Patient and Family Outcomes of Community Neurologist Palliative Education and Telehealth Support in Parkinson Disease.

Importance: Parkinson disease and related disorders (PDRD) are the fastest growing neurodegenerative illness in terms of prevalence and mortality. As evidence builds to support palliative care (PC) for PDRD, studies are needed to guide implementation. Objective: To determine whether PC training for neurologists and remote access to a PC team improves outcomes in patients with PDRD in community settings. Design, Setting, and Participants: This pragmatic, stepped-wedge comparative effectiveness trial enrolled and observed participants from 19 community neurology practices supported by PC teams at 2 academic centers from March 8, 2017, to December 31, 2020. Participants were eligible if they had PDRD and moderate to high PC needs. A total of 612 persons with PDRD were referred; 253 were excluded. Patients were excluded if they had another diagnosis meriting PC, were receiving PC, or were unable or unwilling to follow study procedures. Patients received usual care or the intervention based on when their community neurologist was randomized to start the intervention. Data were analyzed from January 2021 to September 2023. Intervention: The intervention included (1) PC education for community neurologists and (2) team-based PC support via telehealth. Main Outcomes and Measures: The primary outcomes were differences at 6 months in patient quality of life (QOL; measured by the Quality of Life in Alzheimer Disease Scale [QOL-AD]) and caregiver burden (Zarit Burden Interview) between the intervention and usual care. Results: A total of 359 patients with PDRD (233 men [64.9%]; mean [SD] age, 74.0 [8.8] years) and 300 caregivers were enrolled. At 6 months, compared with usual care, participants receiving the intervention had better QOL (QOL-AD score, 0.09 [95% CI, -0.63 to 0.82] vs -0.88 [95% CI, -1.62 to -0.13]; treatment effect estimate, 0.97; 95% CI, 0.07-1.86; P = .03). No significant difference was observed in caregiver burden (Zarit Burden Interview score, 1.19 [95% CI, 0.16 to 2.23] vs 0.55 [95%, -0.44 to 1.54]; treatment effect estimate, 0.64; 95% CI, -0.62 to 1.90; P = .32). Advance directive completion was higher under the intervention (19 of 38 [50%] vs 6 of 31 [19%] among those without directives at the beginning of the study; P = .008). There were no differences in other outcomes. Conclusions and Relevance: PC education for community neurologists and provision of team-based PC via telehealth is feasible and may improve QOL and advance care planning. Overall treatment effects were small and suggest opportunities to improve both the intervention and implementation. Trial Registration: ClinicalTrials.gov Identifier: NCT03076671.

Complementary Therapies in Parkinson Disease: a Review of Acupuncture, Tai Chi, Qi Gong, Yoga, and Cannabis.

Parkinson disease (PD) is a progressive neurodegenerative condition characterized by bradykinesia, rigidity, resting tremor, and postural instability. Non-motor symptoms, including pain, fatigue, insomnia, anxiety, and depression to name a few, are increasingly recognized and often just as disabling at motor symptoms. The mainstay of treatment is dopamine replacement; however, the beneficial effects tend to wane over time with disease progression, and patients often experience motor fluctuations and medication side effects. The lack of a disease-modifying intervention and the shortcomings of traditional symptomatic medications have led many patients to pursue complementary therapies to alleviate motor and non-motor symptoms associated with PD. The term complementary implies that the therapy is used along with conventional medicine and may include supplements, manipulative treatments (chiropractic, massage), exercise-based programs, and mind-body practices. As these practices become more widespread in Western medicine, there is a growing interest in evaluating their effects on a number of medical conditions, PD included. In this review, we provide an update on clinical trials that have evaluated the effectiveness of complementary treatments for patients with PD, specifically focusing on acupuncture, Tai Chi, Qi Gong, yoga, and cannabis.

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.

Movement disorders associated with aripiprazole use: a case series.

