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INTRODUCTION: Bulbar symptoms are frequent in patients with rapid-onset dystonia-parkinsonism (RDP). RDP is caused by ATP1A3 mutations, with onset typically within 30 days of stressor exposure. Most patients have impairments in speech (dysarthria) and voice (dysphonia). These have not been quantified. We aimed to formally characterize these in RDP subjects as compared to mutation negative family controls. METHODS: We analyzed recordings in 32 RDP subjects (male=21, female=11) and 29 mutation negative controls (male=15, female=14). Three raters, blinded to mutation status, rated speech and vocal quality. Dysarthria was classified by subtype. Dysphonia was rated via the GRBAS (Grade, Roughness, Breathiness, Asthenia, Strain) scale. We used general neurological exams and the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) to assess dysarthria, dystonia, and speech/swallowing dysfunction. RESULTS: The presence of dysarthria was more frequent in RDP subjects compared to controls (72% vs. 17%, p< 0.0001). GRBAS voice ratings were worse in the RDP cohort across nearly all categories. Dysarthria in RDP was associated with concordant cranial nerve 9–11 dysfunction (54%, p=0.048), speech/swallowing dysfunction (96%, p=0.0003); and oral dystonia (88%, p=0.001). CONCLUSIONS: Quantitative voice and speech analyses are important in assessing RDP. Subjects frequently experience dysarthria and dysphonia. Dystonia is not the exclusive voice abnormality present in this population. In our analysis, RDP subjects more frequently experienced bulbar symptoms than controls. GRBAS scores are useful in quantifying voice impairment, potentially allowing for better assessments of progression or treatment effects. Future directions include using task-specific diagnostic and perceptual voice evaluation tools to further assess laryngeal dystonia.

BACKGROUND: Botulinum toxin (BoNT) injections were shown to improve muscle tone of limbs in patients with spasticity. However, limited data are available regarding the effects of repeated BoNT injections on walking ability. OBJECTIVE: To assess changes in walking velocity (WV), step length, and cadence under different test conditions after repeated treatment with abobotulinumtoxinA (aboBoNT-A; Dysport) in spastic lower limb muscles. DESIGN: Secondary analysis of an open-label, multiple-cycle extension (National Clinical Trials number NCT01251367) to a phase III, double-blind, randomized, placebo-controlled, single-treatment cycle study, in adults with chronic hemiparesis (NCT01249404). SETTING: Fifty-two centers across Australia, Belgium, the Czech Republic, France, Hungary, Italy, Poland, Portugal, Russia, Slovakia, and the United States. PATIENTS: 352 Ambulatory adults (18-80 years) with spastic hemiparesis and gait dysfunction caused by stroke or traumatic brain injury, with a comfortable barefoot WV of 0.1 to 0.8 m/s. INTERVENTIONS: Up to four aboBoNT-A treatment cycles, administered to spastic lower limb muscles. MAIN OUTCOME MEASUREMENTS: Changes from baseline in comfortable and maximal barefoot and with shoes WV (m/s), step length (m/step), and cadence (steps/minutes). RESULTS: At Week 12 after four injections, WV improved by 0.08 to 0.10 m/s, step length by 0.03 to 0.04 m/step, and cadence by 3.9 to 6.2 steps/minutes depending on test condition (all P < .0001 to .0003 vs baseline). More patients (7% to 17%) became unlimited community ambulators (WV ≥0.8 m/s) across test conditions compared with baseline, with 39% of 151 patients classified as unlimited community ambulators in at least one test condition and 17% in all four test conditions. CONCLUSIONS: Clinically meaningful and statistically significant improvements in WV, step length, and cadence under all four test conditions were observed in patients with spastic hemiparesis after each aboBoNT-A treatment cycle.

Background and purpose\ud Several clinical and demographic factors relate to anatomic spread of adult-onset isolated dystonia, but a predictive model is still lacking. The aims of this study were: (i) to develop and validate a predictive model of anatomic spread of adult-onset isolated dystonia; and (ii) to evaluate whether presence of tremor associated with dystonia influences model predictions of spread.\ud \ud Methods\ud Adult-onset isolated dystonia participants with focal onset from the Dystonia Coalition Natural History Project database were included. We developed two prediction models, one with dystonia as sole disease manifestation (“dystonia-only”) and one accepting dystonia OR tremor in any body part as disease manifestations (“dystonia OR tremor”). Demographic and clinical predictors were selected based on previous evidence, clinical plausibility of association with spread, or both. We used logistic regressions and evaluated model discrimination and calibration. Internal validation was carried out based on bootstrapping.\ud \ud Results\ud Both predictive models showed an area under the curve of 0.65 (95% confidence intervals 0.62–0.70 and 0.62–0.69, respectively) and good calibration after internal validation. In both models, onset of dystonia in body regions other than the neck, older age, depression and history of neck trauma were predictors of spread.\ud \ud Conclusions\ud This predictive modeling of spread in adult-onset isolated dystonia based on accessible predictors (demographic and clinical) can be easily implemented to inform individuals’ risk of spread. Because tremor did not influence prediction of spread, our results support the argument that tremor is a part of the dystonia syndrome, and not an independent or coincidental disorder.

BACKGROUND Poststroke spasticity affects motor function and the ability to perform activities of daily living, with the potential to affect quality of life (QoL) and increase caregiver burden. OBJECTIVE To investigate the effect of repeated incobotulinumtoxinA treatment on spasticity-associated functional disability, caregiver burden, and QoL in the 36-week open-label extension of the phase 3 PURE study (NCT01392300). DESIGN Open-label extension period of a prospective, double-blind, placebo-controlled, randomized, multicenter study. SETTING Forty-six investigation sites in seven countries (Czech Republic, Germany, Hungary, India, Poland, Russia, United States). PARTICIPANTS Adults, aged 18-80 years, ≥12 months since last botulinum neurotoxin injection or entirely toxin naive, with median poststroke upper-limb spasticity of >2 years' duration. METHODS Participants who completed the 12-week, double-blind main period could enter the open-label extension and receive up to three additional incobotulinumtoxinA treatments (fixed total dose 400 U at 12-week intervals) into the affected muscles of one upper limb. MAIN OUTCOME MEASURES Functional disability (Disability Assessment Scale; DAS), caregiver burden (Carer Burden Scale), and quality of life (QoL; EuroQol [EQ] 5-dimensions three-level [EQ-5D-3L]). RESULTS The open-label extension included 296 treated patients. Mean DAS score for the principal target domain improved significantly from the main period baseline to the end-of-study visit (P

