Post-stroke distal lower limb spasticity impairs mobility, limiting activities of daily living, requiring additional caregiver time.
Post-stroke distal lower limb spasticity impairs mobility, limiting activities of daily living, requiring additional caregiver time.
To evaluate the efficacy, safety, and sustained benefit of onabotulinumtoxinA in adults with post-stroke lower limb spasticity (PSLLS).
A multicenter, randomized, double-blind, phase 3, placebo-controlled trial.
60 study centers across North America, Europe, Russia the United Kingdom, and South Korea.
Adult patients (18 to 65 years of age) with PSLLS (Modified Ashworth Scale [MAS] ≥3) of the ankle plantar flexors and the most recent stroke ≥3 months prior to study enrollment. .
During the open-label phase, patients received ≤3 onabotulinumtoxinA treatments (≤400 U) or placebo at approximately 12-week intervals. Treatments were into the ankle plantar flexors (onabotulinumtoxinA 300 U into ankle plantar flexors; ≤100 U, optional lower limb muscles).
The double-blind primary endpoint was MAS change from baseline (average score at weeks 4 and 6). Secondary measures included physician-assessed Clinical Global Impression of Change (CGI), MAS change from baseline in optional muscles, Goal Attainment Scale (GAS), and pain scale.
Of 468 patients enrolled, 450 (96%) completed the double-blind phase and 413 (88%) completed the study. Small improvements in MAS observed with onabotulinumtoxinA during the double-blind phase (onabotulinumtoxinA, –0.8; placebo, –0.6, P=0.01) were further enhanced with additional treatments through week 6 of the third open-label treatment cycle (onabotulinumtoxinA/onabotulinumtoxinA, –1.2; placebo/onabotulinumtoxinA, –1.4). Small improvements in CGI observed during the double-blind phase (onabotulinumtoxinA, 0.9; placebo, 0.7, P=0.01) were also further enhanced through week 6 of the third open-label treatment cycle (onabotulinumtoxinA/onabotulinumtoxinA, 1.6; placebo/onabotulinumtoxinA, 1.6). Physician- and patient-assessed GAS scores improved with each subsequent treatment. No new safety signals emerged.
OnabotulinumtoxinA significantly improved ankle MAS, CGI, and GAS scores compared with placebo; improvements were consistent and increased with repeated treatments of onabotulinumtoxinA over 1 year in patients with PSLLS.
Clinical Trial Registration URL: https://clinicaltrials.gov/ct2/show/NCT01575054?term=NCT01575054&rank=1
Objective: The main aim of this study was to determine
the utilization patterns and effectiveness of onabotulinumtoxinA (Botox®) for treatment of spasticity in clinical practice.
Design: An international, multicentre, prospective, observational study at selected sites in North America, Europe, and Asia.
Patients: Adult patients with newly diagnosed or established focal spasticity, including those who had previously received treatment with onabotulinumtoxinA.
Methods: Patients were treated with onabotulinumtoxinA, approximately every 12 weeks, according to their physician’s usual clinical practice over a period of up to 96 weeks, with a final follow-up interview at 108 weeks. Patient, physician and caregiver data were collected.
Results: Baseline characteristics are reported. Of the 745 patients enrolled by 75 healthcare providers from 54 sites, 474 patients had previously received onabotulinumtoxinA treatment for spasticity. Lower limb spasticity was more common than upper limb spasticity, with stroke the most common underlying aetiology. The Short-Form 12 (SF-12) health survey scores showed that patients’ spasticity had a greater perceived impact on physical rather than mental aspects.
Conclusion: The data collected in this study will guide the development of administration strategies to optimize the effectiveness of onabotulinumtoxinA in the management of spasticity of various underlying
Background: OnabotulinumtoxinA (BoNT-A) can temporarily decrease spasticity following stroke, but whether there is an associated improvement in upper limb function is less clear. This study measured the benefit of adding weekly rehabilitation to a background of BoNT-A treatments for chronic upper limb spasticity following stroke. Methods: This was a multi-center clinical trial. Thirty-one patients with post-stroke upper limb spasticity were treated with BoNT-A. They were then randomly assigned to 24 weeks of weekly upper limb rehabilitation or no rehabilitation. They were injected up to two times, and followed for 24 weeks. The primary outcome was change in the Fugl–Meyer upper extremity score, which measures motor function, sensation, range of motion, coordination, and speed. Results: The ‘rehab’ group significantly improved on the Fugl–Meyer upper extremity score (Visit 1 = 60, Visit 5 = 67) while the ‘no rehab’ group did not improve (Visit 1 = 59, Visit 5 = 59; p = 0.006). This improvement was largely driven by the upper extremity “movement” subscale, which showed that the ‘rehab’ group was improving (Visit 1 = 33, Visit 5 = 37) while the ‘no rehab’ group remained virtually unchanged (Visit 1 = 34, Visit 5 = 33; p = 0.034). Conclusions: Following injection of BoNT-A, adding a program of rehabilitation improved motor recovery compared to an injected group with no rehabilitation.
