Botulinum toxin A in the treatment of the spastic hip in cerebral palsy

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To determine the safety and effectiveness of BTX‐A in treating the spastic hip and preventing hip dislocation in CP.

Background

Description of the condition

Cerebral palsy (CP) is the most common cause of childhood physical disability in developed countries, affecting two children for 1000 live births (Graham 2008).  In geographic regions where prenatal, maternal and perinatal infant care are poor, the overall incidence can be even higher (Renshaw 1990).

Hip involvement is the second most common orthopaedic problem in cerebral palsy, after equinus of the foot (Boyd 2001). About 70 to 90% of the hip problems in CP occur with spastic quadriplegia. The muscular imbalance, acetabular dysplasia and excessive femoral neck anteversion and valgus, frequently leads to subluxation and dislocation (Renshaw 1990). Hip dislocation can lead to pain and worsening of sitting balance. Furthermore, adduction contracture of the hips can make parental care very demanding (Cooperman 1987).

Early recognition and treatment of the "hips at risk" can provide short‐term prevention of subluxation and dislocation (Sharrard 1975). Unfortunately, it is often difficult to detect this condition clinically in the early stages, making regular hip radiographs mandatory in cerebral palsy. In fact, the introduction of hip surveillance programmes allowed earlier identification of subluxation and reduced the late sequelae and the need for surgery on dislocated hips (Gordon 2006).

The soft‐tissue release procedures, including adductor and iliopsoas tenotomy, are commonly employed on the "hips at risk" to prevent dislocation. They are usually indicated as an isolated procedure in patients with less than 30° of abduction, hip migration index higher than 25% and preferably not older than 5 years (Flynn 2002). A small number of complications are related to the surgical treatment, including local hematoma, wound infection, skin ulcers caused by the plaster cast, failure to stop hip migration, extension‐abduction contractures and unilateral abduction contractures in patients with previous windblown deformity (Terjesen 2005). In addition, these children often have respiratory problems, further increasing surgical morbidity.

In this setting, the introduction of minimally invasive procedures, that could be done on an outpatient basis, would be an important addition to the therapeutic possibilities for these children.

Description of the intervention

Botulinum toxin (BTX) is produced by Clostridium botulinum, a gram‐positive anaerobic bacterium. There are seven distinct serological types of the toxin, which are structurally similar. Human botulism usually occurs following ingestion of contaminated food or after wound infection, mainly by BTX types A, B and E (Brin 1997). Common initial symptoms include nausea, vomiting, disphagia, dry mouth and diplopia. Muscular weakness follows, including respiratory muscles paralysis, which can lead to respiratory failure.

The toxin consists of a heavy chain and a light chain connected by disulphide bridges. The heavy chain promotes binding of the BTX to high‐affinity recognition sites on the cholinergic nerve terminals, while the light chain is internalised and decreases acetylcholine release, which induces a neuromuscular blockade (Brin 1997, Kostrzewa 2007).

The therapeutic use of BTX was first suggested by the german physician Justinus Kerner (1786‐1862), who called the toxin "sausage poison". In the 1950's, Dr. Vernon Brookes discovered that intramuscular injections of Botulinum Toxin type A (BTX‐A) could block acetylcholine release from motor nerve endings (Erbguth 1999). During the following years, several authors have published studies on the therapeutic use of BTX‐A in a diversity of medical conditions, showing its safety by inducing focal muscle weakness without serious systemic effects.

In the last decades, BTX has been introduced on the treatment of CP. Most of the research published on the subject, have studied BTX‐A effectiveness on the equinus deformity of the foot (Ackman 2005; Satila 2005; Kay 2004).

How the intervention might work

Initial reports employing BTX‐A to address hip pathology in CP have shown that, by inducing adductor and iliopsoas neuromuscular blockade, spasticity could be substantially reduced in a number of cases, improving overall function (Pascual‐Pascual 1997). Furthermore, non‐randomised studies have shown a short‐term success on preventing hip subluxation, especially in mild cases and in younger children (Pascual‐Pascual 2003, Pidcock 2005).

Recent randomised controlled trials have been conducted to evaluate the role of BTX on controlling adductor spasticity and preventing hip dislocation in CP, as compared to non‐intervention groups (Graham 2008; Jozwiak 2007; Boyd 2001). Nevertheless, the results were contradictory.

A Cochrane review has already addressed the subject of BTX‐A in leg spasticity, although it has not evaluated its use to prevent hip subluxation (Ade‐Hall 2000).

