b, Roslyn N. Boyd c,Mauricio R. Delgado d, Deborah J. Gaebler-Spira e, Mark E. Gormley Jr f,

Barry M. Guyer h, Florian Heinen i, Andrew F. Holton j, Dennis Matthews k,Guy Molenaers l, Francesco Motta m, Pedro J. Garcıa Ruiz n, Jorg Wissel o

a Allergan Inc., Ir6ine, CA, USAb Hospital for Children and Adolescents, Uni6ersity of Helsinki, Helsinki, Finland

c Hugh Williamson Gait Analysis Laboratory, Royal Children’s Hospital, Melbourne, Australiad Texas Scottish Rite Hospital for Children, Dallas, TX, USA

e Department of Clinical Physical Medicine and Rehabilitation, Northwestern Uni6ersity Medical School, Chicago, USAf Department of Physical Medicine and Rehabilitation, Gillette Children’s Hospital, St Paul, MN, USA

g Department of Orthopaedic Surgery, Royal Children’s Hospital, Park6ille, Flemington Road, Melbourne, Victoria 3052, Australiah DuoMed Limited, Wokingham, UK

i Department of Neuropaediatrics, Children’s Hospital, Uni6ersity of Freiburg, Freiburg, Germanyj Department of Paediatrics, Leicester Royal Infirmary, Leicester, UK

k Department of Rehabilitation, Den6er Children’s Hospital, Den6er, CO, USAl Department of Orthopaedics, Uni6ersitaire Ziekenhuizen, Pellenberg, Belgium

m Istituti Clinici di Perfezionamento, Ospedale dei Bambini ‘V. Buzzi’, Milan, Italyn Department of Neurology, Fundacion Jimenez Dıaz, Madrid, Spain

o Uni6ersity Clinic for Neurology, Innsbruck, Austria

Received 9 June 1999; received in revised form 15 November 1999; accepted 18 November 1999

Abstract

Botulinum toxin type A (BTX-A) is increasingly being used for the treatment of childhood spasticity, particularly cerebral palsy.However, until very recently, all such use in this indication has been unapproved with no generally accepted treatment protocols,resulting in considerable uncertainty and variation in its use as a therapeutic agent. In view of the increasing awareness of, andinterest in, this approach to the treatment of spasticity, and also the recent licensing in a number of countries of a BTX-Apreparation for treating equinus deformity in children, it would seem timely to establish a framework of guidelines for the safeand efficacious use of BTX-A for treating spasticity in children. This paper represents an attempt, by a group of 15 experiencedclinicians and scientists from a variety of disciplines, to arrive at a consensus and produce detailed recommendations as toappropriate patient selection and assessment, dosage, injection technique and outcome measurement. The importance ofadjunctive physiotherapy, orthoses and casting is also stressed. © 2000 Elsevier Science B.V. All rights reserved.

Keywords: Cerebral palsy; Botulinum toxin type A; BOTOX®; Guidelines; Consensus document

www.elsevier.com/locate/gaitpost

1. Introduction

The use of botulinum toxin type A (BTX-A) fortreating spasticity and in particular, the motor prob-lems of children with cerebral palsy, has attracted muchattention, both in clinical publications and the popular

* Corresponding author. Tel.: +61-613-9345-5450; fax: +61-613-9345-5447.

E-mail address: grahamk@cryptic.rch.unimelmb.edu.au (H.K. Gra-ham)

0966-6362/00/$ - see front matter © 2000 Elsevier Science B.V. All rights reserved.PII: S 0 9 6 6 -6362 (99 )00054 -5

H.K. Graham et al. / Gait and Posture 11 (2000) 67–7968

press. Until very recently, all such use has been unap-proved for this indication, since BTX-A (BOTOX®,Allergan and Dysport®, Ipsen) has only been approvedfor the treatment of blepharospasm, hemifascial spasm,and in some countries, strabismus and cervical dysto-nia. This, combined with the unusual pharmacokineticproperties and potential toxicity of BTX-A, not tomention the considerable clinical challenge presented bya disorder as complex as cerebral palsy, has resulted inuncertainty about appropriate administration anddosage. Whether widespread use of BTX-A for treatingspasticity is justified by the available clinical evidence[1] has been questioned. The recent licensing ofBOTOX® for the treatment of equinus deformity inchildren in several European countries and Australia,together with pending applications for approval else-where, further increases the need for a discussion aboutthe value, limitations and appropriate use of BTX-A.This paper follows detailed discussions by all of theauthors at a roundtable meeting and represents anattempt, by a group of experienced users of BTX-A, toreview developments and produce a clear, detailed andlogical set of guidelines for the responsible use ofBTX-A in the treatment of children with cerebral palsy.Many of the authors have between 4 and 6 years’experience of treating spasticity in children by injectingBTX-A, and their combined experience represents morethan 1000 children treated for this indication. In manycases this is in addition to an even greater prior experi-ence of using BTX-A for treating dystonia in adults.

2. A review of the therapeutic use of botulinum toxintype A

2.1. Biochemistry

BTX-A is a protein exotoxin derived from Clostrid-ium botulinum. It binds, with high affinity and specific-ity, to the presynaptic membranes of cholinergic motorneurones, and is then internalised [2]. Once inside thecell, one of its two subunits specifically cleaves compo-nents of the cell’s exocytotic machinery (a proteinknown as synaptosome-associated protein of 25 kDa)so that the discharge of acetylcholine-containing vesi-cles, and hence neurotransmission at the neuromuscularjunction, is prevented [3,4]. Injection of BTX-A intoselected muscles, therefore, produces dose-dependentchemical denervation resulting in reduced muscular ac-tivity [5]. After sprouting of new nerve terminals, whichleads to reinnervation, or restoration of the originalterminal, affected muscles recover [6]. Although there isevidence that partially functional neuromuscular junc-tions are re-established within 4 weeks [7], the period ofclinically useful relaxation is usually 12–16 weeks. Thismay be followed by longitudinal muscle growth and

functional carry-over which can continue for up to 6months, or longer in a small percentage of cases.

