Retrospective analyses evaluating the mortality risk associated with pimavanserin or other atypical antipsychotics in patients with Parkinson disease psychosis.

Introduction: Parkinson's disease (PD) is associated with increased mortality risk (MR), reflecting progression of motor and nonmotor symptoms. PD psychosis (PDP), a common nonmotor symptom, increases with prolonged disease and elevates the MR of PD even further. Pimavanserin is the only FDA-approved treatment for PDP. This review summarizes real-world evidence around the MR of patients with PDP treated with pimavanserin versus off-label atypical antipsychotics. Methods: A PubMed search was conducted using the following search terms: pimavanserin AND antipsychotic AND mortality AND Parkinson's disease AND psychosis. Inclusion criteria specified the entry of retrospective, observational, and open-label studies comparing pimavanserin to atypical antipsychotics or untreated controls. Results: A total of 10 of the 32 articles met inclusion criteria. Among five comparisons of pimavanserin with atypical antipsychotics, two were large (n = 21,719; n = 21,975), representative, Medicare-database studies, which demonstrated comparable or lower all-cause pimavanserin MR. Among three pimavanserin versus control studies, two reported lower or comparable pimavanserin MR and one, long-term care study reported higher MR for pimavanserin versus non-pimavanserin treated patients with unknown PDP status. Two open-label extensions reported pimavanserin mortality rates of 6.45 and 18.8 deaths per 100 patient-years, which are comparable to, or lower than, mortality rates for PD, PDP, and other atypical antipsychotics. Most studies (70 %; 7 of 10) demonstrated pimavanserin's MR was lower than or similar to other atypical antipsychotics or untreated controls. Conclusions: Pimavanserin did not increase the MR in PDP. Pimavanserin's MR appears to be comparable to or lower than other atypical antipsychotics prescribed for PDP, including quetiapine.

On the Optimal Diagnosis and the Evolving Role of Pimavanserin in Parkinson's Disease Psychosis.

Parkinson's disease (PD) is associated with the development of psychosis (PDP), including hallucinations and delusions, in more than half of the patient population. Optimal PD management must therefore involve considerations about both motor and non-motor symptoms. Often, clinicians fail to diagnosis psychosis in patients with PD and, when it is recognized, treat it suboptimally, despite the availability of multiple interventions. In this paper, we provide a summary of the current guidelines and clinical evidence for treating PDP with antipsychotics. We also provide recommendations for diagnosis and follow-up. Finally, an updated treatment algorithm for PDP that incorporates the use of pimavanserin, the only US FDA-approved drug for the treatment of PDP, was developed by extrapolating from a limited evidence base to bridge to clinical practice using expert opinion and experience. Because pimavanserin is only approved for the treatment of PDP in the US, in other parts of the world other recommendations and algorithms must be considered.

Istradefylline effects on tremor dominance (TD) and postural instability and gait difficulty (PIGD).

Background: In patients with Parkinson's Disease (PD), two distinct motor subtypes, tremor dominant (TD) and postural instability and gait difficulty (PIGD), can be differentiated using Unified Parkinson's Disease Rating Scale (UPDRS) sub-scores. This post hoc analysis of pooled data from eight pivotal studies examined the effect of treatment with istradefylline, a selective adenosine A2A receptor antagonist, on these subtypes. Methods: In eight randomized, placebo-controlled phase 2b/3 trials, patients on levodopa with carbidopa/benserazide experiencing motor complications received istradefylline (20 or 40 mg/day) or placebo for 12 or 16 weeks. TD subtype was defined by the UPDRS II/III items kinetic and postural tremor in right/left hand and (resting) tremor in the face, lips, chin, hands, or feet; PIGD items were freezing, walking, posture, gait, and postural instability. The ratio of mean scores from TD:PIGD items determined subtype (TD [TD:PIGD ratio ≥ 1.5], PIGD [TD:PIGD ratio ≤ 1.0], mixed-type [ratio 1-1.5]). Results: In total, 2719 patients were included (PIGD, n = 2165; TD, n = 118; mixed-type, n = 188; not evaluable, n = 248). Among TD subtype patients, the least-squares mean change from baseline versus placebo in UPDRS II/III TD-related total score was significant at 20 mg/day istradefylline (-2.21; 95 % CI, -4.05 to -0.36; p = 0.02). For PIGD subtype patients, there was a significant difference from placebo in UPDRS II/III PIGD-related total score at 40 mg/day istradefylline (-0.25; -0.43 to -0.06; p = 0.01). Conclusions: The data from this analysis of UPDRS-based motor subtypes suggest that istradefylline can improve motor disability in PD patients with motor fluctuations regardless of PD subtype. Future research should characterize the effects of istradefylline on tremor.

