Adult Limb Spasticity Research Articles

A randomized, double-blind, placebo-controlled trial of DaxibotulinumtoxinA for Injection for the treatment of upper limb spasticity in adults after stroke or traumatic brain injury.

Intramuscular injection of botulinum toxin type A is a first-line pharmacotherapy for adults with upper limb spasticity (ULS). However, reemergence of symptoms within 12 weeks of treatment is common and longer-lasting treatments are needed. To evaluate the efficacy and safety of three doses of DaxibotulinumtoxinA for Injection (DAXI) for treatment of ULS in adults with stroke or traumatic brain injury. Intramuscular injections of placebo (N = 24), DAXI 250 U (N = 22), DAXI 375 U (N = 19), or DAXI 500 U (N = 18) to the suprahypertonic muscle (SMG) and other muscle groups. Randomized, double-blind, placebo-controlled study. Twenty-six study centers across the United States. Eighty-three adult patients with ULS were randomly assigned to each treatment group and followed for up to 36 weeks. Co-primary endpoints were the Modified Ashworth Scale (MAS) score change from baseline in the designated SMG and Physician Global Impression of Change (PGIC) at Week 6. The mean changes from baseline in MAS score for the designated SMG for placebo and the DAXI 250 U, 375 U, and 500 U groups were -0.6, -0.9, -0.9, and -1.8, respectively, at Week 4 and -0.8, -0.9, -1.0, and -1.5, respectively, at Week 6. Statistically significant improvement in MAS score compared with placebo was reported only for the 500 U dose (Week 4: p < .001; Week 6: p = .049). Significant improvements in PGIC ratings compared with placebo were reported for DAXI 375 U (p = .015) and DAXI 500 U (p = .009) at Week 4 but not for any DAXI doses at Week 6. All DAXI doses were well tolerated with no trend toward more adverse events with increased dose. Results from this Phase 2 study indicate that DAXI 500 U is effective and well tolerated for treatment of adults with ULS.

Recombinant botulinum toxin as a new stage in the development of botulinum toxin therapy. Possibilities and perspectives of use in neurological practice

Currently, eight natural serotypes of botulinum neurotoxin (BNT-A-G, -X) are known. The mechanism of action of all BNT serotypes is presynaptic blockade of SNARE transport proteins (Soluble N-ethylmaleimide-sensitive factor [NSF] Attachment Protein Receptor), as a result of which the release of acetylcholine into the synaptic cleft is disrupted and neuromuscular transmission is blocked. Each botulinum toxin serotype selectively binds to its own presynaptic membrane receptor and causes cleavage of its own SNARE protein. These differences determine the neuronal specificity and activity of botulinum toxins, which leads to their unique pharmacological properties, such as activity, duration of action, and time to onset of action. In the international clinical practice, only two BNT serotypes (A and B) are allowed to be used, however, in recent years, a large number of studies on the efficacy and safety of other BNT serotypes (E, C, F) have been carried out, and technologies for changing their natural properties have been developed. One of the indications for the use of botulinum therapy in neurology is the correction of post-stroke spasticity. Currently, BNT-A is used for this purpose, clinical improvement after its injection occurs after 2 weeks, the therapeutic effect persists for 3 months, and then the symptoms of spasticity increase again, which worsens the patient's quality of life and reduces the possibility of medical rehabilitation. The use of fast-acting recombinant botulinum toxins for this purpose could help overcome this disadvantage of BNT-A therapy. Currently the LANTIMA study, supported by IPSEN company, is going on to evaluate the safety profile and level of efficacy of modified recombinant botulinum toxin type AB in the treatment of upper limb spasticity in adults.