Background and objectives Rapid-onset dystonia-parkinsonism (RDP) is caused by mutations in the ATP1A3 gene, which codes for the α-3 subunit of the Na+ /K+ ATPase. It has been characterized by rapid-onset bulbar dysfunction, limb dystonia, bradykinesia, and a rostrocaudal spatial gradient of expression, usually after a physiologic trigger. We reexamined whether these features were in fact characteristic. Methods We characterized phenotypic variation within a cohort of 50 ATP1A3 mutation-positive individuals (carriers) and 44 mutation-negative family members (noncarriers). Potential participants were gathered through referral for clinical suspicion of RDP or alternating hemiplegia of childhood. Inclusion criteria were having a ATP1A3 mutation or being a family member of such an individual. Results We found RDP is underdiagnosed if only "characteristic" patients are tested. Rapid onset and bulbar predominance were not universally present in carriers. Among those with at least mild symptoms of dystonia, rostrocaudal severity gradient was rare (7%). Symptoms began focally but progressed to be generalized (51%) or multifocal (49%). Arm (41%) onset was most common. Arms and voice were typically most severely affected (48% and 44%, respectively). Triggers preceded onset in 77% of the participants. Rapid onset, dystonia, parkinsonism, bulbar symptoms, headaches, seizures, frontal impairment, and a history of mood disorder and a history of psychosis were more common in carriers. Approximately half of the proband mutations occurred de novo (56%). Conclusions Our findings suggest that patients should not be excluded from ATP1A3 testing because of slow onset, limb onset, absent family history, or onset in middle adulthood. RDP should be strongly considered in the differential for any bulbar dystonia. © 2019 International Parkinson and Movement Disorder Society.

BACKGROUND Several monogenic causes for isolated dystonia have been identified, but they collectively account for only a small proportion of cases. Two genome-wide association studies have reported a few potential dystonia risk loci; but conclusions have been limited by small sample sizes, partial coverage of genetic variants, or poor reproducibility. OBJECTIVE To identify robust genetic variants and loci in a large multicenter cervical dystonia cohort using a genome-wide approach. METHODS We performed a genome-wide association study using cervical dystonia samples from the Dystonia Coalition. Logistic and linear regressions, including age, sex, and population structure as covariates, were employed to assess variant- and gene-based genetic associations with disease status and age at onset. We also performed a replication study for an identified genome-wide significant signal. RESULTS After quality control, 919 cervical dystonia patients compared with 1491 controls of European ancestry were included in the analyses. We identified one genome-wide significant variant (rs2219975, chromosome 3, upstream of COL8A1, P-value 3.04 × 10-8 ). The association was not replicated in a newly genotyped sample of 473 cervical dystonia cases and 481 controls. Gene-based analysis identified DENND1A to be significantly associated with cervical dystonia (P-value 1.23 × 10-6 ). One low-frequency variant was associated with lower age-at-onset (16.4 ± 2.9 years, P-value = 3.07 × 10-8 , minor allele frequency = 0.01), located within the GABBR2 gene on chromosome 9 (rs147331823). CONCLUSION The genetic underpinnings of cervical dystonia are complex and likely consist of multiple distinct variants of small effect sizes. Larger sample sizes may be needed to provide sufficient statistical power to address the presumably multi-genic etiology of cervical dystonia. © 2021 International Parkinson and Movement Disorder Society.

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.

Two randomized, placebo-controlled studies evaluated the pulmonary function safety of onabotulinumtoxinA (onabotA) for treatment of upper and/or lower limb spasticity. Patients with stable baseline respiratory status received one or two treatments with placebo, 240 U, or 360 U of onabotA. Pulmonary function tests, adverse events, and efficacy were measured at least every 6 weeks for 18 weeks (Study 1) or 30 weeks (Study 2). Study 1 enrolled 109 patients (n = 36&ndash, 37/group) and Study 2 enrolled 155 patients (n = 48&ndash, 54/group). Mean baseline forced vital capacity (FVC) was 76&ndash, 78% of predicted per group in Study 1 and 71% of predicted per group in Study 2. In Study 1, change from baseline FVC values were significantly (p &lt, 0.05) decreased vs. placebo at weeks 3 (240 U &minus, 57 mL vs. placebo +110 mL) and 12 (360 U &minus, 6 mL vs. +167 mL placebo). In Study 2, change from baseline FVC values were significantly decreased in the 360 U group vs. placebo at weeks 6 (&minus, 78 mL vs. +49 mL placebo), 13 (&minus, 60 mL vs. +119 mL placebo), 18 (&minus, 128 mL vs. +80 mL placebo), and 24 (&minus, 82 mL vs. +149 mL placebo). Individual pulmonary function-related adverse events were not correlated with PFT decreases. The most frequent pulmonary-related adverse events were nasopharyngitis (Study 1) and upper respiratory tract infection (Study 2). Ashworth scores were significantly improved at multiple time points in both studies. Injection of onabotA for spasticity in patients with decreased pulmonary function, at single and repeated doses of up to 360 U, was associated with small but statistically significant decreases in FVC or forced expiratory volume 1 s (FEV1) (&gt, 12% and 200 mL) that were subclinical and not correlated with any adverse clinical pulmonary events.

ObjectiveTo assess the clinical manifestations and predictors of different types of tremors in individuals with different types of isolated dystonia.MethodsClinical manifestations of tremor were assessed in a multicenter, international cross-sectional, cohort study of 2,362 individuals with all types of isolated dystonia (focal, segmental, multifocal, and generalized) recruited through the Dystonia Coalition.ResultsMethodical and standardized assessments of all participants in this cohort revealed the overall prevalence of any type of tremor was 53.3%. The prevalence of dystonic tremor varied from 36.9% to 48.4%, depending on criteria used to define it. To identify the factors associated with tremors in dystonia, the data were analyzed by generalized linear modeling and cluster analyses. Generalized linear modeling indicated 2 of the strongest factors associated with tremor included body region affected by dystonia and recruitment center. Tremor was also associated with severity of dystonia and duration of dystonia, but not with sex or race. The cluster analysis distinguished 8 subgroups within the whole cohort; defined largely by body region with dystonia, and secondarily by other clinical characteristics.ConclusionThe large number of cases evaluated by an international team of movement disorder experts facilitated the dissection of several important factors that influence the apparent prevalence and phenomenology of tremor in dystonia. These results are valuable for understanding the many differences reported in prior studies, and for guiding future studies of the nosology of tremor and dystonia.