Adenosine A2A antagonists and Parkinson's disease.

Although there is no cure for Parkinson's disease (PD), there are several classes of medications with various mechanisms of action that can help improve the functionality of someone with PD. Dopamine derivatives are first line therapies for PD, hence dopamine receptor agonists (DAs) have been shown to improve functionality of symptoms in PD patients. The two main formulations of dopamine agonist medications in PD therapy are ergoline and non-ergoline derivatives. Additionally, it has been shown that PD can involve irregularities in other neurotransmitters, such as acetylcholine, norepinephrine, and serotonin, hence why non-dopaminergic medications are also vital in PD management. Examples include NMDA receptor antagonists, dopamine antagonists (i.e. neuroleptics), acetylcholine receptor antagonists, serotonin receptor 2A agonists, and adenosine A2 antagonists. In general, dopaminergic medications are the most effective in improving motor involvement with PD, whereas non-dopaminergic medications tend to focus on the non-motor involvement of PD. In this chapter, we will focus on the chemistry and medication background on dopaminergic vs non-dopaminergic therapy, with a focus of adenosine A2 antagonists at the end.

Clinical Use of On-Demand Therapies for Patients with Parkinson's Disease and OFF Periods.

On-demand therapies for Parkinson's disease (PD) provide rapid, reliable relief for patients experiencing OFF periods; however, practical guidelines on the use of these therapies are not generally available. This paper reviews the use of on-demand treatments. Motor fluctuations occur in nearly all patients with PD after long-term use of levodopa. As the goal of PD treatment is to provide good ON time, on-demand treatments that have a more rapid reliable onset than the slower-acting oral medications provide rapid relief for OFF periods. All current on-demand treatments bypass the gastrointestinal tract, providing dopaminergic therapy directly into the blood stream by subcutaneous injection, through the buccal mucosa, or by inhalation into the pulmonary circulation. On-demand treatments are fast acting (10- to 20-min onset), with maximum, reliable, and significant responses reached within 30 min after administration. Oral medications pass through the gastrointestinal tract and thus have slower absorption owing to gastroparesis and competition with food. On-demand therapies, by providing fast-acting relief, can have a positive impact on a patient's quality of life when patients are experiencing OFF periods.

Comparative Effectiveness of Carbidopa/Levodopa Enteral Suspension and Deep Brain Stimulation on Pill Burden Reduction in Medicare Fee-for-Service Patients with Advanced Parkinson's Disease.

