botulinum toxin-a (botox®) intradetrusor injections in children with neurogenic detrusor...

Journal of Pediatric Urology (2009) 5, 156e164

REVIEW ARTICLE

Botulinum toxin-A (Botox�) intradetrusorinjections in children with neurogenicdetrusor overactivity/neurogenic overactivebladder: A systematic literature review

Xavier Game a,*, Pascal Mouracade b, Emmanuel Chartier-Kastler c, ElkeViehweger d, Raphael Moog b, Gerard Amarenco e, Pierre Denys f, MarianneDe Seze g, Francois Haab h, Gilles Karsenty i, Jacques Kerdraon j, BrigittePerrouin-Verbe k, Alain Ruffion l, Jean-Marc Soler m, Christian Saussine b

a Hopital Rangueil, Toulouse, Franceb Hopital Civil, Strasbourg, Francec Hopital Pitie-Salpetriere, Paris, Franced Hopital Timone-Enfants, Marseille, Francee Hopital Rothschild, Paris, Francef Hopital Raymond Poincare, Garches, Franceg Hopital Pellegrin, Bordeaux, Franceh Hopital Tenon, Paris, Francei Hopital Sainte Marguerite, Marseille, Francej Centre Mutualiste de Reeducation et de Readaptation Fonctionnelles de Kerpape, Ploemeur, Francek Hopital St Jacques, Nantes, Francel Hopital Henry Gabrielle, Saint Genis Laval, Francem Centre Bouffard Vercelli, Cerbere, France

Received 25 November 2008; accepted 10 January 2009Available online 4 March 2009

KEYWORDSBotulinum toxin A;Overactive bladder;

* Correspondence to: Dr Xavier GameCedex, France. Tel.: þ335 61 323 229

E-mail address: xaviergame@hotm

1477-5131/$34 ª 2009 Journal of Peddoi:10.1016/j.jpurol.2009.01.005

Abstract Objectives: Describe and discuss the efficacy and safety of botulinum toxin type A(BTX-A) intradetrusor injections in children with neurogenic detrusor overactivity (NDO) andurinary incontinence or overactive bladder symptoms of neurogenic origin (NOAB).

, Service d’Urologie, Andrologie et Transplantation Renale, CHU Rangueil, TSA 50032, 31059 Toulouse; fax: þ335 61 323 230.ail.com (X. Game).

iatric Urology Company. Published by Elsevier Ltd. All rights reserved.

mailto:[email protected]

BTX-A intradetrusor injection for neurogenic overactive bladder 157

Neurogenic;
Urinary incontinence;Urodynamics;Children
Methods: A MEDLINE and EMBASE search for clinical studies involving BTX-A injected into thedetrusor of children with NDO or NOAB was performed, prior to data analysis.Results: A total of six articles evaluating the efficacy and safety of Botox� in patients with NDOand incontinence/NOAB were selected. The underlying neurological disease was myelomenin-gocele in 93% of patients. Most were over 2 years of age. The most common amount of Botoxinjected was 10e12 U/kg with a maximal dose of 300 U, usually as 30 injections of 10 U/ml inthe bladder (excluding the trigone) under cystoscopic guidance and general anaesthesia. Mostof the studies reported a significant improvement in clinical (65e87% became completely dry)as well as urodynamic (in most studies mean maximum detrusor pressure was reduced to<40 cm H2O and compliance was increased >20 ml/cm H2O) variables, without major adverseevents.Conclusions: Botox injections into the detrusor provide a clinically significant improvementand seem to be very well tolerated in children with NDO and incontinence/NOAB refractoryto antimuscarinics.ª 2009 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.

Introduction

In children, the most common neurological disorderresponsible for bladder dysfunction is myelomeningocele(MMC), traumatic and neoplasic spinal cord lesions beingless frequent. In these patients, the bladder can be over-active with detrusor overactivity, and diminished capacityand compliance [1]. Bladder dysfunction often imposesa threat towards the upper urinary tract (UUT) and impairsquality of life (QoL). Therefore, it represents a majorhealth problem within this population.