Introduction The objective of the study was to investigate the efficacy and safety of repeated incobotulinumtoxinA injections for the treatment of upper-limb post-stroke spasticity in adults. Methods Adults 18–80 years of age with post-stroke upper-limb spasticity who completed the 12-week randomized, double-blind, placebo-controlled main period (MP) of a phase 3 trial (NCT01392300) were eligible to enrol in the 36-week open-label extension period (OLEX). The OLEX included three treatment cycles at fixed 12-week injection intervals; subjects were injected with 400 U incobotulinumtoxinA into the affected upper limb. Efficacy assessments included evaluation of muscle tone using the Ashworth Scale (AS) and the Global Impression of Change Scale (GICS) assessed by the investigator, subject, and caregiver. The incidence of adverse events (AEs) was monitored throughout the OLEX. Results A total of 296 of 299 subjects (99.0%) who completed the MP received incobotulinumtoxinA in the OLEX, and 248 subjects completed the 36-week OLEX. The proportion of subjects with at least a 1-point improvement in AS score from each incobotulinumtoxinA treatment to the respective 4-week post-injection visit ranged by cycle from 52.3% to 59.2% for wrist flexors, 49.1% to 52.3% for elbow flexors, 59.8% to 64.5% for finger flexors, 35.5% to 41.2% for thumb flexors, and 37.4% to 39.9% for forearm pronators (P

Background: Injectable daxibotulinumtoxinA (an investigational botulinum toxin, RT002) may offer a more prolonged duration of response – and therefore less frequent dosing – than onabotulinumtoxinA. Objectives: To perform a phase 2, open-label, dose-escalation study to assess the efficacy and safety of daxibotulinumtoxinA in cervical dystonia. Methods: Subjects with moderate to severe isolated cervical dystonia were enrolled in sequential cohorts to receive a single open-label, intramuscular dose of injectable daxibotulinumtoxinA of up to 200U (n=12), 200–300U (n=12), or 300–450U (n=13) (clinicaltrials.gov identifier NCT02706795). Results: Overall, 33/37 enrollees completed the trial. DaxibotulinumtoxinA was associated with reductions in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total score of 16.8 (38%) at week 4, 21.3 (50%) at week 6, and 12.8 (30%) at week 24. The proportion of subjects who were responders (achieved ≥ 20% reduction in TWSTRS-Total score) was 94% at week 6 and 68% at week 24. The median duration of response (time until > 20% of the improvement in TWSTRS-Total score achieved at week 4 was no longer retained or re-treatment was needed) was 25.3 weeks (95% CI, 20.14–26.14 weeks). There were no serious adverse events and there was no apparent dose-related increase in the incidence of adverse events. The most common treatment-related adverse events were dysphagia (14%) and injection site erythema (8%). Conclusions: Preliminary assessments suggest that injectable daxibotulinumtoxinA at doses up to 450U is well tolerated and may offer prolonged efficacy in the treatment of cervical dystonia. Further studies involving larger numbers of patients are now warranted. This article is protected by copyright. All rights reserved.

Author(s): Esquenazi, Alberto; Stoquart, Gaetan; Hedera, Peter; Jacinto, Luis Jorge; Dimanico, Ugo; Constant-Boyer, Francois; Brashear, Allison; Grandoulier, Anne-Sophie; Vilain, Claire; Picaut, Philippe; Gracies, Jean-Michel | Abstract: OBJECTIVE:To examine the safety and efficacy of abobotulinumtoxinA in patients previously treated with botulinum toxin type A (BoNT-A) products other than abobotulinumtoxinA. DESIGN:Secondary analysis from a phase 3, double-blind, single-cycle, randomized, placebo-controlled study. SETTING:Fifty-two centers (11 countries). PATIENTS:Adults with spastic hemiparesis were randomized (1:1:1) to receive abobotulinumtoxinA 1000 U, 1500 U, or placebo in their affected lower limb. MAIN OUTCOME MEASUREMENTS:Muscle tone (6-point Modified Ashworth Scale [MAS], 0-5) for the gastrocnemius-soleus complex (GSC); proportion of MAS responders (≥1-point improvement); angle of catch (XV3 ) and spasticity grade (Y) for the GSC and soleus. Assessments were at weeks 1, 4, and 12 post-injection. Only descriptive statistics are presented. RESULTS:Of 388 patients, 84 received previous BoNT-A treatment (abobotulinumtoxinA 1000 U: N = 30; abobotulinumtoxinA 1500 U: N = 28; placebo: N = 26). At week 4, mean (SD) changes in MAS score in the GSC were - 0.8 (1.1), -0.9 (1.0), and - 0.4 (0.7) for abobotulinumtoxinA 1000 U, 1500 U, and placebo, respectively. Greater MAS responder rates were observed for abobotulinumtoxinA versus placebo at all time points. Mean (SD) changes (week 4) for abobotulinumtoxinA 1000 U, 1500 U, and placebo for XV3 were: GSC, 8° (21), 6° (10) and 1° (7); soleus, 11° (21), 5° (9) and 0° (8), respectively; for Y: GSC, -0.4 (0.7), -0.6 (0.8) and - 0.0 (0.9); soleus, -0.5 (0.7), -0.5 (0.7) and - 0.1 (0.6), respectively. Safety data and adverse events were consistent with the overall known profile of abobotulinumtoxinA. CONCLUSIONS:Patients previously treated with other BoNT-As showed improved muscle tone and spasticity at week 4 following abobotulinumtoxinA injection versus placebo. These findings suggest that abobotulinumtoxinA, at the recommended doses, has a good safety and efficacy profile in adults with lower limb spasticity who were previously treated with other BoNT-A products.

ObjectiveTo define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes.MethodsPatients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/−) to determine the sequence of events in seizure-related cardiac death.ResultsNinety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death.ConclusionsWe found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.