2.2. Clinical experience

BTX-A is now widely used for the treatment of avariety of conditions characterised by muscle hyperac-tivity, and is increasingly being seen as a valuabletreatment option in the management of spasticity, in-cluding cerebral palsy. However, although one of thecurrently commercially available products has recentlybeen granted a limited license for this indication in anumber of countries, the current data sheet recommen-dations for use are limited to the specific indication ofequinus. This means there is a lack of an ‘officialposition’, based on extensive experience, as to guideli-nes for good practice in the use of BTX-A for treatingcerebral palsy in children. This is an unsatisfactorysituation, for a number of reasons. Firstly, the lack ofguidance may lead to unwise use of BTX-A with unde-sirable consequences, not only for the individuals con-cerned, but also because it might lead to a very usefultreatment becoming more difficult to obtain for a largenumber of others. Secondly, because of the publicitybeing attracted by BTX-A treatment, unrealistic expec-tations may be raised, leading to disappointment andloss of confidence. The situation is further complicatedby the non-equivalence of the two commercially avail-able forms of BTX-A, BOTOX® and Dysport®. Theunits used to express the potency of these products arebased on mouse LD50 values. Differing assay methods,and differing bioavailabilities of the two products,mean that the recommended doses are not equivalent,and what is more, there is no straightforward conver-sion between the two commercially available forms.The ratio of potencies appears to depend on the partic-ular animal species and tissue concerned, as well as theway in which the preparation is diluted. As a result,reported comparisons vary widely [8–11].

Rational patient selection demands a sound under-standing of the mode of action of BTX-A and itsclinical effects and limitations. In the past, we acknowl-edge that there have been comparatively few well-con-trolled clinical trials, but we think that there is nowconsiderable and persuasive clinical evidence of its use-fulness [13–17,51].

2.2.1. Animal models: the hereditary spastic mouseThere is good evidence from animal studies that

BTX-A is effective in preventing the development ofcontractures. In a prospective, randomised trial assess-ing the effect of BTX-A injections in the gastrocnemiusmuscles of hereditary spastic mice, Cosgrove and Gra-ham showed that BTX-A, injected during the growthperiod, allowed normal growth of the muscle [12]. Thereduction in combined length of the gastrocnemius and

H.K. Graham et al. / Gait and Posture 11 (2000) 67–79 69

Achilles tendon seen in untreated hereditary spasticmice was 8% compared with normal siblings, and thisresulted from a 13% reduction in muscle length, par-tially offset by a compensatory 7% overgrowth in thetendon. These values are in accordance with the ob-served effects of spasticity on the human calf, andsuggest that the hereditary spastic mouse is a validmodel for study. The effect of BTX-A injections was toprevent both the muscle shortening and tendon length-ening. Although such results cannot be directly extrap-olated to the human therapeutic setting, they doprovide a sound theoretical base on which to study theeffects of BTX-A in cerebral palsy.

2.2.2. Supporting clinical e6idenceIn a recent paper Forssberg and Tedroff argued that

there were few published, well-controlled trials of BTX-A use in cerebral palsy [1]. We would agree with theiranalysis of the published work as far as it went, butwould suggest that there is a large body of workrecently published, in press, or presented at meetings,which strongly supports the usefulness of BTX-A incarefully selected cases [13–17]. As might be expectedin such a rapidly developing field not all the work beingundertaken is yet formally published. As Forssberg andTedroff concede, it can be difficult to measure spasticityin a completely objective way in small children, andconsequently, published double-blind trials are few[13,14,51]. They suggest the use of gait analysis, kine-matics and validated outcome measures. Gait analysis,including use of three-dimensional kinematics, is in-creasingly being used to study the effects of BTX-Atreatment. Cosgrove et al. investigated the changes insagittal plane kinematics using electrogoniometers in agroup of 26 patients who received botulinum toxininjections to the gastrosoleus, tibialis posterior andhamstring muscles. Their study was the first to reportthat gains in dorsiflexion after calf injection were in-versely proportional to the age of the subject, probablybecause of the gradual development of fixed contrac-tures [15]. Sutherland et al. investigated the effects oftreating 26 cases of dynamic equinus with injections ofBTX-A into the gastrocnemius [16]. Patients were as-sessed by kinematic analysis and electromyography(EMG) and the authors concluded that there were‘significant improvements in function as shown by ob-jective gait outcome measures’. In a recently publishedstudy, Corry et al. used three-dimensional gait analysisto compare the relative effectiveness of BTX-A injec-tion and casting [17]. Such studies are indeed valuable,but have distinct limitations. The prime target groupfor intervention with BTX-A is precisely those childrenwho are too small (B1 m) for accurate analysis and/ortoo young (B4 years) to co-operate with conventionalgait analysis. The most frequently used validated objec-tive outcome measure is the gross motor function mea-

sure (GMFM), and although this may be appropriatefor assessing children in the mid-range of disability, itmay not be sensitive enough to detect change in chil-dren with mild disability. At the other end of thespectrum, children with generalised spasticity andsevere disability may not be good candidates for assess-ment by the GMFM.

