Abnormal involuntary movement scale in tardive dyskinesia: Minimal clinically important difference.

BACKGROUND: A minimal clinically important difference has not been established for the Abnormal Involuntary Movement Scale in patients with tardive dyskinesia. Valbenazine is a vesicular monoamine transporter 2 inhibitor approved for the treatment of tardive dyskinesia in adults. Efficacy in randomized, double-blind, placebo-controlled trials was defined as the change from baseline in Abnormal Involuntary Movement Scale total score (sum of items 1-7). OBJECTIVES: To estimate an minimal clinically important difference for the Abnormal Involuntary Movement Scale using valbenazine trial data and an anchor-based method. METHODS: Data were pooled from three 6-week double-blind, placebo-controlled trials: KINECT (NCT01688037), KINECT 2 (NCT01733121), and KINECT 3 (NCT02274558). Valbenazine doses were pooled for analyses as follows: "low dose," which includes 40 or 50 mg/day; and "high dose," which includes 75 or 80 mg/day. Mean changes from baseline in Abnormal Involuntary Movement Scale total score were analyzed in all participants (valbenazine- and placebo-treated) with a Clinical Global Impression of Change-Tardive Dyskinesia or Patient Global Impression of Change score of 1 (very much improved) to 3 (minimally improved). RESULTS: The least squares mean improvement from baseline to week 6 in Abnormal Involuntary Movement Scale total score was significantly greater with valbenazine (low dose: -2.4; high dose: -3.2; both, P < 0.001) versus placebo (-0.7). An minimal clinically important difference of 2 points was estimated based on least squares mean changes in Abnormal Involuntary Movement Scale total score in participants with a Clinical Global Impression of Change-Tardive Dyskinesia score ≤3 at week 6 (mean change: -2.2; median change: -2) or Patient Global Impression of Change score ≤3 at week 6 (mean change: -2.0; median change: -2). CONCLUSIONS: Results from an anchor-based method indicate that a 2-point decrease in Abnormal Involuntary Movement Scale total score may be considered clinically important. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Guidance for switching from off-label antipsychotics to pimavanserin for Parkinson's disease psychosis: an expert consensus.

Patients with Parkinson's disease psychosis (PDP) are often treated with an atypical antipsychotic, especially quetiapine or clozapine, but side effects, lack of sufficient efficacy, or both may motivate a switch to pimavanserin, the first medication approved for management of PDP. How best to implement a switch to pimavanserin has not been clear, as there are no controlled trials or case series in the literature to provide guidance. An abrupt switch may interrupt partially effective treatment or potentially trigger rebound effects from antipsychotic withdrawal, whereas cross-taper involves potential drug interactions. A panel of experts drew from published data, their experience treating PDP, lessons from switching antipsychotic drugs in other populations, and the pharmacology of the relevant drugs, to establish consensus recommendations. The panel concluded that patients with PDP can be safely and effectively switched from atypical antipsychotics used off label in PDP to the recently approved pimavanserin by considering each agent's pharmacokinetics and pharmacodynamics, receptor interactions, and the clinical reason for switching (efficacy or adverse events). Final recommendations are that such a switch should aim to maintain adequate 5-HT2A antagonism during the switch, thus providing a stable transition so that efficacy is maintained. Specifically, the consensus recommendation is to add pimavanserin at the full recommended daily dose (34 mg) for 2-6 weeks in most patients before beginning to taper and discontinue quetiapine or clozapine over several days to weeks. Further details are provided for this recommendation, as well as for special clinical circumstances where switching may need to proceed more rapidly.

The spectrum of "off" in Parkinson's disease: What have we learned over 40 years?

The terms "on" and "off" were used by Marsden and his contemporaries over 40 years ago to describe times when Parkinson's disease patients experienced good motor function ("on") and immobility ("off"). Yet there remains no published consensus definition of "off", leading clinicians and patients to develop individualized impressions of "off" determinations. In this paper, we first discuss the evolution of the terminology and understanding of "off" states since Marsden's time, which now include non-motor as well as motor symptoms. We then review pathophysiology and risk factors for the development of "off" states as well as tools to detect the "off" state, before proposing a practical definition of "off" for consideration. A common, practical definition of the "off" state could improve clinical recognition of "off" symptoms and lead to significant benefit for patients.

