Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson's disease study.

Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.

High rates of blood transfusion associated with Parkinson's disease.

BACKGROUND: As evidence continues to accumulate regarding the multi-organ dysfunction associated with Parkinson's disease (PD), it is still unclear as to whether PD increases the risk of hematological pathology. In this study, the authors investigate the association between PD and hematological pathology risk factors. METHODS: This retrospective cohort analysis was conducted using 8 years of the National Readmission Database. All individuals diagnosed with PD were queried at the time of primary admission. Readmissions, complications, and risk factors were analyzed at 30-, 90-, 180-, and 300-day intervals. Statistical analysis included multivariate Gaussian-fitted modeling using age, sex, comorbidities, and discharge weights as covariates. Coefficients of model variables were exponentiated and interpreted as odds ratios. RESULTS: The database query yielded 1,765,800 PD patients (mean age: 76.3 ± 10.4; 44.1% female). Rates of percutaneous blood transfusion in readmitted patients at 30, 90, 180, and 300 days were found to be 8.7%, 8.6%, 8.3%, and 8.3% respectively. Those with anti-parkinsonism medication side effects at the primary admission had increased rates of gastrointestinal (GI) hemorrhage (OR: 1.02; 95%CI: 1.01-1.03, p < 0.0001) and blood transfusion (OR: 1.06; 95%CI: 1.05-1.08, p < 0.0001) at all timepoints after readmission. PD patients who experienced GI hemorrhage of any etiology, including as a side effect of anti-parkinsonism medication, were found to have significantly higher rates of blood transfusion at all timepoints (OR: 1.14; 95%CI: 1.13-1.16, p < 0.0001). CONCLUSIONS: Blood transfusions were found to be significantly associated with anti-parkinsonism drug side effects and GI hemorrhage of any etiology.

Management Strategies for Comorbid Supine Hypertension in Patients with Neurogenic Orthostatic Hypotension.

PURPOSE OF REVIEW: In autonomic failure, neurogenic orthostatic hypotension (nOH) and neurogenic supine hypertension (nSH) are interrelated conditions characterized by postural blood pressure (BP) dysregulation. nOH results in a sustained BP drop upon standing, which can lead to symptoms that include lightheadedness, orthostatic dizziness, presyncope, and syncope. nSH is characterized by elevated BP when supine and, although often asymptomatic, may increase long-term cardiovascular and cerebrovascular risk. This article reviews the pathophysiology and clinical characteristics of nOH and nSH, and describes the management of patients with both nOH and nSH. RECENT FINDINGS: Pressor medications required to treat the symptoms of nOH also increase the risk of nSH. Because nOH and nSH are hemodynamically opposed, therapies to treat one condition may exacerbate the other. The management of patients with nOH who also have nSH can be challenging and requires an individualized approach to balance the short- and long-term risks associated with these conditions. Approaches to manage neurogenic BP dysregulation include nonpharmacologic approaches and pharmacologic treatments. A stepwise treatment approach is presented to help guide neurologists in managing patients with both nOH and nSH.

Systematic Literature Review of Quetiapine for the Treatment of Psychosis in Patients With Parkinsonism.

OBJECTIVE: The purpose of this article was to determine the efficacy and tolerability of quetiapine compared with placebo or other interventions for psychosis in parkinsonism. METHODS: Participants with a diagnosis of parkinsonism participated in randomized controlled trials (RCTs) investigating the efficacy and tolerability of quetiapine for psychotic symptoms within a defined follow-up period. The authors conducted searches on PubMed, Cochrane Controlled Register of Trials, and EMBASE for articles published from January 1991 to October 2017. Study methodology and patient- and treatment-level data were independently extracted and summarized by using descriptive statistics. Studies underwent quality assessment for risk of bias. RESULTS: A total of 17,615 unique records were identified, and seven RCTs (total N=241) met inclusion criteria. Five RCTs were placebo controlled, and two compared quetiapine against clozapine. The mean study duration was 12 weeks, and the mean daily quetiapine dose was 103 mg per day (range, 12.5-300 mg). In four of five placebo-controlled RCTs, quetiapine failed to demonstrate significant improvement of psychosis in parkinsonism compared with placebo. In two clozapine-comparator RCTs, quetiapine was better tolerated but no more effective than clozapine. Across all RCTs, the mean completion rates for quetiapine, clozapine, and placebo were 66%, 68.5%, and 66%, respectively. Quetiapine did not significantly worsen motor function. CONCLUSIONS: The efficacy of quetiapine in RCTs for psychosis in parkinsonism is no better than that for placebo or clozapine. On the basis of novel data, clinicians should reevaluate traditional viewpoints on the benefits of quetiapine for psychosis in parkinsonism.

