Botulinum neurotoxins for post‐stroke spasticity in adults: A systematic review

The aim of this systematic review was to determine whether botulinum neurotoxin (BoNT) reduce spasticity or improve function in adult patients after stroke. Eleven double‐blind randomized placebo‐controlled trials met inclusion criteria. They encompassed 782 patients, 767 (98%) of whom received BoNT/A, and 15 (2%) BoNT/B. Most studies used the Ashworth scale as primary outcome measure. Differences between treated and control groups were assessed as categorical or continuous comparisons. The overall effect on upper limb spasticity was in favor of BoNT/A. A significantly higher number of patients had a reduction of upper limb spasticity at 4‐week and 8‐week evaluations in the treatment group compared with placebo. Mean changes in joint spasticity revealed improvement 3 to 6 weeks and 9 to 12 weeks after treatment. There were insufficient data to establish BoNT/A efficacy on lower limb spasticity or the effect of BoNT/B on the upper and lower limbs. Because of inconsistency and heterogeneity of the available data, it was not possible to perform a meta‐analysis on disability and patients' reported outcomes. There was an overlapping safety profile between the treatment and the placebo groups. BoNT/A reduces upper limb spasticity in patients post‐stroke, but the improvement in functional ability remains to be established. This gap needs to be filled by new studies to assess the effect of BoNT in the context of multidisciplinary patient management. © 2009 Movement Disorder Society     

Enhancing patient–provider communication for long‐term post‐stroke spasticity management

Stroke is a major public health concern, with estimated 16 million people worldwide experiencing first‐time strokes each year, a number that is expected to rise. Two‐thirds of those experiencing a stroke are younger than 70 years of age. Stroke is a leading cause of disability in adults as a result of major sequelae that include spasticity, cognitive impairment, paresis, and depression. Disabling spasticity, defined as spasticity severe enough to require intervention, occurs in 4% of stroke survivors within 1 year of first‐time stroke. The aim of this report is to focus instead on a discussion of patient–provider communication, and its role in post‐stroke spasticity (PSS) rehabilitation within the context of patient‐centered health care. A discussion based on a review of the literature, mainly since 2000. Problems within communication are identified and suggestion to enhance communication are proposed thus improving patient‐centered goal setting/goal achievement for the effective management of spasticity rehabilitation. These are as follows: (i) involving family members, (ii) educating patients and family members on stroke and rehabilitation, and (iii) establishing a common definition for long‐term goals. Increased communication among physicians, patients, and payers may bridge some of the gaps and increase the effectiveness of PSS rehabilitation and management.     

Botulinum toxin modulates cortical maladaptation in post‐stroke spasticity

Introduction: Maladaptive plasticity involving the unaffected hemisphere (UH) in stroke patients may contribute to post‐stroke deficits, including spasticity. We investigated the central and peripheral effects of botulinum toxin in post‐stroke spasticity to determine whether there is modulation of cortical processes in the UH. Methods: Transcranial magnetic stimulation and peripheral nerve excitability studies were undertaken in 5 stroke patients with upper limb spasticity before (T1) and 6 weeks after (T2) botulinum injection. Results: Transcranial magnetic stimulation demonstrated inexcitable motor cortices of the affected hemisphere at T1 and T2, and short‐interval intracortical inhibition (SICI) in the UH was significantly reduced at T1. At T2, SICI in the UH increased significantly compared with T1, normalizing to controls, and was found to be associated with clinical improvements in spasticity. Peripheral excitability parameters were unchanged after injection. Conclusion: Cortical excitability changes were demonstrated in UH, suggesting that the clinical benefits of botulinum toxin relate to modulation of abnormal central reorganization (maladaptive plasticity) in post‐stroke spasticity. Muscle Nerve, 2013     

A literature review of the pathophysiology and onset of post‐stroke spasticity

Background: Spasticity occurs after stroke and gives rise to substantial burden for patients and caregivers. Although it has been studied for many years, its definition continues to undergo reconsideration and revision. This partly reflects the diversity of its manifestations and that its pathophysiology, although well studied, is still debated. Methods: A literature review was carried out to define the pathophysiology and risk factors for onset of post‐stroke spasticity. Results: It is clear that an acquired brain injury, including stroke, results in an imbalance of inhibitory and excitatory impulses that leads to upper motor neuron symptoms and that the location and extent of the lesions result in differing symptoms and degrees of spastic severity. The onset of spasticity is highly variable and may occur shortly or more than 1 year after stroke. The current understanding of spasticity onset is complicated by the role of contractures, which have been assumed to arise out of spasticity but may have a role in its cause. Other possibly predictive factors for the risk of post‐stroke spasticity have been identified, including early arm and leg weakness, left‐sided weakness, early reduction in activities of daily living, and a history of smoking. Conclusions: Further understanding of spasticity risk factors is necessary for the development and integration of early interventions and preventive measures to reduce spasticity onset and severity.     