It is important that clinical trials in paediatric reha-bilitation should be conducted according to the highestscientific standards possible, but the studies of BTX-Aare not unique in sometimes being limited by practicalconstraints. It could equally be argued that the use ofother well-accepted modalities such as physiotherapy,casting and orthoses could not always be justified byrigorous objective assessment. Further studies are nowbeing conducted, but it is already becoming increasinglydifficult to conduct placebo-controlled trials, due to theunwillingness of parents to submit children to controlgroups. This is understandable in indications where theevidence for BTX-A use is considerable and especiallyin countries where a licence has already been granted. Itis also difficult to conduct long-term follow-up trialswhen the transfer of patients from paediatricians toadult specialists may result in them becoming lost to thestudy. In any case, such studies require the use ofagreed objective outcome measurements, such as gaitanalysis and clinical rating scores, and as yet no con-sensus has been reached as to the most appropriatesystems to use.

Nevertheless, we think that BTX-A treatment ofspasticity in children has a sound scientific basis, andthat a large enough volume of successful clinical experi-ence has now accumulated to formulate a set of basicguidelines for safe and effective treatment.

2.3. Pharmacokinetics

Because of the potency and nature of BTX-A, it isnot possible to perform standard pharmacokinetic stud-ies, and there are few data on its post-injection redistri-bution and metabolism. In particular, the question ofwhether BTX-A is transported to the spinal cord isoften raised. A study which examined the redistributionof 125I-labelled BTX-A after intramuscular injectioninto cats [18] showed some evidence of retrograde ax-onal transport through the sciatic nerve to the ventralroots of the spinal cord. Moreover, ligation of the nerveprevented this transport. This was on the basis ofdetectable radioactivity, but there was no informationon the proportion of detected counts which were stillattached to intact toxin molecules, as opposed to de-graded peptides or free iodine. If BTX-A was trans-ported intact to the spinal cord, it might be expected tomimic the effect of the other clostridial toxin, tetanustoxin, but other studies, in cats, have failed to demon-strate any such effect [19,20]. An Allergan study [21]

H.K. Graham et al. / Gait and Posture 11 (2000) 67–7970

has examined the redistribution of radio-iodinatedBTX-A following injection into the gastrocnemiusmuscle in rats, and confirmed that intact toxin is re-tained at the injection site for at least 24 h. Axonaltransport of radioactivity to the spinal cord and re-distribution to other tissues represents breakdownproducts and free label. Crucially, there is no evi-dence that BTX-A is transmitted from one neuroneto another, in the spinal cord, as tetanus toxin is.

2.4. Safety and side effects

2.4.1. Animal studiesClearly, the potency of BTX-A demands that reli-

able data are available concerning its toxicity, appro-priate dosage, and side-effect profile. Studiesperformed in primates for registration purposes estab-lished a systemic LD50 of 39 U/kg and a recom-mended dose of 4 U/kg for BOTOX®, but this haslimited relevance when considering intramuscular in-jection. An important concept is that of saturation ofinjection sites with BTX-A. Since BTX-A binds withhigh affinity to local targets within the muscle, itshould remain confined to the muscle injected. How-ever, at a certain dose, saturation of an injection sitewill allow spread of toxin to neighbouring structures,or, with very large doses, into the systemic circula-tion. Conversely, a larger dose of BTX-A, if splitbetween a number of injection sites, is quickly boundlocally, and may be safely used without affectingneighbouring tissues or causing systemic toxicity. Thedilution of toxin, and hence the volume injected,might also be expected to have an important influ-ence on the degree of spread, both within the muscle,and if the volume is large enough, beyond it. This islogical, and is a common clinical impression, but itshould be stressed that saturation is still a hypotheti-cal concept which requires further study. In order toprovide safety data relevant to BOTOX® use in child-hood cerebral palsy, an evaluation of doses split be-tween four sites in the gastrocnemius muscles ofjuvenile Cynomolgus monkeys has been undertaken(KR Aoki, personal communication). Total doses of0, 4, 6, 8, or 12 U/kg were injected every 8 weeks forthree cycles (16 weeks), followed by a 4-week obser-vation period. At all doses there was evidence of localatrophy of the gastrocnemius. As expected, there wasno dose response, since 4 U/kg would already pro-duce a maximum local response. Tissue samplesshowed some involvement of the soleus muscle, confi-rming earlier results showing that BTX-A diffusesacross fascial planes [5]. A slight, transient decrease inweight gain was observed in the 12 U/kg group, thecause of which is unclear. However, since failure togain weight is classified as a systemic adverse effect,the safe dose was assessed at 8 U/kg following injec-

tion into four sites, and 12 U/kg was felt to mark theonset of systemic toxicity.

This is useful information which should be takeninto consideration when deciding on appropriatedoses in a clinical situation, but other important vari-ables include dilution of toxin, number and proximityof injection sites, and total dose at a single site. Itshould also be borne in mind that such animal stud-ies, however, well-designed, do not always apply di-rectly to the human therapeutic situation.

2.5. Experience of side effects

The potency of BTX-A understandably, and prop-erly, raises the question of side effects. However, withcareful administration these are uncommon, and usu-ally mild and transient [52]. The commonest is painat the injection site, followed by dose-dependent ef-fects of excessive weakening of the injected muscle, orat higher doses which saturate the muscle, diffusionof BTX-A to adjacent muscles. Careful injection tech-nique and dose calculation minimises the risk of this.Should it occur, the effects are restricted to localfunctional weakening and limited to several days du-ration, with the possible exception of the followingspecial circumstances.

2.5.1. Dysphagia and pharyngeal dysfunctionThe most serious risks in BTX-A administration

relate to aspiration pneumonia due to pharyngealdysfunction in adult patients who have had injectionsin neck muscles, particularly sternocleidomastoid,most commonly to treat cervical dystonia. Althoughthis is a local complication, and might not be consid-ered relevant to treatment for limb spasticity in cere-bral palsy, it does suggest some groups of patientsmight be at most risk should systemic toxicity arise.Children with quadriplegia, particularly those withpseudo-bulbar palsy, should be carefully monitoredfollowing administration of BTX-A. The risk periodis 1–3 weeks post-injection, and it is important thatany problems which arise during this period are re-lated back to the BTX-A treatment and are referredback to the treating physician.

