An Exploratory, Randomized, Double-Blind Clinical Trial of Dipraglurant for Blepharospasm.

BACKGROUND: Blepharospasm is treated with botulinum toxin, but obtaining satisfactory results is sometimes challenging. OBJECTIVE: The aim is to conduct an exploratory trial of oral dipraglurant for blepharospasm. METHODS: This study was an exploratory, phase 2a, randomized, double-blind, placebo-controlled trial of 15 participants who were assigned to receive a placebo or dipraglurant (50 or 100 mg) and assessed over 2 days, 1 and 2 hours following dosing. Outcome measures included multiple scales rated by clinicians or participants, digital video, and a wearable sensor. RESULTS: Dipraglurant was well tolerated, with no obvious impact on any of the measurement outcomes. Power analyses suggested fewer subjects would be required for studies using a within-subject versus independent group design, especially for certain measures. Some outcome measures appeared more suitable than others. CONCLUSION: Although dipraglurant appeared well tolerated, it did not produce a trend for clinical benefit. The results provide valuable information for planning further trials in blepharospasm. © 2024 International Parkinson and Movement Disorder Society.

sPDGFRß and neuroinflammation are associated with AD biomarkers and differ by race: The ASCEND Study.

INTRODUCTION: There remains an urgent need to identify preclinical pathophysiological mechanisms of Alzheimer's disease (AD) development in high-risk, racially diverse populations. We explored the relationship between cerebrospinal fluid (CSF) markers of vascular injury and neuroinflammation with AD biomarkers in middle-aged Black/African American (B/AA) and non-Hispanic White (NHW) participants. METHODS: Adults (45-65 years) with a parental history of AD were enrolled (n = 82). CSF and blood biomarkers were collected at baseline and year 2. RESULTS: CSF total tau (t-tau), phosphorylated tau (p-tau), and amyloid beta (Aß)40 were elevated at year 2 compared to baseline. CSF soluble platelet-derived growth factor receptor ß (sPDGFRß) levels, a marker of pericyte injury, correlated positively with t-tau, p-tau, Aß40 markers of vascular injury, and cytokines at baseline and year 2. CSF sPDGFRß and tau were significantly lower in B/AA than NHW. DISCUSSION: Vascular dysfunction and neuroinflammation may precede cognitive decline and disease pathology in the very early preclinical stages of AD, and there are race-related differences in these relationships. HIGHLIGHTS: Cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers changed over 2 years in high-risk middle-aged adults. Markers of vascular dysfunction were associated with the CSF biomarkers amyloid beta and tau. AD biomarkers were lower in Black compared to non-Hispanic White individuals. Markers of vascular dysfunction were lower among Black individuals.

A Multi-center Genome-wide Association Study of Cervical Dystonia.

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

Movement disorders emergencies.

PURPOSE OF REVIEW: Although movement disorders are traditionally viewed as chronic diseases that are followed electively, a growing number of these patients present with acute, severe syndromes or complications of their underlying neurological problem. Identifying and managing movement disorders emergencies is challenging, even for the specialist. This review summarizes evidence outlining the clinical presentation of acute, life-threatening movement disorders. RECENT FINDINGS: We review the most significant aspects in the most common movement disorders emergencies, including acute complications related to Parkinson's disease and parkinsonism, serotonergic, and neuroleptic malignant syndromes, chorea, ballismus, dystonia, myoclonus, and tics. SUMMARY: The increasing amount of information delineating the descriptions of movement disorders emergencies provides means for more effective prevention, identification, and management for the nonspecialist. Although the commonest of these syndromes eventually have a good outcome, serious conditions such as neuroleptic malignant syndrome and status dystonicus may induce substantial rates of morbidity and mortality. This review re-emphasizes the need for their prompt identification and management.

Prevalence and clinical features of cervical dystonia in Parkinson's disease.