Randomized,placebo‐controlled trial of incobotulinumtoxina for upper‐limb post‐stroke spasticity

Introduction: Efficacy and safety of incobotulinumtoxinA in post‐stroke upper‐limb spasticity were studied. Methods: Subjects randomized 2:1 to incobotulinumtoxinA (fixed dose 400 U) or placebo, with fixed doses for the primary target clinical pattern (PTCP; flexed elbow, 200 U; flexed wrist, 150 U; clenched fist, 100 U). Doses for non‐primary patterns were flexible within predefined ranges. Results: At week 4, incobotulinumtoxinA led to larger improvements in PTCP Ashworth scale (AS) scores than placebo [least‐squares mean change ± standard error: –0.9 ± 0.06 (n = 171) vs. –0.5 ± 0.08 (n = 88); P < 0.001], and more subjects were PTCP AS responders (≥1‐point improvement) with incobotulinumtoxinA (69.6%) than with placebo (37.5%; P < 0.001). Investigator's Global Impression of Change confirmed superiority of incobotulinumtoxinA vs. placebo (P = 0.003). IncobotulinumtoxinA was associated with functional improvements, as demonstrated in responder rates for Disability Assessment Scale principal target at week 4 (P = 0.007). Adverse events were mainly mild/moderate, and were reported by 22.4% (incobotulinumtoxinA) and 16.8% (placebo) of subjects. Conclusions: IncobotulinumtoxinA significantly improved upper‐limb spasticity and associated disability, and was well‐tolerated. Muscle Nerve 53: 415–421, 2016     

Botulinum toxin injection for post‐stroke spasticity

Introduction: The aim of this study was to evaluate test feasibility, validity, and reproducibility of the rate of force development scaling factor (RFD‐SF) for the hip muscles. Methods: Feasibility was assessed as the testing compliance, validity as the ability to compute the RFD‐SF from a linear regression, and reproducibility with a test–retest design in 20 healthy subjects. Reliability and agreement (reproducibility) were evaluated using intraclass correlation coefficient (ICC_3,1) and percent standard error of measurement (SEM), respectively. Results: The RFD‐SF testing protocol was completed successfully by all subjects, although the analysis had to be modified for hip rotators. Reliability was high (ICC_3,1 > 0.70) for all muscles except hip abductors (ICC_3,1 = 0.69) and internal rotators (ICC_3,1 = 0.58). Agreement was high for all muscles (SEM < 10%). Conclusions: Hip adductor, flexor, and external rotator RFD‐SF can be evaluated with confidence, provided the analysis is modified for external rotators, whereas hip abductor and internal rotator RFD‐SF assessment is not recommended. Muscle Nerve 50: 932–938, 2014     

Meta‐analysis of neutralizing antibody conversion with onabotulinumtoxinA (BOTOX®) across multiple indications

This meta‐analysis evaluated the frequency of neutralizing antibody (nAb) conversion with onabotulinumtoxinA (BOTOX®; Allergan) across five studied indications. The analysis was based on large, controlled or prospective, open‐label trials (durations 4 months to ≥2 years). Serum samples were analyzed for nAbs using the Mouse Protection Assay. Subjects who were antibody negative at baseline and had at least one analyzable postbaseline antibody assay result were included. The 16 clinical studies included 3,006 subjects; of these, 2,240 met the inclusion criteria for this analysis. Subjects received 1–15 treatments (mean 3.8 treatments) with onabotulinumtoxinA. Total doses per treatment cycle ranged from 10 or 20 units in glabellar lines to 20–500 units in cervical dystonia. The numbers of subjects who converted from an antibody‐negative status at baseline to antibody‐positive status at any post‐treatment time point were: cervical dystonia 4/312 (1.28%), glabellar lines 2/718 (0.28%), overactive bladder 0/22 (0%), post‐stroke spasticity 1/317 (0.32%), and primary axillary hyperhidrosis 4/871 (0.46%). Across all indications, 11/2,240 subjects (0.49%) converted from antibody negative at baseline to positive at one or more post‐treatment time points, but only three subjects became clinically unresponsive to onabotulinumtoxinA at some point following a positive assay. Based on these large trials, the frequency of antibody conversion after onabotulinumtoxinA treatment is very low, and infrequently leads to loss of efficacy. © 2010 Movement Disorder Society     

A randomized, double-blind, placebo-controlled study of the efficacy and safety of botulinum toxin type A in upper limb spasticity in patients with stroke

