The Clinician's Tardive Inventory (CTI): A New Clinical Tool for Documenting and Rating Tardive Dyskinesia.

Objective: Current clinician-rated tardive dyskinesia (TD) symptom scales have not addressed the expanding clinical signs and functional impact of TD. The study objective was to develop and test the reliability of a new integrated instrument.Methods: A movement disorder neurologist devised the outline of the rating scale. A Steering Committee (5 neurologists and 2 psychiatrists) provided revisions until consensus was reached. The Clinician's Tardive Inventory (CTI) assesses abnormal movements of the eye/eyelid/face, tongue/mouth, jaw, and limb/trunk; complex movements defined as complicated movements different from simple patterned movements or postures; and vocalizations. The CTI rates frequency of symptoms from 0 to 3 (ranging from absent to constant). Functional impairments, including activities of daily living (ADL), social impairment, symptom distress, and physical harm, are rated 0-3 (ranging from unawareness to severe impact). The CTI underwent interrater and test-retest reliability testing between February and June 2022 based on videos and accompanying vignettes, which were reviewed by 2 movement disorder specialists to determine adequacy. Four clinicians rated each video/vignette. Interrater agreement was analyzed via 2-way random-effects intraclass correlation (ICC), and test-retest agreement was assessed utilizing the Kendall tau-b.Results: Forty-five video/vignettes were assessed for interrater reliability and 16 for test-retest reliability. The most prevalent movements were those of the tongue and mouth (77.8%) and jaw (55.6%). ICCs for movement frequency for anatomic symptoms were as follows: anatomic symptom summary score 0.92, abnormal eye movement 0.89, abnormal tongue/mouth movement 0.91, abnormal jaw movement 0.89, abnormal limb movement 0.76, complex movement 0.87, and abnormal vocalization 0.77; ICCs for functional impairments were as follows: total impairment score 0.92, physical harm 0.82, social embarrassment 0.88, ADLs 0.83, and symptom bother 0.92; Retests were conducted a mean (SD) of 15 (3) days later with correlation coefficients ranging from 0.66 to 0.87.Conclusions: The CTI is a new integrated instrument with proven reliability in assessing TD signs and functional impacts. Future validation study is warranted.

Pain in cervical dystonia: mechanisms, assessment and treatment.

INTRODUCTION: In patients with cervical dystonia (CD), pain is a major contributor to disability and social isolation and is often the main reason patients seek treatment. Surveys evaluating patient perceptions of their CD symptoms consistently highlight pain as a troublesome and disabling feature of their condition with significant impact on daily life and work. AREAS COVERED: In this article, the authors review the epidemiology, assessment, possible mechanisms and treatment of pain in CD, including a meta-analysis of randomized controlled trial data with abobotulinumtoxinA. EXPERT OPINION: Mechanisms of pain in CD may be muscle-based and non-muscle based. Accumulating evidence suggests that non-muscle-based mechanisms (such as abnormal transmission and processing of nociceptive stimuli, dysfunction of descending pain inhibitory pathways as well as structural and network changes in the basal ganglia, cortex and other areas) may also contribute to pain in CD alongside prolonged muscle contraction. Chemodenervation with botulinum toxin is considered the first-line treatment for CD. Treatment with botulinum toxin is usually effective, but optimization of the injection parameters should include consideration of pain as a core symptom in addition to the motor problems.

AbobotulinumtoxinA using 2-mL dilution (500 U/2-mL) maintains durable improvement across multiple treatment cycles.