Aripiprazole is an atypical antipsychotic that is a partial agonist at the D2 and 5HT1a receptors and an antagonist at 5HT2a receptors. Despite previous hypotheses that it would be less likely to cause movement disorders, recent reports suggest it actually may be more likely to cause movement disorders than other atypical antipsychotics. This case series illustrates the variety of movement disorders associated with aripiprazole use at three movement disorder clinics. It also suggests that aripiprazole be used with caution in patients with a prior history of dystonia, parkinsonism, or previous tardive dyskinesia.

Optimizing bioavailability in the treatment of Parkinson's disease.

The bioavailability of drugs used to treat chronic diseases such as Parkinson's disease may have important implications for their clinical utility. Drugs with low bioavailability may cause a wide variation in clinical response between patients and even in the same patient. In addition, numerous factors - including gender, age, and gastric motility - may affect a drug's bioavailability. This is especially important in patients with Parkinson's disease, who develop response fluctuations as the disease progresses. Strategies that may improve the bioavailability of levodopa, the most efficacious medication for Parkinson's disease, include coadministering levodopa with carbidopa, a decarboxylase inhibitor, or with a catechol-O-methyltransferase inhibitor or using an alternative route of administration. Other adjunctive therapies used to treat Parkinson's disease have a wide range of bioavailabilities, which may also affect clinical outcomes. The bioavailability of adjunctive medications may be improved by the use of alternative formulations as well, such as orally disintegrating tablets or transdermal delivery. Considering bioavailability of a medication when prescribing drugs to treat Parkinson's disease may improve patient response and minimize adverse effects.

Valbenazine for the treatment of tardive dyskinesia.

INTRODUCTION: Tardive dyskinesia (TD) is a hyperkinetic movement disorder that may result from treatment with antipsychotics or other dopamine receptor blocking agents. Underlying pathophysiology is incompletely understood but since the 1970s dopamine depleting agents have been used to reduce involuntary movements. The search for safe, effective treatments for TD is ongoing. Valbenazine, a novel VMAT2 inhibitor, has recently been FDA approved for treatment of TD. Areas covered: An overview of TD, unmet medical needs and current treatment guidelines are presented. The background, chemistry and clinical development of valbenazine to treat TD is detailed. A competitive market is developing as the treatment gap is identified and potential therapies are discussed in context of a broader market overview. Expert opinion: Antipsychotic use is growing among adults and children in the U.S. Consequently, prevalence of TD is expected to rise. Cessation of antipsychotics is often not possible as the psychiatric condition may deteriorate. Increasing doses of an antipsychotic to suppress involuntary movements is not sustainable long term as underlying TD worsens and movements typically recur. There were no FDA approved treatments for TD. The approval of valbenazine to treat TD is a critical step in addressing this gap in neurologic care.

Carbidopa levodopa enteral suspension.

INTRODUCTION: The search for consistent, effective treatments in Parkinson's disease (PD) is ongoing. The importance of continuous dopaminergic stimulation (CDS) is understood to underlie best medical therapy for PD by providing closer replication of physiological patterns of dopamine release in healthy brains. AREAS COVERED: An overview of interventions to improve motor fluctuations in PD is presented. Significant improvements in off-time are achieved by providing continuous therapy using targeted deep brain stimulation (DBS), subcutaneous apomorphine infusion and carbidopa/levodopa enteral suspension (Duopa). Duopa is a newly approved treatment in the US for advanced PD that delivers levodopa pumped to the intestinal tract through a percutaneous gastrostomy with jejunum tube extension (PEG-J tube). Trials with carbidopa/levodopa enteral suspension show improvement in motor fluctuations, reduction in plasma levodopa variation and improvement in overall "on" time compared with oral immediate release formulation of carbidopa/levodopa. EXPERT OPINION: The degree of improvement in number of off hours per day on carbidopa/levodopa enteral suspension infusion rivals that seen with DBS and apomorphine infusion and makes this new treatment a valuable option in advanced fluctuating PD patients, especially those who are neither candidates for DBS or who do not have access to apomorphine infusion therapy or who have failed either or both therapies.