Standing and Supine Blood Pressure Outcomes Associated With Droxidopa and Midodrine in Patients With Neurogenic Orthostatic Hypotension: A Bayesian Meta-analysis and Mixed Treatment Comparison of Randomized Trials.

BACKGROUND: The comparative effects of droxidopa and midodrine on standing systolic blood pressure (sSBP) and risk of supine hypertension in patients with neurogenic orthostatic hypotension (NOH) are unknown. OBJECTIVE: To perform a Bayesian mixed-treatment comparison meta-analysis of droxidopa and midodrine in the treatment of NOH. METHODS: The PubMed, CENTRAL, and EMBASE databases were searched up to November 16, 2016. Study selection consisted of randomized trials comparing droxidopa or midodrine with placebo and reporting on changes in sSBP and supine hypertension events. Data were pooled to perform a comparison among interventions in a Bayesian fixed-effects model using vague priors and Markov chain Monte Carlo simulation with Gibbs sampling, calculating pooled mean changes in sSBP and risk ratios (RRs) for supine hypertension with associated 95% credible intervals (CrIs). RESULTS: Six studies (4 administering droxidopa and 2 administering midodrine) enrolling a total of 783 patients were included for analysis. The mean change from baseline in sSBP was significantly greater for both drugs when compared with placebo (droxidopa 6.2 mm Hg [95% CrI = 2.4-10] and midodrine 17 mm Hg [95% CrI = 11.4-23]). Comparative analysis revealed a significant credible difference between droxidopa and midodrine. The RR for supine hypertension was significantly greater for midodrine, but not droxidopa, when compared with placebo (droxidopa RR = 1.4 [95% CrI = 0.7-2.7] and midodrine RR = 5.1 [95% CrI = 1.6-24]). Conclusion and Relevance: In patients with NOH, both droxidopa and midodrine significantly increase sSBP, the latter to a greater extent. However, midodrine, but not droxidopa, significantly increases risk of supine hypertension.

A 500 U/2 mL dilution of abobotulinumtoxinA vs. placebo: randomized study in cervical dystonia.

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. MATERIALS AND METHODS: 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. RESULTS: 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, P < 0.001). 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. CONCLUSIONS: 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.

Botulinum Toxin: Preparations for Clinical Use, Immunogenicity, Side Effects, and Safety Profile.

Botulinum toxin (BoNT) formulations are being used for a variety of medical applications. The use of BoNT preparations is continuously expanding with new formulations and indications. Of the seven antigenically distinct BoNTs, only two serotypes, type A and type B are commonly available for therapeutic use. The four available BoNT products are not equivalent and the knowledge of their formulations is crucial for product selection, avoidance of medication errors, therapeutic efficacy and safety. Generally, BoNT injection is a safe procedure when administered by an experienced injector. Side effects are always transient, and in the majority of cases they are mild and tolerable.

Comparative Analysis of Deutetrabenazine and Valbenazine as VMAT2 Inhibitors for Tardive Dyskinesia: A Systematic Review.

