A systematic review: efficacy of botulinum toxin in walking and quality of life in post-stroke lower limb spasticity

Stroke is a common cause of adult disability worldwide [1]. More than two thirds of the stroke survivors develop post-stroke sequelae including impaired motor functions and spasticity [2]. The prevalence of post-stroke spasticity ranges from 19.0 to 42.6% [3]. There have been many recent developments in diagnosis, management, and prevention of stroke, while advances in rehabilitation have been modest [4]. There has, however, been progress with the use of botulinum toxin (BoNTA) as a treatment to improve spasticity in the upper limb [5‐7]. Three systematic reviews [8‐10] have addressed research progress on both the upper and lower limbs, with the conclusion from two of these that the effect on the upper and lower limbs spasticity favored BoNTA [8, 9]; however, these reviews did not fulfill the criteria for inclusion in this study.

As far as the lower limb is concerned, improvement in spasticity while important is only a first stage in post-stroke improvement, and the aim of RCTs should be to address the more important questions of functional activity including walking. How well this outcome has been addressed is the aim of this study. This is also an important question for many countries to resolve, because to date, botulinum toxin A is not approved for use in the post-stroke lower limb spasticity (PSLLS) by the pharmaceutical authorities except in the USA [11].

Lower limb spasticity most commonly involves the foot and the ankle leading to equinovarus (plantarflexion and inversion) deformity. Post-stroke patients with equinovarus deformity fail to achieve optimal contact with the ground leading to a poor stance, loss of heel to toe rhythm while walking and post-stroke patients walk predominantly with plantarflexion/inversion of the foot. Transfers and walking are essentially bipedal activity involving phases like balancing on one leg and swinging the other leg forward. The awkward position of the foot in addition to spasticity impairs balance, transfer, stride, gait, and mobility, besides causing spasm and pain. In many cases, complications like falls, fractures, deep vein thrombosis, and pressure ulcers may also result [12]. Inability to walk is associated with loss of independence and premature residential aged care placement [13, 14] and in the older population contributes substantially to adverse health outcomes including activities of daily living and mortality [15]. Improving and maintaining walking ability and activities of daily living are therefore vital for post-stroke survivors [16] and a major contributor to functional improvements. The overall human and economic cost of spasticity is, therefore, considerable, and interventions potentially can deliver significant benefits [17].

Given the evidence for efficacy of BoNTA in reducing spasticity, the objective of this review was to assess the available evidence of BoNTA injection: (1) to improve mobility (using gait velocity and walking distance as measuring parameters) and quality of life (QOL) and (2) to make appropriate recommendations for further research regarding these questions.

This review shows the evidence for functional improvement such as walking and QOL using BoNTA for PSLLS to be inconclusive, given the variations and shortcomings in study designs and methodologies. Thus, we argue meta-analysis should not be undertaken to assess the efficacy of BoNTA on functional outcomes. We would, however, conclude that the studies do provide some promising indications of improvement in functional outcomes that requires re-investigation in a well-planned RCT with substantial design and analytic changes. About design, appropriate sample calculations must be based on a repeated measures design. The optimum approach to analyze repeated measures data in future RCTs would be to apply repeated measures ANOVA or a linear mixed-effects model, unlike simple linear regression and ANCOVA as applied by Johnson et al. [20]. With these methodological changes, direct comparisons between groups and between time points can be made. They also account for patient correlations with appropriate adjustments to variance estimates hence reducing the risk of reporting a type 1 error. As already mentioned, power calculations were not reported in three studies, and given the small sample assessed, this is likely to be a significant limitation. Kaji et al. [22] did report power calculations and obtained a sample larger than the one required. However, the effect size reported was lower than that assumed for the calculations (3.428 vs. 5.0) with the consequent loss of statistical power. This slipped from 90 to 80% even with the addition of approximately 11 subjects per group. While 80% power is the standard for most studies, more power is often used in clinical trials and should be used in future RCTs. Pittock et al. [23] provided power calculations and recruited a sample that was larger than indicated by the calculations. However, the obtained effect size was not reported for the parameter that was used as the basis for the power calculation, and it is difficult to establish whether the requisite power was obtained although this was likely. Sample sizes need also to take account of stratification in the study analyses. Furthermore, BT injection is a focal injection, and the effect size from such injection is likely to be small, and hence, the optimal sample size needs to be calculated using minimum clinically important difference (MCID) in the primary outcome with adequate power.