Highlights • Cervical dystonia has significant impact on quality of life of those affected. • Dilution options allow for treatment flexibility and individualized patient care. • AboBoNT-A is efficacious with similar safety and tolerability at either dilution., Introduction Cervical dystonia (CD) is a neurologic movement disorder with potentially disabling effects and significant impact on quality of life of those affected. AbobotulinumtoxinA (aboBoNT-A) was initially approved for a dilution of 500 U/1 mL and subsequently for a dilution of 500 U/2 mL, providing flexibility for clinicians to treat CD. Here, we explore the safety and efficacy of the 500 U/2 mL dilution versus 500 U/1 mL dilution of aboBoNT-A in a retrospective analysis based on published clinical trial data. Methods The safety and efficacy of aboBoNT-A in patients with CD was evaluated in three multicenter, double-blind, randomized, placebo-controlled trials and open-label extensions. Trials 1 (NCT00257660) and 2 (NCT00288509) evaluated the 500 U/1 mL dilution in 80 and 116 patients, respectively; Trial 3 (NCT01753310) evaluated the 500 U/2 mL dilution in 125 patients. Results Comparison of the adjusted mean difference in TWSTRS total scores at Week 4 from baseline for aboBoNT-A in Trial 1 (−6.0; 95% CI, −10.8, −1.3), Trial 2 (−8.8; 95% CI, −12.9, −4.7), and Trial 3 (−8.7; 95% CI, −13.2, −4.2) showed similar, significant improvements. Dysphagia and muscle weakness patterns were comparable across the three trials, indicating that an increased dilution of aboBoNT-A does not result in an increased risk of diffusion-related adverse events. Conclusion The results of these trials show that aboBoNT-A is similarly efficacious using either dilution, with similar safety and tolerability across trials. Having the 500 U/1 mL and 500 U/2 mL dilution volumes available provides further flexibility in administration, benefiting patient care.

Purpose/aim: AbobotulinumtoxinA (Dysport®, Ipsen Biopharmaceuticals, Inc., Basking Ridge, NJ, USA) is an acetylcholine release inhibitor and a neuromuscular blocking agent. The United States prescribing information for abobotulinumtoxinA previously indicated only one dilution for cervical dystonia: 500 U/1 mL. Clinical trial data supporting a larger volume with a 500 U/2 mL dilution would offer clinicians flexibility with injection volume to better meet patient needs.We conducted a 12-week, phase 3b, multicenter, randomized, double-blind, placebo-controlled trial (NCT01753310). Adult subjects with a primary diagnosis of cervical dystonia were randomized (2:1) to receive a single injection of either abobotulinumtoxinA, 500 U/2 mL dilution, or placebo. The primary efficacy endpoint was changed from baseline in Toronto Western Spasmodic Torticollis Rating Scale total score at Week 4.A total of 134 subjects (abobotulinumtoxinA, n = 89; placebo, n = 45) were randomized (intent-to-treat population) and 129 (abobotulinumtoxinA, n = 84; placebo, n = 45) completed the Week 4 primary endpoint evaluation (modified intent-to-treat population). In the modified intent-to-treat population, subjects receiving abobotulinumtoxinA experienced significantly greater changes from baseline versus placebo on the primary endpoint (weighted overall treatment difference -8.3, P0.001). The most common treatment-emergent adverse events (TEAEs) were dysphagia, muscle weakness, neck pain and headache. Overall, TEAEs were consistent with those reported in the abobotulinumtoxinA prescribing information (1 mL dilution) for cervical dystonia patients.This trial provides evidence that a 500 U/2 mL dilution is an effective treatment for cervical dystonia and exhibits a safety profile consistent with the known safety profile of abobotulinumtoxinA.

Background AbobotulinumtoxinA has beneficial effects on spasticity and active movements in hemiparetic adults with upper limb spasticity (ULS). However, evidence-based information on optimal dosing for clinical use is limited. Objective To describe joint-specific dose effects of abobotulinumtoxinA in adults with ULS. Design Secondary analysis of a phase 3 study (NCT01313299). Setting Multicenter, international, double-blind, placebo-controlled clinical trial. Participants A total of 243 adults with ULS >6 months after stroke or traumatic brain injury, aged 52.8 (13.5) years and 64.3% male, randomized 1:1:1 to receive a single-injection cycle of placebo or abobotulinumtoxinA 500 U or 1000 U (total dose). Methods The overall effects of injected doses were assessed in the primary analysis, which showed improvement of angles of catch in finger, wrist, and elbow flexors and of active range of motion against these muscle groups. This secondary analysis was performed at each of the possible doses received by finger, wrist, and elbow flexors to establish possible dose effects. Main Outcome Measures Angle of arrest (X V1 ) and angle of catch (X V3 ) were assessed with the Tardieu Scale, and active range of motion (X A ). Results At each muscle group level (finger, wrist, and elbow flexors) improvements in all outcome measures assessed (X V1 , X V3 , X A ) were observed. In each muscle group, increases in abobotulinumtoxinA dose were associated with greater improvements in X V3 and X A , suggesting a dose-dependent effect. Conclusions Previous clinical trials have established the clinical efficacy of abobotulinumtoxinA by total dose only. The wide range of abobotulinumtoxinA doses per muscle groups used in this study allowed observation of dose-dependent improvements in spasticity and active movement. This information provides a basis for future abobotulinumtoxinA dosing recommendations for health care professionals based on treatment objectives and quantitative assessment of spasticity and active range of motion at individual joints. Level of Evidence I

Introduction/Background ULIS-III describes real-life clinical practice in upper limb spasticity (ULS) management using licensed botulinum toxin A (BoNT-A) products and concomitant therapies. ULIS-III assesses long-term impact on patient-centred outcomes and identifies best practice strategies according to patient needs. Baseline data are presented for patients enrolled by June 2017. Material and method This longitudinal, prospective, observational, cohort study of integrated ULS management in adults ( NCT02454803 ) examines impact of repeated BoNT-A injections over 2 years. Person-centred outcomes are assessed using the Upper Limb Spasticity Index, combining individual goal setting with targeted standardised measures, using patient-selected goal areas. Injection practices and physical treatments are recorded, alongside economic and quality-of-life data. Results Baseline data were analysed for 975 patients across 57 sites (14 countries; 5 continents). Table 1 presents baseline characteristics; 82% of patients had spasticity post-stroke; two-thirds had received previous BoNT-A for ULS ( 10 injections, 28%). Median time from diagnosis to first injection and enrolment was 1.0 and 3.4 years, respectively. Baseline muscle tone and disability measures are shown in Table 1 . Upper arm and forearm muscles were most commonly injected; 34% received concomitant BoNT-A for lower limb spasticity ( Table 2 ). Shoulder injection frequency increased since ULIS-II (e.g. pectoralis major: 34 vs. 19%). Instrumental injection guidance techniques were used in 73% of patients. Most common primary goal areas were passive function (31%) and pain (25%), showing notable changes in goal selection since ULIS-II ( Fig. 1 ). Conclusion ULIS-III contributes to greater understanding of achievable treatment goals and developing practice with improved clinical reasoning, as reflected in ULIS-III baseline data. ULIS-III will improve understanding of treatment and outcomes for long-term ULS management. Final data are expected in 2019.

