Do randomised controlled trials evaluating functional outcomes following botulinum neurotoxin-A align with focal spasticity guidelines? A systematic review.

PURPOSE: The impact of botulinum neurotoxin-A (BoNT-A) on functional outcomes when managing focal muscle spasticity remains unclear. It is possible that randomised controlled trial (RCT) design and/or reporting may be a contributing factor. The objective of this review was to determine the extent to which RCTs evaluating functional outcomes following BoNT-A align with focal spasticity guidelines. MATERIALS AND METHODS: RCTs published from 2010 were included if they targeted focal spasticity, included BoNT-A, randomised a physical intervention to the upper/lower limb, or the primary outcome(s) related to the activity/participation domains of the International Classification of Functioning, Disability, and Health. Data extraction and quality appraisal using the Modified PEDro and Modified McMasters Tool were performed independently by two reviewers. General research practices were also extracted such as compliance with therapy reporting guidelines. RESULTS: Fifty-two RCTs were eligible. Individualised goal setting was uncommon (25%). Six studies (11.5%) included multi-disciplinary management, and five (9.6%) included patient/caregiver education. Four studies (7.7%) measured outcomes beyond 6 months. The Median Modified PEDro score was 11/15. CONCLUSIONS: Alignment with focal spasticity guidelines in RCTs was generally low. Our understanding of the impact of focal spasticity management on functional outcomes may be improved if RCT design aligned more closely with guideline recommendations.IMPLICATIONS FOR REHABILITATIONThe influence of BoNT-A on improved functional outcomes is yet to be determined.Individualised goal setting with a multi-disciplinary team is uncommon in an RCT design, despite it being a key guideline recommendation.Given the long-term nature of spasticity management, guidelines recommend short as well as long-term reviews following intervention however RCTs rarely assess beyond 6 months.

A synthesis and appraisal of clinical practice guidelines, consensus statements and Cochrane systematic reviews for the management of focal spasticity in adults and children.

OBJECTIVE: To identify and appraise the existing clinical practice guidelines, consensus statements and Cochrane systematic reviews for the management of adult and paediatric focal spasticity to generate a single synthesized guideline. METHODS: Systematic review of 12 electronic databases. Clinical practice guidelines, consensus statements and Cochrane systematic reviews for focal spasticity in adults and children. Included studies were appraised according to the AGREE II criteria. RESULTS: A total of 25 papers were included in this review, comprising 12 clinical practice guidelines, nine consensus statements and four Cochrane systematic reviews. The areas most strongly endorsed were: (1) management to be provided by a multi-disciplinary team, (2) therapy should be goal-directed, (3) goals to be developed in conjunction with the patient and family, and (4) importance of follow-up evaluations. There was a greater focus on activity outcomes and classification in the paediatric papers. The guidelines varied considerably in their quality, with AGREE II scores ranging from 52.8 to 97.1%. CONCLUSIONS: This systematic review has synthesized the key elements regarding principles of focal spasticity management, outcome measures, physical interventions and educational recommendations into a single, readily applied guideline available for clinical use. Despite considerable variability in the quality of the guidelines, several strong themes emerged.Implications for rehabilitationFocal spasticity management should be multi-disciplinary, patient-centred and goal-directed.Routine measurement of impairment and activity are strongly endorsed.Botulinum toxin A injection should only be provided as part of an integrated approach to focal spasticity management.

Musculoskeletal Pathology in Cerebral Palsy: A Classification System and Reliability Study.