INTRODUCTION: Complex polypharmacy regimens to manage persistent motor fluctuations result in significant pill burden for patients with advanced Parkinson's disease (APD). This study evaluated the effectiveness of carbidopa/levodopa enteral suspension (CLES) and deep brain stimulation (DBS) on reducing pill burden in APD patients. METHODS: We utilized 100% Medicare fee-for-service claims from 2014 to 2018 linked to CLES Patient Support Program (PSP) data. CLES initiators (CLES-I) were propensity matched 1:1 with patients enrolled in PSP who did not initiate treatment (CLES-NI) (N = 188) or undergo DBS, and 1:3 with patients who received DBS (N = 204, N = 612). Average daily pill burden and levodopa equivalent daily dosage (LEDD) were measured at baseline, 0-6 months and 7-12 months follow-up. RESULTS: CLES-I and CLES-NI had higher pill burden than DBS patients at baseline. However, at 6 months post-treatment, CLES-I had significantly fewer pills/day than CLES-NI (4.7 versus 11.4, p < 0.05) and DBS (4.8 versus 7.4, p < 0.05). A significant reduction in pill burden was observed at 0-6 months (46.3%) and 7-12 months (68.3%) follow-up for CLES-I (p < 0.001) versus increased burden for CLES-NI (+10.5%, p < 0.05 and +8.2%, p > 0.05) and insignificant reductions for DBS (-3.9% and -6.1%, p > 0.05). Mean adjusted pill burden showed 57.3% fewer pills at 0-6 months and 74.1% at 7-12 months among CLES-I compared with CLES-NI, and 49.6% and 70.1% reduction compared with DBS. CLES-I showed a decrease in LEDD at 7-12 months compared with baseline (935 to 237 mg) and to CLES-NI (237 mg versus 1112 mg) and DBS patients (236 mg versus 594 mg). CONCLUSION: CLES led to a significant reduction in pill burden and oral LEDD compared with CLES-NI and DBS patients. Pill burden reduction could be considered a treatment goal for patients with APD challenged by complex polypharmacy regimens that interfere with activities of daily living and quality of life.

Management of uncontrollable motor movements in patients with advanced Parkinson's disease rely on oral levodopa-based treatments. Non-motor symptoms such as depression and anxiety are managed with additional oral medications. Over time, higher and more frequent dosing of oral medications is required, resulting in complex medication regimens that impact quality of life and adherence.A real-world study of 10,752 Parkinson's disease patients between 2014 and 2018 evaluated the effectiveness of two device-aided therapies to reduce pill burden, carbidopa/levodopa enteral suspension and deep brain stimulation. Carbidopa/levodopa suspension treatment involves continuous delivery of levodopa to the intestines through a surgical port attached to a portable pump. Brain stimulation involves surgery to attach metal wires to the brain to send electrical pulses via an implanted stimulator.As Parkinson's disease predominately affects the elderly, we compared Medicare patients on carbidopa/levodopa suspension to a matched control group receiving no suspension and to those receiving brain stimulation. Average pill burden/day was measured prior to receiving a device-aided treatment (baseline) and at 0­6 months and 7­12 months post-treatment (follow-up).The top graph shows that by 6-months post-treatment, patients on carbidopa/levodopa suspension required fewer pills than those without suspension (4.7 versus 11.4), with further pill reduction at 12 months (3.5 versus 11.1). The bottom graph shows that by 6 months, patients on carbidopa/levodopa suspension required fewer pills than patients treated with brain stimulation (4.8 versus 7.4), with further reduction at 12 months (3.6 versus 7.0). The reduction in oral pill burden suggests that the carbidopa/levodopa suspension may present an opportunity to simplify treatment regimens.

Unmet needs in the diagnosis and treatment of Parkinson's disease psychosis and dementia-related psychosis.

Dementia due to Parkinson's disease and Alzheimer's disease are associated with behavioural and psychological symptoms, including psychosis. Long-term management presents a challenge for health care providers and caregivers. Symptoms of psychosis include hallucinations and delusions; if untreated, these can lead to institutionalisation, decreased quality of life, and significant patient and caregiver distress. A critical step in the effective management of dementia-related psychosis (DRP) is the identification and diagnosis of affected patients. The lack of a standardised diagnostic approach presents a barrier to treatment and there are no consensus guidelines for DRP. Furthermore, there are no approved therapies for the treatment of DRP. Antipsychotic medications are often prescribed off-label, even though some are associated with an increased risk of adverse events or mortality. We present currently available screening tools and guidelines for the diagnosis and treatment of Parkinson's disease psychosis and DRP in the context of what is needed for effective management of psychosis.KEY POINTSWe present currently available screening tools and guidelines for Parkinson's disease psychosis and dementia-related psychosis, and discuss the unmet need for simple clinical diagnostic tools and treatment guidelines.The identification of psychosis is variable across different settings and specialties, without a unified approach to screening, definition, or diagnosis.Currently used tools for defining and assessing psychosis in a research setting are usually too cumbersome for everyday clinical practice.The development of a standardised set of diagnostic criteria would provide clinicians the opportunity to improve the detection, treatment, and quality of life of patients and their caregivers.