Children with neurogenic bladder are classically treatedwith anticholinergic drugs such as oxybutynin chloride andundergo intermittent daily catheterization (four to fivetimes) [2]. However, this therapy fails in approximately 10e15% of patients and can cause severe systemic side effects,such as dry mouth, constipation and blurred vision, thatnecessitate discontinuation of the drug even when intra-vesically administered. This group of patients are theneither treated with incontinent urinary diversion or recon-structive bladder surgery with augmentation cystoplasty.

Botulinum toxin, first isolated by van Ermengem [3] in1897, is a potent neurotoxin produced by the gram-positiveanaerobic bacterium Clostridium botulinum. The role ofbotulinum toxin at the neuromuscular junction has beenwell described and consists of inhibition of acetylcholineneurotransmitter release resulting in striated musclerelaxation [4]. However, increasing evidence suggestsa much greater range of neurologic effects of botulinumtoxin. Botulinum toxin has been found to inhibit the releaseof a number of neurotransmitters (including acetylcholine,adenosine triphosphate, and neuropeptides such assubstance P) and to down-regulate the expression of puri-nergic and capsaicin receptors on afferent neurons withinthe bladder [5,6]. These data support the belief thatbotulinum toxin works to treat detrusor overactivity andoveractive bladder by both sensory and motor pathways.

Of the seven distinct but structurally similar serotypes ofbotulinum toxin, types A and B have been used with clini-cally beneficial outcomes in various neurological disorders.In children, the serotype A product, botulinum toxin A(BTX-A), is used worldwide and is becoming a standard inthe treatment of spasticity secondary to cerebral palsy [7].

No systemic side effects have been reported when theappropriate dose is used [7].

The use of BTX-A was first investigated in 1990 for thetreatment of detrusor external sphincter dyssynergia inadult patients with spinal cord injury [8]. Following itssuccess for this indication, the effect of injecting BTX-Ainto the detrusor muscle of adults with neurogenic detrusoroveractivity (NDO) was first presented at the InternationalContinence Society meeting in 1999 by Stohrer et al. [9].Encouraged by these results, in 2002, Schulte-Baukloh et al.reported the first study showing the effect of botulinum-Atoxin on children with NDO [10]. Although BTX-A is not yetapproved by the US Food and Drug Administration (FDA) orthe European Medicines Agency (EMEA) for the treatment ofpatients with NDO or neurogenic overactive bladder(NOAB), two toxins are commercially available (Botox�,Allergan, Irvine, CA, USA and Dysport�, Ipsen-Biotech,Paris, France).

The use of BTX-A in the treatment of children with NDOaims to improve urinary symptoms, reduce UUT risk andimprove QoL. This has been developed as a second-linetreatment option (i.e. intolerance or failure after treat-ment and evaluation with an appropriate dose and for anappropriate period, min. 2 months, of antimuscarinics) forchildren with NDO with urinary incontinence or other NOABsymptoms able and willing to perform clean intermittent(self)-catheterization (CIC). Children with clear contrain-dications to BTX-A (e.g. patients with myasthenia gravis)should be excluded from treatment.

There is currently no clear consensus about the optimaluse of this innovative treatment in clinical practice. Issuesof optimal dose, number and location of injections, type ofcystoscope, and required anaesthesia depending ondisorder aetiology, timing to repeat injection and safetycould have an important impact on clinical outcomes andneed further investigation.

Based on the results of a systematic literature review ofclinical studies evaluating the efficacy or safety (or both) ofBTX-A in children with NDO/NOAB and subsequent clinicalexpert discussion of the outcomes, this review will providemore insight into these topics on an evidence-based medi-cine level. We will only discuss the use of Botox, becauseBotox and Dysport are biologic products that differ in terms

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158 X. Game et al.

of intrinsic pharmacodynamic features (due to variability inneurotoxin-derived bacterial strain, excipients andmanufacturing process) and dose contained in each vial [7e9]. Several studies have demonstrated that this leads tosignificant differences in the adverse events (AEs) profilebetween Botox and Dysport [9e12].