Background: Tardive Dyskinesia (TD) is a neurological disorder characterized by involuntary movements, often caused by dopamine receptor antagonists. Vesicular Monoamine Transporter 2 (VMAT2) inhibitors, such as valbenazine and deutetrabenazine, have emerged as promising therapies for TD and several clinical trials have shown their efficacy. This study aims to compare the efficacy and safety profile of VMAT2 inhibitors, focusing on a recent trial conducted in the Asian population. Methods: We reviewed the PubMed, Cochrane Library, Embase database, and clinicaltrials.gov between January 2017 and October 2023, using the keywords "tardive dyskinesia" AND ("valbenazine" [all fields] OR " deutetrabenazine " [all fields]) AND "clinical trial". The reviewed articles were studied for efficacy and side effects. Results: An initial search yielded 230 articles, of which 104 were duplicates. Following the title and abstract screening, 25 additional articles were excluded. A full-text review resulted in the exclusion of 96 more articles. Ultimately, four double-blind clinical trials met the inclusion criteria. The deutetrabenazine studies demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores compared to placebo, with no difference in adverse events. The valbenazine studies showed favorable results in reducing TD symptoms and were well-tolerated. Discussion: The studies reviewed in this analysis underscore the potential of deutetrabenazine and valbenazine as valuable treatment options for TD in diverse populations. Both medications demonstrated significant improvements in AIMS scores, suggesting their effectiveness in managing TD symptoms. Additionally, they exhibited favorable safety profiles, with low rates of serious adverse events and no significant increase in QT prolongation, parkinsonism, suicidal ideation, or mortality. Conclusion: The studies reviewed highlight the promising efficacy and tolerability of deutetrabenazine and valbenazine as treatments for Tardive Dyskinesia, providing new hope for individuals affected by this challenging condition.

Treatment response to onabotulinumtoxinA in cervical dystonia patients with anterocollis and retrocollis.

Anterocollis (AC) and retrocollis (RC) are less common cervical dystonia (CD) subtypes that are often under-represented in CD clinical trials. Herein we describe real-world demographics, disease characteristics, and treatment response to onabotulinumtoxinA (onabotA) in AC or RC patients from an observational, multicenter, prospective registry, CD PROBE. After three onabotA treatments, outcomes (CDIP-58, PGIC, CGIC, CD severity, TWSTRS) in patients with predominant AC or RC were compared to torticollis (TC) and all CD subtypes combined. The mean dosages at each treatment ranged from 153.5 to 195.4 U (AC) to 184.0-213.4 U (RC). After treatment, AC and RC patients reported improvements in the CDIP-58. "Much" or "very much improved" on PGIC and CGIC was reported by AC patients (n = 11/23, 48%) and clinicians (n = 14/23, 61%); and by RC patients (n = 14/24, 58%) and clinicians (n = 19/24, 83%). The mean total TWSTRS decreased from 45.7 (n = 59) to 36.1 (n = 23, 21.0% improvement) for AC patients and from 40.1 (n = 55) to 31.6 (n = 23, 21.2% improvement) for RC patients; the proportion of AC and RC patients with severe CD decreased. Outcomes for AC and RC were generally consistent with those for TC and all subtypes combined. Dysphagia was reported in 4/59 (6.8%) of AC patients (one serious), 7/55 (12.7%) of RC patients (none serious), 29/494 (5.9%) of TC patients (none serious), and 64/1012 (6.3%) of all CD patients (two serious). No new safety signals were identified. In conclusion, treatment with onabotA may relieve CD symptoms in some patients with AC and RC, consistent with results for other CD subtypes and the known safety profile of onabotA for the treatment of CD.

Real-world differences in dosing and clinical utilization of OnabotulinumtoxinA and AbobotulinumtoxinA in the treatment of upper limb spasticity.

