Intermittent Theta Burst Stimulation (iTBS) for Treatment of Chronic Post-Stroke Aphasia: Results of a Pilot Randomized, Double-Blind, Sham-Controlled Trial.

BACKGROUND Research indicates intermittent theta burst stimulation (iTBS) is a potential treatment of post-stroke aphasia. MATERIAL AND METHODS In this double-blind, sham-controlled trial (NCT01512264) participants were randomized to receive 3 weeks of sham (G0), 1 week of iTBS/2 weeks of sham (G1), 2 weeks of iTBS/1 week of sham (G2), or 3 weeks of iTBS (G3). FMRI localized residual language function in the left hemisphere; iTBS was applied to the maximum fMRI activation in the residual language cortex in the left frontal lobe. FMRI and aphasia testing were conducted pre-treatment, at ≤1 week after completing treatment, and at 3 months follow-up. RESULTS 27/36 participants completed the trial. We compared G0 to each of the individual treatment group and to all iTBS treatment groups combined (G1₋3). In individual groups, participants gained (of moderate or large effect sizes; some significant at P<0.05) on the Boston Naming Test (BNT), the Semantic Fluency Test (SFT), and the Aphasia Quotient of the Western Aphasia Battery-Revised (WAB-R AQ). In G1₋3, BNT, and SFT improved immediately after treatment, while the WAB-R AQ improved at 3 months. Compared to G0, the other groups showed greater fMRI activation in both hemispheres and non-significant increases in language lateralization to the left hemisphere. Changes in IFG connectivity were noted with iTBS, showing differences between time-points, with some of them correlating with the behavioral measures. CONCLUSIONS The results of this pilot trial support the hypothesis that iTBS applied to the ipsilesional hemisphere can improve aphasia and result in cortical plasticity.

Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington's Disease Patients-A Randomized Phase 2 Clinical Trial.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington's disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington's Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression.

Tetrabenazine Treatment Patterns and Outcomes for Chorea Associated with Huntington Disease: A Retrospective Chart Review.

BACKGROUND: Huntington disease (HD) is a neurodegenerative disorder characterized by motor impairments (including chorea), along with behavioral, psychiatric, and cognitive symptoms. Tetrabenazine was the first US Food and Drug Administration (FDA)-approved treatment for chorea related to HD. OBJECTIVE: To examine pharmacologic treatment patterns among patients using tetrabenazine, including reasons for treatment initiation, non-initiation, dose adjustments, and discontinuation, and to quantify the burden of chorea based on healthcare resource utilization. METHODS: In this retrospective patient chart review, neurologists were recruited from the Medefield (http://www.medefield.com) opt-in panel, and selected ≤5 medical charts based on the criteria provided and abstracted data on demographics, disease history, healthcare resource use, and treatment patterns. RESULTS: 138 neurologists participated and 512 HD patient charts were reviewed. Among these patients, 26.4% did not initiate tetrabenazine. Most HD patients (66.5%) received a tetrabenazine dose ≤50 mg. The most common reasons for stopping upward titration were optimal chorea control (55.5%), intolerability of higher doses (31.2%), and reaching the maximum recommended dosage despite suboptimal chorea control (11.4%). Chorea severity and non-persistence to tetrabenazine were associated with increased emergency room visits, hospitalizations, and days hospitalized. CONCLUSIONS: Although tetrabenazine was the sole FDA-approved treatment for HD chorea until April 2017, more than one-quarter of respondents never initiated therapy. Tetrabenazine dosing was lower than predicted, and many patients experienced adverse symptoms of intolerability at high doses. New safer and more tolerable treatment options, such as deutetrabenazine, may improve treatment outcomes and reduce healthcare resource use.

Review of deutetrabenazine: a novel treatment for chorea associated with Huntington's disease.

Deutetrabenazine was recently approved for the treatment of chorea in Huntington's disease (HD) and is the first deuterated medication that has been US Food and Drug Administration (FDA)-approved for therapeutic use. In this article, we review deutetrabenazine's drug design, pharmacokinetics, drug interactions, efficacy, adverse events, comparison with tetrabenazine, dosage, and administration. Deutetrabenazine is a deuterated form of tetrabenazine and is a vesicular monoamine transporter 2 (VMAT2) inhibitor. The substitution of deuterium for hydrogen at key positions in the tetrabenazine molecule allows a longer drug half-life and less frequent daily dosing. Deutetrabenazine is administered twice daily up to a maximum daily dose of 48 mg, which corresponds to a similar daily dose of 100 mg of tetrabenazine. In a Phase III clinical trial (First-HD), there was a statistically significant improvement of chorea in HD subjects, as well as improvements in global impression of change as assessed by both patients and clinicians. This improvement was seen without significant adverse effects as the overall tolerability profile of deutetrabenazine was similar to placebo. Somnolence was the most commonly reported symptom in the deutetrabenazine group. In a study where subjects converted from tetrabenazine to deutetrabenazine in an open-label fashion (ARC-HD) and indirect comparison studies between tetrabenazine and deutetrabenazine, there is a suggestion that while efficacy for chorea is similar, the data may slightly favor tetrabenazine, but adverse effects and tolerability strongly favor deutetrabenazine. These data have not been replicated in true head-to-head studies. Current evidence supports that deutetrabenazine is an effective therapeutic treatment option for chorea in HD and may provide a more favorable adverse effect profile than tetrabenazine. However, more data are needed, particularly in the form of head-to-head studies between deutetrabenazine and other treatment options as well as longer term clinical experience with deutetrabenazine.