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Methods

Search strategy

A literature search was performed of the MEDLINE (PubMed)and EMBASE (from 1993 until March 2007) databases inFebruary and March 2007 to retrieve fully published English-language clinical studies on BTX-A. In MEDLINE, the searchwas performed by exploding and combining the followingmedical subject heading (MeSH) terms: ‘Urinary bladder,Neurogenic’ and ‘Botulinum Toxin Type A’. The results werelimited for ‘English-language’. Thereafter, the limitations‘human’, ‘clinical trial’ and ‘all children (0e18 years)’ wereused; recently published (2005e2007) review articles wereidentified by limiting for ‘review’. In EMBASE, the searchwas performed by exploding the EMTREE term ‘Neurogenic-Bladder’ and combining this with ‘Botulinum-Toxin-A’. Theresults were limited to ‘English-language’.

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Selection of studies for data extraction

The abstracts of the MEDLINE and EMBASE English-languagereferences were all read to select articles that concernedclinical studies evaluating the efficacy or safety (or both) ofBTX-A intradetrusor injection in children suffering fromNDO/NOAB. The records of the MEDLINE limitations searchfor ‘human’, ‘clinical trial’ and ‘all child (0e18 years)’were also used to identify these articles/studies. Referencelists of review articles, identified by limiting the MEDLINEsearch for ‘review’, were also checked to pick up anymissed articles/studies. Exclusion criteria included refer-ences that concerned urethral sphincter injection, patientswith detrusor sphincter dyssynergia, or the BTX-A productof Dysport. Studies involving both Botox and Dysportwithout separate analyses were also excluded. Whenselected articles concerned the same study, only the latestreport with the highest number of patients or longestfollow-up was included.

Table

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Schult

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[11]

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2013

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Data extraction

Each of the studies/articles was reviewed for extracting: (1)study and patient characteristics; (2) injection protocolcharacteristics; (3) impact on clinical variables [number ofmicturition and incontinence episodes/24 h, number (%) ofpatients becoming partially or fully continent, impact on useof antimuscarinics]; (4) impact on urodynamic variables[maximum detrusor pressure (Pdetmax), maximum cysto-metric capacity (MCC), reflex detrusor volume (RDV), i.e.bladder volume at first involuntary detrusor contraction, andbladder compliance]; and (5) percentage of patients withAEs, in particular injection site pain, UTI, haematuria,

Table 2 Botox injection protocol characteristics.

Firstauthor

Amount ofBotox (U)

Dilution Type ofcystoscope

Injectionsites

Number ofinjections

Type ofanaesthesia

Schulte-Baukloh [11] 12/kg (max. 300) 12/kg/15e20 ml Rigid Dome and base 30e50Schulte-Baukloh [12] 12/kg (max. 300) 12/kg/15e20 ml Rigid Dome and base 30e50 GeneralRiccabona [13] 10/kg (max. 360) 10 Rigid Dome and base 25e40 GeneralSchulte-Baukloh [14] 12/kg (max. 300) 12/kg/15e20 ml Dome and base 30e40 GeneralAltaweel [15] 5/kg (max. 300) 10 Dome and base 10e30 GeneralKajbafzadeh [16] 10/kg 10/kg/20 ml Dome and base 40 General


urinary retention, de-novo CIC and muscle weakness. Thedata were extracted by one person and thereafter quality-controlled by a second person.

Data interpretation

The extracted data were reviewed, interpreted and dis-cussed to propose recommendations for use in clinicalpractice based on level of evidence and expert opinion. Theoutcome is integrated in the Results and Discussion below.

Results

MEDLINE and EMBASE search

The MEDLINE search identified 52 and the EMBASE search58 English-language papers on the use of BTX-A for NDO/NOAB. After applying the selection criteria and checkingthe reference list of several review articles [7,8,13e16] topick up any missed articles/studies, a total of six articlesconcerning clinical studies with Botox were selected(Table 1).

Study and patient characteristics

Of the 108 patients included in the six selected studies(Table 1), all patients had NDO with urinary incontinenceand/or NOAB and refractory to usually high doses of

Table 3 Impact on the mean incontinence score.

First author No. of patients Mean baseline

Schulte-Baukloh [12]Wk 4 14 2.4Wk 12 15 2.4

Riccabona [13]Wk 12 15a 3.0Wk 36 15a 3.0Wk 52 15a 3.0

Schulte-Baukloh [14] 17 2.4

Kajbafzadeh [16] 26 2.5

Incontinence score is rated from 0 (completely dry) to 3 (wet >50% o***P< 0.001.

a All patients received a second injection after 1 year.b Similar improvement after second injection.

antimuscarinic agents. The underlying neurological diseasewas MMC in 93% of the patients. Mean age was 9.8 years. Itranged from 1 to 20 years. The initial bladder emptyingmodality was CIC in 98.1% of these patients. All studieswere small-scale open-label studies enrolling fewer than 26patients [10e15]. Follow-up ranged from 12 to 26 weeks,except for one study evaluating the impact of repeatedinjections which lasted 1 year [12].