2.6. Incontinence and constipation

There is a published account of two patients whosuffered temporary incontinence following BTX-A in-jection [22]. This effect is thought to be due to aneffect either on the autonomic nervous system or thesphincters controlling bladder and bowel function. Inthese cases, the total doses were not especially high(12 U/kg body weight Dysport®), given to four mus-cles (adductors and hamstrings). There have also beenreports of a positive effect on constipation [52].

H.K. Graham et al. / Gait and Posture 11 (2000) 67–79 71

2.7. Secondary unresponsi6eness

Secondary unresponsiveness is the term used to de-scribe the phenomenon of reduced response to BTX-Aon subsequent administration, following successful ear-lier treatment. A number of theoretical reasons toexplain secondary unresponsiveness to BTX-A havebeen proposed, including inappropriate doses, unrealis-tic patient expectations, change in muscle involvementover time, injection of the incorrect target muscle,misdiagnosis of the condition, poor reconstitution orstorage of BTX-A, and development of neutralisingantibodies [23]. Analysis by mouse protection assay(MPA) of sera from of a total of 1247 patients in tenpublished studies [24–33] shows a 3.4% incidence ofneutralising antibodies. Where it is possible to compareresponders to treatment (66 patients) directly with non-responders (196 patients) in four studies of adult sub-jects, rates of 3 and 31.6%, respectively, were found.This suggests that development of neutralising antibod-ies is an uncommon occurrence, and that incidences ofsecondary unresponsiveness do not necessarily correlatewith the presence of neutralising anti-BTX-A antibod-ies. Indeed, it is far from obvious how circulatingneutralising antibodies, even at the high levels in hyper-immune serum, much less the low concentrations foundin human patients, would block the rapid, high-affinitybinding of BTX-A to cholinergic nerve terminals withinthe intramuscular compartment.

2.7.1. Recommendations of the authorsIt is the authors’ view that by far the most common

cause of ‘secondary’ unresponsiveness is the late com-mencement of treatment in older children, resulting insubsequent development of fixed contractures becauseof the progressive nature of muscle contracture in cere-bral palsy.

2.7.2. Suggestions for dealing with unresponsi6enessIn cases of unresponsiveness, await end of normal

treatment interval, before considering repeat injection.� Do not exceed recommended doses.� Re-evaluate the motor problem and consider

whether another target muscle may be involved.� Do not excessively shorten treatment intervals (mini-

mum of 3 months between injections).� Another alternative to testing sera in the MPA is to

inject a remote site (e.g. the frontalis muscle) with alow dose (10–15 U BOTOX®) of BTX-A to deter-mine the patient’s responsiveness to treatment [34].Absence of the expected muscle relaxation is indica-tive of systemic resistance (such as that due to neu-tralising antibodies). This procedure has a minimaleffect on the patient, does not require blood collec-tion, and avoids the cost of testing by a third party.A new assay system based on inhibition of the nor-

mal mouse startle response (digit abduction scoring —DAS) is currently under development, and may offerthe possibility of obtaining reliable titres for neutralis-ing antibodies in serum samples, and may allow a moresensitive measure to be made of the level of circulatingneutralising antibodies associated with possible failureto respond to BTX-A treatment [35].

3. The use of BTX-A for treating cerebral palsy

3.1. Patient selection and timing of treatment

BTX-A provides a useful way of controlling excessivemuscular contraction in the specific muscles injected. Itfollows that it is most effective in patients with dynamicmuscle shortening which is localised to a few muscles.The more this picture is complicated by long-standingcontractures and deformity, then the less applicable it islikely to be. Results are also likely to be best in patientswho have adequate selective motor control. At whatpoint the spasticity is regarded as ‘generalised’ is amatter for clinical judgement, but for practical reasonsa cut-off at the significant involvement of more thanfour large muscles has been chosen. Beyond this weconsider that oral therapy, intrathecal baclofen and, forlower limb involvement, selective dorsal rhizotomy be-come increasingly applicable [36] (Fig. 1). In thesecircumstances, BTX-A may be successfully used for thetreatment of particular muscle groups, as long as a

Fig. 1. The management of spasticity. Different treatments availablefor cerebral palsy fulfil different roles. Oral therapy and intrathecalbaclofen (ITB) are reversible, but act generally or regionally. Selectivedorsal rhizotomy (SDR) is regional in its effect, and is irreversible.Local corrective surgery (such as tendon lengthening or myotomy) islocal, but may have general effects on biomechanics and alignment,and is semi-permanent. botulinum toxin type A (BTX-A) is local andreversible. Depending on the clinical situation any of these ap-proaches may be appropriate, and BTX-A fills a useful quadrant oftreatment options.

H.K. Graham et al. / Gait and Posture 11 (2000) 67–7972

Table 1Selective motor control scalea

Definition Grade

No ability to activate dorsiflexion of the foot 0Predominantly action of extensor hallucis and/or 1

extensor digitorum longus2Activity of extensor hallucis accompanied by some

activity of tibialis anteriorDorsiflexion (effective tibialis anterior) with knee and/or 3

hip flexionIsolated selective dorsiflexion (knee extended, use of 4

tibialis anterior)

a Adapted from Ref. [41].

A number of standardised methods have been de-vised to differentiate various aspects of motor prob-lems. It has to be said that the most widely accepted,validated outcome measure at present is the GMFM[39], although, as discussed below, it is only well-suitedto moderately affected children.