Dopamine Transporter Imaging has no Impact on Functional Outcomes in de Novo Probable Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) is among the most prevalent neurodegenerative conditions. While motor and non-motor aspects of this disease have been well characterized, no objective biomarker exists to support an accurate clinical diagnosis. However, newer imaging techniques, including [123I]-FP-CIT (DaTSCAN), have demonstrated utility in differentiating between PD and non-neurodegenerative tremor disorders. OBJECTIVE: DaTSCAN has been primarily investigated in situations where diagnostic confusion exists, and in these instances has been shown to significantly impact clinical management. The goal of this pilot study was to evaluate the impact of DaTSCAN on the clinical management of patients with early probable PD, where no diagnostic uncertainty exists. METHODS: This was a prospective, 54-week, comparative pilot study, in which twenty subjects with de novo PD were randomly assigned to DaTSCAN either immediately upon diagnosis (and again at 6 and 12 months) or delayed to 6 months (and again at 12 months). The primary outcome measure was the frequency of deviation from the initial treatment plan from baseline to 54 weeks between the two groups. Secondary outcomes included motor and non-motor assessments. RESULTS: There was no significant difference in the number of treatment changes over the course of the study between the two groups: initial imaging group = 4.2 (SD:2.74) vs. delayed imaging group = 2.3 (SD:2.0, p = 0.11). In addition, there were no group differences in medication requirements, motor performance, or patient expectations of disease. CONCLUSIONS: In patients with early, probable PD, DaTSCAN contributes no additional impact on clinical management or functional outcomes when added to the diagnostic algorithm.

Functional Genomic Analyses of Mendelian and Sporadic Disease Identify Impaired eIF2α Signaling as a Generalizable Mechanism for Dystonia.

Dystonia is a brain disorder causing involuntary, often painful movements. Apart from a role for dopamine deficiency in some forms, the cellular mechanisms underlying most dystonias are currently unknown. Here, we discover a role for deficient eIF2α signaling in DYT1 dystonia, a rare inherited generalized form, through a genome-wide RNAi screen. Subsequent experiments including patient-derived cells and a mouse model support both a pathogenic role and therapeutic potential for eIF2α pathway perturbations. We further find genetic and functional evidence supporting similar pathway impairment in patients with sporadic cervical dystonia, due to rare coding variation in the eIF2α effector ATF4. Considering also that another dystonia, DYT16, involves a gene upstream of the eIF2α pathway, these results mechanistically link multiple forms of dystonia and put forth a new overall cellular mechanism for dystonia pathogenesis, impairment of eIF2α signaling, a pathway known for its roles in cellular stress responses and synaptic plasticity.

Impact of Cervical Dystonia on Work Productivity: An Analysis From a Patient Registry.

BACKGROUND: Cervical dystonia is thought to result in high disease burden, but limited information exists on its impact on employment and work productivity. We utilized data from the Cervical Dystonia Patient Registry for the Observation of OnabotulinumtoxinA Efficacy (ClinicalTrials.gov identifier: NCT00836017) to assess the impact of cervical dystonia on employment and work productivity and examine the effect of onabotulinumtoxinA treatments on work productivity. METHODS: Subjects completed a questionnaire on employment status and work productivity at baseline and final visit. Baseline data were examined by severity of cervical dystonia, predominant subtype, presence of pain, prior exposure to botulinum toxin, and/or utility of a sensory trick. Work productivity results at baseline and final visit were compared in subjects who were toxin-naïve at baseline and received three onabotulinumtoxinA treatments. RESULTS: Of 1,038 subjects, 42.8% were employed full- or part-time, 6.1% unemployed, 32.7% retired, and 11.8% disabled. Of those currently employed, cervical dystonia affected work status of 26.0%, caused 29.8% to miss work in the past month (mean, 5.1 ± 6.4 days), and 57.8% reported decreased productivity. Half of those unemployed were employed when symptoms began, and 38.5% attributed lost employment to cervical dystonia. Pain, increasing severity, and anterocollis/retrocollis had the largest effects on work status/productivity. Preliminary analyses showed that absenteeism and presenteeism were significantly decreased following onabotulinumtoxinA treatments in the subpopulation that was toxin-naïve at baseline. CONCLUSIONS: This analysis confirms the substantial negative impact of cervical dystonia on employment, with cervical dystonia-associated pain being a particularly important driver. OnabotulinumtoxinA treatment appears to improve work productivity.