Injection protocol

The amount of Botox injected ranged from 5 to 12 U/kgwith a maximal dose of 360 U (Table 1), usually as 30injection sites (range: 10e50) of 10 U/ml (range: 10/kg/20 mle12/kg/15 ml) in the bladder (sparing the trigone)under cystoscopic guidance (rigid) and under generalanaesthesia (Table 2).

Efficacy

Clinical variable: continenceIn the studies reporting the impact of Botox on the urinaryincontinence score, the mean reduction from baseline ofurinary incontinence score varied between 40% and 80%(Table 3). Furthermore, between 65% and 87% of patientsbecame completely continent (between CICs) after Botoxtreatment.

Mean endpoint Mean changevs baseline

Mean %change vs baseline

1.1 �1.3 �541.7 �0.7 �29

0.5 �2.5b*** �830.7 �2.3b*** �772.7 �0.3b �10

1.4 �1 �39

0.3 �2.2*** �88

f episodes between CICs).

4235

43 40

22

83

0

10

20

30

40

50

60

70

80

90

Schult

e-Bau

kloh [

10]

Schult

e-Bau

kloh [

11]

Riccab

ona [

12]

Schult

e-Bau

kloh [

13]

Altawee

l [14]

Kajbafz

adeh

[15]

En

dp

oin

t P

det.m

ax (cm

H

2O

)

Figure 1 Mean maximum detrusor pressure (Pdetmax) atendpoint (lowest value per study included). In most of thestudies mean Pdetmax was reduced to <40 cm H2O, thegenerally desired Pdetmax for UUT protection.

160 X. Game et al.

Urodynamic variablesA positive impact of Botox treatment on urodynamic vari-ables was demonstrated. Table 4 shows the impact onPdetmax, with mean Pdetmax at baseline ranging from 43to about 139 cm H2O. All studies showed a significantimpact of Botox in reducing Pdetmax. The percentagemean reduction in Pdetmax from baseline was approxi-mately 33e55% (if considering for each study the largestreduction over time). Moreover, in most of the studies,mean Pdetmax was reduced with Botox to <40 cm H2O,which is generally regarded as the desired Pdetmax for UUTprotection [16] (Fig. 1). The reduction in Pdetmax wasaccompanied by an increase in MCC (Table 5). The meanMCC at baseline was between 110 and 200 ml. In moststudies, the percentage increase in mean MCC from base-line ranged between 35 and 80% with increases of 100e170%in studies of patients with a relatively low mean MCC atbaseline [12,15]. Many studies also assessed the RDV, whichwas significantly increased from baseline after Botoxintradetrusor injection [10e13]. Table 6 shows the impacton RDV. Bladder compliance is a urodynamic variable usefulto monitor long-term safety of treatment using Botox� aswell as an outcome variable in patients with NDO, espe-cially in myelomeningocele patients. Although the meanbaseline value was decreased in the majority of studies (infour of the five studies that reported bladder compliancethe mean baseline value was <20 ml/cm H2O), bladdercompliance increased with treatment compared to baseline(Table 6). In most studies, the percentage increase in meanbladder compliance from baseline ranged between 58% and180%. Moreover, in most studies mean bladder compliancewas improved after intradetrusor injection of Botox� to>20 ml/cm H2O (Table 7).

Table 4 Impact of Botox on Pdetmax (cm H2O).

First author No. of patients Mean baseline

Schulte-Baukloh [11]First injection 10 65.7Third injection 10 73.6First injection 4c 52.0Fifth injection 4 58.5

Schulte-Baukloh [12]Wk 4 14 59.6Wk 12 15 59.6Wk 24 8 59.6

Riccabona [13]Wk 12 15d 78.8Wk 36 15d 78.8Wk 48 15d 78.8

Schulte-Baukloh [14] 17 58.9Altaweel [15] 20 43.0a

Kajbafzadeh [16] 26 139.3

**P< 0.01, and ***P< 0.001.a Results for 13 continent patients.b Similar improvement after second injection.c Same patients who received fifth injection.d All patients received a second injection after 1 year.e Similar improvement after second injection.