The cost-effectiveness of abobotulinumtoxinA (Dysport) and onabotulinumtoxinA (Botox) for managing spasticity of the upper and lower limbs, and cervical dystonia

Objective To evaluate the costs and benefits associated with the use of abobotulinumtoxinA (aboBoNT-A) and onabotulinumtoxinA (onaBoNT-A) for lower limb spasticity in children, upper and lower limb spasticity in adults, and cervical dystonia in adults. Methods This pharmacoeconomic analysis compared aboBoNT-A with onaBoNT-A. A decision tree model with a 1-year time horizon was conducted from a UK National Health Service (NHS) perspective using data from a variety of sources: randomized controlled trials (RCTs), network meta-analyses (NMAs), observational studies, and a physician survey investigating treatment patterns and resource utilization. Four patient populations were included: pediatric patients with lower limb spasticity (PLL), and adults with upper limb spasticity (AUL), lower limb spasticity (ALL), and cervical dystonia (CD). Outcomes included costs, quality-adjusted life years (QALYs) gained, cost per responder, and incremental cost per QALY gained. The effectiveness of each treatment was evaluated as a response to treatment. The base case assumption was that all patients in the model continued to receive botulinum toxin type A (BoNT-A) treatments at regular intervals regardless of treatment response status. Scenario analysis evaluated the impact of discontinuing BoNT-A for patients without a response to the first injection. Results The model found that aboBoNT-A resulted in greater quality-of-life and lower costs compared with onaBoNT-A for the management of spasticity and CD in all included indications. Across populations, cost savings ranged from £304 to £3,963 and QALYs gained ranged from 0.010 to 0.02 over a 1-year time horizon. Results were robust to scenario analyses and were driven by the impact of treatment response on health-related quality-of-life. Conclusions AboBoNT-A was associated with higher treatment response, improved quality-of-life, and reduced costs in spasticity and CD versus onaBoNT-A. These findings could help deliver more effective and efficient healthcare in the NHS.

Pain Reduction in Adults with Limb Spasticity Following Treatment with IncobotulinumtoxinA: A Pooled Analysis.

Some studies have shown that incobotulinumtoxinA reduces spasticity-associated pain, but further evidence is needed. This exploratory analysis pooled pain-relief data from six Phase 2 or 3 studies of incobotulinumtoxinA (four placebo-controlled studies) for treating upper limb spasticity in adults. Spasticity-associated pain was assessed at baseline and 4 weeks post incobotulinumtoxinA injection using the disability assessment scale (DAS) for pain. Only data for patients with pain at baseline were analysed. Overall, 544 (incobotulinumtoxinA, N = 415; placebo, N = 129) of 937 patients (58.1%) experienced pain at baseline. At Week 4, a significantly greater proportion of incobotulinumtoxinA- (52.1%) than placebo-treated patients (28.7%; Chi-square p < 0.0001) showed a response (≥1-point improvement in DAS pain score). In logistic regression analysis, incobotulinumtoxinA-treated patients were 2.6 times more likely to achieve this endpoint than placebo-treated patients. A significant difference between incobotulinumtoxinA and placebo was observed regardless of baseline pain severity. Additionally, 27.1% of incobotulinumtoxinA- versus 12.4% of placebo-treated patients reported complete pain relief at Week 4 (p = 0.0006). Pain relief increased with multiple injection cycles. To achieve patient-centred care, pain relief may be considered a treatment goal in adults with spasticity-associated pain regardless of pain severity. This study contributes to understanding the benefits of incobotulinumtoxinA in treating limb spasticity-associated pain.

Hyperselective neurectomy for the treatment of upper limb spasticity in adults and children: a prospective study.

Hyperselective neurectomy (HSN) procedures in the spastic upper limb aim to reduce tone by excising some branches of the involved peripheral motor nerves, at the point of entry of each motor ramus into the target muscle. In this prospective study, 42 patients with upper limb spasticity were treated by HSN for the muscles of elbow flexion, forearm pronation and wrist flexion and evaluated for their short-term results (average 6 months) and long-term outcomes (average 31 months). Results at both time points showed an effective reduction of the spastic tone, with no decrease of muscle strength in the operated spastic muscles. Comparison of results between the two time points showed durability of the improvement, which remained statistically significant despite a slight relapse in spasticity. The results of HSN compare favourably with the other techniques of partial neurectomy; however, the technique requires a detailed knowledge of upper limb motor anatomy.Level of evidence: II.