BACKGROUND: Cervical dystonia (CD), the most common focal dystonia, is a chronic neurological movement disorder characterized by sustained involuntary contractions of the neck muscles, leading to abnormal postures. AbobotulinumtoxinA (aboBoNT-A) was approved in the US initially as a 500 U per 1-mL dilution and subsequently, as a 500 U/2-mL dilution (or 250 U/mL), thereby providing clinicians with more flexible dosing options to better meet individual patient needs. The objective of this open-label extension study was to evaluate the longer term safety and efficacy of repeat treatments with aboBoNT-A using 2-mL dilutions in adults with cervical dystonia. METHODS: Patients (N = 112) from a 12-week, double-blind lead-in study (NCT01753310) received up to three additional treatments of aboBoNT-A, with re-treatment every 12-16 weeks based on clinical judgment. Safety was assessed through treatment-emergent adverse events (TEAEs). The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total and subscale scores were measured at day 1 of each treatment cycle (C), 4 weeks after each treatment, and 12 weeks after the third treatment. Descriptive statistics were used for all analyses. RESULTS: In cycles 1, 2, 3, and 4, respectively, 35.7, 25.9, 30.2, and 22.8% of patients reported TEAEs. Dysphagia, muscular weakness, and neck pain were each reported by 10.7% of patients, over the full study duration. Mean TWSTRS total score decreased from 37.7 (SD 13.6 [C1, day 1]) to 30.1 (SD 12.8 [C3, week 12]). In each cycle, TWSTRS total and subscale scores decreased from day 1 to week 4 and increased between weeks 4 and 12, though the week 12 scores remained lower than day 1 scores. CONCLUSION: Extended treatment of cervical dystonia with aboBoNT-A (up to 3 additional treatment cycles) using a 2-mL dilution is effective, with a positive risk-benefit profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01753336. Registered 17 Dec 2012.

Safety and Efficacy of RimabotulinumtoxinB for Treatment of Sialorrhea in Adults: A Randomized Clinical Trial.

Importance: RimabotulinumtoxinB (RIMA) may be preferable as an anti-sialorrhea treatment compared with current oral anticholinergic drugs in people with neurological disorders. Objective: To assess the safety, efficacy, and tolerability of RIMA injections for the treatment of sialorrhea in adults. Design, Setting, and Participants: This randomized, parallel, double-blind, placebo-controlled clinical trial of RIMA 2500 U and 3500 U was conducted from November 14, 2013, to January 23, 2017. A total of 249 adult patients with troublesome sialorrhea secondary to any disorder or cause were screened. Of them, 13 refused further participation in the study or were lost to follow-up and 49 did not fulfill the criteria for participation; 187 were ultimately enrolled. Patients had to have a minimum unstimulated salivary flow rate (USFR) of 0.2 g/min and a minimum Drooling Frequency and Severity Scale score of 4. Exposures: Patients were randomized 1:1:1 to RIMA, 2500 U (n = 63); RIMA, 3500 U (n = 64); or placebo (n = 60). Main Outcomes and Measures: Primary outcomes were the change in USFR from baseline to week 4 and the Clinical Global Impression of Change (CGI-C) at week 4. The CGI-C scores were recorded on a 7-point scale ranging from very much improved to very much worse. Adverse events were recorded throughout the trial period. Results: Of 187 patients enrolled (147 men [78.6%]; mean [SD] age, 63.9 [13.3] years), 122 patients had Parkinson disease (65.2%), 13 (7.0%) were stroke survivors, 12 had amyotrophic lateral sclerosis (6.4%), 6 had medication-induced sialorrhea (3.2%), 4 had adult cerebral palsy (2.1%), and 30 had sialorrhea owing to other causes (16.0%). A total of 176 completed the study. Treatment with both doses of RIMA significantly reduced USFR at week 4 vs placebo (mean treatment difference, -0.30 g/min [95% CI, -0.39 to -0.21] for both doses vs placebo, P < .001). The CGI-C scores were statistically significantly improved at week 4 for both treatment groups vs placebo (-1.21 [95% CI, -1.56 to -0.87] for 2500 U, -1.14 [95% CI, -1.49 to -0.80] for 3500 U, both P < .001). Treatment benefits were seen as early as 1 week after injection and were maintained over the treatment cycle of approximately 13 weeks. The RIMA injections were well tolerated compared with placebo. The most common adverse events were self-limited mild to moderate dry mouth, dysphagia, and dental caries. Conclusions and Relevance: Treatment with RIMA (2500 U and 3500 U) in adults was well tolerated and reduced sialorrhea, with the onset of the effect at 1 week after the injection. These data support the clinical use of RIMA in the management of sialorrhea in adults. Trial Registration: ClinicalTrials.gov Identifier: NCT01994109.