Onset, time to maximum, and duration of effect/timingof repeat injectionsSeveral authors noticed the improvement in terms ofcontinence and urodynamic parameters within 2 weeksafter Botox injection. These benefits persisted for 2 weeks,4 weeks, 3 months [11] and 6 months [13]. Schulte-Bauklohand Altaweel reported the persistence of effect afterrepeated injections in patients who received at least tworepeated injections. The mean time interval between

Mean endpoint Mean changevs baseline


60.7 �5.0 �841.8 �31.8 �4348.3 �3.7 �736.0 �22.8 �39

34.9 �24.7** �4146.7 �12.9 �2261.8 2.2 4

42.8 �36.0e*** �4648.3 �30.5e*** �3977.7 �1.1e �1

39.7 �19.2** �3321.6a �21.4b** �5083.2 �56.1** �40

Table 5 Impact of Botox on MCC (ml).

First author No. of patients Mean baseline Meanendpoint

Mean changevs baseline


Schulte-Baukloh [11]First injection 10 111.9 231.3 119.4 107Third injection 10 214.6 220.8 6.2 3First injection 4c 160.3 301.0 140.7 88Fifth injection 4 235.3 403.7 168.4 72

Schulte-Baukloh [12]Wk 4 14 163.1 219.9 56.8** 35Wk 12 15 163.1 200.6 37.5** 23Wk 24 8 163.1 222.4 59.3** 36

Riccabona [13]Wk 12 15d 136.3 297.0 160.7e*** 118Wk 36 15d 136.3 284.0 147.7e*** 108Wk 48 15d 136.3 154.0 17.7e 13

Schulte-Baukloh [14] 17 137.5 215.3 77.8** 57Altaweel [15] 20 215.6a 338.3a 122.7b** 57Kajbafzadeh [16] 26 102.8 270.2 167.4** 163



repeated Botox injections ranged between 6.3 and 9.6months with sustained efficacy both in terms of urinaryincontinence score and urodynamic variables.

SafetyBotox intradetrusor injections were well tolerated in all sixstudies. Although the occurrence of local or systemic AEswas not very well reported in most of the studies, most

Table 6 Impact of Botox on RDV (ml).

First author No. of patients Mean baseline M

Schulte-Baukloh [11]First injection 10 68.1 1Third injection 10 100.2 1First injection 4a 98.8 1Fifth injection 4 172.3 3

Schulte-Baukloh [12]Wk 4 14 97.1 1Wk 12 15 97.1 1Wk 24 8 97.1 1

Riccabona [13]Wk 12 15b 72 2Wk 36 15b 72 2Wk 48 15b 72

Schulte-Baukloh [14] 17 95.0 2

**P< 0.01, and ***P< 0.001.a Same patients who received fifth injection.b All patients received a second injection after 1 year.c Similar improvement after second injection.

frequent AEs appeared to be procedure-related UTI (in 7e20% of patients). Muscle weakness was not reported to haveoccurred in any of the studies.

Discussion

From this systematic literature review and as previouslyreported in adults [17], we can conclude that injection of

ean endpoint Mean changevs baseline

Mean % change vsbaseline

46.7 78.6 11563.3 63.1 6378.3 79.5 8023.7 151.4 88

78.6 81.5** 8462.8 65.7** 6819.3 22.2 23

98 226c*** 31468 196c*** 27283 11c 15

01.5 106.5** 112

162 X. Game et al.

Botox into the detrusor of children with NDO and urinaryincontinence or other NOAB symptoms who have failed anti-muscarinic therapy has beneficial effects both on clinical andurodynamic variables. Complete continence was achieved inaround 65e87% of patients; in most studies mean Pdetmaxwas reduced to at least 40 cm H2O and bladder compliancewas increased to at least 20 cm H2O. However, these resultsare limited by the lack of controlled studies and the fact thatmost of the studies involved small numbers [10e15].