This article presents a classification of lower limb musculoskeletal pathology (MSP) for ambulant children with cerebral palsy (CP) to identify key features from infancy to adulthood. The classification aims to improve communication, and to guide referral for interventions, which if timed appropriately, may optimise long-term musculoskeletal health and function. Consensus was achieved by discussion between staff in a Motion Analysis Laboratory (MAL). A four-stage classification system was developed: Stage 1: Hypertonia: Abnormal postures are dynamic. Stage 2: Contracture: Fixed shortening of one or more muscle-tendon units. Stage 3: Bone and joint deformity: Torsional deformities and/or joint instability (e.g., hip displacement or pes valgus), usually accompanied by contractures. Stage 4: Decompensation: Severe pathology where restoration of optimal joint and muscle-tendon function is not possible. Reliability of the classification was tested using the presentation of 16 clinical cases to a group of experienced observers, on two occasions, two weeks apart. Reliability was found to be very good to excellent, with mean Fleiss' kappa ranging from 0.72 to 0.84. Four-stages are proposed to classify lower limb MSP in children with CP. The classification was reliable in a group of clinicians who work together. We emphasise the features of decompensated MSP in the lower limb, which may not always benefit from reconstructive surgery and which can be avoided by timely intervention.

Botulinum Toxin in the Management of Children with Cerebral Palsy.

During the past 25 years, botulinum toxin type A (BoNT-A) has become the most widely used medical intervention in children with cerebral palsy. In this review we consider the gaps in our knowledge in the use of BoNT-A and reasons why muscle morphology and function in children with cerebral palsy are impaired. We review limitations in our knowledge regarding the mechanisms underlying the development of contractures and the difficulty in preventing them. It is clear from this review that injection of BoNT-A in the large muscles of both the upper and lower limbs of children with cerebral palsy will result in a predictable decrease in muscle activity, which is usually reported as a reduction in spasticity, for between 3 and 6 months. These changes are noted by the use of clinical tools such as the Modified Ashworth Scale and the Modified Tardieu Scale. Decreased muscle over-activity usually results in improved range of motion in distal joints. Injection of the gastrocnemius muscle for toe-walking in a child with hemiplegia or diplegia usually has the effect of increasing the passive range of dorsiflexion at the ankle. In our review, we found that this may result in a measurable improvement in gait by the use of observational gait scales or gait analysis, in some children. However, improvements in gait function are not always achieved and are small in magnitude and short lived. We found that some of the differences in outcomes in clinical trials may relate to the use of adjunctive interventions such as serial casting, orthoses, night splints and intensive therapy. We note that the majority of clinical trials of the use of BoNT-A in children with cerebral palsy have focussed on a single injection cycle and this is insufficient to understand the balance between benefit and harm. Most outcomes were reported in terms of changes in muscle tone and there were fewer studies with robust methodology that reported improvements in function. Changes in the domains of activities and participation have rarely been reported in studies to date. There were no clinical reviews to date that consider the findings of studies in human volunteers and in experimental animals and their relevance to clinical protocols. In this review we found that studies in human volunteers and in experimental animals show muscle atrophy after an injection of BoNT-A for at least 12 months. Muscle atrophy was accompanied by loss of contractile elements in muscle and replacement with fat and connective tissue. It is not currently known if these changes, mediated at a molecular level, are reversible. We conclude that there is a need to revise clinical protocols by using BoNT-A more thoughtfully, less frequently and with greatly enhanced monitoring of the effects on injected muscle for both short-term and long-term benefits and harms.

Antibody responses to botulinum neurotoxin type A of toxin-treated spastic equinus children with cerebral palsy: A randomized clinical trial comparing two injection schedules.

We have conducted a 26-month-long comparative study involving young patients (2-6years old) with a clinical diagnosis of spastic equinus secondary to cerebral palsy who have been treated with BoNT/A (BOTOX®, Allergan) tri-annually or annually. Serum samples were obtained to determine the presence or absence of blocking antibodies (Abs) by a mouse protection assay (MPA) and levels of anti-BoNT/A Abs by radioimmune assay (RIA). HLA DQ alleles were typed using blood samples to determine the possible association of certain HLA type(s) with the disease or with the Ab status. Blocking Abs were detected in only two out of 18 serum samples of the tri-annual group, but none were found in 20 samples of the annual group. The MPA-positive serum samples gave in RIA significantly higher anti-BoNT/A Ab-binding levels than the MPA-negative samples. On the other hand, when two MPA-positive sample data were excluded, serum samples from tri-annual and annual groups showed similar anti-BoNT/A Ab levels. Linkage of the disorder with a particular HLA DQA1 and DQB1 allele types was not observed due to the small sample size. However, by combining results with other studies on BoNT/A-treated Caucasian patients with cervical dystonia (CD), we found that, among Caucasian patients treated with BoNT/A, DQA1*01:02 and DQB1*06:04 were higher in Ab-positive than in Ab-negative patients. The genetic linkage was on the threshold of corrected significance.

