Benjamin Zakine

Botulinum toxin injection for hypertonicity of the upper extremity within 12 weeks after stroke: a randomized controlled trial.

Background. Botulinum neurotoxin type A (BoNT-A) reduces upper-extremity poststroke spasticity when given 6 or more months after stroke. Effects on functional use of the arm and hand are less apparent. Objective. To determine the effect and safety of very early use of BoNT-A for patients with upper-limb spasticity. Methods. The Asia Botulinum Toxin-A Clinical Trial Designed for Early Post-stroke Spasticity (ABCDE-S; NCT00234546) was a multicenter, randomized, placebo-controlled trial conducted in patients recruited within 2 -12 weeks of first-ever stroke. Participants with a Modified Ashworth Scale (MAS) score of 1+ or above received BoNT-A (Dysport) 500 U or placebo to one or more wrist and elbow mover muscles, plus unstructured rehabilitation. The primary outcome was the MAS score in the most affected joint 4 weeks after first injection. Follow-up was 24 weeks. Results. A total of 163 patients were enrolled and assigned to placebo (n = 83) or BoNT-A (n = 80). Mean time since stroke was about 7 weeks. At 4 weeks postinjection, BoNT-A significantly improved MAS scores. Treatment effect-size estimates increased with higher baseline MAS scores from 0.45 (Q1) to 0.70 (Q3). MAS scores for all secondary end points improved with BoNT-A versus placebo at all time points (P < .0001, all visits). The Functional Motor Assessment Scale did not reveal clinically significant differences. No group differences in adverse events were found. Interpretation. BoNT-A 500 U can provide a sustained reduction in poststroke upper-limb spasticity when combined with rehabilitation in Asian patients who have mild-to-moderate hypertonicity and voluntary movement, within 2 -12 weeks of stroke. Functional use of the arm and hand was not affected.

Botulinum toxin A in the treatment of glabellar lines: scheduling the next injection.

BACKGROUND A single intramuscular treatment with botulinum toxin A (BoNT-A) into the facial muscles underlying glabellar rhytids has been shown to effectively attenuate or totally erase these lines for at least 3 months. OBJECTIVE We sought to evaluate the optimal time for a second injection of BoNT-A (Dysport, Ipsen). METHODS One hundred patients with moderate to severe glabellar rhytids at rest were randomized to a first, double-blind injection of 50 U of BoNT-A (n = 50) divided into 5 intramuscular sites, or placebo (n = 50). At monthly intervals between Month 3 and Month 6, the patient and the investigator consensually decided to repeat the injection with open-label BoNT-A in both groups. The main outcome was the time between the first and second injections. Responder ratings (mild or no glabellar lines) after the first and second injections, patient satisfaction, and safety were also assessed. RESULTS At Months 3 and 4 after the first injection, the cumulative percentage of patients having a second injection was lower in the BoNT-A group compared to the placebo group, with a significant difference at Month 4. Following the first double-blind injection, responder rates were significantly higher in BoNT-A group (up to 75%) compared to placebo up to Month 4, and a large majority of patients were significantly satisfied with the BoNT-A treatment at Month 4 (75% satisfied and completely satisfied versus 9.1% with placebo) and Month 5 (86.7% versus 0%, respectively). Headache was the most frequent adverse event in the BoNT-A group (10% versus 6% in the placebo group). No blepharoptosis was reported. CONCLUSIONS The effectiveness of 50 U of BoNT-A was confirmed for the treatment of glabellar lines. A second injection was sought within 3 to 4 months by most patients and investigators. Both injections were safe.

Upper limb international spasticity study: rationale and protocol for a large, international, multicentre prospective cohort study investigating management and goal attainment following treatment with botulinum toxin A in real-life clinical practice

Objectives This article provides an overview of the Upper Limb International Spasticity (ULIS) programme, which aims to develop a common core dataset for evaluation of real-life practice and outcomes in the treatment of upper-limb spasticity with botulinum toxin A (BoNT-A). Here we present the study protocol for ULIS-II, a large, international cohort study, to describe the rationale and steps to ensure the validity of goal attainment scaling (GAS) as the primary outcome measure. Methods and analysis design An international, multicentre, observational, prospective, before-and-after study, conducted at 84 centres in 22 countries across three continents. Participants 468 adults presenting with poststroke upper limb spasticity in whom a decision had already been made to inject BoNT-A (5–12 consecutive participants recruited per centre). Interventions Physicians were free to choose targeted muscles, BoNT-A preparation, injected doses/technique and timing of follow-up in accordance with their usual practice and the goals for treatment. Primary outcome measure: GAS. Secondary outcomes: Measurements of spasticity, standardised outcome measures and global benefits. Steps to ensure validity included: (1) targeted training of all investigators in the use of GAS; (2) within-study validation of goal statements and (3) establishment of an electronic case report form with an in-built tracking facility for separation of baseline/follow-up data. Analysis Efficacy population: all participants who had (1) BoNT-A injection and (2) subsequent assessment of GAS. Primary efficacy variable: percentage (95% CI) achievement of the primary goal from GAS following one BoNT-A injection cycle. Ethics and dissemination This non-interventional study is conducted in compliance with guidelines for good pharmacoepidemiology practices. Appropriate ethical approvals were obtained according to local regulations. ULIS-II will provide important information regarding treatment and outcomes from BoNT-A in real-life upper limb spasticity management. The results will be published separately. Registration ClinicalTrials.gov identifier: NCT01020500.