Introduction: Cervical dystonia is an involuntary movement of the neck muscles, often characterized by disabling pain. The diagnosis is based on clinical presentation and treatment usually involves injections of botulinum toxin Areas covered: The areas covered in this review include non-pharmacologic interventions, oral medications and injections of botulinum toxin, intrathecal baclofen and deep brain stimulation therapy. Expert opinion: First line treatment of cervical dystonia is periodic injection of botulinum toxin into the overactive neck muscles. The formulation depends on the physician's experience and the patients prior exposures. Each formulation is unique and should be considered a separate branch of the treatment paradigm. All injections must be formulated for the individual treatment. Each formulation has been demonstrated in large published trials to be effective. Physicians need to educate themselves on the dosing and side effect profiles of each formulation to best counsel their patients. C...

IncobotulinumtoxinA (Xeomin(®), NT 201), a preparation without accessory (complexing) proteins, has shown comparable efficacy and safety to onabotulinumtoxinA in treating cervical dystonia (CD). This study evaluated the efficacy and safety of repeated incobotulinumtoxinA injections in subjects with CD. Following a ≤20-week placebo-controlled, randomized, double-blind, single-dose main period, subjects could enter a ≤68-week prospective, randomized, double-blind, repeated-dose, flexible-interval (minimum 6 weeks) extension period with 240 U or 120 U of incobotulinumtoxinA (≤5 injections). Outcome measures included the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and adverse events (AEs). Of 219 subjects completing the main period, 214 were randomized in the extension period to receive incobotulinumtoxinA 240 U (n = 111) or 120 U (n = 103); 169 subjects completed the extension period, with 90 receiving five injection sessions. Both doses of incobotulinumtoxinA provided statistically significant and clinically relevant improvements in mean TWSTRS-Total, -Severity, -Disability, and -Pain scores, from each injection session to respective 4-week follow-up visits. The most frequently reported AE was dysphagia (240 U: 23.4 %; 120 U: 12.6 %), which did not result in any study withdrawals. There was no impact of injection interval on the incidence of AEs (post hoc analysis). A major limitation of this study was the fixed dose design requested by regulatory authorities, which does not reflect clinical practice. However, repeated incobotulinumtoxinA injections (240 or 120 U; flexible intervals) provided sustained efficacy and were well tolerated, with no unexpected safety risks following repeated injections. The incidence of AEs was similar in subjects requiring repeated injections at shorter intervals (≤12 weeks) compared with those treated using longer intervals (12 weeks).

Background Botulinum is a potent neurotoxin with increasing indications for neurologic disorders. While clinical benefit manifests primarily due to local actions at the neuromuscular junction, regional and systemic effects do occur. Rarely, systemic symptoms including weakness, dysarthria, dysphagia and other side effects occur as a result of iatrogenic botulinum neurotoxicity. Case A 72 year-old female with right leg dystonia developed head drop, bulbar and systemic weakness following right lower extremity botulinum toxin injection. Routine nerve conduction studies were normal. Repetitive stimulation of the spinal accessory nerve showed decrement; electromyography (EMG) demonstrated slightly small units with subtle signs of denervation, and single fiber EMG revealed increased jitter with blocking, all of which are consistent with systemic botulism. Conclusion This case highlights and reviews the important electrodiagnostic features of iatrogenic systemic botulinum neurotoxicity.

Objective Current botulinum toxin labeling indicates injections once every 12 weeks but few studies have assessed the treatment interval after repeated injections. In a recent double-blind (DB) study followed by an open-label (OL) extension abobotulinumtoxinA (aboBoNT-A, Dysport®) was efficacious and demonstrated a favourable safety profile in adult patients with upper limb spasticity (ULS) after single and repeated injections (Gracies et al. Lancet Neurol 2015; Brashear et al. Am Acad Neurol 2016). This additional analysis focuses on the retreatment intervals after repeated injections of aboBoNT-A. Material/Patients and methods Phase III, international, multicentre, DB, single-treatment study of aboBoNT-A in adults with ULS, followed by a long-term OL extension study with a maximum of 4 additional treatment cycles over a maximum of 18 months. Retreatment was per investigator's clinical judgment and possible at weeks 12, 16, 20, and 24. Results Among the subjects who received aboBoNT-A in the DB study and were treated in cycle 1 of the OL extension, 37% were re-injected at week 16 or later (17% at week 16, 10% at week 20, 10% at week 24 or later). For those who received a second cycle of treatment in the OL phase, 35% of subjects were re-injected at week 16 or later (20% at week 16, 7.0% at week 20, 8% at week 24 or later). For those who received a third cycle of treatment in the OL phase, 24% of subjects were re-injected at week 16 or later (19% were retreated at week 16, 3% at week 20, 2% at week 24 or later). Discussion/Conclusion These data show that 24% to 37% of subjects did not require reinjection before week 16 across multiple cycles. This long duration of clinical effect leads to longer intervals between injections, and thus may reduce the burden associated with frequency of injections for patients and their caregivers/families. This also highlights the needs for a tailored approach in the treatment of patients with ULS.

To evaluate the relationship between disability and both health-related quality of life (HRQoL) and caregiver burden in patients with upper limb poststroke spasticity.Multicenter open-label study.Thirty-five sites in North America.Patients (N = 279) with upper limb poststroke spasticity.Post hoc analyses of data from an open-label study were performed to estimate HRQoL and caregiver burden at study baseline across levels of disability in 4 problem domains: hygiene, dressing, limb posture, and pain. Disability severity in these areas was determined by using the 4-point Disability Assessment Scale rated by the physicians.HRQoL measured by the patient-reported EuroQol 5 Dimensions questionnaire and the Stroke-Adapted Sickness Impact Profile and caregiver burden.At study baseline, increasing disability in the hygiene, dressing, and pain domains of the Disability Assessment Scale was associated with diminishing HRQoL scores (P.002) measured by the EuroQol 5 Dimensions. By using the Stroke-Adapted Sickness Impact Profile, greater disability scores in all problem domains were significantly associated with higher overall dysfunction scores (P ≤ .05). Within the physical dimension of the Stroke-Adapted Sickness Impact Profile, significant associations also were observed in all domains. At baseline, caregiver burden was significantly related to increasing levels of hygiene and dressing domain severity (P ≤ .05). Caregiver assistance requirement increased from approximately 9.0-28.2 hours per week in the hygiene domain and 3.3-32.1 hours per week in the dressing domain as disability increased from "none" to "severe."In patients with upper limb poststroke spasticity, increasing disability in the hygiene, dressing, and pain domains of the Disability Assessment Scale were associated with diminishing HRQoL. Furthermore, these patients required caregiver assistance proportionally related to the severity of their disability in the hygiene and dressing domains.

