Sustained Treatment Response and Global Improvements With Long-term Valbenazine in Patients With Tardive Dyskinesia.

PURPOSE/BACKGROUND: Using data from KINECT® 4, a phase 3, 48-week study of valbenazine, post hoc analyses were conducted to assess long-term outcomes that are relevant to the real-world management of tardive dyskinesia (TD). METHODS/PROCEDURES: Post hoc analyses of the participants of the KINECT 4 study who completed 48 weeks of open-label valbenazine (40 or 80 mg) treatment were conducted. Valbenazine effects on TD were evaluated using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change-TD (CGI-TD), and Patient Global Impression of Change (PGIC). FINDINGS/RESULTS: Of 103 participants completing 48 weeks of treatment, 55% experienced clinically meaningful improvement (defined as ≥2-point reduction in AIMS total score [sum of items 1 - 7, evaluated by site raters]) by week 4; at week 48, 97% met this threshold. The percentage of completers who achieved AIMS total score response thresholds of ≥10% to ≥90% increased over time, with 86% of completers reaching ≥50% improvement. Of the 40 (39%) completers with AIMS ≥50% response at week 8, 38 (95%) sustained this response at week 48; 81% of those who did not meet this threshold at week 8 had achieved it by week 48. At week 48, more than 85% of completers achieved CGI-TD and PGIC ratings of "much improved" or "very much improved." IMPLICATIONS/CONCLUSIONS: The majority of participants who completed 48 weeks of treatment with once-daily valbenazine experienced substantial clinically meaningful and sustained TD improvements. These findings indicate that valbenazine can be a highly effective long-term treatment in patients with TD.

Validation of a New Patient-Reported Outcome Measure of the Functional Impact of Essential Tremor on Activities of Daily Living.

Background: The Essential Tremor Rating Assessment Scale (TETRAS) is a popular scale for essential tremor (ET), but its activities of daily living (ADL) and performance (P) subscales are based on a structured interview and physical exam. No patient-reported outcome (PRO) scale for ET has been developed according to US regulatory guidelines. Objective: Develop and validate a TETRAS PRO subscale. Methods: Fourteen items, rated 0-4, were derived from TETRAS ADL and structured cognitive interviews of 18 ET patients. Convergent validity analyses of TETRAS PRO versus TETRAS ADL, TETRAS-P, and the Quality of Life in Essential Tremor Questionnaire (QUEST) were computed for 67 adults with ET or ET plus. Test-retest reliability was computed at intervals of 1 and 30 days. The influence of mood (Hospital Anxiety and Depression Scale, HADS) and coping behaviors (Essen Coping Questionnaire, ECQ) was examined with multiple linear regression. Results: TETRAS PRO was strongly correlated (r > 0.7) with TETRAS ADL, TETRAS-P, and QUEST and exhibited good to excellent reliability (Cronbach alpha 95%CI = 0.853-0.926; 30-day test-retest intraclass correlation 95%CI = 0.814-0.921). The 30-day estimate of minimum detectable change (MDC) was 6.6 (95%CI 5.2-8.0). TETRAS-P (rsemipartial = 0.607), HADS depression (rsemipartial = 0.384), and the coping strategy of information seeking and exchange of experiences (rsemipartial = 0.176) contributed statistically to TETRAS PRO in a multiple linear regression (R2 = 0.67). Conclusions: TETRAS PRO is a valid and reliable scale that is influenced strongly by tremor severity, moderately by mood (depression), and minimally by coping skills. The MDC for TETRAS PRO is probably sufficient to detect clinically important change.

Blepharoclonus in Parkinsonism.