According to prescribing information, potency units are not interchangeable between botulinum toxin A products. This exploratory study compared real-world dosing and utilization of onabotulinumtoxinA and abobotulinumtoxinA in adults with upper limb spasticity. In this retrospective study, 101 clinicians provided chart data via online surveys for 215 US post-stroke patients treated for upper limb spasticity with ≥3 onabotulinumtoxinA or abobotulinumtoxinA doses (phase 1: 9/18/2020-12/10/2020; phase 2: 9/30/2021-12/7/2021). Most participating clinicians were physicians (70.3%) specializing in neurology (71.3%) or physiatry (20.8%). In the onabotulinumtoxinA (n = 107) and abobotulinumtoxinA (n = 108) groups, ∼75% of patients had moderate-to-severe spasticity. A range of onabotulinumtoxinA:abobotulinumtoxinA dose ratios (1:2.2 [95% CI: 1.8, 2.6] to 1:4.1 [95% CI: 3.0, 6.0]) was observed across muscles. For the most recent dose, mean number of muscles injected was greater for onabotulinumtoxinA (4.3) versus abobotulinumtoxinA (3.1; P = 0.0003). For onabotulinumtoxinA versus abobotulinumtoxinA, the proportion of injections was 81.3% versus 63.9% (P = 0.0067) in forearm muscles and 23.4% versus 3.7% (P = 0.0001) in hand muscles. Mean injection intervals were similar (onabotulinumtoxinA: 102.0 days; abobotulinumtoxinA: 99.1 days). Differences in real-world dosing and utilization of onabotulinumtoxinA and abobotulinumtoxinA for upper limb spasticity were observed. There was no standard dose-conversion ratio, consistent with each product's prescribing information.

Safety and Real-World Dosing of OnabotulinumtoxinA for the Treatment of Adult Spasticity: Post Hoc Analysis of the Adult Spasticity International Registry Study.

OBJECTIVE: The aim of the study is to evaluate the safety of onabotulinumtoxinA treatment for spasticity across dose ranges in real-world practice. DESIGN: Adult Spasticity International Registry was a multicenter, prospective, observational study (NCT01930786) of onabotulinumtoxinA treatment for adult spasticity over 2 yrs. Adverse events, serious adverse events, treatment-related adverse events, and serious treatment-related adverse events were sorted into five categories (≤200, 201-400, 401-600, 601-800, ≥801 U) based on cumulative dose per session. RESULTS: In 3103 treatment sessions ( T ), 730 patients received ≥1 dose of onabotulinumtoxinA. Dose categories included the following: ≤200 U ( n = 312, T = 811), 201-400 U ( n = 446, T = 1366), 401-600 U ( n = 244, T = 716), 601-800 U ( n = 69, T = 149), and ≥801 U ( n = 29, T = 61). Of these patients, 261 reported 827 adverse events, 94 reported 195 serious adverse events, 20 reported 23 treatment-related adverse events, and 2 patients treated with 201-400 U onabotulinumtoxinA reported 3 serious treatment-related adverse events. Treatment-related adverse events reported included ≤200 U (8/811, 0.9%), 201-400 U (7/1366, 0.5%), 401-600 U (6/716, 0.8%), 601-800 U (1/149, 0.7%), and ≥801 U (1/61, 1.6%). CONCLUSIONS: In this post hoc analysis, most treatment sessions were performed with 201-400 U onabotulinumtoxinA. Patients treated with 201-400 U onabotulinumtoxinA had an adverse event profile consistent with onabotulinumtoxinA package inserts globally (e.g., United States, European Union, United Kingdom, Canada). No new safety signals were identified.

Diffusion, spread, and migration of botulinum toxin.

Botulinum toxin (BoNT) is an acetylcholine release inhibitor and a neuromuscular blocking agent used for the treatment of a variety of neurologic and medical conditions. The efficacy and safety of BoNT depends on accurate selection and identification of intended targets but also may be determined by other factors, including physical spread of the molecule from the injection site, passive diffusion, and migration to distal sites via axonal or hematogenous transport. The passive kinetic dispersion of the toxin away from the injection site in a gradient-dependent manner may also play a role in toxin spread. In addition to unique properties of the various BoNT products, volume and dilution may also influence local and systemic distribution of BoNT. Most of the local and remote complications of BoNT injections are thought to be due to unwanted spread or diffusion of the toxin's biologic activity into adjacent and distal muscles. Despite widespread therapeutic and cosmetic use of BoNT over more than three decades, there is a remarkable paucity of published data on the mechanisms of distribution and its effects on clinical outcomes. The primary aim of this article is to critically review the available experimental and clinical literature and place it in the practical context.

