Systemic Symptoms in Huntington's Disease: A Comprehensive Review.

BACKGROUND: Although Huntington's disease (HD) is usually thought of as a triad of motor, cognitive, and psychiatric symptoms, there is growing appreciation of HD as a systemic illness affecting the entire body. OBJECTIVES: This review aims to draw attention to these systemic non-motor symptoms in HD. METHODS: We identified relevant studies published in English by searching MEDLINE (from 1966 to September 2023), using the following subject headings: Huntington disease, autonomic, systemic, cardiovascular, respiratory, gastrointestinal, urinary, sexual and cutaneous, and additional specific symptoms. RESULTS: Data from 123 articles were critically reviewed with focus on systemic features associated with HD, such as cardiovascular, respiratory, gastrointestinal, urinary, sexual and sweating. CONCLUSION: This systematic review draws attention to a variety of systemic and autonomic co-morbidities in patients with HD. Not all of them correlate with the severity of the primary HD symptoms or CAG repeats. More research is needed to better understand the pathophysiology and treatment of systemic and autonomic dysfunction in HD.

Current opinions and practices in post-stroke movement disorders: Survey of movement disorders society members.

BACKGROUND: Post-stroke movement disorders (PSMD) encompass a wide array of presentations, which vary in mode of onset, phenomenology, response to treatment, and natural history. There are no evidence-based guidelines on the diagnosis and treatment of PSMD. OBJECTIVES: To survey current opinions and practices on the diagnosis and treatment of PSMD. METHODS: A survey was developed by the PSMD Study Group, commissioned by the International Parkinson's and Movement Disorders Society (MDS). The survey, distributed to all members, yielded a total of 529 responses, 395 (74.7%) of which came from clinicians with experience with PSMD. RESULTS: Parkinsonism (68%), hemiballismus/hemichorea (61%), tremor (58%), and dystonia (54%) were by far the most commonly endorsed presentation of PSMD, although this varied by region. Basal ganglia stroke (76% of responders), symptoms contralateral to stroke (75%), and a temporal relationship (59%) were considered important factors for the diagnosis of PSMD. Oral medication use depended on the phenomenology of the PSMD. Almost 50% of respondents considered deep brain stimulation and ablative surgeries as options for treatment. The lack of guidelines for the diagnosis and treatment was considered the most important gap to address. CONCLUSIONS: Regionally varying opinions and practices on PSMD highlight gaps in (and mistranslation of) epidemiologic and therapeutic knowledge. Multicenter registries and prospective community-based studies are needed for the creation of evidence-based guidelines to inform the diagnosis and treatment of patients with PSMD.

Safety and efficacy of valbenazine for the treatment of chorea associated with Huntington's disease (KINECT-HD): a phase 3, randomised, double-blind, placebo-controlled trial.

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.

Age Cutoff for Early-Onset Parkinson's Disease: Recommendations from the International Parkinson and Movement Disorder Society Task Force on Early Onset Parkinson's Disease.

Background: Early-onset Parkinson's disease (EOPD)/young-onset Parkinson's disease (YOPD) is defined as Parkinson's disease (PD) with an age at onset (AAO) after age 21 years but before the usual AAO for PD. Consensus is lacking, and the reported maximal age for EOPD/YOPD has varied from 40 to 60 years, leading to a lack of uniformity in published studies and difficulty in harmonization of data. EOPD and YOPD have both been used in the literature, somewhat interchangeably. Objective: To define the nomenclature and AAO cutoff for EOPD/YOPD. Methods: An extensive review of the literature and task force meetings were conducted. Conclusions were reached by consensus. Results: First, the literature has seen a shift from the use of YOPD toward EOPD. This seems motivated by an attempt to avoid age-related stigmatization of patients. Second, in defining EOPD, 56% of the countries use 50 or 51 years as the cutoff age. Third, the majority of international genetic studies in PD use an age cutoff of younger than 50 years to define EOPD. Fourth, many studies suggest that changes in the estrogen level can affect the predisposition to develop PD, making the average age at menopause of 50 years an important factor to consider when defining EOPD. Fifth, considering the differential impact of the AAO of PD on professional and social life, using 50 years as the upper cutoff for the definition of EOPD seems reasonable. Conclusions: This task force recommends the use of EOPD rather than YOPD. It defines EOPD as PD with AAO after 21 years but before 50 years.