Deep Brain Stimulation: A Paradigm Shifting Approach to Treat Parkinson's Disease.

Parkinson disease (PD) is a chronic and progressive movement disorder classically characterized by slowed voluntary movements, resting tremor, muscle rigidity, and impaired gait and balance. Medical treatment is highly successful early on, though the majority of people experience significant complications in later stages. In advanced PD, when medications no longer adequately control motor symptoms, deep brain stimulation (DBS) offers a powerful therapeutic alternative. DBS involves the surgical implantation of one or more electrodes into specific areas of the brain, which modulate or disrupt abnormal patterns of neural signaling within the targeted region. Outcomes are often dramatic following DBS, with improvements in motor function and reductions motor complications having been repeatedly demonstrated. Given such robust responses, emerging indications for DBS are being investigated. In parallel with expansions of therapeutic scope, advancements within the areas of neurosurgical technique and the precision of stimulation delivery have recently broadened as well. This review focuses on the revolutionary addition of DBS to the therapeutic armamentarium for PD, and summarizes the technological advancements in the areas of neuroimaging and biomedical engineering intended to improve targeting, programming, and overall management.

Neuropsychiatric Issues in Parkinson's Disease.

Cognitive and neuropsychiatric symptoms are common in Parkinson's Disease and may surpass motor symptoms as the major factors impacting patient quality of life. The symptoms may be broadly separated into those associated with the disease process and those that represent adverse effects of treatment. Symptoms attributed to the disease arise from pathologic changes within multiple brain regions and are not restricted to dysfunction in the dopaminergic system. Mood symptoms such as depression, anxiety, and apathy are common and may precede the development of motor symptoms by years, while other neuropsychiatric symptoms such as cognitive impairment, dementia, and psychosis are more common in later stages of the disease. Neuropsychiatric symptoms attributed to treatment include impulse control disorders, pathologic use of dopaminergic medications, and psychosis. This manuscript will review the current understanding of neuropsychiatric symptoms in Parkinson's Disease.

Retooling institutional support infrastructure for clinical research.

Clinical research activities at academic medical centers are challenging to oversee. Without effective research administration, a continually evolving set of regulatory and institutional requirements can divert investigator and study team attention away from a focus on scientific gain, study conduct, and patient safety. However, even when the need for research administration is recognized, there can be struggles over what form it should take. Central research administration may be viewed negatively, with individual groups preferring to maintain autonomy over processes. Conversely, a proliferation of individualized approaches across an institution can create inefficiencies or invite risk. This article describes experiences establishing a unified research support office at the Duke University School of Medicine based on a framework of customer support. The Duke Office of Clinical Research was formed in 2012 with a vision that research administration at academic medical centers should help clinical investigators navigate the complex research environment and operationalize research ideas. The office provides an array of services that have received high satisfaction ratings. The authors describe the ongoing culture change necessary for success of the unified research support office. Lessons learned from implementation of the Duke Office of Clinical Research may serve as a model for other institutions undergoing a similar transition.

Disease-Modifying Drugs in Parkinson's Disease.