OBJECTIVE: To study the prevalence and clinical features of cervical dystonia in Parkinson's disease (CD-PD). BACKGROUND: PD features various forms of dystonia, including CD. Yet, the prevalence and clinical features of CD in PD patients are not well-characterized. METHODS: We conducted a single site, prospective study where consecutively evaluated PD patients were examined for the presence of CD to ascertain its prevalence. For each case of CD-PD, a standardized questionnaire assessing demographic and clinical features was completed. Statistical analysis was performed to compare CD-PD characteristics to those of a previously published large idiopathic CD cohort. RESULTS: Of 301 consecutive PD patients evaluated, 28 (9.3 %) had CD, far surpassing estimates of CD prevalence in the general population. This CD-PD cohort was predominantly male (71 %) with a mean age of 70.9 ± 8.1 years. The mean duration of PD was 10.4 ± 6.7 years. In most cases (n = 19, 68 %), CD developed after the onset of PD. Five patients reported dystonia improvements in response to levodopa, while none reported medication-induced worsening. In contrast to CD-PD, those with ICD (n = 209) were on average younger (59.7 ± 10.1) and mostly female (74 %, p < 0.001). In addition, CD-PD was overall less severe as measured by the Global Dystonia Rating Scale (GDRS) (p = 0.002) and featured less head tremor and pain. CONCLUSION: Our findings indicate CD is overrepresented in PD compared to the general population and has clinical features distinct from those of ICD. These results justify larger, more comprehensive studies of CD-PD to better understand its frequency, pathophysiology, clinical characteristics, and associated risk factors.

Exploration of potential immune mechanisms in cervical dystonia.

BACKGROUND: Although there are many possible causes for cervical dystonia (CD), a specific etiology cannot be identified in most cases. Prior studies have suggested a relationship between autoimmune disease and some cases of CD, pointing to possible immunological mechanisms. OBJECTIVE: The goal was to explore the potential role of multiple different immunological mechanisms in CD. METHODS: First, a broad screening test compared neuronal antibodies in controls and CD. Second, unbiased blood plasma proteomics provided a broad screen for potential biologic differences between controls and CD. Third, a multiplex immunoassay compared 37 markers associated with immunological processes in controls and CD. Fourth, relative immune cell frequencies were investigated in blood samples of controls and CD. Finally, sequencing studies investigated the association of HLA DQB1 and DRB1 alleles in controls versus CD. RESULTS: Screens for anti-neuronal antibodies did not reveal any obvious abnormalities. Plasma proteomics pointed towards certain abnormalities of immune mechanisms, and the multiplex assay pointed more specifically towards abnormalities in T lymphocytes. Abnormal immune cell frequencies were identified for some CD cases, and these cases clustered together as a potential subgroup. Studies of HLA alleles indicated a possible association between CD and DRB1*15:03, which is reported to mediate the penetrance of autoimmune disorders. CONCLUSIONS: Altogether, the association of CD with multiple different blood-based immune measures point to abnormalities in cell-mediated immunity that may play a pathogenic role for a subgroup of individuals with CD.

Sex Differences in Dystonia.

BACKGROUND: Prior studies have indicated that female individuals outnumber male individuals for certain types of dystonia. Few studies have addressed factors impacting these sex differences or their potential biological mechanisms. OBJECTIVES: To evaluate factors underlying sex differences in the dystonias and explore potential mechanisms for these differences. METHODS: Data from individuals with various types of dystonia were analyzed in relation to sex. Data came from two different sources. One source was the Dystonia Coalition database, which contains predominantly idiopathic adult-onset focal and segmental dystonias. The second source was the MDSGene database, which contains predominantly early-onset monogenic dystonias. RESULTS: The 3222 individuals from the Dystonia Coalition included 71% female participants and 29% male participants for an overall female-to-male ratio (F:M) of 2.4. This ratio varied according to body region affected and whether dystonia was task-specific. The female predominance was age-dependent. Sex did not have a significant impact on co-existing tremor, geste antagoniste, depression or anxiety. In the 1377 individuals from the MDSGene database, female participants outnumbered male participants for some genes (GNAL, GCH1, and ANO3) but not for other genes (THAP1, TH, and TOR1A). CONCLUSIONS: These results are in keeping with prior studies that have indicated female individuals outnumber male individuals for both adult-onset idiopathic and early onset monogenic dystonias. These results extend prior observations by revealing that sex ratios depend on the type of dystonia, age, and underlying genetics.

