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Background: Deep Brain Stimulation (DBS) has been demonstrated to improve quality of life in patients with refractory dystonia and Tourette's syndrome (TS). Because of the young age at onset of these disorders, and the marked benefit from DBS, pregnancy in patients who have received DBS is becoming a more frequent clinical occurrence, although clear management guidelines are lacking., Cases: We report 14 new pregnancies in patients with dystonia or TS and DBS., Literature Review: Upon review of the literature, 23 pregnancies in patients with dystonia or TS were previously reported in seven articles., Conclusion: Based on the available data from a total of 37 pregnancies, DBS does not seem associated with worse pregnancy outcome. However, careful planning and communication between neurologist, anesthesiologist and obstetrician are key. A registry on pregnancy outcome in patients with DBS should be generated to facilitate the development of guidelines., (© 2024 International Parkinson and Movement Disorder Society.)

Determining the genetic contributions to Parkinson's disease (PD) across diverse ancestries is a high priority as this work can guide therapeutic development in a global setting. The genetics of PD spans the etiological risk spectrum, from rare, highly deleterious variants linked to monogenic forms with Mendelian patterns of inheritance, to common variation involved in sporadic disease. A major limitation in PD genomics research is lack of racial and ethnic diversity. Enrollment disparities have detrimental consequences on the generalizability of results and exacerbate existing inequities in care. The Black and African American Connections to Parkinson's Disease (BLAAC PD) study is part of the Global Parkinson's Genetics Program, supported by the Aligning Science Across Parkinson's initiative. The goal of the study is to investigate the genetic architecture underlying PD risk and progression in the Black and/or African American populations. This cross-sectional multicenter study in the United States has a recruitment target of up to 2,000 individuals with PD and up to 2,000 controls, all of Black and/or African American ancestry. The study design incorporates several strategies to reduce barriers to research participation. The multifaceted recruitment strategy aims to involve individuals with and without PD in various settings, emphasizing community outreach and engagement. The BLAAC PD study is an important first step toward informing understanding of the genetics of PD in a more diverse population., (© 2024. The Author(s).)

Depression is a common psychiatric disorder among individuals with Huntington's disease (HD). Depression in HD and major depressive disorder appear to have different pathophysiological mechanisms. Despite the unique pathophysiology, the treatment of depression in HD is based on data from the treatment of major depressive disorder in the general population. The objective of this systematic review was to conduct a comprehensive evaluation of the available evidence. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Studies on the treatment of depression in HD were identified by searching MEDLINE, Embase, and PsycInfo. The initial search yielded 2,771 records, 41 of which were ultimately included. There were 19 case reports, seven case series, three cross-sectional studies, one qualitative study, nine nonrandomized studies, and two randomized trials among the included studies. The most common assessment tools were the Hospital Anxiety and Depression Scale (N=8), the Beck Depression Inventory (N=6), and the Hamilton Depression Rating Scale (N=6). Only 59% of the included studies assessed depressive symptoms with a scoring system. The pharmacological options for the treatment of depression included antidepressants and antipsychotics. Nonpharmacological approaches were multidisciplinary rehabilitation, psychotherapy, and neurostimulation. Limited evidence on the treatment of depression in HD was available, and this literature consisted mainly of case reports and case series. This systematic review highlights the knowledge gap and the pressing need for HD-specific research to determine the efficacy of treatment approaches for depression in HD., Competing Interests: Dr. Furr Stimming has received research grant support from or served as a consultant, advisory board member, or speakers bureau member for the Cure Huntington’s Disease Initiative Foundation, Cures Within Reach, Genetech, the Houston Area Parkinson Society, the Huntington’s Disease Society of America, the Huntington Study Group, the Michael J. Fox Foundation, Neurocrine Biosciences, Novartis, Prilenia, Roche, Sage Therapeutics, Sunovion, Teva, uniQure, University of Iowa, and Vaccinex. The other authors report no financial relationships with commercial interests.