The underlying neurological disease was almost alwaysa MMC (93% of the patients). However, we believe thatintradetrusor injection of Botox can be proposed in otherneurologic conditions such as SCI and cerebral palsy. Futurestudies should assess the impact of intradetrusor injectionof Botox in these patients. The most common minimal agerequired to propose intradetrusor injection of Botox was 2years. This limit corresponds to that approved by the FDAand EMEA for the treatment of juvenile cerebral palsy.

The most commonly used dose of Botox is 10 U/kg witha maximal dose of 300 U. This dose was given according tothose given for other neuropaediatric indications [7], anddoes not exceed the dose proposed by Schurch et al. inadults [18]. Unfortunately, no dose-study has been per-formed in children and so no conclusions could be reachedregarding the optimal dose.

Usually, 30 injections of 10 U/kg/ml were performed. Asproposed in adults, the number of injections could bereduced. Hence, the long-term risk of fibrosis could poten-tially be reduced and injections consequently be made lesspainful, therefore allowing local anaesthesia, especially inadolescent patients. However, the risk of a false puncture interms of systemic AEs may be increased and should thereforebe assessed. It may be worthwhile to investigate thesepotential differences between 10 and 30 injections.

Table 7 Impact of Botox on bladder compliance (ml/cm H2O).

First author No. of patients Mean baseline M

Schulte-Baukloh [11]First injection 10 11.2 1Third injection 10 9.1 1First injection 4c 21.7 2Fifth injection 4 10.3 2

Schulte-Baukloh [12]Wk 4 14 15.8 5Wk 12 15 15.8 2Wk 24 8 15.8 1

Riccabona [13]Wk 12 15d 18.3 5Wk 36 15d 18.3 4Wk 48 15d 18.3 2

Schulte-Baukloh [14] 17 20.4 4

Altaweel [15] 20 5.2a 1


In all studies, injections have been performed directlyinto the detrusor, sparing trigon, using a rigid cystoscopeand under general anaesthesia. However, we believe thatlocal anaesthesia may be proposed to older patients withnon-preserved bladder and urethral sensibility. Generalanaesthesia may be considered for extremely anxious orsensitive patients, for the youngest patients, and forneurogenic patients who are at risk of autonomicdysreflexia.

Botox has a fast onset of action with significant effectsreached within 2 weeks and maximum effects within 4e6weeks. The longer term repeated injections study suggeststhat the effect of an intradetrusor injection of Botox lastsfor 34 weeks or approximately 7e8 months [13,14]. Theshorter-term studies suggest that the duration of action wasshorter, between 3 and 6 months [11,12]. The duration ofeffect should therefore be further clarified in specificallydesigned studies.

For the vast majority of studies, the antimuscarinicregimen used throughout the study was not clearlydescribed and therefore its potential impact on the efficacyof Botox cannot be assessed. Recently, Neel reported thatoxybutinin had no augmentative effect on Botox [19].Future studies should better describe the antimuscarinicregimen and the policy of dose reduction after treatment todetermine whether adjuvant antimuscarinic drugs have animpact on the efficacy or duration of effect of Botox.

An important question to be answered, based on thecurrently available data and physician experience, is howBotox can be best applied in clinical practice in children? Inour opinion, patients with symptoms related to NDO whohave failed antimuscarinic therapy, being willing and ableto perform CIC, seem to be eligible candidates for Botoxtreatment (according to their own or parents’ choice).

ean endpoint Mean changevs baseline

Mean % change vsbaseline

5.4 4.2 386.3 7.2 791.7 0.0 01.5 11.2 109

0.9 35.1** 2224.9 9.1 584.1 �1.7 �11

1.2 32.9e*** 1808.0 29.7e*** 1620.2 1.9e 10

5.2 24.8** 122

3.0a 7.8b** 150


Before treatment, the patients and their parents have tobe informed about the benefit/risk ratio, i.e. positiveoutcome in term of symptoms and QoL versus potential riskof Botox-related AEs. As most of the articles have reportedAEs, procedure-related UTIs are the common AEsmeasured. Muscle weakness was never reported in childrenafter Botox intradetrusor injections. The use of Botox inchildren is well documented for the treatment of cerebralpalsy. Current standards of Botox treatment usually involvethe treatment of multiple muscles in each session andrequire the administration of high cumulative doses ofBotox, often up to 25 U/kg body weight with maximal dosesof 400e600 U [7,20,21]. Recent analysis of a comprehensivedatabase with long-term follow-up has shown that thecorrect use of higher doses of Botox during multi-muscletreatment is rarely associated with systemic side effects, asthe total dose is distributed over multiple muscles and overmultiple injection sites per muscle [22].

