Spasticity is a complex and often disabling symptom for patients with upper motor neuron syndromes. Although spasticity arises from neurological disease, it often cascades into muscle and soft tissue ...changes, which may exacerbate symptoms and further hamper function. Effective management therefore hinges on early recognition and treatment. To this end, the definition of spasticity has expanded over time to more accurately reflect the spectrum of symptoms experienced by persons with this disorder.
Once identified, clinical and research quantitative assessments of spasticity are hindered by the uniqueness of presentations both for individuals and for specific neurological diagnoses. Objective measures in isolation often fail to reflect the complex functional impact of spasticity. Multiple tools exist to quantitatively or qualitatively assess the severity of spasticity, including clinician and patient‐reported measures as well as electrodiagnostic, mechanical, and ultrasound measures. A combination of objective and patient‐reported outcomes is likely required to better reflect the burden of spasticity symptoms in an individual.
Therapeutic options exist for the treatment of spasticity along a broad spectrum from nonpharmacologic to interventional procedures. Treatment strategies may include exercise, physical agent modalities, oral medications, injections, pumps, and surgery. Optimal spasticity management most often requires a multimodal approach, combining pharmacological management with interventions that match the functional needs, goals, and preferences of the patient. Physicians and other healthcare providers who manage spasticity must be familiarized with the full array of spasticity interventions and must frequently reassess results of treatment to ensure the patient's goals of treatment are met.
Cervical dystonia (CD) is primarily treated with botulinum toxin, at intervals of ≥ 12 weeks. We present efficacy, patient-reported outcomes (PROs), and safety in adults with CD at the last available ...visit after a single set of abobotulinumtoxinA (aboBoNT-A) injections versus placebo using 500 U in a 2-mL injection volume. In this 12-week, randomized, double-blind trial, patients were ≥ 18 years of age with primary idiopathic CD, had a Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total score ≥ 20, and TWSTRS-Severity subscale score > 10 at baseline. Patients (N = 134) were randomized (2:1) to aboBoNT-A (n = 89) or placebo (n = 45), with aboBoNT-A patients treated with 500 units (U) if toxin-naïve, and 250 to 500 U based on previous onabotulinumtoxinA dose if non-naïve. Endpoints included total TWSTRS, Pain Numeric Rating Scale (NRS-Pain; 24-hour), Treatment Satisfaction Questionnaire for Medication, and other PROs for pain, depression, and global health. Results are for the intent-to-treat population, with "Week 12" (Wk12) comprising the last available post-baseline assessment (end-of-study or early withdrawal). Mean TWSTRS total scores improved from 42.5 at baseline to 35.4 at Wk12 with aboBoNT-A and 42.4 to 40.4 with placebo (treatment difference: -4.8; 95% confidence interval CI: -8.5, -1.1; p = 0.011). At Wk12, mean (95% CI) change from baseline in NRS-Pain was -1.0 (-1.59, -0.45) for aboBoNT-A and -0.2 (-0.96, 0.65) for placebo. AboBoNT-A demonstrated numeric improvements in other PROs. More aboBoNT-A-treated patients than patients receiving placebo reported being at least "somewhat satisfied" with treatment (60.4% vs 42.2%, respectively), symptom relief (57.0% vs 40.0%), and time for treatment to work (55.8% vs 33.3%). No new adverse events were reported. Results indicate that in patients with CD, treatment with aboBoNT-A using a 2-mL injection provided sustained improvement in the TWSTRS total score and patient-perceived benefits up to 12 weeks. Trial registration: Clinicaltrials.gov Identified: NCT01753310.
The pooled incidences of treatment-emergent adverse events (TEAEs) were examined by indication using the integrated clinical database of Merz-sponsored, placebo-controlled, or repeat-dose studies of ...incobotulinumtoxinA in adults with cervical dystonia, blepharospasm, limb spasticity, sialorrhea, or essential tremor of the upper limb. Overall incidences of TEAEs, serious TEAEs, TEAEs leading to discontinuation, fatal TEAEs, TEAEs of special interest (TEAESIs; indicating possible toxin spread), and treatment-related (TR) events were determined for incobotulinumtoxinA and placebo after a single injection and for repeated dose cycles of incobotulinumtoxinA. The most frequent events after a single dose of incobotulinumtoxinA are summarized. After a single cycle, incidences of overall TEAEs were similar between incobotulinumtoxinA and the placebo in most indications, although between-indication differences were observed. Few TEAEs led to incobotulinumtoxinA discontinuation; there were no fatal TEAEs with incobotulinumtoxinA. In general, repeated cycles did not increase the incidence of any event. The most frequent TR-TEAEs were indication-dependent, including dysphagia for indications affecting the head or neck. The TR-TEAESIs across all indications were most commonly muscular weakness, dysphagia and dry mouth. Overall, the results of this pooled analysis support and extend the favorable safety and tolerability profile of incobotulinumtoxinA for the treatment of adult neurological disorders established by individual clinical studies.
A strong correlation has been reported between patient-reported quality of life (QoL) and the investigator-rated Disability Assessment Scale (DAS) in patients with spasticity. The current analysis ...evaluates the effect of incobotulinumtoxinA on QoL-related outcomes (limb position abnormality, as well as dressing- and hygiene-related disability, measured with the DAS) in adults with upper limb spasticity, using pooled data from six studies. Separate analyses for each DAS domain were performed using data from patients with disabilities for that domain (DAS score ≥1). Results showed that a significantly greater proportion of incobotulinumtoxinA-treated compared with placebo-treated patients achieved a ≥1-point reduction from baseline in each of the DAS domains (improvement) 4 weeks after the first injection. The benefits of incobotulinumtoxinA were observed regardless of the baseline severity of DAS impairment and of the time elapsed since stroke. The effects of incobotulinumtoxinA 4 weeks after injection were maintained or enhanced over multiple injection cycles for all three DAS domains, supporting the use of repeated injection cycles to provide sustained QoL benefit. IncobotulinumtoxinA represents an important treatment option to achieve better QoL-related outcomes for patients with upper limb spasticity, irrespective of the duration of their condition.