OBJECTIVE: To study the efficacy and safety of botulinum toxin type A (BtxA) in the treatment of upper limb muscle spasticity, caused by stroke. METHODS: This was a randomized, controlled trial. Patients received either placebo injections or a total of 1000 IU of BtxA (Dysport) into five muscles of the affected arm. Muscle tone was assessed using the Modified Ashworth Scale (MAS). Other outcome measures were the change in the joint range of motion (ROM), the Barthel index, pain score, goal attainment and the subjective evaluation of benefit by patients and investigators. The patients were assessed blind to randomization at baseline and 4, 8, 12 and 16 weeks after treatment. RESULTS: Fifty nine patients were recruited and received treatment. One patient was lost to follow-up before the last scheduled visit of the study. The group of patients who received BtxA had a significant reduction in the summed MAS score at week 4 compared with the placebo group (P=0.004). The magnitude of benefit over the 16 week follow-up period was significantly reduced for the BtxA group in the wrist (P=0.004) and the finger joints (P=0.001) when compared with the placebo. There was no statistically significant difference between the groups in the joint ROM, muscle pain, goal-attainment or the Barthel index scores at week 4 of the study. At week 16, the BtxA group showed significantly greater improvement in the passive ROM at the elbow (P=0.036). The patients' global assessment of benefit at the end of the study showed that 16 (50%) patients in the placebo group had 'much improved' or had 'some improvement' compared with 24 (92.3%) patients in the BtxA group (P=0.007). The investigators' rating for the same item was 16 (50%) and 23 (88.4%) patients, respectively (P=0.002). Sixteen and twenty patients in the BtxA and placebo groups, respectively, had an adverse event. The most frequently reported adverse events were accidental injury, respiratory and urinary tract infections and muscle pain. CONCLUSION: The findings of the present study suggest that treatment with BtxA in a dose of 1000 units reduces muscle tone in patients with post-stroke upper limb spasticity. This effect is sustained for at least 16 weeks. BtxA is safe in the dose used in this study. IMPORTANT NOTE: The authors wish to emphasize that the botulinum toxin preparation used in this study was Dysport (Ipsen Ltd) which has a different therapeutic equivalence from other commercially available product, Botox (Allergan Inc.).     

Multidomain intervention for the prevention of cognitive decline after stroke – a pooled patient‐level data analysis

Background and purpose

The aim of this pooled patient‐level data analysis was to test if multidomain interventions, addressing several modifiable vascular risk factors simultaneously, are more effective than usual post‐stroke care for the prevention of cognitive decline after stroke.

Methods

This pooled patient‐level data analysis included two randomized controlled trials using a multidomain approach to target vascular risk factors in stroke patients and cognition as primary outcome. Changes from baseline to 12 months in the trail making test (TMT)‐A, TMT‐B and 10‐words test were analysed using stepwise backward linear mixed models with study as random factor. Two analyses were based on the intention‐to‐treat (ITT) principle using different imputation approaches and one was based on complete cases.

Results

Data from 322 patients (157 assigned to multidomain intervention and 165 to standard care) were analysed. Differences between randomization groups for TMT‐A scores were found in one ITT model (P = 0.014) and approached significance in the second ITT model (P = 0.087) and for complete cases (P = 0.091). No significant intervention effects were found for any of the other cognitive variables.

Conclusion

We found indications that multidomain interventions compared with standard care can improve the scores in TMT‐A at 1 year after stroke but not those for TMT‐B or the 10‐words test. These results have to be interpreted with caution due to the small number of patients.     

Boosting the traditional physiotherapist approach for stroke spasticity using a sensorized ankle foot orthosis: a pilot study

Background: Spasticity is a motor disorder that is commonly treated manually by a physical therapist (PhT) stretching the muscles. Recent data on learning have demonstrated the importance of human-to-human interaction in improving rehabilitation: cooperative motor behavior engages specific areas of the motor system compared with execution of a task alone.

Objectives: We hypothesize that PhT-guided therapy that involves active collaboration with the patient (Pt) through shared biomechanical visual biofeedback (vBFB) positively impacts learning and performance by the Pt during ankle spasticity treatment. A sensorized ankle foot orthosis (AFO) was developed to provide online quantitative data of joint range of motion (ROM), angular velocity, and electromyographic activity to the PhT and Pt during the treatment of ankle spasticity.

Methods: Randomized controlled clinical trial. Ten subacute stroke inpatients, randomized into experimental (EXP) and control (CTRL) groups, underwent six weeks of daily treatment. The EXP group was treated with an active AFO, and the CTRL group was given an inactive AFO. Spasticity, ankle ROM, ankle active and passive joint speed, and coactivation index (CI) were assessed at enrollment and after 15–30 sessions.

Results: Spasticity and CI (p < 0.005) decreased significantly after training only in the EXP group, in association with a significant rise in active joint speed and active ROM (p < 0.05). Improvements in spasticity (p < 0.05), active joint speed (p < 0.001), and CI (p < 0.001) after treatment differed between the EXP and CTRL groups.

Conclusions: PhT–Pt sharing of exercise information, provided by joint sensorization and vBFB, improved the efficacy of the conventional approach for treating ankle spasticity in subacute stroke Pts.