Despite an increased understanding of the pathogenesis of Parkinson's disease (PD), and a number of drugs designed to ameliorate symptoms, finding an effective neuroprotective therapy remains elusive. For decades now, several promising agents targeting different pathways have been explored as potential treatments that could help slow disease progression, but these have met with limited success. There are hurdles to overcome, particularly given that there is no exact animal model of PD and also no reliable biomarkers for PD. Without biomarkers, it is not possible to demonstrate, in the context of a clinical trial, that an intervention prevents neuronal degeneration. However, given the compelling scientific rationale of several compounds, an unrelenting pursuit continues. There have been hundreds of human studies looking at neuroprotection in PD. This article will briefly summarize several of the neuroprotective treatments that have been evaluated in large clinical trials, and will also outline some of the newer therapies that are currently being explored.

CTSA Consortium Consensus Scientific Review Committee (SRC) Working Group Report on the SRC Processes.

Human research projects must have a scientifically valid study design, analytic plan, and be operationally feasible in order to be successfully completed and thus to have translational impact. To ensure this, institutions that conduct clinical research should have a scientific review process prior to submission to the Institutional Review Committee (IRB). This paper reports the Clinical and Translational Science Award (CTSA) Consortium Scientific Review Committee (SRC) Consensus Working Group's proposed framework for a SRC process. Recommendations are provided for institutional support and roles of CTSAs, multisite research, criteria for selection of protocols that should be reviewed, roles of committee members, application process, and committee process. Additionally, to support the SCR process effectively, and to ensure efficiency, the Working Group recommends information technology infrastructures and evaluation metrics to determine outcomes are provided.

Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: A double-blind, randomized, controlled trial.

OBJECTIVE: A 12-month double-blind sham-surgery-controlled trial assessing adeno-associated virus type 2 (AAV2)-neurturin injected into the putamen bilaterally failed to meet its primary endpoint, but showed positive results for the primary endpoint in the subgroup of subjects followed for 18 months and for several secondary endpoints. Analysis of postmortem tissue suggested impaired axonal transport of neurturin from putamen to substantia nigra. In the present study, we tested the safety and efficacy of AAV2-neurturin delivered to putamen and substantia nigra. METHODS: We performed a 15- to 24-month, multicenter, double-blind trial in patients with advanced Parkinson disease (PD) who were randomly assigned to receive bilateral AAV2-neurturin injected bilaterally into the substantia nigra (2.0 × 10(11) vector genomes) and putamen (1.0 × 10(12) vector genomes) or sham surgery. The primary endpoint was change from baseline to final visit performed at the time the last enrolled subject completed the 15-month evaluation in the motor subscore of the Unified Parkinson's Disease Rating Scale in the practically defined off state. RESULTS: Fifty-one patients were enrolled in the trial. There was no significant difference between groups in the primary endpoint (change from baseline: AAV2-neurturin, -7.0 ± 9.92; sham, -5.2 ± 10.01; p = 0.515) or in most secondary endpoints. Two subjects had cerebral hemorrhages with transient symptoms. No clinically meaningful adverse events were attributed to AAV2-neurturin. INTERPRETATION: AAV2-neurturin delivery to the putamen and substantia nigra bilaterally in PD was not superior to sham surgery. The procedure was well tolerated, and there were no clinically significant adverse events related to AAV2-neurturin.

Primary results from the cervical dystonia patient registry for observation of onabotulinumtoxina efficacy (CD PROBE).