Future RCTs should include homogenous post-stroke patients with similar baseline characteristics, intact cognition, and with some walking ability. It is unlikely that patients with significant PSLLS who are unable to move will achieve active functions such as walking post-BoNTA injection. Other studies need to be designed to consider improvements for these more severe post-stroke patients. Significant receptive aphasia impedes participation in rehabilitation, and these patients should be excluded. Best outcomes may be achieved if BoNTA is administered as early as two-week post-stroke [26].

Future studies should also consider gait velocity or 6-min walk test as primary outcomes as per International Classification of Functions (ICF) [27]. Only two studies in our review included this clearly. It is also necessary to document activity limitation and participation restriction according to the International Classification of Functioning, Disability and Health [27]. Oher functional outcomes should be considered for inclusion including balance (by Berg Balance Score), Time Up and Go (TUG), and the Goal Attainment Scale (GAS). Minimization of PSLLS may facilitate recovery of balance [28]. Studies should also consider economic analyses for cost-benefit purposes such as quality-adjusted life years (QALYs) from the quality of life measures. QALYs are measures of disease burden which includes both quality and quantity of life lived and a value of health outcome.

Accuracy of the intervention using BoNTA is also dependent on the use of injection guidance such as electromyograph (EMG) or ultrasound (US). In this review, only three studies did so. The involved muscles should be identified through functional activities such as walking where possible and confirmed by EMG or US prior to proceeding with injection for optimum result. It is important to understand that the equinus component of the equinovarus deformity is caused by the spastic gastrocnemius/soleus with contributions from the tibialis posterior and other long toe flexors, whereas a varus deformity is mostly caused by the tibialis posterior. It is important to identify and inject the specific muscles causing the deformity. Pittock et al. [23] failed to do this. BoNTA works in conjunction with other conventional therapies like physiotherapy and splinting. Once BoNTA has reduced the spasticity, patients need gait training to learn new motor control facilitating the speed of walking and walking distance. Evidence suggests that intensive repetitive practice with incremental difficulty within the tolerance limit can enhance walking ability [29]. A standardized physical therapy should be designed to address intensity, frequency, and duration in future RCTs.

Three other systematic reviews deserve mentioning before concluding. The first of these by Foley et al. [30] reviewed the effects of BoNTA on gait velocity on five RCTs and three uncontrolled studies using small samples and found a small improvement in gait velocity. Two of these studies were included in our review. The second by Baker et al. [31] assessed BoNTA effects on gait speed and quality of life and found no significant effect using two of the studies included in this review. More importantly, this review was not stroke specific. Most recently, Wu et al. [32] used seven studies to assess lower limb spasticity only. The present review included four of the studies included by Wu et al. This review included studies on lower limb spasticity of heterogeneous origin, and some studies were not placebo-controlled RCTs [32].

In conclusion, this systematic review has demonstrated the need for further research into the use of BoNTA for PSLLS. There is a significant lack of well-designed RCTs assessing functional improvement in PSLLS post-BoNTA injection. It is important therefore to invest in a well-designed BoNTA study to investigate more thoroughly the effects on active functioning such as walking and functional ability in PSLLS. The compound has already demonstrated the ability to reduce spasticity, but to argue, BoNTA is a standard treatment for PSLLS, its effects on walking and functional ability must be established. It is highly recommended that study initiatives should be directed toward achieving functional outcomes and participation goals [33]. We propose an adequately powered placebo-controlled study of BoNTA on a homogenous group of patients with PSLLS who have some walking ability. The study should have the sample size calculated from the MCID of the primary functional outcome of gait velocity or other important functional outcomes including QOL, which may require larger sample size than used in studies to date. Appropriate muscle selection and targeted injection, standardized adjuvant therapy, and proper statistical methods are essential in finding the benefits on the lower-limb functions. Finally, we return to the purpose of using BoNTA for lower limb functionality. If the aim of such studies is only to reduce spasticity, this is already proven, the real challenge is improving function and quality of life. This review has informed us to design our own RCT (currently underway) in our hospital looking at the improvement of lower limb functioning such as walking and quality of life in post-stroke lower limb spasticity using botulinum toxin [34].