Obsessive-compulsive and perseverative behaviors (OCBs/PBs) are characteristic features of Huntington's Disease (HD). Although a few recent research have attempted to discriminate between OCBs and PBs, most of the available evidence on OCBs does not consistently make this distinction. In this article, we aimed to explore the current inconsistencies in assessing and reporting OCBs/PBs and map the body of existing evidence. Up to half of the patients with motor manifest HD can experience OCBs. Separate reporting of PBs in HD patients has been uncommon among the studies and was frequently reported as a part of obsessive-compulsive symptoms. The structural limitation of the currently used rating scales and the overlaps in neuropathology and definition of OCBs and PBs are among the main reasons for the mixed reporting of OCBs/PBs. Perseverative thinking or behavior as a separate item is found in a few assessment tools, such as the Problem Behaviors Assessment - Short form (PBA-s). Even when the item exists, it is commonly reported as a composite score in combination with the obsessive-compulsive item. In addition to the significant psychological burden in individuals with HD, PBs are associated with somatic effects (e.g., cardiovascular symptoms) and high-risk behaviors (e.g., suicide). Recognition and monitoring of PBs in HD can aid in early detection of concerning symptoms and differentiating overlapping illnesses., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: To describe the characteristics of patients receiving a clinical referral for neuropsychological evaluation in two Huntington's Disease Society of America Centers of Excellence (HDSA COE). In this exploratory pilot study, we used an empirically supported clinical neuropsychological battery to assess differences in cognitive performance between premanifest and manifest HD patient groups (compared with each other and normative expectations)., Method: Clinical data from 76 adult genetically confirmed patients referred for neuropsychological evaluations was retrospectively collected from two HDSA COEs. ANOVA and Chi-square tests were used to compare variables between pre-manifest (n = 14) and manifest (n = 62) groups for demographic, cognitive, neuropsychiatric, and disease severity variables., Results: Our clinics serviced a disproportionate number of motor manifest patients. Six measures were excluded from analyses due to infrequent administration. The full WAIS-IV Digit Span was disproportionately administered to the manifest group. The premanifest group showed stronger cognitive performance with effect sizes in the large range on subtests of the WAIS-IV Digit Span, HVLT-R, SDMT, and verbal fluency., Conclusions: This is the first study to assess an empirically supported neuropsychological research battery in a clinical setting with a relatively large sample size given the rarity of HD. The battery adequately captured areas of impairment across the disease spectrum. Application of the current battery with larger premanifest samples is warranted., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Valbenazine is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for treatment of tardive dyskinesia. To address the ongoing need for improved symptomatic treatments for individuals with Huntington's disease, valbenazine was evaluated for the treatment of chorea associated with Huntington's disease., Methods: KINECT-HD (NCT04102579) was a phase 3, randomised, double-blind, placebo-controlled trial, performed in 46 Huntington Study Group sites in the USA and Canada. The study included adults with genetically confirmed Huntington's disease and chorea (Unified Huntington's Disease Rating Scale [UHDRS] Total Maximal Chorea [TMC] score of 8 or higher) who were randomly assigned (1:1) via an interactive web response system (with no stratification or minimisation) to oral placebo or valbenazine (≤80 mg, as tolerated) for 12 weeks of double-blinded treatment. The primary endpoint was a least-squares mean change in UHDRS TMC score from the screening and baseline period (based on the average of screening and baseline values for each participant) to the maintenance period (based on the average of week 10 and 12 values for each participant) in the full-analysis set using a mixed-effects model for repeated measures. Safety assessments included treatment-emergent adverse events, vital signs, electrocardiograms, laboratory tests, clinical tests for parkinsonism, and psychiatric assessments. The double-blind placebo-controlled period of KINECT-HD has been completed, and an open-label extension period is ongoing., Findings: KINECT-HD was performed from Nov 13, 2019, to Oct 26, 2021. Of 128 randomly assigned participants, 125 were included in the full-analysis set (64 assigned to valbenazine, 61 assigned to placebo) and 127 were included in the safety-analysis set (64 assigned to valbenazine, 63 assigned to placebo). The full-analysis set included 68 women and 57 men. Least-squares mean changes from the screening and baseline period to the maintenance period in the UHDRS TMC score