3.2.1. Lower limb assessmentA detailed assessment should consider the following

parameters:1. Passi6e range of motion: This provides an estimate

of passive muscle length and the presence of jointcontracture. The range of movement should be mea-sured by goniometry, and recorded in a standard-ised format. Although passive range of motion dataare routinely collected by the authors, the limitationof such data is recognised, as has been reported bySutherland et al.[16].

2. Dynamic range of motion: The assessment of dy-namic muscle length is by the modified TardieuScale [40,41]. This looks at the resistance to a fastvelocity stretch. A ‘catch’ may be seen in the rangeof motion at a particular angle. For instance, indynamic equinus the child may walk on their toes,although they may have nearly a full passive rangeof motion. However, there may be a point at 20° ofplantar flexion where there is a stiffness, or a catch(indicating an ‘overactive stretch reflex’), corre-sponding to the range of motion in gait [41].

3. Muscle strength: This is recorded on the MedicalResearch Council (MRC) scale, and is graded 1–5according to the full (F) or limited (L) availablepassive range. Inability to isolate muscle activity(UL) or inability to assess (UA) due to lack ofco-operation or comprehension should also berecorded.

4. Muscle o6eracti6ity/spasticity: This is usually as-sessed according to the modified Ashworth scale[42].

5. Selecti6e motor control: This is tested as follows: thechild rests in long sitting with knees comfortablyextended, with vision of their feet, and with theheight between feet and pelvis adjusted for ham-string muscle length. The child is asked to dorsiflextheir foot to a target in the mid-position above theankle joint. The balance of activity of tibialis ante-rior, extensor hallucis and extensor digitorum isobserved, along with the ability to selectively dor-siflex the ankle without the accompaniment of kneeflexion (i.e. as a total pattern). The result is scoredfor both legs according to the scale in Table 1 (Ref.[41]).

Careful assessment according to this format allowsformulation of a detailed treatment plan which takesaccount of the complex interactions of these factors. Atreatment algorithm for spasticity has been developed

clear functional goal is identified, and in view of itsdifferent modes of action, there seems to be no reasonwhy systemic medication and BTX-A should not beused in combination.

Early treatment is preferable for maximum responseand prolonged effects, and because of the potential toreduce contractures and delay surgery. In older chil-dren, responses are generally less marked, shorter-livedand increasingly inhibited by the presence of fixedcontractures. In our experience, the optimal timing forBTX-A treatment is between 1 and 5 years of age,during the period of dynamic motor development,where there is the greatest chance of modifying thecourse of the disease [36]. The majority of childrentreated will eventually require corrective surgery, butthere are clear advantages to delaying this until theyreach 6–12 years of age, allowing surgical interventionsto be fewer, and more definitive [36]. There is, however,a small, but very important proportion of children(perhaps 5–10%) for whom the early use of BTX-A,together with active motor training and suitable or-thotic treatment, may modify the natural course of thedisease.

BTX-A may also be successfully used for treatingmuscular hyperactivity in childhood resulting from anumber of other causes, particularly traumatic braininjury [37], as well as hereditary spastic paraplegia [36],and spina bifida [38]. In such children, particularly asthey grow older, more limited, but still highly valuable,functional goals may be appropriate, such as improvedease of personal hygiene, or peri-operative preparation.

3.2. Patient assessment: baseline measures

Any rational treatment plan requires the use of ob-jective clinical measurements to establish a baselineassessment before treatment and to record the degreeand duration of response. This section includes someobservations that are based on the extensive clinicalexperience of the 15 authors and not solely on pub-lished research studies.

H.K. Graham et al. / Gait and Posture 11 (2000) 67–79 73

[35] illustrating a logical strategy for treatmentplanning.

3.2.2. Upper limb assessmentFor upper limbs the same basic rules apply using

similar approaches to clinical measures. For instance,function is measured by reference to specific tasks anda modified version of the Physician’s Rating Scale(PRS) (for instance, as shown in Table 2). Measure-ments of speed and fluency of movement include mod-

ifications of Erhardt’s prehension test [43] and the Boxand Block test [44,45]. Analysis should focus on allthree levels (palm, forearm and elbow) and determinewhether there is an isolated functional impairment,such as thumb in palm (adductor pollicis or opponenspollicis), or restricted supination (pronator teres); orwhether there is a total flexion pattern, with thumb inpalm (adductor pollicis), wrist in flexion (flexor carpiradialis and ulnaris), forearm supinated (pronator teres)and elbow flexed (biceps brachii, brachialis and/or bra-

Table 2Upper limb PRS

DefinitionParameter Score Remarks

0Active elbow extension (normal 180°) \10° reduction0–10° reduction 1

2No reductionActive supination in extension (elbow extended, forearm supinates). 0None

Mid-position: palm 90° to horizontalUnder mid-position 1To mid-position 2Past mid-position 3

Active supination in flexion (elbow flexed 90°, forearm supinates) 0None1Under mid-position

To mid-position 23Past mid-position

Active wrist dorsiflexion (forearm supported, active dorsiflexion of wrist). None 0Mid-position: palm level with forearm

Under mid-position 12To mid-position3Past mid-position0With ulnar deviationWrist dorsiflexion (angle of movement)

With radial deviation 0Neutral 1

Finger opening Only with wrist flexion 01With wrist in neutral

position2With wrist in dorsiflexion0Thumb in function Within palm

Pressed laterally against 1index fingerPartly assists in grasp 2

3Thumb-finger grasp possible4Active abduction

In all manipulative functionAssociated increase in muscle tone 0Only with fine motor manip- 1ulationOnly with walking or 2running