Background and Objectives: In clinical practice, we have observed that patients with Parkinson disease (PD) often have blepharoclonus, but its prevalence is not well described in the literature. Understanding the relative frequencies of blepharoclonus in PD and atypical parkinsonian syndromes may shed light on the diagnostic utility of this clinical sign. We aimed to assess (1) the frequency of blepharoclonus in patients with PD in a single-center cohort; (2) the association of blepharoclonus with disease stage, tremor severity, and non-motor symptoms; and (3) the frequency of blepharoclonus in synucleinopathy vs non-synucleinopathy-associated parkinsonism. Methods: We prospectively enrolled 85 patients, 75 with PD and 10 with atypical parkinsonism. Blepharoclonus was considered present if eyelid fluttering was sustained for >5 seconds after gentle eye closure. For each patient, demographics were collected, and we completed selected questions from the MDS-UPDRS (Unified Parkinson's Disease Rating Scale) part 2, REM Sleep Behavior Disorder Questionnaire, and MDS-UPDRS part 3 tremor assessments and recorded the presence/absence of dyskinesia. Results: 63 of 75 patients with PD (84%) had blepharoclonus. Among the 10 patients with atypical parkinsonism, 5 had synucleinopathy syndromes. Blepharoclonus was present in 3 of 5 patients with synucleinopathy and 0 of 5 patients with non-synucleinopathy-associated parkinsonian syndromes. Discussion: Blepharoclonus is prevalent in our PD cohort, suggesting possible utility as a clinical marker for PD. The absence of blepharoclonus in a patient with parkinsonism may suggest a non-synucleinopathy (e.g., tauopathy). Analysis of a larger cohort of both PD and atypical parkinsonism would be needed to establish whether blepharoclonus distinguishes PD from atypical parkinsonism, or synucleinopathy from non-synucleinopathy.

Ulotaront, a Trace Amine-Associated Receptor 1/Serotonin 5-HT1A Agonist, in Patients With Parkinson Disease Psychosis: A Pilot Study.

Background and Objectives: Ulotaront (SEP-363856) is a trace amine-associated receptor 1 agonist with 5-HT1A receptor agonist activity currently in phase 3 clinical development for the treatment of schizophrenia. In this exploratory, flexibly dosed study, ulotaront was evaluated for the treatment of Parkinson disease psychosis (PDP). Methods: Patients with PDP requiring antipsychotic therapy were randomized, double-blind to ulotaront (25, 50, or 75 mg/d) or placebo. Mixed Model for Repeated Measures was used to assess change from baseline in the Scale for the Assessment of Positive Symptoms for Parkinson Disease (SAPS-PD) at 6 weeks (primary end point). Results: The efficacy analysis sample comprised 38 patients (ulotaront, n = 24; placebo, n = 14). SAPS-PD total scores were numerically reduced in ulotaront-treated vs placebo-treated patients from week 1 to week 6: Least squares mean (95% confidence interval) difference in change from baseline at week 6 was -1.1 (-6.5, 4.3, p = 0.681). PDP symptom complete remission (≥100% improvement [reduction] from baseline in SAPS-PD total score) was observed in 25% of ulotaront-treated vs 0% of placebo-treated patients. SAPS-PD and Neuropsychiatric Inventory hallucinations subscales were numerically reduced vs placebo, and SAPS-PD total scores were reduced in patients with greater cognitive impairment (baseline Mini-Mental State Examination [MMSE] scores ≤24). Ulotaront improved Scales for Outcomes in Parkinson Disease Sleep Scale - Daytime Sleepiness scores (p = 0.022). There was no worsening of Unified Parkinson Disease Rating Scale Part III motor score, MMSE, or vital signs. Adverse events (≥10%) with ulotaront vs placebo included hallucinations (24% vs 14%), confusional state (20% vs 14%), dizziness (16% vs 7%), nausea (12% vs 7%), and falls (12% vs 21%). Discussion: In this exploratory pilot study, ulotaront may decrease PDP symptoms without worsening motor function, particularly in patients with cognitive impairment. Trial Registration Information: ClinicalTrials.gov identifier: NCT02969369; submitted: November 17, 2016; study start date: December 31, 2016. Classification of Evidence: This Class II study was an exploratory pilot study that was underpowered to detect a statistically significant difference between ulotaront and placebo in the treatment of patients with Parkinson disease psychosis without worsening motor function.