Oral ENT-01 Targets Enteric Neurons to Treat Constipation in Parkinson Disease : A Randomized Controlled Trial.

BACKGROUND: Parkinson disease (PD) is associated with α-synuclein (αS) aggregation within enteric neurons. ENT-01 inhibits the formation of αS aggregates and improved constipation in an open-label study in patients with PD. OBJECTIVE: To evaluate the safety and efficacy of oral ENT-01 for constipation and neurologic symptoms in patients with PD and constipation. DESIGN: Randomized, placebo-controlled phase 2b study. (ClinicalTrials.gov: NCT03781791). SETTING: Outpatient. PATIENTS: 150 patients with PD and constipation. INTERVENTION: ENT-01 or placebo daily for up to 25 days. After baseline assessment of constipation severity, daily dosing was escalated to the prokinetic dose, the maximum dose (250 mg), or the tolerability limit, followed by a washout period. MEASUREMENTS: The primary efficacy end point was the number of complete spontaneous bowel movements (CSBMs) per week. Neurologic end points included dementia (assessed using the Mini-Mental State Examination [MMSE]) and psychosis (assessed using the Scale for the Assessment of Positive Symptoms adapted for PD [SAPS-PD]). RESULTS: The weekly CSBM rate increased from 0.7 to 3.2 in the ENT-01 group versus 0.7 to 1.2 in the placebo group (P < 0.001). Improvement in secondary end points included SBMs (P = 0.002), stool consistency (P < 0.001), ease of passage (P = 0.006), and laxative use (P = 0.041). In patients with dementia, MMSE scores improved by 3.4 points 6 weeks after treatment in the ENT-01 group (n = 14) versus 2.0 points in the placebo group (n = 14). Among patients with psychosis, SAPS-PD scores improved from 6.5 to 1.7 six weeks after treatment in the ENT-01 group (n = 5) and from 6.3 to 4.4 in the placebo group (n = 6). ENT-01 was well tolerated, with no deaths or drug-related serious adverse events. Adverse events were predominantly gastrointestinal, including nausea (34.4% [ENT-01] vs. 5.3% [placebo]; P < 0.001) and diarrhea (19.4% [ENT-01] vs. 5.3% [placebo]; P = 0.016). LIMITATION: Longer treatment periods need to be investigated in future studies. CONCLUSION: ENT-01 was safe and significantly improved constipation. PRIMARY FUNDING SOURCE: Enterin, Inc.

Should "on-demand" treatments for Parkinson's disease OFF episodes be used earlier?

We discuss a shift in the treatment paradigm for OFF episode management in patients with Parkinson's disease, based on clinical experience in the United States (US). Three "on-demand" treatments are currently available in the US as follows: subcutaneous apomorphine, levodopa inhalation powder, and sublingual apomorphine. We empirically propose that "on-demand" treatments can be utilized as a complementary treatment when OFF episodes emerge and can be utilized when needed rather than reserving these treatments only until other treatment approaches (adjustment of baseline treatment and/or addition of adjunctive treatment with "ON-extenders") have failed. Current treatment approaches combine "ON-extenders" with increasing levodopa dosing and/or frequency to treat OFF episodes. Yet, OFF episodes often persist, with a substantial amount of daily OFF time. OFF episode treatment is hindered by variable gastrointestinal (GI) absorption of oral levodopa, reflecting GI dysmotility and protein competition. Novel "on-demand" treatments bypass the gut and can improve OFF symptoms more rapidly and reliably than oral levodopa. With the emergence of novel "on-demand" treatments, we conclude that a shift in treatment paradigm to the earlier, complementary use of these medications be considered.

Screening, Diagnosis, and Management of Parkinson's Disease Psychosis: Recommendations From an Expert Panel.