Introduction/Background Patients with chronic hemiparesis following stroke or traumatic brain injury (TBI) often experience restricted walking performance. Our previous double-blind (DB) trial of 388 patients demonstrated that abobotulinumtoxinA (aboBoNT-A) treatment improves muscle tone and functional outcomes in adults with lower limb spastic paresis. This sub-analysis from the open-label (OL) study extension phase assesses changes in walking speed (WS), step length (SL) and cadence in these patients. Material and method Phase 3, prospective, multicentre, double-blind (DB), randomised study (single injection of aboBoNT-A 1000U or 1500U or placebo; NCT01249404 ), followed by an OL study extension (≤ 4 cycles of aboBoNT-A 1000U or 1500U; NCT01251367 ). Participants were ambulatory adults with spastic hemiparesis causing gait dysfunction, comfortable barefoot WS 0.1–0.8 m/s in 10-metre WS test without walking aids, and stroke or TBI ≥ 6 months before study enrolment. Patients receiving either aboBoNT-A dose were assessed relative to DB baseline for WS, SL and cadence using 10-metre WS tests under different conditions (maximal and comfortable WS, barefoot and with shoes). Week 12 data are shown for the last treatment cycle with available data (cycle 3). Results Relative to baseline, improvements in WS, SL and cadence by OL Cycle 3 Week 12 were observed in all four categories ( Table 1 ). Mean percentage of improvements in WS were +19.7–23.6% across categories. Mean percentage improvements of +9.4–13.8% and +7.2–9.7% were observed for SL and cadence, respectively. The highest mean percentage improvements were at comfortable barefoot WS for WS and SL, and at maximal barefoot WS for cadence. The least improvements from DB baseline were observed with shoes compared with barefoot, across all categories. Conclusion Substantial improvements in WS, SL and cadence were achieved over time in hemiparetic adults with repeated administration of aboBoNT-A.

Introduction/Background Long-term safety and efficacy of repeated abobotulinumtoxinA (aboBoNT-A) injections in patients with upper limb spasticity (ULS) after stroke or traumatic brain injury have been described in an open-label study (Gracies et al. Muscle Nerve, 2018). Continuous improvements in active movements, and perceived and active function were reported, with no unexpected safety signals identified. Here, we describe the frequency of repeated aboBoNT-A injections over the open-label study. Material and method A phase 3, international, double-blind, single-treatment study ( NCT01313299 ) of aboBoNT-A in the hemiparetic upper limb, followed by a 12-month open-label extension study ( NCT01313312 ) with up to four additional treatment cycles, at least 12 weeks apart. Re-treatment was per investigator's clinical judgement, based on muscle tone, spasticity measures and other findings. Patients not requiring re-treatment completed the study. Results A total of 254 patients entered in open-label cycle 1 ( Table 1 ). In cycle 1, 14/254 patients withdrew and 240 completed the cycle. After cycle 1, 10 patients completed the study without subsequent aboBoNT-A injections. In cycle 2, 219/229 patients completed the cycle (10 withdrew) and 44 did not require subsequent injections. Of 175 patients entered cycle 3, six withdrew and 169 completed the cycle, 88 of whom did not require subsequent injections. Overall, 55.9% (n = 142) of patients required three or fewer injections of aboBoNT-A over the course of the 12-month study, 21.6% required two or fewer injections, and 3.9% required one injection. Conclusion Over half of the patients (55.9%) enrolled in this phase 3 study required three or fewer injections of aboBoNT-A over the course of a year, based on physician clinical assessment. This decreased injection frequency, with respect to usual practice, may reduce the burden associated with treatment for patients and their caregivers/families.

Allison BrashearDept of Neurology, Wake Forest University Baptist, Medical Center, Winston Salem, NC, USAAbstract: Dystonia is an involuntary movement involving twisting and turning of agonist and antagonist muscles. Cervical dystonia is isolated to neck musculature. Botulinum toxin type A is a safe and effective treatment of this disabling and often painful syndrome. Three forms of botulinum toxin type A are available worldwide to treat patients with cervical dystonia. This is a review of the studies of botulinum toxin type A to treat cervical dystonia.Keywords: dystonia, botulinum toxin type A, cervical dystonia

While spasticity is commonly treated with oral agents or botulinum neurotoxin (BoNT) injection, these treatments have not been systematically compared.This study performed a randomised, double-blind, placebo-controlled trial to compare injection of BoNT-Type A into spastic upper limb muscles versus oral tizanidine (TZD), or placebo, in 60 subjects with upper-limb spasticity due to stroke or traumatic brain injury (TBI). Wrist flexors were systematically injected, while other upper limb muscles were injected as per investigator judgement. Participants were randomised into three groups: (1) intramuscular BoNT plus oral placebo; (2) oral TZD plus intramuscular placebo; (3) intramuscular placebo plus oral placebo. The primary outcome was the difference in change in wrist flexor modified Ashworth score (MAS) between groups. Other outcome measures included MAS at elbow and finger joints, Disability Assessment Scale (DAS) and adverse events (AE).BoNT produced greater tone reduction than TZD or placebo in finger and wrist flexors at week 3 (p0.001 vs TZD; p0.02 vs placebo) and 6 (p = 0.001 vs TZD; p = 0.08 vs placebo), and greater improvement in the cosmesis domain of the DAS at week 6 (p0.01). TZD was not superior to placebo in tone reduction at either time point (por=0.09). The incidence of AE related to study treatment was higher with TZD than in the BoNT (p0.01) or placebo groups (p = 0.001).BoNT is safer and more effective than TZD in reducing tone and disfigurement in upper-extremity spasticity, and may be considered as first-line therapy for this disorder.

The expanding uses of botulinum neurotoxin (BoNT) for a growing number of clinical indications, including cervical and other dystonias, adult and childhood spasticity, and hyperhidrosis, in conjunction with the emergence of new formulations of BoNT, prompt discussion of the differences in formulations, serotypes, and indications for different neurologic diseases.This review will evaluate evidence from preclinical studies, prospective treatment studies, and direct comparative trials to discuss the differences among BoNTs and the clinical implications of using these different drugs. Data from these sources indicate that formulations of BoNT are distinct; even the same serotype formulations of BoNT serotype A have different molecular structures and sizes and therapeutic indices (reflected in different safety and efficacy profiles).Taken together, these findings confirm that the different BoNT serotypes, including the different BoNTA formulations, are distinct therapeutic entities.