PND35 Modeling The Economic Impact Of Incorporating AbobotulinumtoxinA Into An Institutional Formulary For FDA-Approved Indications

Botulinum toxins A (BoNT-As) are widely used for various neurologic indications, including cervical dystonia (CD) and upper and lower limb spasticity. The objective of this analysis is to estimate the overall costs of 2 BoNT-A products—onabotulinumtoxinA (onaBoNT-A) and abobotulinumtoxinA (aboBoNT-A)—for CD in adults, and limb spasticity in adults and children (aged ≥2 years), using an economic model that evaluates a formulary conversion from onaBoNT-A to aboBoNT-A.

Epidemiological Burden of Lower Limb Spasticity in Adults: A Systematic Review

Objective: The objective of this study was to investigate the burden of disease associated with lower limb spasticity (LLS) and its complications in adults.&#x0D; Methods: A systematic search of MEDLINE and EMBASE identified 9 studies published between November 2012 and July 2019 that assessed the epidemiological burden associated with LLS.&#x0D; Results: LLS was found to occur in one-third of adults after neuromyelitis optica spectrum disorder (NMOSD), one quarter to one third with multiple sclerosis, one quarter to half with Parkinson’s disease and roughly half with stroke. LLS reduces mobility and diminishes the quality of life. LLS complications, especially injuries following falls are a common occurrence.&#x0D; Conclusion: Given the high prevalence among adults with common disorders, such as stroke; the evidence on the burden of LLS is somewhat finite. Further research is needed to explore the trends over time and across different geographical regions in the incidence and prevalence of LLS. The dearth of high-quality evidence for LLS suggests a lack of awareness of the problem and interest in it, and hence, the unmet need among patients and their carers.

Casting as an adjunct to botulinum neurotoxin injection for limb spasticity in adults: A systematic review

Casting as an adjunct to botulinum neurotoxin injection for limb spasticity in adults: A systematic review

Methodology of a phase 2, randomized, double-blind, placebo-controlled, parallel group, dose-ranging, 36-week, multicenter trial to evaluate the efficacy and safety of daxibotulinumtoxinA for injection for the treatment of upper limb spasticity in adults after stroke or traumatic brain injury

Methodology of a phase 2, randomized, double-blind, placebo-controlled, parallel group, dose-ranging, 36-week, multicenter trial to evaluate the efficacy and safety of daxibotulinumtoxinA for injection for the treatment of upper limb spasticity in adults after stroke or traumatic brain injury

Evaluation of selective peripheral neurotomies in the treatment of refractory lower limb spasticity in adults

Background“Selective peripheral neurotomies” (SPNs) are indicated for the treatment of refractory focal and multifocal spasticity of lower limbs in adults. ObjectiveTo evaluate the surgical results of selective peripheral neurotomies in 20 adult patients who had refractory focal & multifocal spasticity of the lower limbs, follow up period of one year. Patients and MethodsProspective study included 20 adult patients who had refractory spasticity of the lower limbs. Preoperative evaluation for muscle tone using Modified Ashworth Score (MAS), muscle power using Medical Research Council Scale (MRCS), functional assessment using Oswestry Functional Scale (OFS) and Range Of Motion (ROM) using manual goniometry were done for all patients. All cases underwent surgery in the form of SPN of tibial, obturator, sciatic and/or femoral nerves. Follow up of the patients was done at 10th day, 3, 6months and one year postoperatively. ResultsThe mean age of patients was 31.35±12.42years. There were statistically significant improvement of muscle tone, muscle power, functional assessment and range of motion between preoperative and one year postoperative values. Improvement of the muscle tone was from a preoperative Mean±SD of 3.60±0.68 on MAS to a postoperative 2.30±0.86 at one year, improvement of muscle power on MRCS was from preoperative Mean±SD 3.75±1.08 to postoperative 4.08±0.69 at one year, There was a functional improvement from a preoperative Mean±SD of 3.0±0.73 on OFS to 3.60±0.60 at one year postoperatively. Also, there was a significant improvement between preoperative ROM Mean±SD 61.25±15.29 and one year postoperatively 72.25±12.19. ConclusionsSelective peripheral neurotomies could effectively improve muscle tone, muscle power, functional performance & range of motion in patients with refractory focal and multifocal spasticity in the lower limbs.