Gaps, Controversies, and Proposed Roadmap for Research in Poststroke Movement Disorders.

Poststroke movement disorders (PSMDs) are a common cause of secondary movement disorders. Although prior studies have highlighted the clinical spectrum and phenomenology of PSMDs, there are many knowledge gaps worth addressing. Some of the most important include lack of clinical definitions, variable stroke symptom latencies, and lack of biomarkers for vulnerability for or resilience against developing PSMDs. Collectively, the association between stroke localization and phenomenology is less than 30%, and the long-term clinical prognosis and treatment responses are highly variable. After summarizing the accumulated evidence regarding the phenomenology, pathophysiology, neuroimaging, and treatment of PSMDs, highlighting the many gaps and controversies including diagnostic challenges, we propose a roadmap for future research to fill these gaps and resolve the related controversies. More research is warranted concerning the phenomenology, classification, diagnostic criteria, and pathophysiology of PSMDs. Further, there is an urgent need for treatment guidelines for the management of PSMDs. © 2022 International Parkinson and Movement Disorder Society.

Validation of the Arabic Version of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale.

BACKGROUND: The Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) has become the gold standard for evaluating different domains in Parkinson's disease (PD), and it is commonly used in clinical practice, research, and clinical trials. OBJECTIVES: The objectives are to validate the Arabic-translated version of the MDS-UPDRS and to assess its factor structure compared with the English version. METHODS: The study was carried out in three phases: first, the English version of the MDS-UPDRS was translated into Arabic and subsequently back-translated into English by independent translation team; second, cognitive pretesting of selected items was performed; third, the Arabic version was tested in over 400 native Arabic-speaking PD patients. The psychometric properties of the translated version were analyzed using confirmatory factor analysis (CFA) as well as exploratory factor analysis (EFA). RESULTS: The factor structure of the Arabic version was consistent with that of the English version based on the high CFIs for all four parts of the MDS-UPDRS in the CFA (CFI ≥0.90), confirming its suitability for use in Arabic. CONCLUSIONS: The Arabic version of the MDS-UPDRS has good construct validity in Arabic-speaking patients with PD and has been thereby designated as an official MDS-UPDRS version. The data collection methodology among Arabic-speaking countries across two continents of Asia and Africa provides a roadmap for validating additional MDS rating scale initiatives and is strong evidence that underserved regions can be energically mobilized to promote efforts that apply to better clinical care, education, and research for PD. © 2022 International Parkinson and Movement Disorder Society.

Movement Disorders in Multiple Sclerosis and Other Demyelinating Diseases: A Retrospective Review From a Tertiary Academic Center.

BACKGROUND: Movement disorders (MDs) have been described in demyelinating diseases (DDs). However, data is lacking in the effective treatment of these MD as well as in a potential correlation between DD lesions localization and the phenomenology of the MD and its response to treatment. METHODS: Retrospective review of 185 patients with MD and DD seen at our center over a period of 7 years. Clinical imaging, medications, and therapeutic responses to both MD and DD treatments were reviewed. RESULTS: Of the 185 patients, 62 were excluded because of a diagnosis of spasticity without any other MD. One hundred twenty three patients with DD (75% female, age 48.8±12.8 y) had one or more MD. The most common MD was ataxia followed by isolated tremor. Forty-two patients (34%) received any treatment for MD, 29 (69%) of which responded at least partially to a first MD agent and 78.6% responded at least partially to a second or third agent. Responders to the first MD therapy were more likely to have a lesion in the basal ganglia or the cerebellum, and less likely to have a lesion in the brainstem or the spinal cord, but these results could be biased by a lower-than-expected frequency of tonic spasms in our series. No correlation between DD lesions localization and the phenomenology of the MD was discovered. CONCLUSIONS: MD are common in DD and are frequently overlooked or undertreated. MD in this sample have a 69% therapeutic response to a first trial. Greater awareness of potential therapeutic options is needed to decrease disability.