Assessing the Severity of Cervical Dystonia: Ask the Doctor or Ask the Patient?

Background: Assessing disease severity can be performed using either clinician-rated scales (CRS) or patient-rated outcome (PRO) tools. These two measures frequently demonstrate poor correlations. Objectives: To determine if the correlation between a CRS and PRO for motor features of cervical dystonia (CD) improves by accounting for non-motor features. Methods: Subjects with CD (N = 209) were evaluated using a CRS (Toronto Western Spasmodic Torticollis Rating Scale, TWSTRS) and a PRO (Cervical Dystonia Impact Profile, CDIP-58). Results: Linear regression revealed a weak correlation between the two measures, even when considering only the motor subscales of each. The strength of this relationship improved with a regression model that included non-motor symptoms of pain, depression, and disability. Conclusions: These results argue that the results of motor assessments in a PRO for CD cannot be fully appreciated without simultaneous assessment of non-motor co-morbidities. This conclusion might apply to other disorders, especially those with frequent non-motor co-morbidities.

Thyroid disease in cervical dystonia.

There are many possible etiologies for cervical dystonia (CD), but a cause cannot be identified in most cases. Most recent attention has focused on genetic causes, although a few prior studies have highlighted autoimmune mechanisms instead. Because autoimmune disorders frequently co-exist, the current study evaluated the hypothesis that autoimmune disorders might be more common in CD than neurological controls. The frequency of 32 common autoimmune disorders was evaluated using a systematic survey comparing 300 subjects with CD with 391 neurological controls. The frequency of thyroid disease was significantly higher in CD (20%) compared with controls (6%). Regression analyses that accounted for age and sex revealed an odds ratio of 4.5 (95% CI 2.5-8.1, p < 0.001). All other autoimmune disorders occurred with similar frequencies in CD and controls. Although these studies do not establish a mechanistic link between CD and autoimmune disease, they suggest the need for further attention to a potential relationship, and more specifically with thyroid disease.

Patients with Cognitive Impairment in Parkinson's Disease Benefit from Deep Brain Stimulation: A Case-Control Study.

Background: Deep brain stimulation (DBS) for Parkinson's disease (PD) is generally contraindicated in persons with dementia but it is frequently performed in people with mild cognitive impairment or normal cognition, and current clinical guidelines are primarily based on these cohorts. Objectives: To determine if moderately cognitive impaired individuals including those with mild dementia could meaningfully benefit from DBS in terms of motor and non-motor outcomes. Methods: In this retrospective case-control study, we identified a cohort of 40 patients with PD who exhibited moderate (two or more standard deviations below normative scores) cognitive impairment (CI) during presurgical workup and compared their 1-year clinical outcomes to a cohort of 40 matched patients with normal cognition (NC). The surgery targeted subthalamus, pallidus or motor thalamus, in a unilateral, bilateral or staged approach. Results: At preoperative baseline, the CI cohort had higher Unified Parkinson's Disease Rating Scale (UPDRS) subscores, but similar levodopa responsiveness compared to the NC cohort. The NC and CI cohorts demonstrated comparable degrees of postoperative improvement in the OFF-medication motor scores, motor fluctuations, and medication reduction. There was no difference in adverse event rates between the two cohorts. Outcomes in the CI cohort did not depend on the target, surgical staging, or impaired cognitive domain. Conclusions: Moderately cognitively impaired patients with PD can experience meaningful motor benefit and medication reduction with DBS.