Efficacy of IncobotulinumtoxinA in Treatment of Lower Limb Spasticity in Adults (P4.035)

Efficacy of IncobotulinumtoxinA in Treatment of Lower Limb Spasticity in Adults (P4.035)

OnabotulinumtoxinA for Lower Limb Spasticity: Guidance From a Delphi Panel Approach

BackgroundOnabotulinumtoxinA is approved for the treatment of upper and lower limb spasticity in adults. Guidance on common postures and onabotulinumtoxinA injection paradigms for upper limb spasticity has been developed via a Delphi Panel; however, similar guidance for lower limb spasticity has not been established. ObjectiveTo define a clinically recommended treatment paradigm for the use of onabotulinumtoxinA for each common posture among patients with poststroke lower limb spasticity (PSLLS) and to identify the most common PSLLS aggregate postures. DesignClinical experts provided insight regarding onabotulinumtoxinA treatment for PSLLS using an adaptation of the Delphi consensus process. SettingDelphi panel. ParticipantsTen expert clinicians in neurology and physical medicine and rehabilitation who treat PSLLS. MethodsA minimum of 2 rounds of anonymous voting occurred for each recommendation until consensus was reached (≥66% agreement). The first round was conducted via a survey; the second round was an in-person meeting. Main Outcome MeasurementsReached consensus on muscle selection for injection, overall and per-muscle dose of onabotulinumtoxinA, number of injection sites/muscle, onabotulinumtoxinA dilution, and use of localization techniques. The most common PSLLS postures were reviewed. Recommendations were tailored toward injectors with less experience. ResultsConsensus was reached on targeted subsets of muscles for each posture. Doses ranged from 20 to 150 U for individual muscles and 50 to 300 U for limb postures. OnabotulinumtoxinA dilution 50 U/mL (2:1 ratio) was considered most appropriate but varied based on muscles selected (range, 2:1-4:1). Experts agreed that localization techniques for muscle identification during injection for all postures would be useful. For suboptimal response to injection, all panel members would increase the dose, and the majority (89%) would increase the number of treated muscles. The panel identified 3 common aggregating lower limb postures: (1) equinovarus foot and flexed toes; (2) extended knee and plantar flexed foot/ankle; and (3) plantar flexed foot/ankle and flexed toes. The recommended starting doses for each aggregate posture were 400 U, 400 U, and 300 U, respectively. ConclusionThe modified Delphi panel process provided consensus on common muscles and corresponding onabotulinumtoxinA treatment paradigms for postures associated with PSLLS that can be used for guidance in optimizing care delivery. Level of EvidenceV

Epidemiological, humanistic, and economic burden of illness of lower limb spasticity in adults: a systematic review

BackgroundThe purpose of this study was to investigate the epidemiological, humanistic, and economic burden of illness associated with adult lower limb spasticity (LLS) and its complications.MethodsA systematic search of MEDLINE and EMBASE identified 23 studies published between January 2002 and October 2012 that assessed the epidemiology, impact, and resource use associated with LLS. A hand-search of four neurology conferences identified abstracts published between 2010 and 2012.ResultsLLS was found to occur in one third of adults after stroke, half to two thirds with multiple sclerosis, and three quarters with cerebral palsy. LLS limits mobility and reduces quality of life. No clear association was found between LLS and occurrence of pain, development of contractures, or risk of falls.ConclusionThe evidence on the burden of LLS and its complications is surprisingly limited given the condition’s high prevalence among adults with common disorders, such as stroke. Further research is needed to clarify the impact of LLS, including the likelihood of thrombosis in spastic lower limbs. The dearth of high-quality evidence for LLS suggests a lack of awareness of, and interest in, the problem, and therefore, the unmet need among patients and their carers.