INTRODUCTION: Hallucinations and delusions present with psychosis are debilitating non-motor symptoms of Parkinson's disease, with a prevalence of up to 50-70% at some point during the course of the disease. Often patients and caregivers do not report the presence of hallucinations or delusions unless specifically questioned. A panel of experts in neurology and geriatric psychiatry convened to develop a simple screening tool and guidance on diagnosis and treatment of Parkinson's disease psychosis (PDP). METHODS: The working group reviewed literature for existing PDP guidelines on diagnosis and management and identified gaps in recommendations. The group discussed and developed a screening tool and treatment guidance that addressed the gaps in existing methodology based on their clinical experience. RESULTS: The proposed screening tool consists of two parts: (1) a brief pre-visit screening portion to be completed by the patient and caregiver, and (2) a clinician portion to be completed via clinical interview of the patient and caregiver. If psychotic symptoms are present, an appropriate treatment plan is developed for PDP based on evaluation. CONCLUSIONS: This simple screening tool and treatment guidance offers a practical clinical approach for clinicians in the diagnosis and management of PDP.

Symptoms relating to psychosis are debilitating, progressive, and often emerge in patients with Parkinson's disease. Symptoms of Parkinson's disease psychosis include illusions, a false sense of presence, and hallucinations or delusions or both. While there are established consensus criteria for the diagnosis of Parkinson's disease psychosis, there is currently a lack of simple and standardized criteria for the screening of Parkinson's disease psychosis. This can make it challenging to identify patients who may benefit from treatment for Parkinson's disease psychosis symptoms. A group of clinical experts met to discuss guidance for the screening, clinical diagnosis, and management of Parkinson's disease psychosis. The group identified a paucity of screening tools, weaknesses in existing criteria for diagnosing Parkinson's disease psychosis, and variability in treatment recommendations. The group proposed a screening tool that includes two parts: (1) a simple pre-visit screening to be completed by the patient and caregiver before an appointment, and (2) a clinician portion to be discussed with the patient and caregiver during the appointment. If a patient has hallucinations and/or delusions that require treatment, the proposed guidance includes potential interventions or medications, which were established by review of evidence-based literature and the US Food and Drug Administration guidelines. This provides a quick and relatively simple clinical tool for a patient and caregiver to report symptoms of Parkinson's disease psychosis, and for the clinician to formulate an accurate diagnosis and a decision tree to consider treatment options.

Safety, target engagement, and biomarker effects of bosutinib in dementia with Lewy bodies.

Introduction: Bosutinib, a dual Abelson/Src inhibitor, was investigated in individuals with dementia with Lewy bodies (DLB). Methods: A single site, randomized, double-blind, placebo-controlled study of the effects of oral bosutinib, 100 mg once daily for 12 weeks on primary safety and pharmacokinetics and secondary biomarker outcomes. Results: Twenty-six participants were randomized and included male and female (12:1) in the bosutinib arm and all male (13) in the placebo arm. The average age was 72.9 ± 8.1 (year ± standard deviation). There were no serious adverse events and no dropouts. Bosutinib was measured in the cerebrospinal fluid (CSF) and inhibited Abelson. Bosutinib reduced CSF alpha-synuclein and dopamine catabolism. Discussion: Bosutinib is safe and well tolerated and penetrates the blood-brain barrier to inhibit Abelson and reduce CSF alpha-synuclein and dopamine catabolism, suggesting that bosutinib (100 mg) may be at or near the lowest effective dose in DLB. These results will guide adequately powered studies to determine the efficacy of a dose range of bosutinib and longer treatment in DLB. Highlights: Bosutinib is a dual Abl/Src inhibitor that penetrates the blood brain barrierBosutinib is safe and tolerated in individuals with dementia with Lewy bodiesBosutinib engages its target via inhibition of Abl and SrcBosutinib reduces CSF alpha-synuclein and attenuates breakdown of dopamineBosutinib improves activities of daily living in dementia with Lewy bodies.

Comparative Effectiveness of Carbidopa-Levodopa Enteral Suspension and Deep Brain Stimulation on Parkinson's Disease-Related Pill Burden Reduction in Advanced Parkinson's Disease: A Retrospective Real-World Cohort Study.