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To investigate a new botulinum neurotoxin type A, termed letibotulinumtoxinA(Botulax®) and compare its efficacy and safety for post-stroke upper limb spasticity with that of onabotulinumtoxinA(Botox®).
A prospective, double-blinded, multicenter, randomized controlled clinical study.
Six university hospitals in Korea.
A total of 187 stroke participants with upper limb spasticity.
Two kinds of botulinum neurotoxin type A were used. One set of injection was performed and total injected doses were 309.21±62.48U(Botulax) and 312.64±49.99U(Botox)(P>0.05).
Primary outcome was measured using the modified Ashworth scale for wrist flexors at week 4 and secondary outcome was measured using modified Ashworth scale for wrist flexors, elbow flexors, finger flexors, and thumb flexors as well as Global Assessment in spasticity, Disability Assessment Scale, and Caregiver Burden Scale. Safety measures including adverse events, vital signs and physical examination, and laboratory tests were also monitored.
The mean ages for the Botulax group were 56.81±9.49 and which for the Botox group were 56.93±11.93(P>0.05). In primary outcome, the change in modified Ashworth scale for wrist flexors was -1.45±0.61 in the Botulax group and -1.40±0.57 in the Botox group, and the difference between the two groups was -0.06(95% CI:-0.23–0.12,P>0.05). In secondary outcome, both groups demonstrated significant improvements with respect to modified Ashworth scale, Global Assessment in spasticity, Disability Assessment Scale, and Caregiver Burden Scale (P<0.05), and no significant difference was observed between the two groups (P>0.05). In addition, safety measures showed no significant differences between the two groups (P>0.05).
The efficacy and safety of Botulax were comparable with those of Botox in treatment of post-stoke upper limb spasticity.
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Patients with post-stroke spasticity (PSS) commonly experience pain in affected limbs, which may impact quality of life.
To assess onabotulinumtoxinA for pain in patients with PSS from the BOTOX® Economic Spasticity Trial, a multicenter, randomized, double-blind, placebo-controlled trial.
Patients with PSS (N=273) were randomized to 22- to 34-weeks double-blind treatment with onabotulinumtoxinA + standard care (SC) or placebo injection + SC and were eligible to receive open-label onabotulinumtoxinA up to 52 weeks. Assessments included change from baseline on the 11-point pain numeric rating scale, proportion of patients with baseline pain ≥4 achieving ≥30% and ≥50% improvement in pain, and pain interference with work at week 12, end of double-blind treatment, and week 52.
At baseline, most patients (74.3%) experienced pain and 47.4% had pain ≥4 (pain subgroup). Mean pain reduction from baseline at week 12 was significantly greater with onabotulinumtoxinA + SC (–0.77, 95% CI –1.14 to –0.40) than placebo + SC (–0.13, 95% CI –0.51 to 0.24; P < 0.05). Higher proportions of patients in the pain subgroup achieved ≥30% and ≥50% reductions in pain at week 12 with onabotulinumtoxinA + SC (53.7% and 37.0%, respectively) compared with placebo (28.8% and 18.6%, respectively;P<0.05). Reductions in pain were sustained through week 52. Compared with placebo + SC, onabotulinumtoxinA consistently reduced pain interference with work.
This is the first randomized, placebo-controlled trial demonstrating statistically significant and clinically meaningful reductions in pain and pain interference with work with onabotulinumtoxinA in patients with PSS.
Pain prevalence varies widely (10–70%) among post-stroke patients 1, 2, 3 and 4. Several mechanisms may contribute to this range (e.g., peripheral nerve damage, soft tissue trauma, central post-stroke pain, complex regional pain syndrome 5, 6, 7 and 8). Spasticity and pain are factors contributing to “learned non-use” of the affected limb and are often disabling, interfering with daily activities, sleep, walking, physiotherapy, leisure activities, and ultimately affecting patients’ quality of life 9, 10 and 11.
In randomized, double-blind, placebo-controlled trials, onabotulinumtoxinA has been shown to significantly reduce excess muscle tone and decrease disability among patients with upper-limb spasticity 12 and 13, and to further reduce spasms and improve gait in patients with lower-limb spasticity 14 and 15. OnabotulinumtoxinA is effective at reducing pain in patients with cervical dystonia and chronic migraine 16. Prospective open-label studies have shown that onabotulinumtoxinA can reduce pain in patients with post-stroke spasticity (PSS) 8, 17 and 18. However, the efficacy of onabotulinumtoxinA in reducing pain in patients with PSS has not been demonstrated in a large, randomized, placebo-controlled study.