Intra- and Interrater Reliability of the Modified Tardieu Scale for the Assessment of Lower Limb Spasticity in Adults With Neurologic Injuries

ObjectiveTo examine the intra- and interrater reliability of the Modified Tardieu Scale (MTS) for lower limb assessment of adults with chronic neurologic injuries. DesignSingle-center intra- and interrater reliability study. SettingOutpatient neurorehabilitation unit. ParticipantsAdults (N=30; mean age ± SD, 54.1±12.5y) with various chronic neurologic injuries and lower limb spasticity. InterventionsTwo experienced physiotherapists performed slow (R2) and fast (R1) passive movements for lower limb muscles half an hour apart on the same day (interrater reliability), while a third physiotherapist took goniometric measurements only. One physiotherapist repeated the assessment 1 to 3 days earlier or later (intrarater reliability). Assessors qualitatively rated the resistance to fast passive movements. Main Outcome MeasuresIntraclass correlation coefficients (ICCs) and limits of agreement (LOA) were calculated for R1, R2, and R2–R1. Kappa coefficients were calculated for tibialis range of movement and qualitative spasticity ratings. ResultsIntra- and interrater R1 and R2 measurements showed moderate to high reliability for the affected hamstrings, rectus femoris, gastrocnemius, soleus (mean ICC ± SD, .79±.08), and tibialis anterior (mean κ ± SD, .58±.10). Only intrarater measurements of the affected tibialis posterior were moderately reliable (R1=.57, R2=.77). Seven of 16 spasticity angle measurements of the affected muscles were moderately reliable. LOA were mostly unacceptably wide. Qualitative spasticity ratings were moderately reliable for affected hamstrings, gastrocnemius, and tibialis muscles (mean κ ± SD, .52±.10). ConclusionsThe MTS is reliable for assessing spasticity in most lower limb muscles of adults with chronic neurologic injuries. Repeated MTS measurements of spasticity are best based on R1 measurements rather than spasticity angle or qualitative ratings of spasticity. Optimally, MTS measurements should be undertaken by the same clinician.

Multidisciplinary rehabilitation following botulinum toxin and other focal intramuscular treatment for post-stroke spasticity

Spasticity may affect stroke survivors by contributing to activity limitations, caregiver burden, pain and reduced quality of life (QoL). Spasticity management guidelines recommend multidisciplinary (MD) rehabilitation programmes following botulinum toxin (BoNT) treatment for post-stroke spasticity.However, the evidence base for the effectiveness of MD rehabilitation is unclear. To assess the effectiveness of MD rehabilitation, following BoNT and other focal intramuscular treatments such as phenol, in improving activity limitations and other outcomes in adults and children with post-stroke spasticity. To explore what settings, types and intensities of rehabilitation programmes are effective. We searched the Cochrane Stroke Group Trials Register (February 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 12), MEDLINE (1948 to December 2011), EMBASE (1980 to January 2012), CINAHL (1982 to January 2012), AMED (1985 to January 2012), LILACS (1982 to September 2012), PEDro, REHABDATA and OpenGrey (September 2012). In an effort to identify further published, unpublished and ongoing trials we searched trials registries and reference lists, handsearched journals and contacted authors. We included randomised controlled trials (RCTs) that compared MD rehabilitation (delivered by two or more disciplines in conjunction with medical input) following BoNT and other focal intramuscular treatments for post-stroke spasticity with placebo, routinely available local services, or lower levels of intervention; or studies that compared MD rehabilitation in different settings, of different types, or at different levels of intensity. We excluded RCTs that assessed the effectiveness of unidisciplinary therapy (for example physiotherapy only) or a single modality (for example stretching, casting, electrical stimulation or splinting only). The primary outcomes were validated measures of activity level (active and passive function) according to the World Health Organization's International Classification of Functioning, Disability and Health. Secondary outcomes included measures of symptoms, impairments, participation, QoL, impact on caregivers and adverse events. We independently selected the trials, extracted data, and assessed methodological quality using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE). Due to the limited number of included studies, with clinical, methodological and statistical heterogeneity, quantitative meta-analysis was not possible. Therefore, GRADE provided qualitative synthesis of 'best evidence'. We included three RCTs involving 91 participants. All three studies scored 'low quality' on the methodological quality assessment, implying high risk of bias.All studies investigated various types and intensities of outpatient rehabilitation programmes following BoNT for upper limb spasticity in adults with chronic stroke. Rehabilitation programmes included: modified constraint-induced movement therapy (mCIMT) compared with a neurodevelopmental therapy programme; task practice therapy with cyclic functional electrical stimulation (FES) compared with task practice therapy only; and occupational, manual therapy with dynamic elbow extension splinting compared with occupational therapy only. There was 'low quality' evidence for mCIMT improving upper limb motor function and spasticity in chronic stroke survivors with residual voluntary upper limb activity, up to six months, and 'very low quality' evidence for dynamic elbow splinting and occupational therapy reducing elbow range of movement at 14 weeks. Task practice therapy with cyclic FES did not improve upper limb function more than task practice therapy alone, only at 12 weeks. No studies addressed interventions in children and those with lower limb spasticity, or after other focal intramuscular treatments for spasticity. At best there was 'low level' evidence for the effectiveness of outpatient MD rehabilitation in improving active function and impairments following BoNT for upper limb spasticity in adults with chronic stroke.No trials explored the effect of MD rehabilitation on 'passive function' (caring for the affected limb), caregiver burden, or the individual's priority goals for treatment. The optimal types (modalities, therapy approaches, settings) and intensities of therapy for improving activity (active and passive function) in adults and children with post-stroke spasticity, in the short and longer term, are unclear. Further research is required to build evidence in this area.