Clinical Features and Evolution of Blepharospasm: A Multicenter International Cohort and Systematic Literature Review.

Objective: Blepharospasm is a type of dystonia where the diagnosis is often delayed because its varied clinical manifestations are not well recognized. The purpose of this study was to provide a comprehensive picture of its clinical features including presenting features, motor features, and non-motor features. Methods: This was a two-part study. The first part involved a systematic literature review that summarized clinical features for 10,324 cases taken from 41 prior reports. The second part involved a summary of clinical features for 884 cases enrolled in a large multicenter cohort collected by the Dystonia Coalition investigators, along with an analysis of the factors that contribute to the spread of dystonia beyond the periocular region. Results: For cases in the literature and the Dystonia Coalition, blepharospasm emerged in the 50s and was more frequent in women. Many presented with non-specific motor symptoms such as increased blinking (51.9%) or non-motor sensory features such as eye soreness or pain (38.7%), photophobia (35.5%), or dry eyes (10.7%). Non-motor psychiatric features were also common including anxiety disorders (34-40%) and depression (21-24%). Among cases presenting with blepharospasm in the Dystonia Coalition cohort, 61% experienced spread of dystonia to other regions, most commonly the oromandibular region and neck. Features associated with spread included severity of blepharospasm, family history of dystonia, depression, and anxiety. Conclusions: This study provides a comprehensive summary of motor and non-motor features of blepharospasm, along with novel insights into factors that may be responsible for its poor diagnostic recognition and natural history.

Telemedicine in an Academic Movement Disorders Center during COVID-19.

OBJECTIVE: Telemedicine has rapidly gained momentum in movement disorder neurology during the coronavirus disease (COVID-19) pandemic to preserve clinical care while mitigating the risks of in-person visits. We present data from the rapid implementation of virtual visits in a large, academic, movement disorder practice during the COVID-19 pandemic. METHODS: We describe the strategic shift to virtual visits and retrospectively examine elements that impacted the ability to switch to telemedicine visits using historical prepandemic in-person data as a comparator, including demographics, distance driven, and diagnosis distribution, with an additional focus on patients with deep brain stimulators. RESULTS: A total of 686 telemedicine visits were performed over a five-week period (60% of those previously scheduled for in-office visits). The average age of participants was 65 years, 45% were female, and 73% were Caucasian. Men were more likely to make the transition (p = 0.02). Telemedicine patients lived farther from the clinic than those seen in person (66.47 km vs. 42.16 km, p < 0.001), age was not associated with making the switch, and patient satisfaction did not change. There was a significant shift in the distribution of movement disorder diagnoses seen by telemedicine compared to prepandemic in-person visits (p < 0.001). Patients with deep brain stimulators were more likely to use telemedicine (11.5% vs. 7%, p < 0.001). CONCLUSION: Telemedicine is feasible, viable and relevant in the care of movement disorder patients, although health care disparities appear evident for women and minorities. Patients with deep brain stimulators preferred telemedicine in our study. Further study is warranted to explore these findings.

Neuropathology of blepharospasm.

BACKGROUND: The dystonias are a group of disorders characterized by excessive muscle contractions leading to abnormal repetitive movements or postures. In blepharospasm, the face is affected, leading to excessive eye blinking and spasms of muscles around the eyes. The pathogenesis of blepharospasm is not well understood, but several imaging studies have implied subtle structural defects in several brain regions, including the cerebellum. OBJECTIVE: To delineate cerebellar pathology in brains collected at autopsy from 7 human subjects with blepharospasm and 9 matched controls. METHODS: Sections from 3 cerebellar regions were sampled and processed using Nissl and silver impregnation stains. Purkinje neurons were the focus of the evaluation, along with as several other subtle pathological features of cerebellar dysfunction such as Purkinje neuron axonal swellings (torpedo bodies), proliferation of basket cell processes around Purkinje neurons (hairy baskets), empty baskets (missing Purkinje neurons), and displacement of cell soma from their usual location (ectopic Purkinje neurons). RESULTS: The results revealed a significant reduction in Purkinje neuron and torpedo body density, but no changes in any of the other measures. CONCLUSIONS: These findings demonstrate subtle neuropathological changes similar to those reported for subjects with cervical dystonia. These findings may underly some of the subtle imaging changes reported for blepharospasm.