Expanded and Independent Spanish Validation of the MDS-Non Motor Rating Scale.

Background: The Movement Disorder Society-sponsored Non-motor Rating Scale (MDS-NMS) assess the severity and disability caused by non-motor symptoms (NMS) in Parkinson's disease (PD). Objective: This article encapsulates the formal process for completing this program and the data on the first officially approved non-English version of the MDS-NMS (Spanish). Methods: The MDS-NMS translation program involves four steps: translation and back-translation; cognitive pre-testing to ensure that raters and patients understand the scale and are comfortable with its content; field testing of the finalized version; analysis of the factor structure of the tested version against the original English language version for the nine domains that could be analyzed in a confirmatory factor analysis. To be designated an "Official MDS translation," the confirmatory factor analysis Comparative Fit Index had to be ≥0.90. Results: The Spanish MDS-NMS was tested in 364 native-Spanish-speaking patients with PD from seven countries. For all subjects with fully computable data with all domains of the MDS-NMS (n = 349), the Comparative Fit Index was ≥0.90 for the nine eligible domains. Missing data were negligible and moderate floor effect (42.90%) was found for the Non-Motor Fluctuations subscale. Item homogeneity coefficient was adequate, and the correlation of the MDS-NMS domains with other measures for related constructs was acceptable (r s ≥ 0.50). Conclusions: The Spanish version of the MDS-NMS followed the IPMDS Translation Program protocol, reached the criterion to be designated as an Official Translation, and is now available on the MDS website.

Amantadine Revisited: A Contender for Initial Treatment in Parkinson's Disease?

The best practice for the initiation of symptomatic motor treatment for Parkinson's disease is an ongoing topic of debate. Fueled by interpretation of the results of the LEAP and MED Parkinson's disease studies, many practitioners opt for early initiation of levodopa formulations, avoiding dopamine agonists to circumvent potential deleterious side effects, namely impulse control disorder. Compared with levodopa, monoamine oxidase inhibitors may lack necessary potency. Ignored in this academic debate is another therapeutic option for patients with Parkinson's disease requiring treatment initiation: amantadine. Amantadine was first reported effective in the treatment of Parkinson's disease in 1969 and several studies were published in the 1970s supporting its efficacy. Currently, amantadine is mainly utilized as an add-on therapy to mitigate levodopa-related dyskinesia and, more recently, new long-acting amantadine formulations have been developed, with new indications to treat motor fluctuations. Amantadine has not been reported to cause dyskinesia and is rarely implicated in impulse control disorder.

Do Benzodiazepines Impair Motor and Nonmotor Symptoms in a Sample of Parkinson's Disease Patients?

Background Anxiety and sleep disturbances are prevalent in Parkinson's disease (PD). Benzodiazepines (BZDs) are commonly used to treat these symptoms; however, they are associated with unfavorable side effects such as falls and cognitive slowing in the general non-PD population. Examining the effects of BZDs in PD is imperative as these medications could pose an increased risk to PD patients who are already vulnerable to falls and cognitive deficits. Methods Eighty-four patients diagnosed with idiopathic PD, of which 60% were Hispanic, underwent clinical evaluations including the Unified Parkinson's Disease Rating Scale (UPDRS) and comprehensive neuropsychological testing examining global cognition, language, visuospatial skills, memory, executive function, mood, and sleep quality. Thirty-six patients taking BZDs (BZD+) were compared to forty-eight patients not using any BZDs (BZD-) employing appropriate statistical tests depending on the measures' characteristics. Results BZD+ PD patients performed below the BZD- group on short-term memory but not on delayed recall, and performed better on a measure of visuospatial judgment. The BZD+ group endorsed more symptoms of anxiety and depression as well as poorer sleep quality. No significant differences were noted on other measures of cognition or motor function. Conclusion PD patients taking BZDs may experience select changes in cognition and mood. These changes are isolated and mild, and suggest that for some patients, BZDs may be a viable pharmacologic intervention that does not alter cognitive and motor function compared to those not taking these medications.