were -4·6 for valbenazine and -1·4 for placebo (least-squares mean difference -3·2, 95% CI -4·4 to -2·0; p<0·0001). The most commonly reported treatment-emergent adverse event was somnolence (ten [16%] with valbenazine, two [3%] with placebo). Serious treatment-emergent adverse events were reported in two participants in the placebo group (colon cancer and psychosis) and one participant in the valbenazine group (angioedema because of allergic reaction to shellfish). No clinically important ch anges in vital signs, electrocardiograms, or laboratory tests were found. No suicidal behaviour or worsening of suicidal ideation was reported in participants treated with valbenazine., Interpretation: In individuals with Huntington's disease, valbenazine resulted in improvement in chorea compared with placebo and was well tolerated. Continued research is needed to confirm the long-term safety and effectiveness of this medication throughout the disease course in individuals with Huntington's disease-related chorea., Funding: Neurocrine Biosciences., Competing Interests: Declaration of interests EFS has received honoraria as an advisory board member, consulted for, received research funding from, and served on the speakers’ bureau for Cures Within Reach, the Cure Huntington's Disease Initiative, Huntington's Disease Society of America, Neurocrine Biosciences, Prilenia, Roche/Genentech, UniQure, Novartis, Teva Pharmaceuticals, Vaccinex, and Sunovion. DOC has received research funding from Vaccinex, the Cure Huntington's Disease Initiative, Huntington's Disease Society of America, Griffin Foundation, Genentech, Wave Life Sciences, Neurocrine Biosciences, Teva Pharmaceuticals, AbbVie, and Biogen. DOC has also served as a consultant to Neurocrine Biosciences, Wave Life Science, Teva Pharmaceuticals, Acadia, Alterity, Genentech/Roche, and Lundbeck. RM served as a consultant for Global Kinetic Corporation and was on the speaker bureau for Teva Pharmaceuticals, Adamas Pharmaceuticals, Kyowa Kirin, Sunovion, and Accorda Therapeutics. DOC has received research grants from Prilenia, Global Kinetic Corporation, Northera, Neurocrine Biosciences, and Cerevel. EK and JG have no conflicts to disclose. HZ, GSL, and DH are full-time employees of Neurocrine Biosciences and own stock in the company., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Training of students and residents in outpatient settings requires adequate exposure to a broad range of neurologic diseases. A competency-based method has been frequently used to provide a framework for the design and assessment of medical curriculums. However, it is the responsibility of the faculty within a medical school to design the curriculum and ensure its quality. In this article, we review learning objectives, assessment of core competencies, the current status of outpatient neurology education, and the flaws that may affect its quality. We also discuss potential strategies and approaches for the improvement of education and learning process in the outpatient setting, including early clinical exposure of students, cross-disciplinary courses, balancing case mix, near-peer teaching, active learning, electronic and online education, and virtual modules., Competing Interests: Disclosure Dr E. Furr Stimming has served on the speakers’ bureau for Sunovion Pharmaceuticals and as a consultant or on an advisory board for Teva Pharmaceuticals and Norvartis. She has received publishing royalties from McGraw Hill. Her institution has received research funding from Cures within Reach, CHDI, HDSA, Neurocrine Biosciences/HSG, Prilenia, Roche/Genetech, UniQure, Vaccinex. She has no conflicts nor has she received any funding related to this article. Dr M. Soni has nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The Renin-Angiotensin System (RAS) is expressed in the central nervous system and has important functions that go beyond blood pressure regulation. Clinical and experimental studies have suggested that alterations in the brain RAS contribute to the development and progression of neurodegenerative diseases. However, there is limited information regarding the involvement of RAS components in Huntington's disease (HD). Herein, we used the HD murine model, (BACHD), as well as samples from patients with HD to investigate the role of both the classical and alternative axes of RAS in HD pathophysiology. BACHD mice displayed worse motor performance in different behavioral tests alongside a decrease in the levels and activity of the components of the RAS alternative axis ACE2, Ang-(1-7), and Mas receptors in the striatum, prefrontal cortex, and hippocampus. BACHD mice also displayed a significant increase in mRNA expression of the AT1 receptor, a component of the RAS classical arm, in these key brain regions. Moreover, patients with manifest HD presented higher plasma levels of Ang-(1-7). No significant changes were found in the levels of ACE, ACE2, and Ang II. Our findings provided the first evidence that an imbalance in the RAS classical and counter-regulatory arms may play a role in HD pathophysiology.