Botulinum toxin type A (BoNT/A) is the principal therapy for patients with cervical dystonia. Repeated treatments over many years are required in most cases. This retrospective review evaluates the dose of BoNT/A used to treat cervical dystonia and the interval between treatments during a 2-year observation period. Outcomes data were abstracted from the medical records of 172 patients at 3 different sites who had received BoNT/A between January and December 1998. A total of 1059 treatments were assessed. Mean per-treatment doses throughout the 2-year study ranged from 241.80 to 254.07 units. The mean interval between treatments was 108.48 days during the first year of observation and 114.14 days during the second year. These findings indicate that doses of and intervals between BoNT/A treatments for cervical dystonia were consistent throughout 2 years of observation.

Childers MK, Brashear A, Jozefczyk P, Reding M, Alexander D, Good D, Walcott JM, Jenkins SW, Turkel C, Molloy PT. Dose-dependent response to intramuscular botulinum toxin type A for upper-limb spasticity in patients after a stroke. Arch Phys Med Rehabil 2004;85:1063–9. Objective To test the hypothesis that intramuscular (IM) botulinum toxin type A (BTX) reduces excessive muscle tone in a dose-dependent manner in the elbow, wrist, and fingers of patients who experience spasticity after a stroke. Design Randomized, double-blind, placebo-controlled, multicenter, 24-week trial. Setting Six academic and 13 private US outpatient medical centers. Participants Ninety-one patients with a mean age of 60 years (range, 30–79y). Mean time elapsed from ischemic or hemorrhagic stroke to study enrollment was 25.8 months (range, 0.9–226.9mo). Interventions Up to 2 treatments of placebo, or 90, 180, or 360U of BTX. Concurrent splinting and physical therapy protocols were permitted, but no changes were allowed during the study. Main outcome measures Wrist, elbow, and finger flexor tone assessed by the Modified Ashworth Scale, physician and patient global assessments, pain, FIM instrument, and Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). Results Muscle tone decreased more with injections of BTX than with placebo in the wrist flexors at weeks 1, 2, 3, 6, and 9 ( P ≤.026); in the elbow flexors at weeks 1, 2, 3, 4, 5, and 9 ( P ≤.033); and in the finger flexors at weeks 1 and 3 ( P ≤.031). A dose-dependent response was generally observed in tone reduction but not in pain, FIM, or SF-36 measures. Conclusions IM BTX reduced muscle tone in a dose-dependent manner in the elbow, wrist, and fingers of patients who experience spasticity after a stroke but did not appear to affect global quality of life or disability.

ervical dystonia is an abnormal involuntary movement f the head and neck that is frequently associated with ain. Typically presenting in middle to late adulthood and sually with no identifiable cause, cervical dystonia (also eferred to in some texts as “spasmodic torticolli”) often esults in permanent disability caused by a decreased ange of motion, involuntary movements, and pain in the eck and head muscles. The prevalence of cervical dysonia has been estimated to be 9 per 100,000, but this stimate is thought to be conservative because it is based n a retrospective chart review. In the United States, The ystonia Medical Research Foundation estimates that 50,000 people suffer from cervical dystonia; however, it is uspected that many more are undiagnosed and/or unreated. The discovery of botulinum toxin produced by Clostridum botulinum as a localized injectable treatment to relax veractive muscles is one of the interventional neuroloist’s most potent tools in treating dystonia. The introuction of botulinum toxin type A in 1989 in the United tates has dramatically improved the ability of physicians o treat dystonic movements of the head and neck. The ddition of botulinum toxin type B as an alternative treatent, particularly in those patients who develop resisance to type A, has further expanded the resources availble to treat this disabling disease. The bacteria Clostridium botulinum produces 7 immunoogically distinct serotypes, but only serotype A, B, nd F have been used in clinical practice. There are 2 orms of botulinum toxin type A (BTX-A)—BOTOX (Alergan, Irvine, CA), available worldwide, and Dysport Ipsen), available outside of the United States. Serotype B s available as botulinum toxin type B (BTX-B; formulated s MyoblocTM in the United States and NeuroBloc elsehere), and serotype F (BTX-F) is available only on a imited basis in Japan. Each of the 7 toxins is synthesized as a single-chain olypeptide with a molecular weight of 150 kDa. The isulfide bond holding the heavy chain and light chain ogether must be cleaved and the light chain internalized nto the cytosol by the process of chemodenervation. Chemical denervation is a 3-step process. First, after njection into the target muscle, the heavy chain of the oxin recognizes a specific receptor on the presynaptic erve terminal in the neuromuscular junction. Second, the oxin is internalized by endocytosis and translocated to the ytosol of the presynaptic nerve terminal. Third, the light

Brashear A, McAfee AL, Kuhn ER, Fyffe J. Botulinum toxin type B in upper-limb poststroke spasticity: a double-blind, placebo-controlled trial. Arch Phys Med Rehabil 2004;85:705-9. Objective To determine whether botulinum toxin type B (BTX-B) is effective in controlling upper-limb spasticity. Design A single-site, double-blind, placebo-controlled, randomized trial and open-label study. Setting Outpatient. Participants Subjects with an Ashworth Scale score of 2 or more at the elbow, wrist, and fingers. Interventions Subjects were injected with 10,000U of BTX-B or placebo at the elbow, wrist, and finger flexors. Main outcome measures Measures recorded at weeks 0, 2, 4, 8, 12, and 16, with a 12-week open-label study. Ashworth Scale score, a global assessment of change (GAC), adverse events and mouse neutralization antibody testing. Results BTX-B did not decrease muscle tone in the elbow, wrist, or finger flexors at 10,000U over the 16-week period. A decrease in Ashworth Scale score for the BTX-B patient group was present at the wrist at week 2 of the double-blind study ( P =.003) but was not statistically significant at other visits. In the open-label study, improvement was noted at week 4 for the elbow ( P =.039), wrist ( P =.002), finger ( P =.001), and thumb flexors ( P =.002). In the double-blind study, the Physician GAC did not reach significance. Dry mouth was reported by 8 of 9 BTX-B subjects in the double-blind study. Mouse neutralization antibodies were negative. Conclusions Our study does not show a significant decrease in tone from 10,000U of BTX-B. Dry mouth was common.