The BOTOX® Economic Spasticity Trial (BEST) was a prospective clinical trial designed to compare the efficacy of onabotulinumtoxinA or placebo (in addition to standard care [SC]) in helping patients with PSS achieve their personal functional goals 19. Here we present results from BEST comparing the effectiveness of onabotulinumtoxinA + SC versus placebo + SC on pain.
Abstract: Poststroke spasticity affects up to one-half of stroke patients and has debilitating effects, contributing to diminished activities of daily living, quality of life, pain, and functional impairments. Botulinum toxin (BoNT) is proven to be safe and effective in the treatment of focal poststroke spasticity. The aim of this review is to highlight BoNT and its potential in the treatment of upper and lower limb poststroke spasticity. We review evidence for the efficacy of BoNT type A and B formulations and address considerations of optimal injection technique, patient and caregiver satisfaction, and potential adverse effects of BoNT.
Spasticity is a velocity-dependent increase in muscle tone as a part of the upper motor neuron syndrome and is seen in a wide variety of neurologic diseases including stroke.1 Poststroke spasticity can develop as early as 1 week after stroke,2 and it is estimated to occur in up to one-half of stroke survivors.3 The most frequent predictors of spasticity include weakness and reduced motor control.2 Long-term spasticity may lead to tendon contractures and limb deformities that can cause significant pain and functional impairment. Depending on the location of the spasticity, this can impact mobility, activities of daily living such as toileting, dressing, and transferring, and quality of life (QoL) and increase the dependence on caregivers.4
The aim of the treatment in poststroke spasticity is focused on muscle limb overactivity reduction. Treatment modalities are used to alleviate spasticity including physical therapy, systemic and intrathecal medications, and surgery. Systemic medications can be helpful if spasticity is generalized. Agents such as baclofen (gamma-aminobutyric acid [GABA]-B receptor agonist) diazepam (GABA-A receptor agonist), dantrolene (decreases calcium release from skeletal muscle sarcoplasmic reticulum), or tizanidine (TZD; alpha-2 adrenergic receptor agonist) often have systemic side effects such as dry mouth, dizziness, sedation, or generalized weakness.5 After several months of treatment, tolerance may develop to systemic medications.
Chemodenervation and neurolytic procedures with alcohol or phenol may be utilized as second-line management. These techniques are more localized and are injected perineurally to destroy the nerve causing spasticity. The effect may be limited by partial nerve regeneration and adverse effects such as bladder, bowel, and sexual dysfunction.6 Intrathecal baclofen acts on GABA receptors in the lumbar spinal cord and may improve walking speed and functional mobility in poststroke spasticity. However, this therapy is invasive and limited by side effects including nausea, vomiting, and urinary retention. Overdosing may lead to death.7,8
The aim of this review is to highlight botulinum toxin (BoNT) and its potential in the treatment of upper and lower limb poststroke spasticity. Optimal treatment may include BoNT injections into focal muscles in conjunction with an integrated multidisciplinary team approach and intensive rehabilitation programs or to help utilize affected muscles.9 Higher-intensity rehabilitation programs (≥3 1-hour weekly session for ~10 weeks) may help patients achieve more upper limb goals following BoNT injections for spasticity when compared with usual care programs (≤2 1-hour weekly sessions).10 A recent consensus panel of 44 neurologists and physiatrists with experience in BoNT therapy recommended starting a rehabilitation program during the first week after BoNT injection therapy.11
Spasticity gives rise to impairment in motor functions and activities of daily living. Botulinum toxin (BTX) can be injected to temporarily paralyze the affected muscles, which provides a window of opportunity for rehabilitation. We present our 2.5-year experience with BTX injection and a patient-specific rehabilitation program provided by a multidisciplinary team, which consists of neurosurgeons, nurses, physiotherapists, occupational therapists and prosthetic orthotists.
It is a retrospective study of prospectively collected data in a local hospital including twenty-two patients suffering from spasticity. Outcome measures include goal attainment, caregiver burden and biomechanical assessment by Modified Ashworth Scale and Modified Tardieu Scale (MTS).
OnabotulinumtoxinA injection together with rehabilitation facilitates the attainment of patient-centred physical goals in daily activities. It reduces caregiver burden. Spasticity is reduced particularly for finger and wrist flexors as well as hip adductors. Responses of ankle plantarflexors are less satisfactory which may be due to inadequate dosages. Initial improvement in the R2 component of the MTS for ankle plantarflexors and hip adductors may be attributable to the application of ankle-foot orthosis and abduction pillow.
Multidisciplinary management for spasticity is feasible within our healthcare setting and our promising findings indicate its wider adoption in this locality.