Background: Depression and suicidality are commonly experienced by Huntington disease (HD) gene carriers. Research on these behavioral symptoms is imperative, not only to increase our understanding of the symptoms and how they relate to HD, but also to contribute to improving patients' care and quality of life., Objective: To identify clinical variables associated with a history of depression and suicidality in HD gene carriers., Method: We conducted a cross-sectional study of HD gene carriers from the Enroll-HD database PDS4 (periodic data set 4; N = 11,582). Data from baseline visits were obtained, and binary logistic regression models were used to ascertain the effects of clinical variables on the likelihood that HD gene carriers would have previous depression and suicidal ideation/attempts., Results: Approximately 65% (n = 7526) of the HD gene carriers had a history of depression, and ~27% (n = 3152) had previous suicidal ideation/attempts. Female sex; diagnosis of manifest HD; history of perseverative/obsessive behavior, apathy, and psychosis; and previous suicidal ideation/attempts were significantly associated with a history of depression in the HD gene carriers. Medical history of apathy, psychosis, and depression, as well as worse scores on the Total Functional Capacity and Irritability Scales, were significantly associated with previous suicidal ideation/attempts in the HD gene carriers., Conclusion: The prevalence of depression and suicidality is high among HD gene carriers. An improved understanding of the risk factors for depression and suicide in HD gene carriers can assist providers in recognizing at-risk individuals and allow providers to implement therapeutic strategies., Competing Interests: E.F.S. has received honoraria as an advisory board member, consulted for, received research funding from, and/or served on the speakers’ bureau for Cures within Reach, CHDI, HDSA, Neurocrine Biosciences/HSG, Prilenia, Roche/Genetech, UniQure, Novartis, Teva, Vaccinex, and Sunovion. The remaining authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

IntroductionSome patients with cervical dystonia (CD) receiving long-term botulinum neurotoxin (BoNT) therapy report early waning of treatment benefit before the typical 12-week reinjection interval., Methods: This phase 4, open-label, randomized, noninferiority study (CD Flex; NCT01486264) compared 2 incobotulinumtoxinA injection schedules (Short Flex: 8 ± 2 weeks; Long Flex: 14 ± 2 weeks) in CD patients. Previous BoNT-responsive subjects who reported acceptable clinical benefit lasting < 10 weeks were recruited. Efficacy and safety were evaluated after 8 injection cycles. The primary endpoint was change in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) severity subscale 4 weeks after the eighth injection. Secondary endpoints included TWSTRS total and subscale scores. Immunogenicity was assessed in a subset of patients., Results: Two hundred eighty-two CD patients were randomized and treated (Short Flex, N = 142; Long Flex, N = 140), and 207 completed the study. Significant improvements in TWSTRS severity from study baseline to 4 weeks after cycle 8 were observed in both the Short Flex (4.1 points; P  < 0.0001) and Long Flex (2.4 points; P  = 0.002) groups; Short Flex was noninferior to Long Flex (LS mean difference = 1.4 points; 95% CI = [-2.9, 0.1] < Δ = 2.0). Key secondary endpoints favored Short Flex intervals. Adverse events (AEs) were comparable between groups. There was no secondary loss of treatment effect., Conclusion: Injection cycles < 10 weeks for incobotulinumtoxinA are effective (and noninferior to longer intervals) for treating CD patients with early waning of clinical benefit. Shorter injection intervals did not increase AEs or lead to loss of treatment effect., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Disclosures: Cynthia Comella serves on the editorial board of Clinical Neuropharmacology and Sleep Medicine. She has received compensation/honoraria for services as a consultant or an advisory committee member for Acadia Pharmaceuticals, Acorda Therapeutics, Adamas Pharmaceuticals, AEON Biopharma, Allergan, Ipsen Pharmaceuticals, Jazz Pharmaceuticals, Lundbeck, Merz Pharmaceuticals, Neurocrine Biosciences, Revance Therapeutics, and Sunovion Pharmaceuticals. She receives royalties from Wolters Kluwer. Robert Hauser has received consulting fees from AbbVie, Acadia, Acorda, Adamas, Alterity, Amneal, Aptinyx, Britannia, Cerevance, Curium Pharma, Enterin, Inhibikase, Jazz, KeiferRx, Kyowa