Rasagiline: time to onset of antiparkinson effect is similar when used as a monotherapy or adjunct treatment.

OBJECTIVE: Rasagiline, a monoamine oxidase type B inhibitor, is indicated for both the initial treatment of Parkinson disease (PD) and as adjunctive (add-on) treatment for patients already taking dopaminergic therapy. This open-label prospective community-based clinical trial was designed to determine the time-to-onset and the magnitude of the beneficial effects of rasagiline in PD patients. METHODS: Patients received rasagiline of 1.0 mg once daily as monotherapy or 0.5 mg once daily as adjunct therapy (adjunct therapy dose could be increased to 1 mg/d if clinically indicated) for 12 weeks. Dietary restrictions and recommendations regarding concurrent antidepressant treatment consistent with the Food and Drug Administration (FDA) regulations were in keeping with typical usage. Effectiveness was measured as change from baseline in bradykinesia scores and physicians' and patients' global impression. Patients were prospectively monitored for treatment emergent dopaminergic side effects, tyramine reactions, and possible interactions with commonly used antidepressants. RESULTS: Objective and subjective measures of symptom severity improved at 1 week in 272 PD patients treated with once-daily rasagiline (n=123 monotherapy, n=149 adjunct therapy). The magnitude of beneficial effect was similar in monotherapy and adjunct therapy patients. No significant dopaminergic side effects, tyramine reactions, or interactions with antidepressants were observed in the 12-week trial. CONCLUSIONS: Rasagiline has a measurable beneficial effect on PD symptoms within 1 week of treatment. Rasagiline has a similar magnitude of benefit in monotherapy and adjunct therapy patients. Adverse interactions between antidepressants and rasagiline were not observed in patients in this trial. The usual use of rasagiline in community neurology practice, consistent with the FDA labeling, seems safe and effective.

Examination of the UPDRS bradykinesia subscale: equivalence, reliability and validity.

Administering items or subscales separately from the measure for which they were designed to be a part may have unintended consequences for research and practice in Parkinson's disease (PD). The current study tested the equivalence of the bradykinesia subscale when administered alone versus as a component of the full 14-item Unified Parkinson's Disease Rating Scale (UPDRS) motor examination, as well as examined the reliability and validity of the bradykinesia subscale. The study sample consisted of 112 patients with PD. Patients were randomly assigned to either the bradykinesia subscale alone group (n = 56), who were administered the bradykinesia subscale separately from the rest of the UPDRS motor examination, or the full scale group (n = 56), who were administered the UPDRS motor examination in its standard format. The two one-sided t-test (TOST) procedure was used to test for mean equivalency between the two administration groups. Additionally, reliability and validity analyses were performed. The bradykinesia subscale mean scores from the full scale group and the subscale alone group were not statistically equivalent. However, in both groups, the bradykinesia subscale had exceptional reliability and was strongly and similarly related to age, activities of daily living, disability, and other assessments of motor symptom severity. The bradykinesia subscale is a valid and reliable assessment when administered separately from the rest of the UPDRS motor examination; however, caution should be taken when comparing mean scores across studies or occasions when different administrations are used.

Levodopa/carbidopa/entacapone in Parkinson's disease.