Gastrointestinal disorders in hyperkinetic movement disorders and ataxia.

BACKGROUND: Gastrointestinal (GI) disorders have been thoroughly investigated in hypokinetic disorders such as Parkinson's disease, but much less is known about GI disorders in hyperkinetic movement disorders and ataxia. The aim of this review is to draw attention to the GI disorders that are associated with these movement disorders. METHODS: References for this systematic review were identified by searches of PubMed through May 2020. Only publications in English were reviewed. RESULTS: Data from 249 articles were critically reviewed, compared, and integrated. The most frequently reported GI symptoms overall in hyperkinetic movement disorders and ataxia are dysphagia, sialorrhea, weight changes, esophago-gastritis, gastroparesis, constipation, diarrhea, and malabsorption. We report in detail on the frequency, characteristics, pathophysiology, and management of GI symptoms in essential tremor, restless legs syndrome, chorea, and spinocerebellar ataxias. The limited available data on GI disorders in dystonias, paroxysmal movement disorders, tardive dyskinesias, myoclonus, and non-SCA ataxias are also summarized. CONCLUSION: The purpose of our systematic review is to draw attention that, although primarily motor disorders, hyperkinetic movement disorders and ataxia can involve the GI system. Raising awareness about the GI symptom burden in hyperkinetic movement disorders and ataxia could contribute to a new research interest in that field, as well as improved patient care.

Are functional movement disorder phenotypes or age at onset correlated with perfectionism or history of abuse?

OBJECTIVE: To assess if the phenotype or age at onset of Functional Movement Disorders (FMD) vary as a function of presence of a perfectionism or history of abuse. Detecting such a potential association might help guide future research into the pathophysiology of FMD. METHODS: Charts of all patients diagnosed with FMD by a movement disorder specialist using the commonly accepted clinical diagnostic criteria for FMD seen at a tertiary center over 8 years were reviewed. Data collected were sex, age at the onset of the first FMD, phenotype of the first predominant FMD, history of perfectionism and history of childhood abuse (physical, sexual, emotional, or neglect). Statistical analyses were performed as appropriate. RESULTS: 68 patients with FMD were identified from which 12 were excluded for incomplete documentation. 56 patients were included in the analysis, 43 (76.8%) were women, with average age at onset 41.5y (range 13-74.4). The most frequent predominant initial FMD phenotypes were tremor (39%), dystonia (20.3%) and gait disorders (20.3%).Perfectionism was reported in 30 (53.6%) patients and history of abuse in 27 (48.2%).There was no significant correlation between each of the FMD phenotypes and perfectionism or history of childhood abuse. There was also no correlation between the age at symptoms onset and perfectionism or history of abuse. CONCLUSION: We could not demonstrate a significant correlation between FMD phenotype or age at onset and perfectionist personality trait or history of abuse. Factors leading to the development of one specific FMD phenotype rather than another are still to be elucidated.

Comparing subjective and objective response to medications in Parkinson's disease patients using the Personal KinetiGraph™.