Kirin, Lundbeck A/S, Merck, Merz, Neurocrine Biosciences, Novus, Pharma Two B, Pharmather, Revance Therapeutics, Roche, Sage Therapeutics, Scion NeuroStim, Sio Gene Therapies, Sunovion, Supernus, Tolmar, US WorldMeds, and Vivifi Biotech and has received speaker fees from AbbVie, Acorda, Adamas, Amneal, Kyowa Kirin, Neurocrine Biosciences, and Sunovion. He holds stock in Axial Biotherapeutics and Inhibikase. His institution, University of South Florida, received research fees from AbbVie, Axovant Sciences, Biogen, Bukwang Pharmaceuticals, Cavion, Centogene, Cerevance, Cerevel Therapeutics, Cynapsus Therapeutics, Enterin, F. Hoffmann-La Roche, Genentech, Global Kinetics Corporation, Impax Specialty Pharma, Intec Pharma, Integrative Research Laboratories Sweden AB, Jazz Pharmaceuticals, MJFF, Neuraly, NeuroDerm, Neurocrine Biosciences, Northwestern University, Pfizer, Pharma Two B, Revance Therapeutics, Sanofi US Services, Sun Pharma Advanced Research Company, Sunovion Pharmaceuticals, and UCB Biopharma SPRL. Stuart Isaacson has received honoraria for CME for, was a consultant for, received research grants from, and/or was a promotional speaker on behalf of Abbvie, Allergan, Ipsen, Merz, Revance, Supernus, and US World Meds. Daniel Truong has received research funding from Abbvie, Acorda, Aeon, Auspex, Biogen, Bukwang, Cerevel, Cynapsus, Daiichi Sankyo Pharma, Eli Lilly, Enterin, Ipsen, Kyowa, Lundbeck, Merz, National Institute of Neurological Disorders and Stroke, Neurocrine, Neuroderm, Parkinson’s Foundation, Prilenia, Revance, and Sunovion. He has received honoraria for consulting and speaker activities from Acorda, Neurocrine, TEVA, an US Worldmed. Odinachi Oguh is a paid speaker and consultant for Sunovion Pharmaceuticals. Jennifer Hui is an advisory board member for Acorda, serves as a consultant for Sunovion, and receives grant support from Roche. Eric Molho is on the speakers bureau for Neurocrine Biosciences; received research funding from Amneal Pharmaceuticals, Biohaven Pharmaceuticals, Cerevel Therapeutics, CHDI/HSG, and Enterin; and received educational grants from AbbVie and Merz Pharmaceuticals. Matthew Brodsky has no conflicts of interest to disclose. Erin Furr-Stimming receives research funding from Cures within Reach, HDSA, Neurocrine, Prilenia, Roche/Genetech, and Uniqure; has consulted for Teva; and is on the speakers bureau for Sunovion; none of these are related to Xeomin or conflict with work being presented. Georg Comes and Michael Hast and are employees of Merz Pharmaceuticals. David Charles received income from Alliance for Patient Access, Merz, Newronika, Revance, and Supernus for consulting services. His institution, Vanderbilt University Medical Center, receives income from grants or contracts with Abbott, AbbVie, Aeon, Boston Scientific, Impax, Intec, Ipsen, Lundbeck, Medtronic, Merz, Novartis, Pharma Two B, and Supernus for research or educational programs that he has led., (© 2022 Published by Elsevier Ltd.)

Background: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off-label treatments., Objectives: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for HD gene expansion carriers., Methods: We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eligible randomized controlled trials were identified via an electronic search of the CENTRAL, MEDLINE, and EMBASE databases. All eligible trials that evaluated one or more of 33 predetermined clinical questions were included. Risk of bias was evaluated using the Cochrane Risk of Bias tool. A framework was adapted to allow for efficacy and safety conclusions to be drawn from the balance between the GRADE level of evidence and the importance of the benefit/harm of the intervention., Results: Twenty-two eligible studies involving 17 interventions were included, providing data to address 8 clinical questions. These data supported a likely effect of deutetrabenazine on motor impairment, chorea, and dystonia and of tetrabenazine on chorea. The data did not support a disease-modifying effect for premanifest and manifest HD. There was no eligible evidence to support the use of specific treatments for depression, psychosis, irritability, apathy, or suicidality. Similarly, no evidence was eligible to support the use of physiotherapy, occupational therapy, exercise, dietary, or surgical treatments., Conclusions: Data for therapeutic interventions in HD are limited and support only the use of VMAT2 inhibitors for specific motor symptoms. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)