3None0Two-handed function None1Poor, no use of hidden

functions2Use of all functions, but

limited in ADLUse of all functions, not 3limited in ADL

Total score 47

WorseChange −1None 0

1Slight improvementClear clinical improvement 2

H.K. Graham et al. / Gait and Posture 11 (2000) 67–7974

Table 3Observational gait scale for BTX-A management (Boyd, Carpenter, Carmen and Delgado) adapted from Physician’s Rating scale (PRS) [13,17]a

RightParameter LeftDefinition

Knee position in mid-stance 0Crouch Severe\15 degrees 0Moderate\10–15 degrees 1 1MildB10 degrees 2 2

3Neutral 3ToeInitial foot contact 0 0Forefoot 1 1

2Foot-flat 23Heel 3

−1Toe/toe (equinus) −1Foot contact at midstanceFoot flat/early heel rise 0 0

1 1Foot flat/no early heel rise2Occasional heel/foot flat 2

Heel/toe (normal roll over) 3 3No heel contact (fixed equinus)Timing of heel rise 0 0

1Before 25% stance (very early) 1Between 25–50% (slightly early) 2 2At terminal stance 3 3

0No heel rise (after foot flat i.e. crouch) 00 0Hindfoot at midstance Varus1Valgus 1

Neutral 2 20Base of support 0Frank scissoring1Narrow base (poor knee clearance) 1

Wide base 2 23 3Normal base (width of shoulders)0Walker (forward/posterior) with assistance 0Gait assistive devices

Walker (independent) 1 12 2Crutches, sticks3None, independent for 10m 3

WorseChange −1 −1None 1 1

2Better 2Total score (perfect score=25)

a Total score can be adjusted to account for categories tested.

chioradialis). It is worth noting that the dynamic phaseof spasticity generally persists longer in the upper limbthan in the lower, and that, almost invariably, the firstmuscle to develop a fixed contracture is pronator teres.

3.3. The effecti6eness of botulinum toxin treatment:outcome measures

Dynamic muscle testing may be the most sensitivemeasure of the effectiveness of BTX-A and changes instatic muscle length may take longer to become appar-ent. The initial effect of BTX-A is to reduce musclestiffness, while changes in muscle length due to stretch-ing may take slightly longer (in the diplegic group oftenearlier than in the hemiplegic group) [36]. Active carry-over into new functional skills will often not take placeimmediately in children with cerebral palsy; as motorlearning to utilise the new available biomechanical con-ditions will often occur after the lengthening and reduc-tion in muscle stiffness. Split-screen video with

slow-motion facility, together with the use of amodified version of the PRS [41] (Table 3) gives highlyreproducible qualitative assessments for calf injection.Instrumental gait analysis is necessary to answer spe-cific questions, or for detailed quantitative analysis ofBTX-A injection.

Assessing treatment outcomes in more severely af-fected children is more difficult. In the most severelyaffected group, there is currently no adequate assess-ment scale available.

3.4. The effecti6eness of botulinum toxin treatment:e6idence from instrumented gait analysis studies

1. Temporospatial characteristics of gait: In a study of26 patients with cerebral palsy who were managedby injections of BTX-A into the gastrocnemius forequinus gait, Sutherland et al. reported increasedvelocity, increased step length and increased stridelength at follow-up compared with baseline values[16]. Wissel et al. [46] carried out a double-blind

H.K. Graham et al. / Gait and Posture 11 (2000) 67–79 75

controlled study of a ‘high-’ (200 U BOTOX®/treated leg) versus ‘low-dose’ (100 U BOTOX®/treated leg) BTX-A treatment in 33 children andteenagers with cerebral palsy and crouch and/orequinus gait pattern. Following a single two-levelinjection session (injections distributed to four orfive muscles: hamstrings and/or rectus femoris and/or triceps surae muscles) children with the ‘high-dose’ regimen (mean dose 11.6 U BOTOX®/kg bodyweight) gained a significant increase in gait velocityand stride length compared with baseline values.

2. Two-dimensional kinematics: In an ‘open label’study, Cosgrove et al. reported the effects of BTX-Ainjections in 26 children with cerebral palsy usingelectrogoniometers [15]. These devices are applied inthe sagittal plane of the ankle, knee or hip and arecapable of recording two-dimensional kinematicswith a hand-held data logger, with the facility oflater downloading to a personal computer. In thisstudy, improvements were noted in such parametersas ankle dorsiflexion in stance and swing, and kneeextension in stance and swing, following injection ofthe calf and hamstrings, respectively.

3. Three-dimensional kinematics: The effects of BTX-Ainjections were compared with casting by Corry etal. in a randomised clinical trial using two-dimen-sional video-PRS as the principal outcome measurefor the younger/less co-operative children and three-dimensional kinematics for the older/more co-opera-tive children [17]. Both groups showed a significantimprovement in ankle dorsiflexion at 2 weeks post-intervention. After 12 weeks the cast group hadrelapsed to baseline but the BTX-A group main-tained their improvement. The cost of both inter-ventions was comparable and BTX-A was thereforeconsidered to be more cost effective, because of thelonger duration of effect. There was a non-signifi-cant increase in walking velocity in the group whoreceived BTX-A injections and a decrease in velocityin the group managed by casting. Three-dimensionalkinematics were also reported in the study of 26patients by Sutherland et al. with statistically signifi-cant improvements in both stance and swing phaseankle dorsiflexion following BTX-A injections intothe calf [16].

4. Modelling of muscle length: Eames et al. used three-dimensional kinematics to study changes in muscleextension as a measure of muscle length after inject-ing the calf with BTX-A in a prospective study of 39patients [47]. Temporary muscle lengthening wasconfirmed with possible reduction in the presumednatural history of progressive shortening withgrowth. At 1 year after injection, 30% of injectedmuscles were longer than baseline.