Physician perceptions of pharmacologic treatment options for chorea associated with Huntington disease in the United States.

OBJECTIVE: To survey neurologists and obtain clinical perceptions of tetrabenazine for the treatment of chorea in patients with Huntington disease (HD). METHODS: Board-certified/board-eligible neurologists, in practice for ≥5 years, who had treated treat ≥3 HD patients in the past 2 years, were recruited from an online physician panel to participate in a cross-sectional, web-based survey. Respondents provided information about themselves, their practice, approaches to HD chorea management and perceptions of available treatments. RESULTS: Two hundred neurologists responded to the survey. Based on clinician responses, the most common reasons to treat chorea are impairment in activities of daily living (54%) and quality of life (41%). Although tetrabenazine was the only approved treatment for chorea in HD patients at the time of this analysis, it was only prescribed to ∼50% of patients with HD-related chorea. More than half of physicians perceive tetrabenazine as having minimal or no effectiveness in improving chorea. More than 40% of physicians consider tetrabenazine to be a non-optimal treatment, and 51% of physicians agree that they are unable to titrate to efficacious doses due to adverse side effects or tolerability concerns. Physicians report that side effects leading to dose interruptions (33%) and reductions (30%) occur in their patients "often" or "almost always". The most common side effects that led to insufficient dosing and disruptions in titration were sedation and somnolence (41%), depression (24%) and anxiety (22%). CONCLUSIONS: Many physicians who treat HD-related chorea report that tolerability issues with tetrabenazine impact their ability to effectively use tetrabenazine in their clinical practice.

Retrospective Analysis of Healthcare Resource Use, Treatment Patterns, and Treatment-related Events in Patients with Huntington's Disease-associated Chorea Initiated on Tetrabenazine.

BACKGROUND: Huntington's disease (HD) is a multifaceted neurodegenerative disorder characterized by involuntary movements, specifically chorea, as well as behavioral and psychiatric disturbance, and cognitive dysfunction. Tetrabenazine was the first approved treatment for chorea, although tolerability concerns exist. OBJECTIVES: To characterize demographic and clinical characteristics of HD patients with chorea based on tetrabenazine use and examine treatment persistence with tetrabenazine in a real-world setting. METHODS: Patients with a claim for HD-associated chorea (ICD-9-CM code 333.4) between 1/1/08 and 9/30/15 were selected from the MarketScan® Commercial and Medicare Supplemental databases. The first diagnosis date during the study period was considered the index date, with ≥6 months of continuous medical and prescription coverage before and after the index date. Treatment persistence was defined as the number of days from initiation to discontinuation or end of follow-up period. Discontinuation was defined as a gap in therapy of ≥60 days. RESULTS: 1644 patients met selection criteria (mean age ± standard deviation: 54.5 ± 15.5), of which 151 (9.2%) were treated with tetrabenazine during the study period. The average (median) daily dose of tetrabenazine during the treatment period was 45.5 (42.3) mg/day. A total of 41.8% (59/141) of HD patients who initiated tetrabenazine experienced a ≥60-day gap in tetrabenazine therapy, with a median time to discontinuation of 293.5 days. During the 6-month post-index period after HD diagnosis, HD patients incurred higher all-cause healthcare costs ($20 204) vs the 6-month pre-index period ($6057), driven by higher hospitalization and pharmacy costs. CONCLUSIONS: A small percentage of HD patients with chorea were treated with tetrabenazine and discontinuation rates were high among those receiving treatment, with a median time to discontinuation of 9 months.

The relationship between clinical phenotype and early staged bilateral deep brain stimulation in Parkinson disease.

OBJECT: While many centers place bilateral deep brain stimulation (DBS) systems simultaneously, unilateral subthalamic nucleus (STN) DBS followed by a staged contralateral procedure has emerged as a treatment option for many patients. However, little is known about whether the preoperative phenotype predicts when staged placement of a DBS electrode in the opposite STN will be required. The authors aimed to determine whether preoperative clinical phenotype predicts early staged placement of a second STN DBS electrode in patients who undergo unilateral STN DBS for Parkinson disease (PD). METHODS: Eighty-two consecutive patients with advanced PD underwent unilateral STN DBS contralateral to the most affected hemibody and had at least 2 years of follow-up. Multivariate logistic regression analysis determined preoperative characteristics that predicted staged placement of a second electrode in the opposite STN. Preoperative measurements included aspects of the Unified Parkinson's Disease Rating Scale (UPDRS), motor asymmetry index, and body weight. RESULTS: At 2-year follow-up, 28 (34%) of the 82 patients had undergone staged placement of a contralateral electrode while the remainder chose to continue with unilateral stimulation. Statistically significant improvements in UPDRS total and Part 3 scores were retained at the end of the 2-year follow-up period in both subsets of patients. Multivariate logistic regression analysis showed that the most important predictors for early staged placement of a second subthalamic stimulator were low asymmetry index (OR 13.4, 95% CI 2.8-64.9), high tremor subscore (OR 7.2, CI 1.5-35.0), and low body weight (OR 5.5, 95% CI 1.4-22.3). CONCLUSIONS: This single-center study provides evidence that elements of the preoperative PD phenotype predict whether patients will require early staged bilateral STN DBS. These data may aid in the management of patients with advanced PD who undergo STN DBS.