Novel Variants in LRRK2 and GBA Identified in Latino Parkinson Disease Cohort Enriched for Caribbean Origin.

Background: The Latino population is greatly understudied in biomedical research, including genetics. Very little information is available on presence of known variants originally identified in non-Hispanic white patients or novel variants in the Latino population. The Latino population is admixed, with contributions of European, African, and Amerindian ancestries. Therefore, the ancestry surrounding a gene (local ancestry, LA) can be any of the three contributing ancestries and thus can determine the presence or risk effect of variants detected. Methods: We sequenced the major exons and exons of reported Latino-specific variants in GBA and LRRK2 and performed genome-wide genotyping for LA assessments in 79 Latino Parkinson disease (PD) patients, of which ~80% identified as Caribbean Latino. Results: We observed five carriers of LRRK2 p.G2019S, one GBA p.T408M, and three GBA p.N409S on European as well as three GBA p.L13R on African LA backgrounds. Previous Latino variant GBA p.K237E was not observed in this dataset. A novel highly conserved and predicted damaging variant LRRK2 p.D734N was identified in two unrelated individuals with African LA. Additionally, we identified rare, functional variants LRRK2 p.P1480L and GBA p.S310G in one individual each heterozygous for European/Amerindian LA. Discussion: Additional functional analysis will be needed to determine the pathogenicity of the novel variants in PD. However, the identification of novel disease variants in the Latino cohort potentially contributing to PD supports to importance of inclusion of Latinos in genetics research to provide insight in PD genetics in Latinos specifically as well as other populations with the same ancestral contributions.

The retina as a window to the basal ganglia: Systematic review of the potential link between retinopathy and hyperkinetic disorders in diabetes.

There is evidence that glycemic fluctuations trigger vascular-mediated dysfunction in both the retina and the striatopallidal regions in patients with diabetes. The latter is associated with a variety of hyperkinetic disorders that are rare but disabling and potentially preventable. We conducted a systematic review of the potential association between diabetic retinopathy and the risk and prognosis of hyperkinetic disorders in patients with diabetes. We identified a total of 461 articles and 147 were eligible for review. Nine out of 147 articles (6.12%) reported 13 patients with information on diabetic retinopathy. Glycemic fluctuations were present at onset in 10 patients (77%) and retinopathy was present in nine of them (69.23%). The degree of retinopathy was reported in four patients. Two had severe, bilateral proliferative retinopathy, one had moderate-to-severe non-proliferative retinopathy and one had non-proliferative retinopathy. In the nine patients with retinopathy, hyperkinesia persisted, required higher doses of dopamine receptor antagonists or deep brain stimulation. Retinopathy was absent in four cases (30.77%). In these patients, hyperkinesia resolved spontaneously or with lower doses of dopamine receptor antagonists. Diabetic retinopathy could be an indirect marker of striatopallidal microangiopathy in patients with diabetes. The severity of retinopathy may be associated with increased risk or worse prognosis for patients who develop hyperkinetic disorders of the diabetic striatopathy spectrum. Early detection of retinopathy could identify patients in which avoiding glycemic fluctuations may prevent the development of striatopathy and hyperkinetic disorders.

Minority Enrollment in Parkinson's Disease Clinical Trials: Meta-Analysis and Systematic Review of Studies Evaluating Treatment of Neuropsychiatric Symptoms.