Why it is important to do this review

CP is a relatively common disorder and hip instability, which if untreated may result in hip dislocation, is one of its most serious musculoskeletal complications. Hip dislocation can be a very demanding condition to treat, especially in a child with physical disabilities. Traditional surgical approaches can be associated with increased morbidity in this patient group.

There is evidence suggesting that the use of BTX‐A to treat hip spasticity may be a safer alternative to operative treatment in the patient with CP (Pascual‐Pascual 2003, Pidcock 2005, Jozwiak 2007).  However, to date, there has been no systematic review of therapeutic strategies on this subject.

Therefore, we intended to systematically review the published evidence pertaining to the effectiveness and safety of BTX‐A therapy to treat the spastic hip in CP and prevent hip displacement, in order to provide evidence based information to guide clinical practice.

Objectives

To determine the safety and effectiveness of BTX‐A in treating the spastic hip and preventing hip dislocation in CP.

Methods

Criteria for considering studies for this review

Types of studies

We evaluated all randomised and quasi‐randomised controlled trials. A quasi‐randomised trial (qRCT) uses a pseudo‐random sequence generation method. We planned to include qRCTs following the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008), which state that:

"A trial is eligible if, on the basis of the best available information (usually from one or more published reports), it is judged that the individuals (or other units) followed in the trial were definitely or possibly assigned prospectively to one of two (or more) alternative forms of health care using: (1) random allocation or (2) some quasi‐random method of allocation (such as alternation, date of birth, or case record number)."

Types of participants

Children with spastic CP (diplegic, hemiplegic and quadriplegic) associated with hip adductor and/or iliopsoas spasticity.

Trials including individuals with other diagnoses were not included.

Types of interventions

We included clinical trials that compared BTX‐A injections (associated or isolated) on adductors and/or iliopsoas with any of the following interventions:

• Surgical soft‐tissue release

• Physical therapy

• Conservative therapy

• Orthosis

• Others

Trials studying BTX‐A injections in other muscles in addition to adductors and/or iliopsoas were included only if subgroup data could be extracted separately.

Types of outcome measures

From the studies reviewed, the following outcomes were identified by the authors as relevant outcome measures of success on the use of BTX‐A to control hip spasticity and prevent dislocation in CP.

Primary outcomes

‐ Progression of the Hip Migration Percentage (Reimers 1980)

‐ Progression to surgery

Secondary outcomes

‐ Gross Motor Function Measure (GMFM) ‐ (Russel 1989)

‐ Spasticity as assessed by the modified Ashworth scale (Bohannon 1987)

‐ Passive hip abduction

‐ Knee‐knee distance

‐ Adverse events and Complications

Search methods for identification of studies

Electronic searches

We used the search strategy recommended by the Cochrane Movement Disorders Group to find relevant articles for the review, by using search terms and synonyms for "Botulinum toxin A", "Cerebral Palsy" (Appendix 1) and filters to recruit clinical trials. Our search strategy was designed to retrieve the largest possible number of references regarding CP and BTX‐A, in order not to miss studies addressing lower limb spasticity that could be evaluating the hip as a subgroup.

We searched MEDLINE via PubMed (1966 to June 2013), Cochrane Central Register of Clinical Trials (CENTRAL) via Wiley (Issue 6 of 12, June 2013), EMBASE via OVID (1966 to June 2013), CINAHL via EBSCO (1982 to June 2013), PEDro (June 2013) and LILACS via BIREME (1982 to June 2013).

The following bibliographic databases were searched using the filters outlined below: MEDLINE (Appendix 2), EMBASE (Appendix 3), LILACS (Appendix 4), CINAHL (Appendix 5). However, too few articles were retrieved from the LILACS database when we used the filter to recruit RCTs, which lead us to proceed with an unrestricted search. There were no date or language restrictions in the electronic searches for trials.

Searching other resources

We manually searched references of relevant studies and meetings, as well as contacted authors to obtain information on additional non‐published studies. Ongoing trials were searched in the Current Controlled Trials web site (http://www.controlled‐trials.com/).

Data collection and analysis

Selection of studies

Two independent review authors (FCB, BNGS) screened the titles and abstracts of the citations produced by the literature search to determine if the inclusion criteria were met. Any disagreements were resolved through negotiation with a third review author (JAP) serving as an arbitrator if necessary. We classified abstracts as relevant, potentially relevant, or not relevant for this review according to the following criteria:

Relevant:

• Intervention: Use of Botulinum Toxin in adductors and/or iliopsoas.