BACKGROUND: Management of motor symptoms in Parkinson's Disease(PD) relies on subjective information provided by patients, the quality of which can be affected by many factors. RATIONALE: Objective data collected during daily life could complement this information and improve management of motor symptoms. OBJECTIVES: To assess the usefulness of the Personal KinetiGraph (PKG) in characterizing the intensity and timing of motor symptoms in PD patients. METHODS: Retrospective study of all PD patients followed at a tertiary academic movement disorders center assessed by PKG between December 1, 2016 and October 30, 2018. PKG was worn for 7 days prior to the clinical visit. We compared the information obtained from the interview and the clinical visit, and assessed the impact of the PKG on treatment decision making. RESULTS: 170 PKG results were reviewed. PKG complemented patient input in 82.9%(141/170) and led to medication changes in 71%(100/141) of the complemented inputs. PKG contributed the least to correcting or complementing patients' input when patients self-reported as undertreated (22%) and the most when patient were unable to answer all questions regarding motor response to individual doses (100%) (Fisher, p < 0.0001). The majority of patient undergoing 3 or 4 PKG encounters did not reach a controlled state as defined by PKG until the 3rd or 4th encounter, suggesting that repeated use of the PKG might be needed to help optimize motor control as therapy changes done after one encounter might not be enough. CONCLUSIONS: PKG might be useful in supplementing patient-provided information for accurate assessment and treatment plan.

Influence of Intraoperative Microelectrode Recording in Deep Brain Stimulation.

BACKGROUND: There is considerable debate regarding the use of intraoperative microelectrode recording (MER) in deep brain stimulation (DBS). OBJECTIVE: To determine if the use of intraoperative MER impacts the final position of the lead implant in DBS of the subthalamic nucleus (STN) and globus pallidus (GPi) and to evaluate the incidence of complications. METHODS: The authors conducted a retrospective chart review of all patients who underwent STN and GPi DBS with MER, at the University of Texas Health Science Center in Houston from June 1, 2009 to October 1, 2013 to compare initial and final coordinates. Hemorrhagic and infectious complications were reviewed. RESULTS: A total of 90 lead implants on 46 patients implanted at the center during this time period were reviewed and included in the study. A statistically significant difference between the initial and final coordinates was observed in the superior-inferior direction with a mean difference of 0.40 mm inferiorly (±0.96 mm, P<0.05) and 0.96 mm inferiorly (±1.32 mm, P<0.05) in the STN and GPi locations, respectively. A nonstatistically significant difference was also observed in the anterior-posterior direction in both locations. There were no intraparenchymal hemorrhages on postoperative computed tomography. Two patients developed postoperative seizures (7.4%). One STN electrode (1.1%) required revision because of a suboptimal response. CONCLUSIONS: Intraoperative MER in STN and GPi DBS implant does not seem to have a higher rate of surgical complications compared with historical series not using MER and might also be useful in determining the final lead location.

End of life: Expert care and support, not physician-hastened death.

In legal physician-hastened death, a physician prescribes medication with the primary intent of causing the death of a willing terminally ill patient. This practice differs radically from palliative sedation, intended to relieve a patient's suffering rather than cause a patient's death. In this position paper, we argue that the practice of physician-hastened death is contrary to the interests of patients, their families, and the sound ethical practice of medicine. Therefore, the American Academy of Neurology should advise its members against this practice, as it had done until 2018.

Drug induced parkinsonism: Symptomatic beyond 22 months.

We report 2 cases of drug induced Parkinsonism followed longitudinally that remained symptomatic 22 and 27 months after stopping causative agents with normal dopamine ioflupane iodine-123 (DaT) single-photon emission computed tomography (SPECT) scans at 8 and 16 months.

Young-onset Parkinson's disease: Its unique features and their impact on quality of life.

Young-onset Parkinson's disease (YOPD), defined as age at onset between 21 and 40 years, presents unique motor and non-motor features that differentiate this subtype from the typical late onset Parkinson's disease (LOPD), starting after age 61. Because it affects patients in the prime of their life, it often has an extraordinary impact on their family, social, and professional life. While typically progressing at a slower rate than LOPD, patients with YOPD are more prone to develop levodopa-related motor complications, including dyskinesia. In this article we will review the clinical features and epidemiology of YOPD with focus on its impact on pregnancy, employment and family, as well as its particular diagnostic and management challenges.

Parkinsonism and neurosarcoidosis: Cause and effect or coincidence?

Movement disorders in demyelinating diseases can be coincidental or secondary to a demyelinating lesion. We here report the first case of coincidental association of neurosarcoidosis and idiopathic Parkinson's disease.