Impact of abobotulinumtoxinA on the clinical features of cervical dystonia in routine practice.

INTRODUCTION: The efficacy and safety of abobotulinumtoxinA in the management of cervical dystonia has been established in randomized, controlled trials that use a selected trial population. In this meta-analysis of observational data, we evaluated the real-life effectiveness of abobotulinumtoxinA as delivered in routine clinical practice. METHODS: Meta-analysis of patient-level data for adult patients with cervical dystonia treated with abobotulinumtoxinA from three prospective, multicenter, observational studies (NCT01314365, NCT00833196 and NCT01753349). RESULTS: We report data for patients treated with abobotulinumtoxinA over one injection cycle at 181 neurology centers in 35 countries. CD clinical features as assessed by Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total scores (N = 920) significantly reduced by a mean [95%CI] of -12.9 [-13.9, -11.8] points at Week 4 (N = 449) and -3.2 [-3.8, -2.7] points at the end of the injection cycle (N = 890). All three TWSTRS domains (symptom severity, disability and pain) contributed to the overall improvement. Patients were generally content with symptom control at peak effect of the treatment cycle, with 86% reporting overall satisfaction. CONCLUSION: Findings from this meta-analysis of observational studies confirm the effectiveness of abobotulinumtoxinA in routine practice. Despite inclusion of a broader population sample, the magnitude of improvements observed is consistent with that seen in the pivotal, randomized controlled trials.

Spectrum of practice in the routine management of cervical dystonia with abobotulinumtoxinA: findings from three prospective open-label observational studies.

BACKGROUND: Cervical dystonia is a heterogeneous disorder with several possible presentations, for which first-line therapy is often botulinum toxin (BoNT). In routine clinical practice the success of each BoNT injection is dependent on several variables, including individual presentation and injection technique. Large multicenter, observational studies provide important information on individualized administration strategies that cannot be otherwise ascertained from controlled clinical trials. In this meta-analysis of patient level data, we aimed to evaluate the clinical characteristics of patients with cervical dystonia undergoing routine treatment with botulinum toxin, specifically abobotulinumtoxinA. We also aimed to characterize current abobotulinumtoxinA injection techniques and parameters and to explore international differences in patient presentation and treatment. METHODS: This was a meta-analysis of baseline data from three prospective, international, multicenter, observational studies (NCT01314365, NCT00833196 and NCT01753349) of botulinum toxin treatment for the routine management of adult cervical dystonia. RESULTS: Data presented illustrate the significant heterogeneity of CD presentation in routine practice. Most subjects presented with a complex pattern of dystonic movements and the majority had additional components of shoulder elevation, tremor and/or jerk. Dosing was generally in accordance with that recommended in the abobotulinumtoxinA prescribing information, although the range of dosing also indicates that injections are tailored to individual presentation. Sub-group analyses at the country level revealed distinct differences in injection practice. CONCLUSIONS: This meta-analysis is based on the largest dataset of subjects with cervical dystonia studied to date. The heterogeneity revealed in our baseline findings support the need to develop consistent, practical and comprehensive best practice guidelines.

Minimal clinically important change in the Toronto Western Spasmodic Torticollis Rating Scale.