• Participants: Children with cerebral palsy.

• Study type: Randomised Controlled Trial.

Potentially Relevant:

• Intervention: Use of Botulinum Toxin for lower limb spasticity without describing which muscle groups were addressed.

• Participants: Children with cerebral palsy

• Study type: Prospective study (not describing whether it is a randomised and/or controlled trial)

• Other: Articles without abstracts in which it can be inferred by the title that the intervention and participants criteria might be fulfilled. Articles without abstracts described as "Comparative Study" in the electronic database.

Not Relevant:

• Intervention: Isolated use of Botulinum Toxin for lower or upper limb spasticity without addressing adductors or iliopsoas.

• Participants: Adults with cerebral palsy, or children with any other diagnosis.

• Study type: Retrospective, case‐control, cohort or case report studies.

• Other: Articles without abstracts described as Review in the electronic database.

We obtained full article copies for those abstracts that were designated relevant or potentially relevant.

Data extraction and management

Data was extracted by two authors (FCB, BNGS) and, in case of discrepancy, a third author (JAP) was consulted for further discussion and reliability.

Data collection was undertaken according to the following criteria using specially designed extraction forms (Figure 1).

Figure 1.

Form of data extraction

‐ Study methods: randomisation procedure, method of allocation, blindness, design, duration;

‐ Participants: country of origin, sample size, age, gender, inclusion criteria, motor distribution, GMFCS (Gross Motor Function Classification Level), number of participants after randomisation and proportion of follow‐up losses;

‐ Intervention: BTX‐A (dose, time), physical therapy, orthosis, surgery;

‐ Control: placebo, physical therapy, orthosis, no treatment, other;

‐ Outcomes: primary and secondary outcomes as mentioned in the section on outcome measures.

Assessment of risk of bias in included studies

The evaluation of methodological quality and assessment of risk of bias of the selected trials were done by two authors (FCB, BNGS) by using the Cochrane Collaboration’s tool for assessing risk of bias, as described in section 8.5 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). The following items were considered in the assessment: random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting and other sources of bias.

Measures of treatment effect

Dichotomous data

For binary data, results for each study were expressed as relative risk (RR) with 95% confidence intervals (95% CI). For all statistically significant differences, data was made available as NNT (number needed to treat), meaning the number of patients who need to be treated to avoid one negative event (inverse of risk difference).

Continuous data

For continuous data, the mean post‐treatment/intervention values and standard deviation for each group were reported and the mean differences (MD) with 95% CI were calculated in a meta‐analysis whenever possible. In case there were different scales measuring the same variable, the standardised mean difference (SMD) with 95% CI was calculated.

Unit of analysis issues

The patient was used as the unit of analysis by most studies. However, whenever the included studies reported the results considering each side as a separate unit, we planned to conduct the analysis per hip or per lower extremity as to match the original data.

Dealing with missing data

Whenever possible, analyses were done in an intention‐to‐treat basis, with the purpose to include all patients randomised to any intervention. When there was insufficient information pertaining to estimate effects, we contacted the main authors from the included studies via e‐mail. Missing data was not imputed, as the strategies for imputation of data are subjective (Higgins 2008).

When adequate data to build the forest plots was not obtained (e.g. means and standard deviations), we presented the results descriptively in the main text.

Assessment of heterogeneity

Heterogeneity was assessed by examining study characteristics and forest plots of the results. We used the I‐squared test to assess the impact of statistical heterogeneity, interpreting an I‐squared of 50% or more as significant.

Assessment of reporting biases

We planned to assess publication bias by preparing a funnel plot, if sufficient number of studies were available. However, as only nine studies reporting different outcomes were included in this review this was not possible.

Data synthesis

Qualitative information

Qualitative information pertaining to methods, risk of bias, description of participants and outcomes measures were synthesized and presented in the table of Characteristics of included studies.

Quantitative information

For all statistical methods of pooling data, 95% confidence intervals (95% CI) were reported. When considered appropriate, we planned to pool results of comparable groups of trials using the fixed‐effect model. We also planned to use the random‐effects model where there was diversity in clinical or methodological characteristics between the studies included in a meta‐analysis

Subgroup analysis and investigation of heterogeneity

We planned, whenever sufficient data was available, to carry on subgroup analysis by: age, GMFCS and motor distribution. If substantial heterogeneity was found between studies on the I‐squared test, further analysis would be carried on to investigate its potential sources.