Nonmotor symptoms in Parkinson's disease: expanding the view of Parkinson's disease beyond a pure motor, pure dopaminergic problem.

Nonmotor symptoms (NMS) of Parkinson's disease (PD) are critical to identify and treat because of their impact on quality of life. Despite growing evidence of the importance of NMS on patients' quality of life, gaps remain in their recognition and treatment. The result is a need for increased information and understanding of specific NMS and the clinical approaches for their assessment and management in the context of PD as a whole. This article discusses the NMS of PD, their relationship to the pathologic basis of PD, and how NMS can be best managed.

Isolated CNS Whipple disease with normal brain MRI and false-positive CSF 14-3-3 protein: a case report and review of the literature.

Whipple disease (WD) is usually a systemic infectious disease that can have central nervous system (CNS) involvement. WD confined to the CNS is extremely rare and difficult to diagnose, but can be fatal if not treated in a timely fashion. We present the case of a 42-year-old man with a subacute dementia accompanied by a movement disorder consisting of progressive supranuclear gaze palsy, myoclonus, and ataxia. Our patient lacked the typical magnetic resonance imaging (MRI) findings reported with isolated CNS WD and had a false-positive cerebrospinal fluid (CSF) 14-3-3 protein. The patient expired, and definitive diagnosis of isolated CNS WD was made by autopsy with characteristic macrophage accumulations found in the brain but not in the gastrointestinal tract. We examine the literature on isolated CNS WD and discuss how these previously unreported findings make a rare diagnosis even more challenging. The reported patient is the first in the literature with tissue diagnosis of isolated CNS WD in the setting of normal brain MRI and positive CSF 14-3-3 protein. Isolated CNS WD should be added to the list of considerations for a false-positive CSF 14-3-3 protein. Even in the absence of typical MRI lesions, a patient with subacute progressive dementia, supranuclear gaze palsy, and other various neurologic abnormalities should have the diagnosis of isolated CNS WD considered.

Low medication adherence and the incidence of stroke symptoms among individuals with hypertension: the REGARDS study.

The authors analyzed data on 9950 participants taking antihypertensive medications in the nationwide Reasons for Geographic and Racial Differences in Stroke (REGARDS) study to determine the association between medication adherence and incident stroke symptoms. Medication adherence was assessed using a validated 4-item self-report scale and participants were categorized into 4 groups (scores of 0, 1, 2, and 3 or 4, with higher scores indicating worse adherence). The incidence of 6 stroke symptoms (sudden weakness on one side of the body, numbness, painless loss of vision in one or both eyes, loss of half vision, losing the ability to understand people, and losing the ability to express oneself verbally or in writing) was assessed via telephone interviews every 6 months. During a median of 4 years, the incidence of any stroke symptom was 14.6%, 17.9%, 20.2%, and 24.9% among participants with adherence scores of 0, 1, 2, and 3 or 4, respectively (P<.001). The multivariable adjusted hazard ratio (95% confidence interval) for any stroke symptom associated with adherence scores of 1, 2, and 3 or 4, vs 0, was 1.20 (1.04-1.39), 1.23 (0.94-1.60), and 1.59 (1.08-2.33), respectively (P<.001). Worse adherence was also associated with higher multivariable adjusted hazard ratios for each of the 6 stroke symptoms.

Sensitivity and specificity of stroke symptom questions to detect stroke or transient ischemic attack.

BACKGROUND/AIMS: Undiagnosed stroke is a major public health problem. The Questionnaire for Verifying Stroke-Free Status (QVSS) includes eight items and was originally designed to detect stroke-free individuals. Its six symptom-related questions could potentially be used to screen for undiagnosed stroke or transient ischemic attack (TIA), but the sensitivity and specificity of just the six symptom-related questions are unknown. METHODS: A research assistant administered the QVSS to outpatients from Veterans Administration stroke and general medicine clinics. Neurologists, blinded to QVSS scores, interviewed and examined all subjects to determine stroke status. Responses to the six symptom questions of the QVSS were compared against the neurologist-determined stroke/TIA status. RESULTS: The sensitivity of the individual symptom questions ranged from 0.22 to 0.60, and the specificity ranged from 0.79 to 0.95. The sensitivity of any of the six symptom questions was 0.82, and the specificity was 0.62. CONCLUSION: The six symptom-related questions of the QVSS demonstrate a high sensitivity and moderate specificity for the diagnosis of stroke or TIA compared with neurological exam. Though these findings should be validated in a more representative general population, these questions have potential for meeting the public health objective of detecting clinically unrecognized but symptomatic stroke.