Poststroke spasticity often negatively affects functional activities and daily living and frequently is accompanied by pain, abnormal limb postures, and contractures. The purpose of this case report ...is to describe the long-term benefit of botulinum toxin A in a patient with poststroke spasticity.
A 35-year-old woman with poststroke upper-limb spasticity who had lost function in her left hand was treated with onabotulinumtoxinA and physical therapy. Over 25 months, the patient received a physical therapy and occupational therapy program and received onabotulinumtoxinA injections into muscles of the left hand and arm, significantly reducing tone and facilitating recovery of function. Practical assessments, the Ashworth Scale, and electrophysiology were used to measure changes over time. No functional scales or dexterity scales were used to measure changes.
OnabotulinumtoxinA injections were discontinued when treatment goals were attained, and no further improvements were achieved. After more than 2½ years without further onabotulinumtoxinA treatments, the patient maintained range of motion and some functional use and dexterity in her left hand.
This case report illustrates the efficacy and long-term benefit of onabotulinumtoxinA, combined with physical therapy and occupational therapy, in the successful treatment of poststroke spasticity.
Background
OnabotulinumtoxinA 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.
Objective
To 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.
Design
Clinical experts provided insight regarding onabotulinumtoxinA treatment for PSLLS using an adaptation of the Delphi consensus process.
Setting
Delphi panel.
Participants
Ten expert clinicians in neurology and physical medicine and rehabilitation who treat PSLLS.
Methods
A 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 Measurements
Reached 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.
Results
Consensus 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.
Conclusion
The 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 Evidence
V
Introduction
The safety and efficacy of both abobotulinumtoxinA and onabotulinumtoxinA for upper limb spasticity are well established, but head-to-head comparisons are lacking.
Methods
DIRECTION is ...an international, randomized, double-blind, crossover study comparing the safety and efficacy of abobotulinumtoxinA with onabotulinumtoxinA in the management of upper limb spasticity at doses at or near maximum recommended in product labelling. Participants (18–75 years) will be randomized (1:1) to either one cycle of abobotulinumtoxinA (900U) followed by onabotulinumtoxinA (360U) or vice versa. To maintain blinding, a fixed volume (3.6 ml) will be injected into the target upper limb muscles (four wrist and finger flexors and biceps brachii). The second treatment cycle will begin at Week 12 if retreatment criteria are fulfilled, and if not, they will be reassessed every 4 weeks until they meet retreatment parameters.
Planned Outcomes
The primary hypothesis is that there is comparable safety between products; non-inferiority will be tested based on treatment-emergent adverse event (TEAE) rates from injection to Week 12. A secondary hypothesis is that abobotulinumtoxinA has longer duration of effect than onabotulinumtoxinA. This hypothesis will be tested with secondary efficacy endpoints, including injection cycle duration, Modified Ashworth Scale, Disability Assessment Scale and Physician Global Assessment.
Trial Registration
EudraCT (
http://eudract.ema.europa.eu
): 2021-000161-32 and Clinicaltrials.gov (
http://clinicaltrials.gov
): NCT04936542.
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Overview of the study protocol by the principal investigator (MP4 185265 KB)
The aim of this study in patients with post-stroke lower limb spasticity (PSLLS) was to evaluate the relationship between time of onabotulinumtoxinA treatment relative to stroke and efficacy ...outcomes. This was a phase 3, international, multicenter, randomized, 12-week, double-blind study, followed by a repeated treatment, open-label extension. Patients were aged 18–85 years with PSLLS (Modified Ashworth Scale MAS ≥ 3) of the ankle with the most recent stroke occurring ≥ 3 months before screening. Patients (double-blind phase) were randomized (
n
= 468) to onabotulinumtoxinA 300–400 U (300 U, mandatory ankle muscles (gastrocnemius, soleus, tibialis posterior); and ≤ 100 U, optional lower limb muscles (flexor digitorum longus, flexor hallucis longus, flexor digitorum brevis, extensor hallucis, and rectus femoris) or placebo. Primary endpoint: MAS change from baseline (average score of weeks 4 and 6). Secondary endpoints: physician-assessed Clinical Global Impression of Change (CGI) average score of weeks 4 and 6 and physician-assessed Goal Attainment Scale (GAS; active and passive, weeks 8 and 12). When stratified by time since stroke (≤ 24 months,
n
= 153; > 24 months,
n
= 315, post hoc), patients treated ≤ 24 months post-stroke experienced greater improvements from baseline versus placebo in MAS (− 0.31 vs − 0.17), CGI (0.49 vs 0.12), and passive GAS scores (week 12, 0.37 vs 0.26). A ≥ − 1-point improvement in active (week 12;
p
= 0.04) and passive (week 8;
p
= 0.02) GAS scores versus placebo was achieved by more patients treated ≤ 24 months post-stroke; in patients treated > 24 months post-stroke, improvements were only observed in active scores (week 8;
p
= 0.04). OnabotulinumtoxinA 300–400 U was well tolerated, with no new safety findings.
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