Sensitivity analysis

We planned, where possible, to conduct sensitivity analyses exploring aspects of trial and review methodology, including the effects of missing data and study quality. We also planned to analyse the impact of adding quasi‐randomised studies and unpublished data to our results.

Appendices

Appendix 1. Search terms and synonymous for Cerebral Palsy (clinical condition) and Botulinum toxin A (intervention)

#1 CP

#2 Cerebral Palsy Atonic

#3 Atonic Cerebral Palsy

#4 Cerebral Palsy Hypotonic

#5 Hypotonic Cerebral Palsies

#6 Hypotonic Cerebral Palsy

#7 Cerebral Palsy Congenital

#8 Congenital Cerebral Palsy

#9 Cerebral Palsy Diplegic Infantile

#10 Cerebral Palsy Diplegia Infantile

#11 Diplegic Infantile Cerebral Palsy

#12 Diplegia Infantile Cerebral Palsy

#13 Infantile Cerebral Palsy Diplegic

#14 Infantile Cerebral Palsy Diplegia

#15 Cerebral Palsy Dystonic‐Rigid

#16 Cerebral Palsies Dystonic‐Rigid

#17 Cerebral Palsy Dystonic Rigid

#18 Dystonic‐Rigid Cerebral Palsies

#19 Dystonic‐Rigid Cerebral Palsy

#20 Monoplegic Cerebral Palsy

#21 Monoplegia Cerebral Palsy

#22 Cerebral Palsies Monoplegic

#23 Cerebral Palsies Monoplegia

#24 Cerebral Palsy Monoplegic

#25 Cerebral Palsy Monoplegia

#26 Monoplegic Cerebral Palsies

#27 Monoplegia Cerebral Palsies

#28 Cerebral Palsy Monoplegic Infantile

#29 Cerebral Palsy Monoplegia Infantile

#30 Monoplegic Infantile Cerebral Palsy

#31 Monoplegia Infantile Cerebral Palsy

#32 Infantile Cerebral Palsy Monoplegic

#33 Infantile Cerebral Palsy Monoplegia

#34 Cerebral Palsy Quadriplegic Infantile

#35 Cerebral Palsy Quadriplegia Infantile

#36 Quadriplegic Infantile Cerebral Palsy

#37 Quadriplegia Infantile Cerebral Palsy

#38 Infantile Cerebral Palsy Quadriplegic

#39 Infantile Cerebral Palsy Quadriplegia

#40 Cerebral Palsy Rolandic Type

#41 Rolandic Type Cerebral Palsy

#42 Cerebral Palsy Spastic

#43 Spastic Cerebral Palsies

#44 Spastic Cerebral Palsy

#45 Little Disease

#46 Little's Disease

#47 Spastic Diplegia

#48 Diplegias Spastic

#49 Spastic Diplegias

#50 Diplegia Spastic

#51 Cerebral Palsy Athetoid

#52 Athetoid Cerebral Palsy

#53 Cerebral Palsies Athetoid

#54 Cerebral Palsy Dyskinetic

#55 Cerebral Palsies Dyskinetic

#56 Dyskinetic Cerebral Palsy

#57 Cerebral Palsy Mixed

#58 Mixed Cerebral Palsies

#59 Mixed Cerebral Palsy

#60 Cerebral Palsy

#61#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46 OR #47 OR #48 OR #49 OR #50 OR #51 OR #52 OR #53 OR #54 OR #55 OR #56 OR #57 OR #58 OR #59 OR #60

#62 Botulinum Toxins

#63 Toxins Botulinum

#64 Botulinum Toxin

#65 Toxin Botulinum

#66 Clostridium botulinum Toxins

#67 Toxins Clostridium botulinum

#68 botulinum Toxins Clostridium

#69 Botulin

#70 Botulinum Toxin Type A

#71 Botulinum Neurotoxin A

#72 Neurotoxin A Botulinum

#73 Clostridium Botulinum Toxin Type A

#74 Botulinum A Toxin

#75 Toxin Botulinum A

#76 Clostridium botulinum A Toxin

#77 Dysport

#78 Lasa Brand of Botulinum A Toxin

#79 Speywood Brand of Botulinum A Toxin

#80 Ipsen Brand of Botulinum A Toxin

#81 Oculinum

#82 Botox

#83 Merz Brand of Botulinum A Toxin

#84 Allergan Brand of Botulinum A Toxin

#85#62 OR #63 OR #64 OR #65 OR #66 OR #67 OR #68 OR #69 OR #70 OR #71 OR #72 OR #73 OR #74 OR #75 OR #76 OR #77 OR #78 OR #79 OR #80 OR #81 OR #82 OR #83 OR #84