Factors influencing response to Botulinum toxin type A in patients with idiopathic cervical dystonia: results from an international observational study

Objectives Real-life data on response to Botulinum toxin A (BoNT-A) in cervical dystonia (CD) are sparse. An expert group of neurologists was convened with the overall aim of developing a definition of treatment response, which could be applied in a non-interventional study of BoNT-A-treated subjects with CD. Design International, multicentre, prospective, observational study of a single injection cycle of BoNT-A as part of normal clinical practice. Setting 38 centres across Australia, Belgium, Czech Republic, France, Germany, The Netherlands, Portugal, Russia and the UK. Participants 404 adult subjects with idiopathic CD. Most subjects were women, aged 41–60 years and had previously received BoNT-A. Outcome measures Patients were classified as responders if they met all the following four criteria: magnitude of effect (≥25% improvement Toronto Western Spasmodic Torticollis Rating Scale), duration of effect (≥12-week interval between the BoNT-A injection day and subject-reported waning of treatment effect), tolerability (absence of severe related adverse event) and subjects positive Clinical Global Improvement (CGI). Results High rates of response were observed for magnitude of effect (73.6%), tolerability (97.5%) and subjects clinical global improvement (69.8%). The subjective duration of effect criterion was achieved by 49.3% of subjects; 28.6% of subjects achieved the responder definition. Factors most strongly associated with response were age (<40 years; OR 3.9, p<0.05) and absence of baseline head tremor (OR 1.5; not significant). Conclusions Three of four criteria were met by most patients. The proposed multidimensional definition of response appears to be practical for routine practice. Unrealistically high patient expectation and subjectivity may influence the perception of a quick waning of effect, but highlights that this aspect may be a hurdle to response in some patients. Clinical registration number (NCT00833196; ClinicalTrials.gov).

Poster 343: Reconstitution Dilution Volumes and Botulinum Toxin Type A (Dysport) Doses Used to Treat Cervical Dystonia in 5 European Union Countries

codes. Preoperative VAS ranged from 1.5-10 (mean 5.94, SD 2.00). Of the patients, 70.7% had more than 6 months of symptoms before evaluation. The population was 41% men, 9.8% older than 65 years old, 2.4% with diabetes, 7.3% actively smoking, and 36.6% on opiates. Of the patients, 39.0% had medial dye spread with TFESI. Medial dye spread is not associated with differential response to the procedure (P .64 by Fisher test, P .59 by Barnard test). Age, gender, diabetes, smoking, and opiates are not associated with differential response to the treatment. However, obese patients (BMI 25) are more likely to respond positively to the injection (OR 9.34 [CI, 1.77-68.3]). Conclusions: TFESI is an effective treatment for radicular back pain. Medial dye spread is not associated with differential response to the procedure. We discovered that BMI is associated with greater pain relief with TFESI. Further studies across institutions will be needed to validate these findings.

Poster 344: Reconstitution Dilution Volumes and Botulinum Toxin Type A (Dysport) Doses Used to Treat Pediatric Cerebral Palsy in the European Union

Disclosures: M. Warnick, Ipsen, US, Employment. Objective: To assess reconstitution techniques, dosing, and injectors’ perceptions of potential adverse events (AE) when using botulinum toxin type A to treat pediatric cerebral palsy in the European Union (EU). Design: Telephone interviews were conducted with botulinum toxin type A experienced injectors about their experience and knowledge of this intervention. The survey included questions about reconstitution dilution volumes, botulinum toxin type A doses and AEs. Setting: Twenty-minute telephone interviews with EU physicians. Participants: Botulinum toxin type A experienced injectors in 5 EU countries (France [n 18], Germany [n 20], Greece [n 6], Sweden [n 4], and the UK [n 26]). Interventions: Not applicable. Main Outcome Measures: Reconstitution dilution volumes used, the average total dose and maximum dose used, and AEs. Results: The reconstitution dilution volume was typically reported as 2.5 mL/500 U. The average total Dysport doses reported by the physicians during the interviews were 375 U, 544 U, 700 U, 400 U, and 600 U for France, Germany, Greece, Sweden, and the UK, respectively. The mean maximum dose reported by the physicians during the interviews were 637 U, 906 U, 600 U, 467 U, and 1148 U for France, Germany, Greece, Sweden, and the UK, respectively. When treating pediatric cerebral palsy with botulinum toxin type A, 17% to 40% of the surveyed physicians in the different countries specified potential AEs. The most common AE noted for patients with pediatric cerebral palsy was leg muscle weakness (29%-100% of physicians). Conclusions: Most surveyed physicians reported using a reconstitution dilution volume of 2.5 mL/500 U (ie, 200 U/mL), but they reported using a range of average total botulinum toxin type A doses in the different countries (range, 375-700 U). Leg muscle weakness was the most common potential AE specified by physicians for pediatric cerebral palsy.