BACKGROUND: Randomized clinical trials (RCTs) in Parkinson's disease (PD) have historically enrolled a low number of underrepresented minorities, lessening the generalizability of therapeutic developments. Although there are racial disparities in PD, little is known regarding neuropsychiatric symptoms and other nonmotor manifestations across all races/ethnicities. OBJECTIVE: To assess minority participation in PD trials evaluating the treatment of neuropsychiatric symptoms and explore underlying reasons. METHODS: We systematically searched PubMed and Embase for RCTs with a primary goal of treating neuropsychiatric symptoms in PD patients from 2000-2019. The pooled prevalence and 95% confidence interval (CI) of being white and enrolled in a clinical trial was calculated using the inverse variance method. I-square was calculated as a measure of heterogeneity and meta-regression was used to evaluate temporal trends. RESULTS: We included 63 RCTs with a total of 7,973 patients. In pooled analysis, 11 (17.5%) RCTs reported race/ethnicity. Of studies reporting this data, 5 African American (0.2%), 16 Hispanics (0.64%), and 539 Asians (21.44%) were enrolled. The pooled prevalence of being white in clinical trials was 98% (CI 0.97-0.98, p < 0.001), with 1,908 patients (75.8%). NIH-funded studies were most likely to report racial data when compared to non-NIH trials (p = 0.032). CONCLUSION: This large pooled analysis found a small percentage of RCTs reporting race/ethnicity when evaluating treatment of neuropsychiatric symptoms in PD. There was a disproportionally high number of white patients when compared to African Americans and Hispanics. More studies are needed to investigate this discrepancy and improve rates of & minority enrollment in PD trials.

Trends of inpatient palliative care use among hospitalized patients with Parkinson's disease.

INTRODUCTION: Palliative care in Parkinson's Disease (PD) is an effective intervention to improve quality of life, although historically, access and availability have been very restricted. METHODS: We performed a retrospective cohort study using the National Inpatient Sample (NIS) data from 2007 to 2014. Diagnostic codes were used to identify patients with PD and palliative care referral. Trends were calculated and logistic analysis performed to identify predictors of palliative care use. RESULTS: We identified 397,963 hospitalizations from 2007 to 2014 for patients with PD. Of these, 10,639 (2.67%) were referred to palliative care. The rate of consultation increased from 0.85% in 2007 to 4.49% in 2014. For 1 unit in year increase, there was 1.23 time the odds of receiving palliative consultation (OR 1.23, CI 1.21-1.25, p < 0.0001). Hispanics (OR 0.90, CI 0.81-1.01, p = 0.0550), Black (OR 0.90, CI 0.81-1.01, p = 0.0747) and White patients had similar rates of referral after adjustment. Women were less likely to be referred to palliative care (OR 0.90, CI 0.87-0.94, p < 0.0001). Other factors strongly associated with a higher rate of referrals included private insurance when compared to Medicare (OR 2.14, CI 1.89-2.41, p < 0.0001) and higher income (OR 1.41, CI 1.30-1.53, p < 0.0001). CONCLUSION: There has been a significant increase in palliative care referrals among hospitalized patients with PD in the US, although the overall rate remains low. After controlling for confounders, racial and ethnic disparities were not found. Women, patients with Medicare/Medicaid, and those with lower income were less likely to be referred to palliative care.

Management of Urologic and Sexual Dysfunction in Parkinson Disease.

Parkinson disease (PD) is a complex of motor and nonmotor symptoms. Among the nonmotor symptoms, urinary and sexual dysfunctions are common and negatively affect the quality of life. More than 50% of patients with PD complain of urinary dysfunction and 20% have sexual dysfunction. Understanding the anatomy and physiology of the urogenital system informs the rationale for the mechanism of action of drug therapies. The management of urinary and sexual dysfunction in PD, including behavioral, medical, and procedural interventions, is reviewed in this article.

A Phase 3, 1-Year, Open-Label Trial of Valbenazine in Adults With Tardive Dyskinesia.