Abstract: Spasticity is a common disabling symptom for several neurological conditions. Botulinum toxin type A injection represents the gold standard treatment for focal spasticity after stroke showing efficacy, reversibility, and low prevalence of complications. In recent years, incobotulinumtoxinA, a new Botulinum toxin type A free of complexing proteins, has been used for treating several movement disorders with safety and efficacy. IncobotulinumtoxinA is currently approved for treating spasticity of the upper limb in stroke survivors, even if several studies described the use also in lower limb muscles. In the present review article, we examine the safety and effectiveness of incobotulinumtoxinA for the treatment of spasticity after stroke.
Spasticity with muscle paresis and loss of dexterity represents one of the most common and discomforting complications affecting stroke survivors. It can have a disabling effect on stroke patients through pain and reduced mobility, affecting quality of life, and can be highly detrimental to daily functioning. Previous studies, based on the estimates of health care professionals, suggested that the prevalence of poststroke spasticity was ~60%, even if this value can be lower than the real value considering the difficulties in measuring spasticity routinely in rehabilitative settings.1
In a recent study, conducted in a clinical setting, 39% of patients with first-ever stroke were spastic after 12 months.2 Lundström et al reported that an estimated prevalence of spasticity 1 year after the first-ever stroke was 17% and that it was more prevalent in the upper limb than in the lower limb.3
In another study, spasticity was present in only 19% of the 95 subjects investigated 3 months after stroke.4 The same group of authors reported that 13 subjects out of 63 displayed spasticity after 18 months of stroke.5
There is no consensus concerning the number of patients developing spasticity. The discrepancies about the prevalence of spasticity onset after stroke might be related to various study settings and samples as well as the difficulty to measure and to identify its early development, discriminating between spastic-dystonia, muscle contracture, increase of stiffness, and other biomechanical factors. It is known that spastic hypertone can be responsible for motor impairments and activity limitations as well as for forced limb posture and pain at rest and during passive movements. The degree of spasticity may change according to the position of the patients, the task being performed, and the presence of aggravating factors such as pressure ulcers, skin infections, or urinary tract infections. Therefore, considering the variability of clinical features of stroke survivors, the assessment of spasticity is difficult as well as the need for treatment. In fact, for example, it has also been suggested that for stroke patients, the overactivity of leg extensor muscles enables them to support their body, standing position, and stance phase of gait cycle but interferes with knee flexion during the swing phase, so in this case, a botulinum toxin (BoNT) injection into rectus femoris or vastus intermedius muscles can be useful to reduce this impairment.6
Spasticity is also divided into generalized and focal when few muscles are involved. This type of classification can influence the choice of treatment considering not only the therapy but also the aim to improve limb posture and body image, to apply splinting, to consent hygiene, to increase passive articular range of motion, to walk and stand, to decrease pain and discomfort, to reduce the burden of care, or to prevent contracture. The purpose of this review article is to evaluate the effectiveness of the employment of incobotulinumtoxinA, a recent marked formulation of botulinum toxin type A (BoNT-A), to reduce spasticity in stroke survivors through an analysis of published clinical studies.
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Objective: To review gait alterations and evaluate the effects of OnabotulinumtoxinA on spatiotemporal walking parameters of patients with hemiparetic gait.
Design: Retrospective pre- and post-intervention analysis.
Setting: Gait analysis laboratory in a tertiary level rehabilitation hospital.
Participants: 42 patients with hemiparesis. 19 males and 23 females, age 18-78 years were included.
Intervention: Spatiotemporal parameters collected before and within 4 to 10 weeks after OnabotA injection to the ankle muscles. Data was recorded at self-selected velocity on a 12 meter instrumented walkway. The most common muscles injected were medial and lateral gastrocnemius, soleus and tibialis posterior. Average total OnabotulinumtoxinA dose was 320±107 units.
Main Outcome: Spatiotemporal parameters of walking assessed before (T0) and within 4 to 10 weeks post injection (T1). Paired t-test was used to compare pre- and post-intervention data. A sequential Holm-Bonferroni procedure was used to adjust for multiple comparisons and minimize the risk of type I error. Statistical significance was set at p<0.05.
Results: Statistically significant increases were seen for walking velocity (20%) (T0=0.40±0.26 m/s and T1=0.48±0.29 m/s; p=0.006), and increased cadence (T0=63.48±23.93 steps/min, and T1=70.88±23.65 steps/min; p=0.006) following OnabotulinumtoxinA injections.
Conclusion: This study demonstrates that injection of OnabotulinumtoxinA 320 units to ankle muscles selected with the aid of dynamic electromyography can significantly increase gait velocity and enhance functional ambulation in adults with hemiparesis due to upper motor neuron syndrome.