Clinical Measurement of Limb Spasticity in Adults

Spasticity is a neuromuscular dysfunction characterized by tight or stiff muscles. Spasticity occurs across the spectrum of upper motor neuron disease and complicates the course and quality of life of those affected. Accurate and precise assessment of spasticity is the first step in providing safe and effective treatments to patients for management of spasticity. Examiner evaluations (Ashworth Scale, Modified Ashworth, and Visual Analog Scale) and patient self-reports (Visual Analog Scale and Numeric Rating Scale) are used to assess spasticity in clinical practice. We reviewed the biology of spasticity and summarized research that assessed properties of scores obtained from clinical scales when used in a variety of upper motor neuron diseases. The definition of spasticity was inconsistent. Rater reliability or agreement on clinical scales varied widely. Correspondence with electromyogram results was mixed. There was dissimilarity in patient reports and examiner assessments. Scores from clinical scales are responsive (decrease after initiation of treatment with known effectiveness), but the utility of scores for indexing individual change associated with the natural history of upper motor neuron disease is unknown. Future research incorporating patient reports and examiner findings over time will help to clarify the definition and capture the essence of spasticity.

Botulinum toxin for the management of adult patients with upper motor neuron syndrome

The upper motor neuron (UMN) syndrome is a collection of interactive positive signs (associated with spastic hypertonia) and negative signs, such as muscle weakness and loss of voluntary control. In clinical practice, the distinction between active and passive functions allows identifying appropriate treatment objectives. During the last decades, many studies have evaluated the possibility to treat UMN syndromes with botulinum neurotoxin (BoNT). They have shown that BoNT is effective in controlling upper limb spasticity in adults. The clinical improvement is more consistent in the distal joints and the reduction of muscle hypertonia is dose-dependent. The functional efficacy of BoNT for lower limb spasticity has not been documented as well, as some series report efficacy in reducing muscle tone in the lower limb, but not in improving walking. The functional benefit arising from the reduction of spasticity is often difficult to judge in the context of the complex phenomenology of the UMN syndrome. Certain data indicate that some disabilities related to passive and active function in the upper limb can improve with treatment. However, to date, the functional improvement after BoNT treatment in patients with UMN symptoms remains a point of ambiguity in the literature. BoNT is overall well tolerated and must be regarded as a safe treatment intervention. Safety data are abundant in the literature for type-A toxin and scant for type-B toxin. There is no clear evidence to suggest the best time to introduce BoNT injections in the management of UMN syndromes. A common sense approach would be to introduce BoNT treatment as early as possible, in order to prevent further complications including contractures.