#86 #61 AND #85

Appendix 2. Cochrane sensitivity‐maximizing search strategy for identifying randomised trials in MEDLINE via PUBMED

#1 randomised controlled trial [pt]

#2 controlled clinical trial [pt]

#3 randomised [tiab]

#4 placebo [tiab]

#5 drug therapy [sh]

#6 randomly [tiab]

#7 trial [tiab]

#8 groups [tiab]

#9 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8

#10 humans [mh]

#11 #9 and #10

Appendix 3. Search strategy for identifying randomised trials in EMBASE via OVID

#1 random$

#2 factorial$

#3 crossover$

#4 cross over$

#5 placebo$

#6 doubl$ adj blind$

#7 singl$ adj blind$

#8 assign$

#9 allocat$

#10 volunteer$

#11 crossover‐procedure

#12 double‐blind procedure

#13 randomised controlled trial

#14 single‐blind procedure

Appendix 4. Search strategy for identifying randomised trials in LILACS via BIREME

#1 pt ensaio controlado aleatorio

#2 pt ensaio clinico controlado

#3 mh ensaios controlados aleatorios

#4 mh distribuicao aleatoria

#5 mh método duplo‐cego

#6 mh método simples‐cego

#7 pt estudo multicentrico

#8 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7

#9 tw ensaio

#10 tw ensayo

#11 tw trial

#12 #9 OR #10 OR #11

#13 tw azar

#14 tw acaso

#15 tw placebo

#16 tw control$

#17 tw aleat$

#18 tw random$

#19 #13 OR #14 OR #15 OR #16 OR #17 OR #18

#20 tw duplo

#21 tw cego

#22 #20 AND #21

#23 tw doble

#24 tw ciego

#25 #23 AND #24

#26 tw double

#27 tw blind

#28 #26 AND #27

#29 #19 OR #22 OR #25 OR #28

#30 tw clinic$

#31 #12 AND #29 AND #30

#32 #8 OR #31

Appendix 5. Search strategy for identifying randomised trials in CINAHL via EBSCO

S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11

S11 TX allocat* random*

S10 (MH "Quantitative Studies")

S9 (MH "Placebos")

S8 TX placebo*

S7 TX random* allocat*

S6 (MH "Random Assignment")

S5 TX randomi* control* trial*

S4 TX ( (singl* n1 blind*) or (singl* n1 mask*) ) or TX ( (doubl* n1 blind*) or (doubl* n1 mask*) ) or TX ( (tripl* n1 blind*) or (tripl* n1 mask*) ) or TX ( (trebl* n1 blind*) or (trebl* n1 mask*) )

S3 TX clinic* n1 trial*

S2 PT Clinical trial

S1 (MH "Clinical Trials+")

What's new

Last assessed as up‐to‐date: 30 June 2013.

Date	Event	Description
30 June 2013	Amended	Search Updated ‐ June 2013

Contributions of authors

Conceiving the review: FCB, JAP, AI

Co‐ordinating the review: FCB, JCB

Screening search results: FCB, BNGS

Organizing retrieval of papers: FCB

Screening retrieved papers against inclusion criteria: FCB, BNGS, JAP

Appraising quality of papers: FCB, BNGS, JAP

Abstracting data from papers: FCB, BNGS

Writing to authors of papers for additional information: FCB, ETD

Providing additional data about papers: FCB, JCB

Obtaining and screening data on unpublished studies: FCB, BNGS, JAP, AI, ETD

Data management for the review: FCB, BNGS

Entering data into Review Manager (RevMan 5.0): FCB, BNGS

RevMan statistical data: FCB, BNGS, JAP, JCB

Other statistical analysis not using RevMan: FCB, BNGS

Interpretation of data: FCB, BNGS

Statistical inferences: FCB, BNGS, ETD

Writing the review: FCB, BNGS, JAP, AI, ETD

Guarantor for the review (one author) FCB

Person responsible for reading and checking review before submission: FCB, BNGS, JAP, AI, ETD, JCB

Sources of support

Internal sources

• Universidade Federal de São Paulo, Brazil.

  Educational support

External sources

• No sources of support supplied

Declarations of interest

The authors of this review have none conflict of interest known.

Notes

The protocol is out of date and does not meet the current methodological standards of The Cochrane Collaboration.

Withdrawn from publication for reasons stated in the review