A metabolomic study of cervical dystonia.

INTRODUCTION: Cervical dystonia is the most common of the adult-onset focal dystonias. Most cases are idiopathic. The current view is that cervical dystonia may be caused by some combination of genetic and environmental factors. Genetic contributions have been studied extensively, but there are few studies of other factors. We conducted an exploratory metabolomics analysis of cervical dystonia to identify potentially abnormal metabolites or altered biological pathways. METHODS: Plasma samples from 100 cases with idiopathic cervical dystonia and 100 controls were compared using liquid chromatography coupled with mass spectrometry-based metabolomics. RESULTS: A total of 7346 metabolic features remained after quality control, and up to 289 demonstrated significant differences between cases and controls, depending on statistical criteria chosen. Pathway analysis revealed 9 biological processes to be significantly associated at p < 0.05, 5 pathways were related to carbohydrate metabolism, 3 pathways were related to lipid metabolism. CONCLUSION: This is the first large scale metabolomics study for any type of dystonia. The results may provide potential novel insights into the biology of cervical dystonia.

Oromandibular Dystonia: A Clinical Examination of 2,020 Cases.

Objective: The goal of this study is to better characterize the phenotypic heterogeneity of oromandibular dystonia (OMD) for the purpose of facilitating early diagnosis. Methods: First, we provide a comprehensive summary of the literature encompassing 1,121 cases. Next, we describe the clinical features of 727 OMD subjects enrolled by the Dystonia Coalition (DC), an international multicenter cohort. Finally, we summarize clinical features and treatment outcomes from cross-sectional analysis of 172 OMD subjects from two expert centers. Results: In all cohorts, typical age at onset was in the 50s and 70% of cases were female. The Dystonia Coalition cohort revealed perioral musculature was involved most commonly (85%), followed by jaw (61%) and tongue (17%). OMD more commonly appeared as part of a segmental dystonia (43%), and less commonly focal (39%) or generalized (10%). OMD was found to be associated with impaired quality of life, independent of disease severity. On average, social anxiety (LSA score: 33 ± 28) was more common than depression (BDI II score: 9.7 ± 7.8). In the expert center cohorts, botulinum toxin injections improved symptom severity by more than 50% in ~80% of subjects, regardless of etiology. Conclusions: This comprehensive description of OMD cases has revealed novel insights into the most common OMD phenotypes, pattern of dystonia distribution, associated psychiatric disturbances, and effect on QoL. We hope these findings will improve clinical recognition to aid in timely diagnosis and inform treatment strategies.

Dystonia and Tremor: A Cross-Sectional Study of the Dystonia Coalition Cohort.

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

Soft Nanomembrane Sensors and Flexible Hybrid Bioelectronics for Wireless Quantification of Blepharospasm.

Blepharospasm (BL) is characterized by involuntary closures of the eyelids due to spasms of the orbicularis oculi muscle. The gold standard for clinical evaluation of BL involves visual inspection for manual rating scales. This approach is highly subjective and error prone. Unfortunately, there are currently no simple quantitative systems for accurate and objective diagnostics of BL. Here, we introduce a soft, flexible hybrid bioelectronic system that offers highly conformal, gentle lamination on the skin, while enabling wireless, quantitative detection of electrophysiological signals. Computational and experimental studies of soft materials and flexible mechanics provide a set of key fundamental design factors for a low-profile bioelectronic system. The nanomembrane soft electrodes, mounted around the eyes, are capable of accurately measuring clinical symptoms, including the frequency of blinking, the duration of eye closures during spasms, as well as combinations of blinking and spasms. The use of a deep-learning, convolutional neural network, with the bioelectronics offers objective, real-time classification of key pathological features in BL. The wearable bioelectronics outperform the conventional manual clinical rating, as shown by a pilot study with 13 patients. In vivo demonstration of the bioelectronics with these patients indicates the device as an easy-to-use solution for objective quantification of BL.