Spasticity is a disabling complication of stroke, and it is uncertain whether intramuscular injections of botulinum toxin type A reduce disability in persons with spasticity of the wrist and fingers after a stroke.We performed a randomized, double-blind, placebo-controlled, multicenter trial to assess the efficacy and safety of one-time injections of botulinum toxin A (200 to 240 units) in 126 subjects with increased flexor tone in the wrist and fingers after a stroke. The primary outcome measure was self-reported disability in four areas: personal hygiene, dressing, pain, and limb position (on a four-point scale ranging from no disability to severe disability) at six weeks; at base line, each subject selected one of these areas in which there was moderate-to-severe disability as the principal target of treatment.Subjects who received botulinum toxin A had greater improvement in flexor tone in the wrist and fingers at all follow-up visits through 12 weeks than did subjects who received placebo (P0.001 for all comparisons). Subjects treated with botulinum toxin A had greater improvement in the principal target of treatment at weeks 4, 6, 8, and 12 (P0.001, P0.001, P=0.03, and P=0.02, respectively); at week 6, 40 of the 64 subjects in the botulinum-toxin group (62 percent), as compared with 17 of the 62 in the placebo group (27 percent), reported improvement of at least one point on the Disability Assessment Scale in the principal target of treatment (P0.001). There were no major adverse events associated with injection of botulinum toxin A.Intramuscular injections of botulinum toxin A reduce spasticity of the wrist and finger muscles and associated disability in patients who have had a stroke.

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.

Objective There are limited data on improvements of active limb movement and function following treatment with botulinum toxin in chronic spastic paresis. We report the effect of repeated injections of abobotulinumtoxinA (aboBoNT-A) on these parameters from two Phase III multicenter open-label (OL) trials in adults with spasticity post-stroke/traumatic brain injury; one trial in upper limb spasticity, the other in lower limb spasticity. These are extensions to respective double-blind studies (DB) in which adults received a single aboBoNT-A injection (Gracies et al. Lancet Neurol 2015; Esquenazi et al. AAPM&R 2016). Material/Patients and methods Subjects (18–78 years) received aboBoNT-A (500 to 1500U) over a year (injections ≥ 12 weeks apart) in their affected limb. Active movement was assessed by active range of motion (XA) against elbow, wrist and finger flexors or active ankle dorsiflexion. Active function was assessed by Modified Frenchay Scale (MFS) (upper limb) or the 10-meter walking speed test (lower limb). Results for cycle 4 week 4 of the OL phase are presented. Results Eighty-one subjects received 5 injections in their UL and 139 subjects in their LL. XA improved in the upper limb across injection cycles, with active finger extension (most frequently injected muscle group) increasing by a mean (SD) of +38.0 (53.4)°. The overall increase in MFS was +0.40 (0.75), an improvement that was more pronounced with 1500U (500U in shoulder muscles): +0.62 (0.48) vs. +0.30 (0.83) for 1000U. Active ankle dorsiflexion improved by +6.5(10.9)° with knee extended. Comfortable walking speed improved by +0.088 (0.144) (mean increase of 25% from baseline of DB phase). Discussion/Conclusion Improvement in active movement and function in subjects with chronic upper or lower limb spasticity was observed following repeat injections of aboBoNT-A over a year. A more pronounced efficacy with 1500U versus 1000U aboBoNT-A for active function in the upper limb may suggest the importance of shoulder muscle injections.

Rapid-onset dystonia parkinsonism (RDP) is a rare disorder characterized by abrupt onset of dystonia and parkinsonism. The condition is the result of mutations in ATP1A3. Careful characterization of neurological manifestations associated with ATP1A3 mutations, which can cause RDP and alternating hemiplegia of childhood (AHC), is important to understand how specific mutations can lead to different presentations. This case of RDP is notable because (1) the patient harbored an ATP1A3 variant at the c.2267G>A site, resulting in a nonsynonymous p.R756H mutation, which has not been reported in typical adolescent-onset RDP, and (2) reports of Asian cases are very rare and this is the first patient of pure Chinese descent. Our patient, of pure Southern Chinese ancestry, was previously healthy until 9 May 2002 (at the age of 10 years), when she became clumsy. This was preceded by a self-limited febrile episode a week earlier. The next day, she had dysarthria, drooling, unsteady gait, and poor handwriting. This progressed over 10 days to a state of being unable to speak, swallow, or walk. She was recognized to have a severe dystonic syndrome when assessed by a pediatric neurologist 3 weeks later. By this time, she had made some recovery and was able to walk with assistance and swallow. Investigations were unremarkable, including routine blood tests, cerebrospinal fluid analysis, brain MRI, and EEG. Slit-lamp examination was negative for Kayser-Fleischer rings. She was diagnosed with postviral encephalitis and given levodopa/carbidopa (100/25 mg, 2 tablets three times daily [TID]), but this was ineffective. The patient was first assessed at the University of Malaya, Kuala Lumpur, in August 2011, at age 19. She had made gains in functional activities (e.g., no longer falling frequently and able to type fairly quickly on a computer). She was eating a normal diet without choking episodes. The patient was a top scorer in her school examinations, and there were no psychiatric manifestations. There was no relevant family history and no parental consanguinity. Her parents were also examined by us and confirmed to be neurologically intact. Examination revealed facial grimacing and jaw-opening dystonia, especially when speaking, severely slurred speech, and antecollis. There was severe and generalized nonpainful dystonia affecting all limbs and the trunk. Her movements were slow, but this was considered to probably be a result of the severe dystonia and there were no other parkinsonian features, such as rigidity or tremor (limb tone at rest was, in fact, reduced; these findings were confirmed by S.-Y.L. and A.E.L.). There was no ataxia, upper motor neuron signs, or abnormalities of eye movements or hearing. The patient’s DNA was analyzed for ATP1A3 mutations, and she was found to have a mutation in exon 17 at cDNA position c.2267G>A (NM_152296.4), resulting in a p.R756H amino acid substitution (NP_689509; laboratory of L.J.O.). Neither of the patient’s parents had this mutation. DNA profiling was performed using short tandem repeat (STR) analysis at 15 STR loci (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, TH01, D13S317, D16S539, D2S1338, D19S433, vWA, TPOX, D18S51, D5S818, and FGA) by an accredited national forensics laboratory; this confirmed that the patient was the biological child of the parents in question. Benzhexol 2 mg TID subjectively reduced limb stiffness and improved speech, but caused sleepiness and dizziness and was stopped. Her condition has remained stable (see accompanying Video 1 from November 2013), with a Burke-Fahn-Marsden Dystonia Rating Scale Movement Scale score of 67, a Disability Scale score of 13; an RDP Severity Scale score of 4; and the following UPDRS scores (largely felt to be a result of the severe dystonia; see Video 1): Total of 55.5, Parts I of 0, II of 16, III of 38.5, and IV of 1; and Montreal Cognitive Assessment score of 29/30. To our knowledge, the ATP1A3 p.R756H mutation has not been reported in typical adolescent-onset RDP. This mutation