Mental health disparities and the role of perceived discrimination among Latinx individuals living with Parkinson's disease.

INTRODUCTION: Parkinson's disease (PD) is a neurodegenerative disorder with motor and non-motor symptoms including depression and cognitive impairment. There is underrepresentation of Latinxs in PD research as most of the research consists of non-Latinx white participants. The current study investigates longitudinal differences in health disparities among Latinx and White non-Latinx individuals living with PD. As a second aim, we examined the associations between perceived discrimination in healthcare and outcomes from aim 1. METHODS: The present study consisted of 25,298 individuals with PD who enrolled in the Fox Insight (FI) online study. Participants were followed annually for up to 3 years. Participants completed measures of depressive symptoms, health-related quality of life (HRQOL), cognitive complaints, subjective motor symptom severity, self-reported income, and perceived discrimination in healthcare. Multilevel models examined the longitudinal differences in non-motor and motor outcomes among Latinx (n = 1161) and White non-Latinx individuals (n = 24,137). RESULTS: Latinx participants reported significantly more depressive symptoms and worse HRQOL than non-Latinx individuals. No significant differences were found in cognitive complaints, or motor severity between Latinx and non-Latinx participants. The main effect of perceived discrimination was associated with both depressive symptoms and HRQOL. CONCLUSIONS: The current study provides initial evidence of mental health discrepancies among Latinx individuals living with PD and White non-Latinx counterparts. The combination of underrepresentation in research and possible health disparities among Latinx communities may affect the quality of clinical trials/studies and patient care.

Sleep disturbances in Parkinson's disease with emphasis on rapid eye movement sleep behavior disorder.

Sleep disturbances are common in patients with Parkinson's disease (PD). These disturbances can primarily affect the patient's quality of life and may worsen the symptoms of PD. Among the multiple sleep disturbances in PD patients, there has been a marked growing interest in rapid eye movement (REM) sleep behavior disorder (RBD). This is likely due to the fact that RBD has been proven to precede the motor symptoms of PD by many years. The aim of this article is to examine the sleep disturbances found in PD, with special attention to RBD as a premotor symptom of PD, as well as to assess its proposed related pathophysiology. MEDLINE (1966-March 2010), American Academy of Sleep Medicine's, The International Classification of Sleep Disorders, and current textbooks of sleep medicine were searched for relevant information. Search terms: RBD, sleep disturbances, Parkinson's disease, and pre-motor were used. Excessive daytime sleepiness (EDS), sleep attack, insomnia, restless leg syndrome (RLS), sleep-disordered breathing (SDB), and RBD are sleep disturbances commonly found in the literature related to PD. Sleep benefit has been proven to lessen PD motor symptoms. RBD has been described as a premotor symptom of PD in several prospective, retrospective, and cross-sectional studies. Sleep disturbances in PD can result secondarily to natural disease progression, as a side effect of the medications used in PD, or in result of pre-clinical pathology. Treatment of sleep disturbances in PD patients is crucial, as what is termed as, "sleep benefit effect" has been shown to improve the symptoms of PD.

The Effect of Low Dose OnabotulinumtoxinA on Cervical Dystonia in Hypermobile Ehlers-Danlos Syndrome.

Background: Many patients with hypermobile Ehlers-Danlos Syndrome (EDS) suffer from cervical dystonia. Intramuscular injection of botulinum toxin may exacerbate myeloradiculopathy or atlantoaxial subluxation in this patient population. Case: Three patients with hypermobile EDS underwent low-dose OnabotulinumtoxinA injections for cervical dystonia into myofascial sites selected using Fascial Manipulation diagnostic sequencing technique. All patients improved in clinical symptoms without complications. Results: Patients clinically improved on the TWSTRS by 16 points with demonstrated changes in deep fascia thickness decrease of 0.28 mm. Discussion: Low-dose OnabotulinumtoxinA injections into carefully selected sites is a safe and effective treatment in hypermobile EDS patients suffering from cervical dystonia.