5. Kinetics: Boyd et al. introduced a simple means ofquantifying the previously described characteristic

kinetic patterns in children with spastic equinus andtoe walking including the ‘double bump’ ankle mo-ment and the ‘triphasic power curve’ [48]. The ab-normal kinetic patterns showed a significanttendency to normalise after injection of BTX-A. Inresponsive children there was a paradoxical increasein the A2 power burst after injection.

6. Electromyography: Sutherland et al. demonstratedimprovements in both stance phase and swing phaseactivity of tibialis anterior after injection of thegastrocnemius muscle and hypothesised that thechanges were a response to the correction of thedynamic equinus gait pattern, reported above [16].

7. Energy studies: Corry et al. carried out a controlledtrial of hamstring injection in children with cerebralpalsy and crouch gait [49]. Results were variable butsome children did particularly well. Those childrenwho had improved knee extension on kinematicstudies, had a significant decrease in energy con-sumption as measured by the Cosmed K2. Massinand Allington studied 15 children with cerebralpalsy aged 4–13 years by means of oxygen uptakeduring a standardised exercise protocol [50]. At 2months after injection 13 of the patients showed animprovement, which was maintained in some pa-tients at the 6-month follow-up.

4. Recommendations for the role of BTX-A withadjunctive treatment

4.1. Physiotherapy

An active physiotherapy programme remains centralto treatment, with targeted motor training aiming toachieve carry-over improvements which persist beyondthe effects of the injections. Paediatric physiotherapistshave an important role in selecting and teaching specificmotor tasks for children to practice under the guidanceof their caregivers. The physiotherapist encouragespractice in an appropriate environment to achieve re-tention and carry-over of motor skills, as well asmaintenance of muscle length and flexibility. Physio-therapists have many of the necessary skills to helpselect patients who might obtain the most benefit fromBTX-A treatment. The physiotherapist’s experience inthe analysis of movement should be utilised to adopt abiomechanical approach to selecting the appropriatetarget muscle(s) [41].

4.2. Orthoses

Orthoses are used in conjunction with physiotherapyto facilitate carry-over of improved motor control fol-lowing BTX-A injection, particularly in the lower limb.They are effective in stretching muscles which may not

H.K. Graham et al. / Gait and Posture 11 (2000) 67–7976

be adequately stretched by weight-bearing alone, suchas adductors, and perhaps, hamstrings. Orthoses supplythe appropriate biomechanical alignment to achievepractice and functional carry-over outside periods oftargeted motor training conducted by the paediatricphysiotherapist.

4.3. Serial casting

This is an area in which there is still considerabledebate as to the optimal timing and the value ofcombining with BTX-A injection. Most clinicians preferto delay casting for 2 weeks to distinguish between theeffects of BTX-A and the casting. It may also be thatthe response to the BTX-A is better than expected andcasting may prove unnecessary. Review at 2–3 weekspost-injection to assess the peak effect of BTX-A. Oth-ers cast immediately after BTX-A injection, feeling thatthis improves the response. It should be realised that, inmany cases, there are components of both dynamicmuscle shortening and of early contractures, so variouscombinations of injection with or without long or shortperiods of casting may be appropriate. If the contrac-ture is early, soft and mild, then weight bearing to-gether with appropriate use of orthoses and stretchingmay be sufficient for management of calf and hamstringfollowing injection. For injection of adductors, thecombination of BTX-A and use of a variable hipabduction orthosis may be indicated. If the muscle

contracture is more fixed but some dynamic range ofmotion is available consider BTX-A supplemented after3 weeks by a short period of casting to alleviate theresidual contracture [36].

There is evidence that BTX-A alone is as effective ascasting alone in the management of dynamic equinus,having a similar magnitude of response, but a longerduration [17].

5. Summary of treatment recommendations

5.1. Muscle selection

5.1.1. Lower limbWhat follows are brief guidelines only. A full under-

standing of the biomechanics of movement at the hip,knee and ankle during gait is crucial to the correct andappropriate use of BTX-A injection.� Consider the whole child; evaluate all three levels of

the lower limb (i.e. trunk/pelvis in relation to thehip, knee, ankle/foot).

� Focus on one or two levels and select the mostappropriate target muscles for injection. In moresevere cases consider the medial hamstrings andadductors, in less severe cases consider the ham-strings or calf, or occasionally adductors and calf. Asa general guide: in hemiplegia, the primary targetmuscle is the calf, with the secondary target thehamstring; in diplegia, the hamstrings may be thekey muscles, with the calf the secondary target; inquadriplegia, the adductors may be the key muscles,with the calf and hamstrings secondary [36].

� For reasons of safety and efficacy, in more severeand generalised cases, involving more than four largemuscles, consider the appropriateness of oral medica-tion, intrathecal baclofen and selective dorsalrhizotomy.

5.1.2. Upper limbMost benefit is found by treating dynamic contrac-

tion where there is selective antagonist activity andfairly good sensory awareness.

5.2. Dosage

Note once again that these dosages refer to BOTOX®

units.� Per muscle

3–6 U/kg: lower limb2–3 U/kg: upper limb above the elbow0.5–2 U/kg: forearm, tibialis posterior, flexor hal-lucis longus, other small muscles. Exceptions in-clude the small muscles of the palm (adductorpollicis, opponens pollicis, lumbricales) which mayrequire lower doses than this if useful function is

Fig. 2. Injection sites in the gastrocnemius. The two bellies of thegastrocnemius requires the use of two or four injection sites, depend-ing on the involvement of the soleus and the availability of conscioussedation or general anaesthetic facilities (see text).

H.K. Graham et al. / Gait and Posture 11 (2000) 67–79 77

to be retained. As a guide, for adductor pollicis, atotal of 5–7.5 U per muscle is recommended if thethumb contributes to grasp, 10 U if not.