In patients with MMC or cerebral palsy, when settingambulatory goals, the presence of additional neurologicalsymptoms such as spasticity and inadequate balance shouldbe taken into consideration for planning the multidisci-plinary therapy program [23]. Extensive spasticity discor-dant with the level of the MMC lesion, upper extremitydysfunction and cognitive impairment are suggestive ofconcomitant cerebral palsy due to neglected hydroceph-alus, meningitis or other brain lesions [24]. Neurosurgicaltreatment of the underlying pathology such as hydromyeliaand tethered cord may be successful, but failures are notuncommon. Satisfactory improvement of the leg may beachieved after local injections of botulinum-A toxin,allowing for adequate functional motor development [25].An optimal global treatment approach may includeconcomitant Botox intradetrusor and lower limb muscleinjections, possibly under the same general anaesthesia.Considering that the most commonly used dose of Botox forthe intradetrusor injections is 10 U/kg with a maximal doseof 300 U, it would be possible to treat further multiplelower limb muscles in each session with the reportedcumulative doses of Botox, up to the 25 U/kg body weightwith maximal doses of 400e600 U [7,20,21]. This treatmentapproach has to be further explored in specifically designedstudies.

The incidence of side effects is recognized to be lessthan 10% and the events are usually mild and transient innature. To adequately assess the incidence of specific AEsand prevent underevaluation after intradetrusor Botox�

injections, future studies should put more effort intoadequate documenting and reporting of local and systemicAEs.

Moreover, in children, there is no study that assesses theimpact of repeated injections on bladder wall, and on therisk of fibrosis and of bladder compliance alteration in time.These impacts have to be further clarified in specificallydesigned studies.

Lastly, the optimal policy for reinjections and whenpatients should return for additional injection are questionsof utmost importance. Three main options may be evalu-ated and compared: (1) reinjection after a predefined timeinterval of 7e8 months based on literature data on durationof effect, (2) reinjection after same delay as thefirst injection was active, which takes into account

interindividual variation, and (3) reinjection only based onsymptoms or urodynamic worsening. In our opinion, it is atleast clear that patients suffering from NDO/NOAB shouldnot receive repeated injections in case of remainingcompliance problems, no or limited urodynamic or symp-tomatic improvement after two injection sessions, orsevere AEs whatever the number of injections.

To further improve the future application of Botox, webelieve that research should focus on assessing the optimaldose (including dilution volume, number and location ofinjections) of Botox, also in terms of onset and duration ofeffect/timing of repeated injections. The current reportingof data does not allow us to discriminate whether theeffect on incontinence and duration of effect are only dueto Botox or also to adjuvant use of antimuscarinics. It mayalso be that combination therapy is more beneficial or mayallow the use of lower doses of antimuscarinics or Botox(with a lower rate of AEs). All of these questions should beof help in preparing further, adequately powered, well-designed, randomized and controlled trials.

Conclusion

In children with NDO/NOAB resistant to antimuscarinics,Botox intradetrusor injections have a clinically significanteffect. Treatment with Botox seems to be very well toler-ated with minimal injection site and systemic side effects.So, this treatment exhibits a very promising risk-to-benefitratio for chronic treatment of NDO/NOAB. However, well-designed, randomized controlled trials are necessary toconfirm efficacy and safety, and to assess the optimal dosewith the longest duration of efficacy. Future studies shouldalso put more effort into adequate reporting of AEs andlong-term data.

Acknowledgement

The authors are grateful to Ismar Healthcare NV, Belgiumfor conducting the systematic literature search and forproviding assistance with data extraction.

Conflict of interest

G. Karsenty is a consultant for Allergan and Medtronic.P. Denys is a consultant for Allergan, Medtronic, and OnoPharma.F. Haab is a consultant for Bayer, Astellas, Pfizer, andAllergan.E. Chartier-Kastler is a consultant for Allergan, Med-tronic, Astellas, and Coloplast.

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