BACKGROUND: The Cervical Dystonia Patient Registry for Observation of OnabotulinumtoxinA Efficacy (CD PROBE; NCT00836017) is a prospective, observational, multicenter, real-world registry designed to assess the safety, effectiveness, and treatment utilization following multiple treatments of onabotulinumtoxinA. METHODS: Subjects were naïve to botulinum toxin, new to practice, or had not received toxin in ≥ 16 weeks if in a clinical trial. Dosages and treatment intervals varied due to the real-world design. Descriptive and inferential statistics evaluated changes over 3 treatments. RESULTS: 1046 subjects enrolled. Subjects were 74.4% female, 63.5% toxin-naïve, mean age 58.0 ± 14.7 years. The mean dose over 2481 treatment sessions was 189. 8 ± 87.1U, with average treatment intervals of 14.6 and 15.1 weeks. The mean Toronto Western Spasmodic Torticollis Rating Scale Total score in subjects who completed all assessments (n=479) decreased from 39.2 at baseline to 27.1 at final visit (P<.0001). A high percentage of physicians reported improvement in Clinician Global Impression of Change after initial assessment; this significantly increased at final assessment (n=479, 91.2% vs 95.0%; P<.0001). Similarly, a high percentage of subjects reported improvement in Patient Global Impression of Change after initial assessment, which significantly increased at final assessment (n=470, 83.0% vs 91.7%; P<.0001). Significant reductions in all Cervical Dystonia Impact Profile-58 scores were observed (n=407). Overall, 26.2% of subjects reported adverse events, including muscular weakness (7.0%) and dysphagia (6.4%). CONCLUSIONS: Results indicate robust improvement in clinical ratings and excellent tolerability following onabotulinumtoxinA treatment of CD.

Clinical spectrum of impulse control disorders in Parkinson's disease.

Impulse control disorders (ICDs), including compulsive gambling, buying, sexual behavior, and eating, are a serious and increasingly recognized psychiatric complication in Parkinson's disease (PD). Other impulsive-compulsive behaviors (ICBs) have been described in PD, including punding (stereotyped, repetitive, purposeless behaviors) and dopamine dysregulation syndrome (DDS; compulsive PD medication overuse). ICDs have been most closely related to the use of dopamine agonists (DAs), perhaps more so at higher doses; in contrast, DDS is primarily associated with shorter-acting, higher-potency dopaminergic medications, such as apomorphine and levodopa. Possible risk factors for ICDs include male sex, younger age and younger age at PD onset, a pre-PD history of ICDs, and a personal or family history of substance abuse, bipolar disorder, or gambling problems. Given the paucity of treatment options and potentially serious consequences, it is critical for PD patients to be monitored closely for development of ICDs as part of routine clinical care.

ClinicalTrials.gov reporting: strategies for success at an academic health center.

The Food and Drug Administration Amendments Act of 2007 (FDAAA 2007, US Public Law 110-98) mandated registration and reporting of results for applicable clinical trials. Meeting these registration and results reporting requirements has proven to be a challenge for the academic research community. Duke Medicine has made compliance with registration and results reporting a high priority. In order to create uniformity across a large institution, a written policy was created describing requirements for clinical trials disclosure. Furthermore, a centralized resource group was formed with three full time staff members. The group not only ensures compliance with FDAAA 2007, it also acts as a resource for study teams providing hands-on support, reporting, training, and ongoing education. Intensive resourcing for results reporting has been crucial for success. Due to implementation of the institutional policy and creation of centralized resources, compliance with FDAAA 2007 has increased dramatically at Duke Medicine for both registration and results reporting. A consistent centralized approach has enabled success in the face of changing agency rules and new legislation.

Rapid-onset dystonia-parkinsonism associated with the I758S mutation of the ATP1A3 gene: a neuropathologic and neuroanatomical study of four siblings.

Rapid-onset dystonia-parkinsonism (RDP) is a movement disorder associated with mutations in the ATP1A3 gene. Signs and symptoms of RDP commonly occur in adolescence or early adulthood and can be triggered by physical or psychological stress. Mutations in ATP1A3 are also associated with alternating hemiplegia of childhood (AHC). The neuropathologic substrate of these conditions is unknown. The central nervous system of four siblings, three affected by RDP and one asymptomatic, all carrying the I758S mutation in the ATP1A3 gene, was analyzed. This neuropathologic study is the first carried out in ATP1A3 mutation carriers, whether affected by RDP or AHC. Symptoms began in the third decade of life for two subjects and in the fifth for another. The present investigation aimed at identifying, in mutation carriers, anatomical areas potentially affected and contributing to RDP pathogenesis. Comorbid conditions, including cerebrovascular disease and Alzheimer disease, were evident in all subjects. We evaluated areas that may be relevant to RDP separately from those affected by the comorbid conditions. Anatomical areas identified as potential targets of I758S mutation were globus pallidus, subthalamic nucleus, red nucleus, inferior olivary nucleus, cerebellar Purkinje and granule cell layers, and dentate nucleus. Involvement of subcortical white matter tracts was also evident. Furthermore, in the spinal cord, a loss of dorsal column fibers was noted. This study has identified RDP-associated pathology in neuronal populations, which are part of complex motor and sensory loops. Their involvement would cause an interruption of cerebral and cerebellar connections which are essential for maintenance of motor control.