Injection frequency of botulinum toxin A for spastic equinus: a randomized clinical trial.

AIM: We compared two botulinum toxin A (BoNT-A) injection frequency regimens, 12-monthly versus 4-monthly, for spastic equinus in a randomized clinical trial. The primary outcome measure was passive ankle dorsiflexion. METHOD: Forty-two ambulant children with spastic equinus, secondary to cerebral palsy (23 males and 19 females; mean age 3y 6mo, SD 13mo; GMFCS levels I [n=20], II [n=19], III [n=3]) were randomized to receive either 12-monthly or 4-monthly BoNT-A injections to the calf, over a 26-month period. Twenty-one children had spastic hemiplegia, 21 children had spastic diplegia. A fixed 6U/kg dose of Botox was injected into the gastrocnemius muscle of both limbs in children with diplegia and the gastrocsoleus of the affected limb in children with hemiplegia, under mask anaesthesia. RESULTS: Forty-two children entered the trial with 21 participants randomized to each group. There were three withdrawals and two children received serial casting midway through the trial. There was no significant difference in passive dorsiflexion between 12-monthly and 4-monthly regimens (p=0.41). There were also no significant between group differences on secondary outcome measures. There were no serious adverse events - the rate was 1.2 adverse events per child per year in the 12-monthly group and 2.2 adverse events per child per year in the 4-monthly group. Subgroup analysis revealed a significant difference in passive dorsiflexion between children with hemiplegia and diplegia (p=0.01). INTERPRETATION: There was no significant difference between 12-monthly and 4-monthly injection regimens on passive dorsiflexion or secondary outcome measures. BoNT-A injections for spastic equinus may be recommended on a 12-monthly basis.

Reproducibility of an instrumented measure for passive ankle dorsiflexion in conscious and anaesthetized children with cerebral palsy.

AIM: The aims of this study were to (1) determine whether an instrumented measure will reduce measurement error to less than 5° in children with cerebral palsy (CP), (2) determine agreement and reliability of this instrumented measure in both conscious and anaesthetized participants, and (3) compare the method with previously reported measures. METHOD: Thirty-four ambulant children (15 males, 19 females), aged 3 to 9 years, with spastic CP were studied in a tertiary-care paediatric hospital (21 with hemiplegia, 11 with diplegia, and two with quadriplegia). The majority of children functioned at Gross Motor Function Classification System level I (n=11) or II (n=18), with five children at level III. Ankle dorsiflexion at 50% bodyweight was photographed and measured. Each child was measured when conscious and when under mask anaesthesia by two experienced assessors. RESULTS: The standard error of measurement (SEM) ranged from 3.9° (anaesthetized; 95% confidence interval [CI] 3.3-4.0°) to 6.7° (conscious; 95% CI 5.3-8.0°). This compared favourably with previously reported dorsiflexion measures (SEM range 6.5-7.8°) in conscious children with CP. Intrarater reliability was good in both conditions (intraclass correlation coefficient [ICC]: range 0.95 [anaesthetized; 95% CI 0.92-0.98] to 0.86 [conscious; 95% CI 0.76-0.95]). The ICC for interrater reliability ranged from 0.87 (anaesthetized; 95% CI 0.81-0.93) to 0.65 (conscious; 95% CI 0.50-0.81). INTERPRETATION: Passive ankle dorsiflexion using an instrumented measure has face validity and may assist in the improvement of reproducibility under anaesthesia for clinical research. When an individual is conscious, this technique is not better than trained assessors using conventional goniometry reported in the literature and is not recommended for routine clinical use.