OBJECTIVES: To characterize the minimal clinically important change (MCIC) after treatment in cervical dystonia patients using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). METHODS: Changes in the TWSTRS from an observational study of abobotulinumtoxinA in the routine management of cervical dystonia (NCT01314365) were analyzed using the Patient Global Impression of Change (PGIC) as anchor. RESULTS: For the overall population (N = 304, baseline TWSTRS-Total score 43.4 ±â€¯19.4), the MCIC for the TWSTRS Total score was -11.9 (95%CI: -13.9, -10.0; p < 0.0001). However, thresholds ranged from -3.2 to -18.0 dependent on baseline severity. TWSTRS-Total scores improved linearly by 3 points for every one-point PGIC increase. There was similar linearity between the graded PGIC categories and TWSTRS subscale scores (severity, disability, and pain). CONCLUSIONS: A 3-point change is the minimal clinically important change after treatment using TWSTRS as endpoint with higher cutoffs for greater baseline disease severity. For an average trial population (TWSTRS-total: 40-45), a 12-point decrease is clinically meaningful.

Multicenter observational study of abobotulinumtoxinA neurotoxin in cervical dystonia: The ANCHOR-CD registry.

BACKGROUND: The ANCHOR-CD prospective observational registry study evaluated the effectiveness of abobotulinumtoxinA in adult idiopathic cervical dystonia (CD) in clinical practice. METHODS: Adults with CD were eligible. Treating physicians determined abobotulinumtoxinA dose and treatment interval. The primary endpoint was patient response rate (Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] score reduction≥25% and Patient Global Impression of Change [PGIC] score of +2 or +3 at Week 4 of Cycle 1). RESULTS: 350 patients enrolled (75% women; mean age 59±13.6years; 27.4% botulinum neurotoxin-naive) and 347 received at least 1 treatment. The median abobotulinumtoxinA dose for Cycle 1 was 500 Units. At Week 4, the responder rate was 30.6% (n=304) and the TWSTRS total score decreased 27.4% from baseline. PGIC of at least "Much improved" was documented in 43.6% of patients and maintained in Cycles 2 through 4 (43.3%, 48.9%, and 52.8%, respectively). A total of 39 adverse events (31 study drug-related) were reported in 17 patients (5%); the most common were dysphagia (n=6), muscle weakness (n=4), and neck pain (n=3). CONCLUSION: This study confirmed the beneficial effect of abobotulinumtoxinA on CD in routine clinical practice as measured by improvements in TWSTRS and PGIC. No new safety concerns were identified.

Physicians' experience with RYTARY (carbidopa and levodopa) extended-release capsules in patients who have Parkinson disease.

A discussion between Dr. Dee Silver and Dr. Richard Trosch provides insight and advice for physicians considering a switch from immediate-release carbidopa-levodopa (IR CD-LD) to RYTARY as a treatment for patients with Parkinson disease (PD). The dialogue describes how they identify patients with PD who may and may not be successful switching to RYTARY, how they approach the conversion process and patient compliance, and how they address some side effects that may occur after patients begin taking RYTARY. The clinicians also discuss their experiences with how long it takes to establish a stable regimen as well as provide general advice regarding conversion from treatment with IR CD-LD to RYTARY.

A Retrospective, Single-Center Comparative Cost Analysis of OnabotulinumtoxinA and AbobotulinumtoxinA for Cervical Dystonia Treatment.