INTRODUCTION: In advanced Parkinson's disease (PD), a high pill burden is associated with poor compliance, reduced control of symptoms, and decreased quality of life. We assessed the impact of carbidopa-levodopa enteral suspension (CLES) and deep brain stimulation (DBS) on PD-related pill burden. METHODS: A retrospective cohort analysis was conducted in the IBM MarketScan and Medicare Supplemental databases. Patients with advanced PD, taking only PD medications, and initiating CLES or DBS between 9 January 2015 and 31 July 2019 were identified. CLES patients were matched to DBS patients in a 1:3 ratio based on a propensity score to balance patient characteristics. Pill burden was measured as a 30-day average number of PD-related pills per day and was captured monthly. Pill-free status was evaluated as the percentage of patients receiving CLES or DBS monotherapy. Descriptive statistics were used to compare pill counts and assess the proportion of patients on monotherapy at 6 and 12 months after initiating CLES or DBS. RESULTS: The cohorts included 34 CLES patients matched to 97 DBS patients. A significant reduction in PD-related pill burden was observed at 6 months after initiation of CLES or DBS (∆CLES: -5.62, p < 0.0001; ∆DBS: -1.48, p = 0.0022). PD-related pill burden reduction in CLES patients was significantly greater than in matched DBS patients at 6 months (∆: -4.14, p < 0.0001), which was sustained at 12 months after initiation. At 12 months, nearly three times more CLES patients were pill free than DBS patients (29.41% and 10.31%, respectively, p = 0.0123). CONCLUSIONS: Device-aided therapies such as CLES and DBS are effective in significantly reducing PD-related pill burden. Patients treated with CLES were more likely to achieve pill-free status than patients receiving DBS.

Movement Disorder Specialists Survey Regarding Use of Telemedicine During the COVID-19 Pandemic.

Aim: To assess the overall satisfaction level of movement disorder specialists using a virtual platform during the COVID-19 pandemic. Methods: This was a multicenter cross-sectional survey for a 6-month period during the beginning of the COVID-19 pandemic. Movement disorder specialists, who utilized telehealth visits from March 2020 to August 2020, were included. The study surveys, including provider's satisfaction with the care that they were able to provide and visit quality, were completed by the provider after each visit. Results: A total of 206 visits, provided by movement disorder specialists, were analyzed. Zoom was the most popular platform used for remote visits (70, 34%). A backup platform was not needed in the majority of movement disorder visits (171, 83%). The majority of physicians were very satisfied or satisfied with the care provided (72.9%) and visit quality (61%). Conclusions: The satisfaction level of specialists using telemedicine during COVID-19 was high despite having encounters with elderly patients with cognitive impairment or lacking advanced skills with technology.

CSF MicroRNAs Reveal Impairment of Angiogenesis and Autophagy in Parkinson Disease.

BACKGROUND AND OBJECTIVES: We assessed longitudinal changes in CSF microRNAs (miRNAs) in patients with moderately severe Parkinson disease. METHODS: We used next-generation whole-genome miRNA sequencing to determine CSF miRNA expression in 75 patients with Parkinson disease after single random ascending doses of nilotinib and longitudinal miRNA expression after daily nilotinib, 150 and 300 mg, vs placebo for 1 year. RESULTS: Significant changes in the expression of miRNAs that control genes and pathways that regulate angiogenesis, autophagy, and the blood-brain-barrier components, primarily collagen, were observed over 1 year, suggesting impairment of these pathways in Parkinson progression in these patients. Different miRNAs that indicate activation of genes associated with autophagy flux and clearance and angiogenesis were significantly altered in the nilotinib, 300 mg vs 150 mg, or placebo group, and these changes correlated with clinical outcomes. No changes were observed in miRNAs after a single dose of nilotinib vs placebo. DISCUSSION: This study suggests vascular and autophagy defects in Parkinson progression. Nilotinib, 300 mg, reverses these effects via alteration of miRNA expression, suggesting epigenomic changes that may underlie long-term disease-modifying effects. TRIAL REGISTRATION INFORMATION: Clinical trial registration number: NCT02954978.

Duration and onset of effect of incobotulinumtoxinA for the treatment of blepharospasm in botulinum toxin-naïve subjects.