PURPOSE/BACKGROUND: Valbenazine is approved to treat tardive dyskinesia (TD) in adults. KINECT 4 (NCT02405091) was conducted to explore the long-term effects of once-daily valbenazine in patients with TD. METHODS/PROCEDURES: The study included a 48-week, open-label treatment period and 4-week washout. Dosing was initiated at 40 mg/d, with escalation to 80 mg/d at week 4 based on efficacy and tolerability. Standard safety methods were applied, including treatment-emergent adverse event (TEAE) reporting. Valbenazine effects on TD were assessed using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change-TD, and Patient Global Impression of Change. FINDINGS/RESULTS: After week 4, <15% of all participants had a serious TEAE (13.7%) or TEAE leading to discontinuation (11.8%). Participants experienced TD improvements during long-term treatment as indicated by mean change from baseline to week 48 in AIMS total score (sum of items 1-7, evaluated by site raters) with valbenazine 40 mg/d (-10.2 [n = 45]) or 80 mg/d (-11.0 [n = 107]). At week 48, most participants had ≥50% improvement from baseline in AIMS total score (40 mg/d, 90.0%; 80 mg/d, 89.2%), Clinical Global Impression of Change-TD rating of much or very much improved (40 mg/d, 90.0%; 80 mg/d, 95.9%), and Patient Global Impression of Change rating of much or very much improved (40 mg/d, 90.0%; 80 mg/d, 89.2%). No dose effects were apparent by week 36. Week 52 results indicated some loss of effect after washout. IMPLICATIONS/CONCLUSIONS: Valbenazine was generally well tolerated, and no new safety concerns were detected. Substantial clinician- and patient-reported improvements were observed in adults with TD who received once-daily valbenazine for up to 48 weeks.

Motivations for Participation in Parkinson Disease Genetic Research Among Hispanics versus Non-Hispanics.

Involvement of participants from different racial and ethnic groups in genomic research is vital to reducing health disparities in the precision medicine era. Racial and ethnically diverse populations are underrepresented in current genomic research, creating bias in result interpretation. Limited information is available to support motivations or barriers of these groups to participate in genomic research for late-onset, neurodegenerative disorders. To evaluate willingness for research participation, we compared motivations for participation in genetic studies among 113 Parkinson disease (PD) patients and 49 caregivers visiting the Movement Disorders clinic at the University of Miami. Hispanics and non-Hispanics were equally motivated to participate in genetic research for PD. However, Hispanic patients were less likely to be influenced by the promise of scientific advancements (N = 0.01). This lack of scientific interest, but not other motivations, was found to be likely confounded by lower levels of obtained education (N = 0.001). Overall, these results suggest that underrepresentation of Hispanics in genetic research may be partly due to reduced invitations to these studies.

The Parkinson's Disease Sleep Scale-2 (PDSS-2): Validation of the Spanish Version and Its Relationship With a Roommate-Based Version.

BACKGROUND: Because of the prevalence and impact of sleep disorders in Parkinson's disease (PD), valid instruments for their evaluation and monitoring are necessary. However, some nocturnal sleep disorders may go unnoticed by patients themselves. OBJECTIVES: To validate a pan-Spanish version of the Parkinson's Disease Sleep Scale Version 2 (PDSS-2) and to test the relationships between the PDSS-2 and a PDSS-2 roommate version. METHODS: PD patients (n = 399) from seven Spanish-speaking countries were included. In addition to the tested PDSS-2 scales, valid measures for sleep disorders and both motor and nonmotor manifestations were applied. Acceptability, dimensionality, reliability, precision, and construct validity were explored, as well as discrepancies and agreement between the PDSS-2 and the roommate version. RESULTS: PDSS-2 showed negligible floor and ceiling effects. Four factors (57% of the variance) were identified. Reliability parameters were satisfactory: alpha = 0.84; item homogeneity coefficient = 0.27; corrected item total correlation = 0.28 to 0.61; and test-retest reliability (average kappa = 0.70; intraclass correlation coefficient [ICC] = 0.83). The standard error of measurement was 5.84, and correlations with other scales assessing nocturnal sleep were high (rS = 0.62-0.56). In comparison to the patient-based total score, the by proxy total score showed no significant difference, high correlation (rS = 0.70), and acceptable agreement (ICC = 0.69), but there were discrepancies in two or more points in 18% of item scores. CONCLUSIONS: The Spanish version of the PDSS-2 has shown satisfactory clinimetric attributes. Acceptability and precision data are presented for the first time. The PDSS-2 roommate version could be useful to complement the patient-based evaluation, but additional studies are needed.