BACKGROUND: Chemodenervation with botulinum neurotoxin (BoNT) is recommended as first-line treatment for the management of cervical dystonia. The choice of BoNT for treatment is subject to the consideration of several factors, including cost. OBJECTIVE: To compare the costs incurred by patients and payers for onabotulinumtoxinA (ONA) or abobotulinumtoxinA (ABO) for the treatment of cervical dystonia. METHODS: We conducted a retrospective, noninterventional closed cohort study of cervical dystonia patients within a single U.S. private neurological practice. Patient and payer incurred costs from medical billing records for patients satisfying inclusion and exclusion criteria treated from November 1, 2009, through January 1, 2013, were de-identified and included in the analysis. Forty-seven patients initially treated with at least 3 consecutive cycles of ONA, followed by at least 3 consecutive cycles of ABO were included, representing 282 injection cycles available for analysis. Patients were required to have had a positive response to treatment with both agents and no concomitant treatment with BoNT for any other condition during the analysis period. The analysis compared the primary endpoint of median overall payer and patient incurred costs reimbursed to the clinic under each treatment regimen. For the purposes of this cost analysis, comparable clinical outcomes on both therapies was assumed.   RESULTS: Switching from ONA to ABO resulted in an overall incurred reimbursement cost savings for payers and patients. Median costs per injection cycle for ONA were $1,925 ($0-$2,814) compared with $1,214 ($229-$2,899; P less than 0.0001) for ABO, representing an approximate 37% reduction in incurred reimbursement costs inclusive of toxin and procedure. Overall toxin reimbursement costs, patient out-of-pocket toxin costs, and the cost of unavoidable waste were also lower when patients were treated with ABO.  CONCLUSIONS: For patients treated for cervical dystonia, switching from ONA to ABO resulted in payer and patient reimbursement cost reductions in a single U.S. private practice with outcomes assumed to be similar.

Mutations in GNAL cause primary torsion dystonia.

Dystonia is a movement disorder characterized by repetitive twisting muscle contractions and postures. Its molecular pathophysiology is poorly understood, in part owing to limited knowledge of the genetic basis of the disorder. Only three genes for primary torsion dystonia (PTD), TOR1A (DYT1), THAP1 (DYT6) and CIZ1 (ref. 5), have been identified. Using exome sequencing in two families with PTD, we identified a new causative gene, GNAL, with a nonsense mutation encoding p.Ser293* resulting in a premature stop codon in one family and a missense mutation encoding p.Val137Met in the other. Screening of GNAL in 39 families with PTD identified 6 additional new mutations in this gene. Impaired function of several of the mutants was shown by bioluminescence resonance energy transfer (BRET) assays.

Comparison of dysphagia before and after deep brain stimulation in Parkinson's disease.

Although dysphagia is a common problem for many Parkinson's disease (PD) patients, the effect of deep brain stimulation (DBS) on swallowing is unclear. Fourteen subjects with advanced PD underwent videofluorographic swallowing studies prior to bilateral DBS of the subthalamic nucleus (STN) and at 3 and 12 months postprocedure. They were tested under several stimulation and medication conditions. Subjects completed the Dysphagia Handicap Index at each time. There was a strong trend toward improved swallowing response for solid intake in the medication-free condition with the stimulator on compared with the stimulator off (P = .0107). Also, there was a trend toward improved oral preparation of thin liquids (P = .0368) in the medication-free condition when the stimulator was on versus off 12 months later. The remaining swallowing parameters showed no change or worsening of swallowing function regardless of stimulator or medication status. Results of the Dysphagia Handicap Index revealed significant improvement in subject self-perception of swallowing 3 and 12 months following the procedure compared with baseline on the functional subscale (P = .020 and P = .010, respectively), the emotional subscale (P = .013 and P = .003, respectively), and the total score (P = .025 and P = .003, respectively). These data suggest that bilateral STN-DBS does not substantively impair swallowing in PD. In addition, it may improve motor sequencing of the oropharyngeal swallow for solid consistencies (which are known to provide increased sensory feedback to assist motor planning of the oropharyngeal swallow). Subjects with advanced PD who are undergoing DBS may perceive significant improvement in swallowing ability despite the lack of objective improvements in swallowing function.

Intermittent subcutaneous apomorphine therapy for 'off' episodes in Parkinson's disease: a 6-month open-label study.