Lurasidone-Induced Tardive Syndrome.

INTRODUCTION: Tardive syndrome (TS) is an often irreversible movement disorder caused by dopamine receptor-blocking agents (DRBAs). Although TS are well recognized to occur with typical antipsychotics, less well appreciated is that atypical antipsychotics also carry a risk of TS. METHODS: Case series. RESULTS: We describe 4 patients who developed tardive dystonia, tardive akathisia, and drug-induced parkinsonism with the use of the atypical antipsychotic, lurasidone, which was U.S. Food and Drug Administration approved in 2013 for use in bipolar disorder and schizophrenia. CONCLUSION: Movement disorders are reported as a rare side effect of lurasidone, and, as such, prescribers may perceive a false sense of security regarding this potential complication. Our cases indicate that this relatively new atypical antipsychotic may cause irreversible disabling TS as well as parkinsonism. Caution must be taken when prescribing lurasidone.

Soft Material-Enabled, Active Wireless, Thin-Film Bioelectronics for Quantitative Diagnostics of Cervical Dystonia.

Recent advances in flexible materials, nanomanufacturing, and system integration have provided a great opportunity to develop wearable flexible hybrid electronics for human healthcare, diagnostics, and therapeutics. However, existing medical devices still rely on rigid electronics with many wires and separate components, which hinders wireless, comfortable, continuous monitoring of health-related human motions. Here, we introduce advanced materials and system integration technologies that enable a soft, active wireless, thin-film bioelectronics. The low-modulus, highly flexible wearable electronic system incorporates a nanomembrane wireless circuit and functional chip components, enclosed by a soft elastomeric membrane. The bioelectronic system offers a gentle, seamless mounting on the skin, while offering a comfortable, highly sensitive and accurate detection of head movements. We utilize the wireless wearable hybrid system for quantitative diagnostics of cervical dystonia (CD) that is characterized by involuntary abnormal head postures and repetitive head movements, sometimes with neck muscle pain. A set of analytical and experimental studies shows a soft system packaging, hard-soft materials integration, and quantitative assessment of physiological signals detected by the SKINTRONICS. In vivo demonstration, involving ten human subjects, captures the device feasibility for use in CD measurement.

VMAT2 inhibitors for the treatment of tardive dyskinesia.

Tardive dyskinesia (TD) is an often disabling hyperkinetic movement disorder caused by exposure to dopamine receptor blocking agents. Although initially thought to most commonly occur with typical antipsychotics, the incidence is likely similar with atypical antipsychotics and antiemetics such as metoclopramide. Increased prescribing of these agents as well as low rates of remission have contributed to a rising prevalence of TD. Although this condition was described nearly 60 years ago, it is only within the past year that two novel therapeutic agents were FDA approved. Characterization of the VMAT2 inhibitor tetrabenazine, which was identified as a therapeutic agent for TD in older clinical trials, has yielded two distinct pharmacologic strategies to optimize response. The first strategy, used to create deutetrabenazine, employed deuterization of tetrabenazine to stabilize the pharmacokinetics and eliminate high peak plasma levels. The second strategy was the creation of a prodrug, valbenazine, for the two most active isoforms of tetrabenazine that also resulted in more stable pharmacokinetics and eliminated peak plasma levels. Both agents have been demonstrated to be effective and safe for the treatment of TD in multicenter, controlled trials and their development has led to a resurgence of interest in the characterization and treatment of this movement disorder.