OBJECTIVE: Blepharospasm is a focal dystonia whereby excessive eyelid muscle contractions cause involuntary eye closure. Botulinum neurotoxin type A (BoNT-A) injections are an approved treatment. This randomized placebo-controlled trial (NCT01896895; EudraCT number 2012-004821-26) assessed the efficacy, safety, and treatment effect duration of incobotulinumtoxinA (Xeomin, Merz Pharmaceuticals GmbH), a BoNT-A formulation without complexing proteins, in BoNT-A-naïve adults with blepharospasm. METHODS: Subjects received incobotulinumtoxinA 50 U, 25 U (total dose) or placebo during a main study period (MP; 6-20 weeks). Patients needing a second injection received incobotulinumtoxinA ≤70 U in an open-label extension period (EP; 6-20 weeks). Treatment effect durations were time from first injection to EP injection or final MP visit and from EP injection to end-of-study visit. Times to effect onset and to waning of effect (MP) were time from injection to first subject-assessed onset effect and time from injection to subject-reported waning of effect, respectively. RESULTS: Of 61 subjects, 39 entered the EP. During the MP, median duration of treatment effect was longer with incobotulinumtoxinA 50 U (20 weeks) versus incobotulinumtoxinA 25 U (11 weeks) or placebo (6 weeks). Median duration of treatment effect was 20 weeks during the EP. Median time to effect onset was 5, 7, and 14 days with 50 U, 25 U, and placebo, respectively (p = .022 for 50 U versus placebo). Median time to waning of treatment effect was comparable between groups. CONCLUSION: Subjects reported an effect onset from 5 days after injection lasting up to 20 weeks (maximum observation period). Data indicate that incobotulinumtoxinA re-treatment of blepharospasm may not be required at fixed 12-week intervals and provide evidence for a patient-tailored approach.

PLAIN LANGUAGE SUMMARYBlepharospasm is a condition in which involuntary contractions of the eyelid muscles cause the eye to close. The condition can be treated with botulinum neurotoxin type A (BoNT-A) injections. This study assessed the duration of effect and time to onset of effect for the BoNT-A formulation incobotulinumtoxinA (Xeomin, Merz Pharmaceuticals GmbH) in adults with blepharospasm. Subjects received a single injection of one of two doses of incobotulinumtoxinA (total dose 25 or 50 U) or placebo and received a second injection of incobotulinumtoxinA only (total dose ≤70 U; the second injection was not compared with placebo) if needed 6­20 weeks after the first injection. After the first injection, the median (mid-point of values from all subjects) duration of treatment effect was longer with the higher incobotulinumtoxinA dose (20 weeks) than with the lower dose (11 weeks) and was longer with both incobotulinumtoxinA doses than with placebo (6 weeks). After the second incobotulinumtoxinA injection, the median duration of treatment effect was 20 weeks. The time to onset of effect was quicker with both incobotulinumtoxinA doses (5 and 7 days for the higher and lower doses, respectively) than with placebo (14 days) and the difference was statistically significant for the higher incobotulinumtoxinA dose compared with placebo. The time to waning of treatment effect was similar for the two incobotulinumtoxinA doses and placebo. This study shows that incobotulinumtoxinA is an effective treatment for blepharospasm, with a fast onset of action. In addition, the effects of one injection can last for up to 20 weeks.

Combination targeting of subthalamic nucleus and ventral intermediate thalamic nucleus with a single trajectory in deep brain stimulation for tremor-dominant Parkinson's disease.