PURPOSE: The outpatient follow-up phase of the apomorphine (APO) 303 study assessed the long-term efficacy and safety of intermittent subcutaneous apomorphine for 'off' episodes in patients with advanced Parkinson's disease. METHODS: We conducted a 6-month open-label outpatient extension of an in-office dose-escalation study. Patients received apomorphine at a dose considered optimal based on safety and efficacy assessments during the dose-titration phase. Outpatient evaluation visits were scheduled at 1 and 2 weeks, and 1, 4 and 6 months. Efficacy parameters included changes in Unified Parkinson's Disease Rating Scale (UPDRS) motor scores; safety assessments included blood pressure (BP) monitoring. RESULTS: Apomorphine significantly (p<0.05) reduced UPDRS motor scores at 20, 40 and 90 minutes post-dose versus pre-dose at all evaluation visits. Significant (p<0.1) reductions from pre-dose in seated and standing systolic BP and diastolic BP were noted at various timepoints post-dose at evaluation visits; however, the changes did not increase over the course of the outpatient phase. The incidence of symptomatic hypotension also did not increase with long-term apomorphine use. CONCLUSIONS: The efficacy and general tolerability of subcutaneous apomorphine throughout this open-label outpatient study suggest that it is suitable for the long-term acute treatment of 'off' episodes in patients with advanced Parkinson's disease.

Botulinum toxin type B (Myobloc) in subjects with hemifacial spasm: results from an open-label, dose-escalation safety study.

OBJECTIVE: Evaluate the safety of botulinum toxin type B (BoNT-B) in subjects with hemifacial spasm (HFS). METHODS: This open-label, sequential dose-escalation study evaluated BoNT-B in subjects with HFS. Eligible subjects were enrolled and received a single injection of one of four sequential BoNT-B doses (100, 200, 400, or 800 U). Following injection, subjects were evaluated in person at Weeks 2 and 8 and by phone at Weeks 1, 4, and 10 and every 2 weeks thereafter until benefit was lost. Safety was assessed by adverse events (AEs), vital signs and clinical laboratory evaluation. The severity of HFS was assessed using a patient social impairment visual analog scale (VAS), subject severity of contraction VAS, the HFS physician assessment, and subject HFS frequency and severity assessment. RESULTS: Nineteen predominately Caucasian (92%) and female (67%) subjects (aged 36-80 years) with HFS participated in this study. Subjects remained in the study an average of 88 days (range of 41-332 days) after receiving a single dose of BoNT-B. No deaths, serious AEs or AEs leading to trial discontinuation occurred during the study period. Two subjects in the 400 U dose group requested early withdrawal, whereas all other subjects completed the study. A reduction in HFS severity was observed in subjects treated with doses of 200 U or more. Improvements in subject HFS assessments tended to return to baseline values by 8 weeks following injection. CONCLUSION: BoNT-B was well-tolerated and reduced HFS severity in subjects who received injections of 200 to 800 U. Additional investigation is necessary to confirm the findings from this open-label study.

Subcutaneous apomorphine in patients with advanced Parkinson's disease: a dose-escalation study with randomized, double-blind, placebo-controlled crossover evaluation of a single dose.

OBJECTIVE: To further explore the efficacy and safety of subcutaneous apomorphine (APO) in treating off episodes in APO-naïve patients with advanced Parkinson's disease (PD). METHODS: 56 patients receiving optimized oral anti-PD medication were evaluated on separate days for response to single increasing doses of APO. Acute response to oral anti-PD medication and APO dose escalation (2-10 mg) was evaluated under unblinded conditions. At the 4 mg APO dose, placebo was randomly introduced under double-blind crossover conditions. RESULTS: Mean changes from pre-dose in Unified Parkinson's Disease Rating Scale motor scores indicated significant improvement following APO 4 mg versus placebo at 20 min (p=0.0002), 40 min (p<0.0001; maximum improvement) and 90 min (p=0.0229). Improvements showed significant dose-response at 20 min, 40 min (both p<0.0001) and 90 min (p=0.0049). Adverse events were more common with APO than placebo, and also showed significant dose-response (p<0.0001). Common adverse events associated with APO included yawning, dizziness, nausea, somnolence and dyskinesias, and were generally mild to moderate. There were no significant differences between APO and placebo in the incidence of hypotension associated with a postural change from a sitting to standing position. CONCLUSIONS: Subcutaneous APO provided rapid, effective relief of off episodes associated with advanced PD.