Levodopa is the most efficacious agent for the treatment of motor features of Parkinson's disease but its chronic use is associated with the development of motor complications. Mounting evidence indicates the short half-life of levodopa and resultant pulsatile stimulation of striatal dopamine receptors leads to wearing off, motor fluctuations and dyskinesias. Longer acting dopaminergic agents, such as dopamine agonists, are less likely to cause motor fluctuations and dyskinesias but are not as efficacious for control of motor symptoms. Therefore, there is interest in exploring ways to deliver levodopa in a more continuous fashion, in an effort to maintain benefit through the day and reduce the development of motor fluctuations and dyskinesias. A dopa decarboxylase inhibitor (DDCI), such as carbidopa or benserazide, is administered with levodopa to attenuate its peripheral conversion to dopamine, reduce nausea and increase central bioavailability. When levodopa is administered with a DDCI, its main route of peripheral metabolism is via catechol-O-methyl transferase (COMT). A COMT inhibitor can be added to the combination of levodopa and a DDCI to further extend the levodopa peripheral half-life and increase central bioavailability. Stalevo is a combination tablet comprised of levodopa, carbidopa, and the COMT inhibitor entacapone. It is available in fixed-dose combinations of levodopa/carbidopa/entacapone, 50/12.5/200, 75/18.75/200, 100/25/200, 125/31.25/200, 150/37.5/200 and 200/50/200 mg. Stalevo is currently approved for use in Parkinson's disease patients with end-of-dose wearing off.

MS vs. HD: can white matter and subcortical gray matter pathology be distinguished neuropsychologically?

This study was conducted to examine the neuropsychological effects of white matter and subcortical gray matter pathology. Nineteen patients with multiple sclerosis (MS), 16 with Huntington's disease (HD), and 17 normal controls (NC) participated. Participants completed the California Verbal Learning Test (CVLT), Rotary Pursuit (RP) and Mirror Tracing (MT) tasks, and the Symbol Digit Modalities Test (SDMT). The principal findings pertain to a dissociation in procedural memory: on RP, the HD group demonstrated impaired sequence learning compared to the MS group, which performed similarly to the NC group, yet on MT, the MS and HD groups demonstrated normal perceptual-motor integration learning. On the CVLT, both patient groups performed better on recognition than on recall. On the SDMT, both patient groups performed worse than the NC group, with the HD group performing more poorly than the MS and NC groups. These results suggest that involvement of white and subcortical gray matter may produce different neuropsychological effects.

Efficacy and safety of botulinum type A toxin (Dysport) in cervical dystonia: results of the first US randomized, double-blind, placebo-controlled study.

Botulinum toxin type A (Dysport) has been shown in European studies to be a safe and effective treatment for cervical dystonia. This multicenter, double-blind, randomized, controlled trial assessed the safety and efficacy of Dysport in cervical dystonia patients in the United States. Eighty patients were randomly assigned to receive one treatment with Dysport (500 units) or placebo. Participants were followed up for 4 to 20 weeks, until they needed further treatment. They were assessed at baseline and weeks 2, 4, 8, 12, 16, and 20 after treatment. Dysport was significantly more efficacious than placebo at weeks 4, 8, and 12 as assessed by the Toronto Western Spasmodic Torticollis Rating Scale (10-point vs. 3.8-point reduction in total score, respectively, at week 4; P < or = 0.013). Of participants in the Dysport group, 38% showed positive treatment response, compared to 16% in the placebo group (95% confidence interval, 0.02-0.41). The median duration of response to Dysport was 18.5 weeks. Side effects were generally similar in the two treatment groups; only blurred vision and weakness occurred significantly more often with Dysport. No participants in the Dysport group converted from negative to positive antibodies after treatment. These results confirm previous reports that Dysport (500 units) is safe, effective, and well-tolerated in patients with cervical dystonia.

By carrot or by stick: cognitive reinforcement learning in parkinsonism.

To what extent do we learn from the positive versus negative outcomes of our decisions? The neuromodulator dopamine plays a key role in these reinforcement learning processes. Patients with Parkinson's disease, who have depleted dopamine in the basal ganglia, are impaired in tasks that require learning from trial and error. Here, we show, using two cognitive procedural learning tasks, that Parkinson's patients off medication are better at learning to avoid choices that lead to negative outcomes than they are at learning from positive outcomes. Dopamine medication reverses this bias, making patients more sensitive to positive than negative outcomes. This pattern was predicted by our biologically based computational model of basal ganglia-dopamine interactions in cognition, which has separate pathways for "Go" and "NoGo" responses that are differentially modulated by positive and negative reinforcement.