Pimavanserin Treatment for Parkinson's Disease Psychosis in Clinical Practice.

BACKGROUND: Parkinson's disease psychosis (PDP) is a common, nonmotor symptom of Parkinson's disease (PD), which may affect up to 60% of patients and is associated with impaired quality of life, increased healthcare costs, and nursing home placement, among other adverse outcomes. Characteristic symptoms of PDP include illusions; visual, auditory, tactile, and olfactory hallucinations; and delusions. PDP symptoms typically progress over its course from being mild, infrequent, and often untroubling to complex, sometimes constant, and potentially highly disturbing. PDP has traditionally been treated with atypical antipsychotics (e.g., clozapine and quetiapine) although these are not approved for this indication and clozapine requires frequent white blood cell count monitoring due to the risk of agranulocytosis. Pimavanserin is a newer atypical antipsychotic with highly selective binding to serotonergic receptors, no evidence for worsening motor symptoms in PD, and no need for white blood cell count monitoring. It is currently the only approved medication indicated for PDP treatment. However, because it was approved relatively recently (2016), clinical experience with pimavanserin is limited. Case Presentations. A wide variety of representative clinical scenarios are presented, each with distinct variables and complications. Issues addressed include distinguishing PDP from similar symptoms caused by other disorders such as dementia, coordinating pimavanserin with other PD medications and with deep brain stimulation, adapting pimavanserin dosing for optimal benefit and tolerability, and recognizing variability of PDP symptoms due to patients' changing life circumstances. CONCLUSIONS: These scenarios provide multiple insights regarding PDP management and the role of pimavanserin. Effective treatment of PDP may reduce disturbing symptoms of psychosis, thus improving patient function and quality of life. In addition, effective pharmacotherapy for PDP may also facilitate the use of other medications needed to treat neurological symptoms of PD (e.g., tremor, bradykinesia, and dyskinesia), although they may also have adverse effects that contribute to symptoms of PDP.

AbobotulinumtoxinA provides flexibility for the treatment of cervical dystonia with 500 U/1 mL and 500 U/2 mL dilutions.

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.

Correction: Sustained functional benefits after a single set of injections with abobotulinumtoxinA using a 2-mL injection volume in adults with cervical dystonia: 12-week results from a randomized, double-blind, placebo-controlled phase 3b study.

[This corrects the article DOI: 10.1371/journal.pone.0245827.].

Sustained functional benefits after a single set of injections with abobotulinumtoxinA using a 2-mL injection volume in adults with cervical dystonia: 12-week results from a randomized, double-blind, placebo-controlled phase 3b study.

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.

VMAT2 inhibitors for the treatment of hyperkinetic movement disorders.

Hyperkinetic movement disorders comprise a variety of conditions characterized by involuntary movements, which include but are not limited to tardive dyskinesia, chorea associated with Huntington's Disease, and tic disorders. The class of medications that have been used to treat these conditions includes Vesicular Monoamine Transporter-2 (VMAT2) inhibitors. In 2008, the FDA approved tetrabenazine as a treatment for chorea associated with Huntington's Disease. Optimization of the pharmacology of tetrabenazine has since led to the approval of two new VMAT2 inhibitors, deutetrabenazine and valbenazine. The objective of this review is to provide background on the role of VMAT in monoamine neurotransmission, the mechanism of VMAT2 inhibition on the treatment of hyperkinetic disorders (specifically tardive dyskinesia and chorea associated with Huntington's Disease), the pharmacology and pharmacokinetics of the commercially available VMAT2 inhibitors, and a summary of the clinical data to support application of these medications.