� Per kg total body weight: 12 U/kg proven dosage� Maximum dose per child per session: 300 U� Frequency: not more than one injection every 3

months. Usually once per 6–12 months� Dilution: 100 U in 1 or 2 ml 0.9% sodium chloride� Maximum dose per injection site: 50 U

The number of injection sites per muscle variesaccording to morphology, for example, one or twosites in each head of the gastrocnemius (the lower sitein each side can be placed deeper to allow somespread to the soleus, alternatively this may be injecteddirectly, Fig. 2). Two sites are usual in the adductorsand hamstrings. In practice, the number of sites usedmay reflect the availability of conscious sedation orgeneral anaesthetic facilities (see below).

Example: lower limbA common situation is that of a child of

approximately 20 kg with spastic diplegia, requiringtreatment for bilateral dynamic equinus. Calculatingthe dose on the basis of 4 U/kg per muscle (8 U/kgtotal), gives a dose of 80 U per calf. This may bedivided as either 40 U into each head of thegastrocnemius, or 20 U into each of two sites perhead of the gastrocnemius.

Example: upper limbA 5-year-old child with hemiplegia, weighing about

20 kg, right upper limb involved. There isdecreased two-handed function which has worsenedin the last year, increased tone and flexion patternwhich includes thumb in palm, wrist in palmarflexion with ulnar deviation, no active supination,and the forearm is flexed. There is increased toneassociated with fine motor manipulation and nocontractures. Doses: 5 U adductor pollicis, 25 Uflexor carpi ulnaris, 25 U pronator teres and 40 Ubiceps brachii.

5.3. Injection procedures

� Local anaesthesia: topical anaesthetic cream is fre-quently used, although its effectiveness is question-able unless applied for at least 0.5–1 h prior toinjection.

� Conscious sedation: oral, nasal or rectal benzodi-azepines, such as midazolam, is very useful inyoung or anxious children. This technique does re-quire close observation and the availability of re-suscitation facilities.

� General anaesthesia may be required for multipleinjections in multiple target muscles, especially if

electrical stimulation is to be used. The availabilityof general anaesthesia may have a bearing on thenumber of injection sites used. Under generalanaesthesia, injections may be arranged optimallyusing a large number of injection sites. Where gen-eral anaesthesia is not possible, or desirable, it maybe necessary to compromise, using fewer sites, de-pending on what the child will tolerate.

� Electromyographic guidance and/or electrical stim-ulation may be helpful for location of muscleswhich can be difficult to locate accurately, such astibialis posterior, flexor hallucis longus and smallmuscles of the forearm, hands and feet. Adductors,hamstrings, calf and biceps are usually identifiedby manual palpation.

5.4. Patient selection

� Favourable factors:Focal goals with specific anticipated functionalbenefitsIncreased dynamic muscle stiffnessMuscular hypertonia with a functional goal.

� Negative factors:Severe fixed contractures (mild contractures mayrespond to treatment combined with casting)Bony torsion and joint instabilityBleeding disordersToo many target muscles — consider othertreatment options, or prioritise.

5.5. Timing of treatment

� For the lower extremity, early treatment is prefer-able to give maximum response: 1–5 years of age

� For the upper extremity, a maximum response isobserved: \4 years of ageTreatment during the dynamic phase of motor de-

velopment maximises the chance of permanent modifi-cation of the disease.

Early treatment may allow postponement, simplifi-cation or even, occasionally, avoidance of surgery.

Later treatment can still be valuable in terms ofpain relief, ease of care, and functional goals such assitting or standing.

5.6. Training

Adequate training of new users of BTX-A is cru-cial. From our clinical experience, we feel that this isbest achieved in an ‘apprenticeship’ situation, withtrainees attending courses and ideally, being attachedfor a period to a recognised centre with expertise inthis area.

H.K. Graham et al. / Gait and Posture 11 (2000) 67–7978

6. Conclusions

The contributors to this paper represent a wide rangeof clinical experience and backgrounds, and yet it wasremarkable how quickly a consensus on the core issuesdiscussed (patient selection, dosage, injection proce-dures) was reached. As a result, we feel that we can putforward these recommendations with some confidence.Clearly, on matters of more complexity, such as the useand timing of adjunctive treatments, and the treatmentof difficult cases with more generalised spasticity, thereis considerable room for clinical judgement of the indi-vidual situation, but even here, the underlying princi-ples were acknowledged. There was also agreement thatsome important topics required considerable furtherresearch.1. A better understanding is required of how much

BTX-A may be injected at a particular point beforethe muscle becomes ‘saturated’ with consequentleakage of BTX-A to neighbouring structures. Itseems clear that larger total doses may be givensafely if they are split between different injectionsites, but such an important point requires morethorough investigation, and more precise guidelineson the limits of this principle would be welcome.

2. Better definition of the anatomical location of con-centrations of motor endplates (motor points)within the most frequently injected muscles is re-quired. If BTX-A could be more accurately injectedat the point where it will have the most effect, thenlower doses and volumes might be used with thesame clinical effect.

3. Strategies for treatment of the different clinicalmanifestations of cerebral palsy with BTX-A needto be developed.

4. The role of adjunctive treatments such as orthosesand casting together with BTX-A needs to be fur-ther evaluated, in order to optimise the benefitsavailable from combining these forms of treatment.

5. The development of more relevant, agreed and vali-dated outcome measurements and functional toolsto detect significant change due to a treatment inchildren with cerebral palsy, and the use of these infuture well-designed clinical trials.

6. The long-term effect of serial injections on longitu-dinal muscle growth and functional improvements,rather than on short-lived increased muscleexcursion.

7. The careful reporting of side effects and unintendedeffects with special reference to dysphagia andincontinence.

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