Cervical dystonia and pain: characteristics and treatment patterns from CD PROBE (Cervical Dystonia Patient Registry for Observation of OnabotulinumtoxinA Efficacy).

To compare profiles of subjects with and without cervical dystonia (CD)-associated pain, to evaluate the contribution of pain and the motor component of CD on quality of life, and to compare the initial botulinum toxin treatment paradigm between pain groups, baseline data were used from the CD Patient Registry for Observation of OnabotulinumtoxinA Efficacy (CD PROBE), a multicenter, prospective, observational registry designed to capture real-world practices and outcomes for onabotulinumtoxinA CD treatment. Subjects were divided into no/mild pain [Pain Numeric Rating Scale (PNRS) score 0-3] and moderate/severe pain groups (PNRS score 4-10). Descriptive and differential statistics were utilized to compare groups. 1,037 subjects completed the first treatment session, reported baseline botulinum toxin status, and completed baseline PNRS. Those with no/mild pain were significantly older at baseline. Those subjects with moderate/severe pain had higher Toronto Western Spasmodic Torticollis Rating Scale Severity (17.7 ± 5.1 vs. 16.2 ± 5.6, p < 0.0001) and Disability (12.7 ± 6.1 vs. 7.5 ± 5.6, p < 0.0001). CD subjects with moderate/severe pain received a higher mean dose (177.3 ± 82.9 vs. 158.0 ± 67.1 U, p = 0.0001) of onabotulinumtoxinA and were injected in more muscles (4.1 ± 1.4 vs. 3.7 ± 1.2, p < 0.0001) at initial treatment. CD PROBE clearly demonstrates the frequency of pain in CD and substantiates its importance when determining an optimal treatment paradigm. Future analyses of CD PROBE will further our understanding of the treatment patterns and outcomes related to onabotulinumtoxinA therapy for this disabling condition.

Cognitive impairment in rapid-onset dystonia-parkinsonism.

Rapid-onset dystonia-parkinsonism (RDP) is caused by mutations in the ATP1A3 gene. This observational study sought to determine if cognitive performance is decreased in patients with RDP compared with mutation-negative controls. We studied 22 familial RDP patients, 3 non-motor-manifesting mutation-positive family members, 29 mutation-negative family member controls in 9 families, and 4 unrelated RDP patients, totaling 58 individuals. We administered a movement disorder assessment, including the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and the Unified Parkinson's Disease Rating Scale (UPDRS) and a cognitive battery of memory and learning, psychomotor speed, attention, and executive function. The cognitive battery was designed to evaluate a wide range of functions; recognition memory instruments were selected to be relatively pure measures of delayed memory, devoid of significant motor or vocal production limitations. Comparisons of standardized cognitive scores were assessed both with and without controlling for psychomotor speed and similarly for severity of depressive symptoms. A majority of RDP patients had onset of motor symptoms by age 25 and had initial symptom presentation in the upper body (face, mouth, or arm). Among patients, the BFMDRS (mean ± SD, 52.1 ± 29.5) and UPDRS motor subscore (29.8 ± 12.7) confirmed dystonia-parkinsonism. The affected RDP patients performed more poorly, on average, than mutation-negative controls for all memory and learning, psychomotor speed, attention, and executive function scores (all P ≤ 0.01). These differences persisted after controlling for psychomotor speed and severity of depressive symptoms. Impaired cognitive function may be a manifestation of ATP1A3 mutation and RDP.