The effects of botulinum toxin injection frequency on calf muscle growth in young children with spastic cerebral palsy: a 12-month prospective study.

PURPOSE: This study was a 12-month prospective investigation of changes in the medial gastrocnemius (MG) muscle morphology in children aged 2-5 years with spastic cerebral palsy (CP) who had received no previous intramuscular injections of botulinum neurotoxin type-A (BoNT-A) and were randomised to receive either single or multiple (three) BoNT-A injections to the gastrocsoleus. MG morphological changes were compared to age-matched typically developing (TD) peers. METHODS: Thirteen children with spastic CP with a mean age of 45 (15) months and 18 TD children with a mean age of 48 (14) months participated in the study. The principal outcome measures were MG muscle volume, fascicle length, pennation angle and physiological cross-sectional area (PCSA), which were obtained using 2D and 3D ultrasound. RESULTS: The single and multiple injection frequency groups significantly increased MG muscle volume at 12 months relative to the baseline by 13 and 15 %, respectively. There were no significant differences in the MG muscle volume 28.5 (12.3) versus 30.3 (3.8) ml, fascicle length 48.0 (10.4) versus 44.8 (1.2) mm or PCSA 7.0 (1.2) versus 6.6 (1.7) cm(2) between the single and multiple injection groups, respectively, at 12 months follow-up. The change in MG muscle volume in the single and multiple injection groups was significantly lower than the TD peers by 66 and 60 %, respectively. INTERPRETATION: In young children with spastic CP, naive to BoNT-A treatment, MG muscle growth over 12 months does not appear to be influenced by intramuscular BoNT-A injection frequency. However, MG muscle growth in the spastic CP groups was significantly lower than the age-matched TD peers. It is unclear whether this is an effect of intramuscular BoNT-A injections or reduced growth rates in children with spastic CP in general. Controlled investigations and longitudinal studies with multiple measurement time points are required in order to determine the influence of BoNT-A treatment on muscle physiological and mechanical growth factors in young children with spastic CP.

Medial gastrocnemius muscle volume and fascicle length in children aged 2 to 5 years with cerebral palsy.

AIM: The aim of this article was to compare medial gastrocnemius muscle volume, physiological cross-sectional area (PCSA), muscle length, fascicle length, and pennation angle in children aged 2 to 5 years with spastic cerebral palsy (CP) and in typically developing children. method: Fifteen children with spastic CP (11 males, four females; mean age 45 mo [SD 15 mo]; five with hemiplega; 10 with diplega; 10 classified at Gross Motor Function Classification System (GMFCS) level I, five at GMFCS level II) and 20 typically developing children (11 males, nine females; mean age 48 mo [SD 14 mo]) participated in the study. Individuals with spastic CP were included if they had a minimum range of motion of 0° ankle dorsiflexion with the knee extended and were excluded if they had had previous botulinum toxin treatment to the calf muscles or previous calf surgery. Typically developing children were included if they were able to walk independently and were excluded if there was a history of previous lower leg injury or other developmental disorder affecting the lower limb. Freehand two-dimensional and three-dimensional ultrasound was used to assess muscle properties of the relaxed medial gastrocnemius muscle at three ankle joint angles: maximum dorsiflexion, neutral and maximum plantarflexion. PCSA was calculated as a function of muscle volume and muscle fascicle length and pennation angle was recorded at the neutral ankle joint angle. RESULTS: Medial gastrocnemius muscle volume was 22% lower in the group with spastic CP than in the typically developing group, which in the absence of significant group differences in neutral fascicle length gave rise to an equivalent reduction in PCSA for the group with spastic CP. Significant positive correlations were found between muscle volume and age (r=0.63-0.65) and between muscle length and age (r=0.72-0.81) in both groups. Maximum ankle dorsiflexion angle was also reduced in the group with spastic CP (8°) compared with the typically developing group (26°). INTERPRETATION: The observed reduction in muscle PCSA in the group with spastic CP would be expected to contribute to the clinically observed muscle weakness in spastic CP and suggests the need for early intervention in order to minimize loss of muscle PCSA in spastic CP.