Deep brain stimulation (DBS) has traditionally been used to target the subthalamic nucleus (STN) or globus pallidus internus (GPi) to treat Parkinson's disease (PD) and the ventral intermediate thalamic nucleus (VIM) to treat essential tremor (ET). Recent case reports have described targeting both the STN and VIM with a single trajectory and electrode to treat patients with tremor-dominant PD, yet outcome data for this procedure remains sparse. Our objective is to determine the safety and efficacy of combination STN-VIM DBS. We conducted a single-center retrospective case series of all patients who underwent combined STN-VIM DBS. Demographic, perioperative, and outcome data, including Unified Parkinson Disease Rating Scale-III (UPDRS) and tremor scores (OFF-medication), and levodopa equivalent daily dose (LEDD), were collected and analyzed. Nineteen patients underwent this procedure. Patients were 89% male and 11% female, with a mean age of 63.6 years. Mean preoperative UPDRS was 24.1, and LEDD was 811.8. At a mean follow-up of 33.8 months, UPDRS and LEDD decreased by an average of 9.2 (38.2%) and 326.3 (40.2%), respectively. Tremor scores decreased by 4.9 (59.0%), and 58% were able to decrease total medication burden. One patient developed transient left-sided weakness, yielding a complication rate of 5.3%. Combined targeting of STN and VIM thalamus via a single frontal trajectory for tremor-dominant Parkinson's Disease results in similar UPDRS outcomes to STN DBS and improved control of tremor symptoms. Larger multicenter studies are necessary to validate this as the optimal DBS target for tremor-dominant PD.

QTc Interval Prolongation with Therapies Used to Treat Patients with Parkinson's Disease Psychosis: A Narrative Review.

In addition to the classic motor symptoms of Parkinson's disease (PD), people with PD frequently experience nonmotor symptoms that can include autonomic dysfunction and neuropsychiatric symptoms such as PD psychosis (PDP). Common patient characteristics, including older age, use of multiple medications, and arrhythmias, are associated with increased risk of corrected QT interval (QTc) prolongation, and treatments for PDP (antipsychotics, dementia medications) may further increase this risk. This review evaluates how medications used to treat PDP affect QTc interval from literature indexed in the PubMed and Embase databases. Although not indicated for the treatment of psychosis, dementia therapies such as donepezil, rivastigmine, memantine, and galantamine are often used with or without antipsychotics and have minimal effects on QTc interval. Among the antipsychotics, data suggesting clinically meaningful QTc interval prolongation are limited. However, many antipsychotics have other safety concerns. Aripiprazole, olanzapine, and risperidone negatively affect motor function and are not recommended for PDP. Quetiapine is often sedating, can exacerbate underlying neurogenic orthostatic hypotension, and may prolong the QTc interval. Pimavanserin was approved by the US Food and Drug Administration (FDA) in 2016 and remains the only FDA-approved medication available to treat hallucinations and delusions associated with PDP. However, pimavanserin can increase QTc interval by approximately 5-8 ms. The potential for QTc prolongation should be considered in patients with symptomatic cardiac arrhythmias and those receiving QT-prolonging medications. In choosing a medication to treat PDP, expected efficacy must be balanced with potential safety concerns for individual patients.

A Pragmatic Approach to the Perioperative Management of Parkinson's Disease.

Patients with Parkinson's disease (PD) may undergo several elective and emergency surgeries. Motor fluctuations, the presence of a wide range of non-motor symptoms (NMS), and the use of several medications, often not limited to dopaminergic agents, make the perioperative management of PD challenging. However, the literature on perioperative management of PD is sparse. In this descriptive review article, we comprehensively discuss the issues in the pre-, intra-, and postoperative phases which may negatively affect the PD patients and discuss the approach to their prevention and management. The major preoperative challenges include accurate medication reconciliation and administration of the dopaminergic medications during the nil per os (NPO) state. While the former can be addressed with staff education and PD-specific admission protocols, knowledge of non-oral formulations of dopaminergic agents (apomorphine, inhalational levodopa, and rotigotine transdermal patch) is the key to the management of the Parkinsonian symptoms in NPO state. Deep brain stimulation (DBS) devices should be turned off to avert potential electromagnetic interference with surgical appliances. Choosing the appropriate anesthesia and avoiding and managing respiratory issues and dysautonomia are the major intraoperative challenges. Timely reinitiation of dopaminergic medications, adequate management of pain, nausea, and vomiting, and prevention of postoperative infections and delirium are the postoperative challenges. Overall, a multidisciplinary approach is pivotal to prevent and manage the perioperative complications in PD. Administration of anti-Parkinson medications during NPO state, prevention of anesthesia-related complications, and timely rehabilitation remain the key to healthy surgical outcomes.