Optimization of inpatient medication administration among persons with Parkinson's disease: recommendations on pharmacy technology and workflow.

Individuals with Parkinson's disease (PD) are vulnerable during hospitalizations due to the underlying complexities o1f symptoms, and acute illness or medication changes often lead to decompensation. Complications during hospitalizations are often due to worsening motor and nonmotor symptoms and commonly result from inaccurate medication regimens. Although the accuracy of medication administration relies on an interplay of factors, including patient status, transitions of care, coordination between the hospital prescriber and outpatient neurologist, etc., hospital pharmacists play an integral role in pharmacotherapy. The main aspects of pharmacy strategies aim to achieve timely administration of levodopa-containing medications, reduction of substitution and omissions of antiparkinsonian medications, and avoidance of antidopaminergic medications. This paper highlights critical areas for improvement and recommendations to minimize the impact of other factors from the pharmacy standpoint.

MRI-based multivariate gray matter volumetric distance for predicting motor symptom progression in Parkinson's disease.

While Parkinson's disease (PD)-related neurodegeneration is associated with structural changes in the brain, conventional magnetic resonance imaging (MRI) has proven less effective for clinical diagnosis due to its inability to reliably identify subtle changes early in the disease course. In this study, we aimed to develop a structural MRI-based biomarker to predict the rate of progression of motor symptoms in the early stages of PD. The study included 88 patients with PD and 120 healthy controls from the Parkinson's Progression Markers Initiative database; MRI at baseline and motor symptom scores assessed using the MDS-UPDRS-III at two time points (baseline and 48 months) were selected. Group-level volumetric analyses revealed that the volumetric reductions in the left striatum were associated with the decline in motor functioning. Then, we developed a patient-specific multivariate gray matter volumetric distance and demonstrated that it could significantly predict changes in motor symptom scores (P < 0.05). Further, we classified patients as relatively slower and faster progressors with 89% accuracy using a support vector machine classifier. Thus, we identified a promising structural MRI-based biomarker for predicting the rate of progression of motor symptoms and classifying patients based on motor symptom severity.

The Parkinson's disease waiting room of the future: measurements, not magazines.

Utilizing technology to precisely quantify Parkinson's disease motor symptoms has evolved over the past 50 years from single point in time assessments using traditional biomechanical approaches to continuous monitoring of performance with wearables. Despite advances in the precision, usability, availability and affordability of technology, the "gold standard" for assessing Parkinson's motor symptoms continues to be a subjective clinical assessment as none of these technologies have been fully integrated into routine clinical care of Parkinson's disease patients. To facilitate the integration of technology into routine clinical care, the Develop with Clinical Intent (DCI) model was created. The DCI model takes a unique approach to the development and integration of technology into clinical practice by focusing on the clinical problem to be solved by technology rather than focusing on the technology and then contemplating how it could be integrated into clinical care. The DCI model was successfully used to develop the Parkinson's disease Waiting Room of the Future (WROTF) within the Center for Neurological Restoration at the Cleveland Clinic. Within the WROTF, Parkinson's disease patients complete the self-directed PD-Optimize application on an iPad. The PD-Optimize platform contains cognitive and motor assessments to quantify PD symptoms that are difficult and time-consuming to evaluate clinically. PD-Optimize is completed by the patient prior to their medical appointment and the results are immediately integrated into the electronic health record for discussion with the movement disorder neurologist. Insights from the clinical use of PD-Optimize has spurred the development of a virtual reality technology to evaluate instrumental activities of daily living in PD patients. This new technology will undergo rigorous assessment and validation as dictated by the DCI model. The DCI model is intended to serve as a health enablement roadmap to formalize and accelerate the process of bringing the advantages of cutting-edge technology to those who could benefit the most: the patient.

A novel MRI-based volumetric index for monitoring the motor symptoms in Parkinson's disease.

BACKGROUND: Conventional MRI scans have limited usefulness in monitoring Parkinson's disease as they typically do not show any disease-specific brain abnormalities. This study aimed to identify an imaging biomarker for tracking motor symptom progression by using a multivariate statistical approach that can combine gray matter volume information from multiple brain regions into a single score specific to each PD patient. METHODS: A cohort of 150 patients underwent MRI at baseline and had their motor symptoms tracked for up to 10 years using MDS-UPDRS-III, with motor symptoms focused on total and subscores, including rigidity, bradykinesia, postural instability, and gait disturbances, resting tremor, and postural-kinetic tremor. Gray matter volume extracted from MRI data was summarized into a patient-specific summary score using Mahalanobis distance, MGMV. MDS-UPDRS-III's progression and its association with MGMV were modeled via linear mixed-effects models over 5- and 10-year follow-up periods. RESULTS: Over the 5-year follow-up, there was a significant increase (P < 0.05) in MDS-UPDRS-III total and subscores, except for postural-kinetic tremor. Over the 10-year follow-up, all MDS-UPDRS-III scores increased significantly (P < 0.05). A higher baseline MGMV was associated with a significant increase in MDS-UPDRS-III total, bradykinesia, postural instability and gait disturbances, and resting tremor (P < 0.05) over the 5-year follow-up, but only with total, bradykinesia, and postural instability and gait disturbances during the 10-year follow-up (P < 0.05). CONCLUSIONS: Higher MGMV scores were linked to faster motor symptom progression, suggesting it could be a valuable marker for clinicians monitoring Parkinson's disease over time.

End of life care of hospitalized patients with Parkinson disease: a retrospective analysis and brief review.

Background: Towards the end of life (EOL), persons with parkinsonism (PwP) have complex needs and can present with unique palliative care (PC) challenges. There are no widely accepted guidelines to aid neurologists, hospitalists, or PC clinicians in managing the symptoms of PwP at EOL. We examined a population of PwP at EOL, aiming to describe trends of in-hospital management and utilization of PC services. Methods: All PwP admitted to two hospitals during 2018 (N = 727) were examined retrospectively, assessing those who died in hospital or were discharged with hospice (EOL group, N = 35) and comparing them to the main cohort. Their demographics, clinical data, engagement of multidisciplinary and palliative services, code status changes, invasive care, frequency of admissions, and medication administration were assessed. Results: Among the EOL group, 8 expired in hospital, and 27 were discharged to hospice. Forty-six percent of EOL patients received a PC consultation during their admission. The median interval from admission to death was 37 days. Seventy-seven percent had a full code status on admission. Compared to hospice patients, those who expired in hospital had higher rates of invasive procedures and intensive care unit transfers (41% vs. 75%, in both variables), and lower rates of PC involvement (52% vs. 25%). The transition of code status change for the EOL group from Full code to Do Not Resuscitate (DNR) occurred at a median 4-5 days from admission. For patients that passed in the hospital, the median days from transition of code status to death was 0(IQR 0-1). Levodopa dose deviations were frequent in both EOL and non-EOL group, but contraindicated medications were infrequently administered (11% in EOL group vs. 9% in non-EOL group). Conclusion: Our data suggest a low utilization of PC services and delayed discussions of goals of care. More work is needed to raise awareness of inpatient teams managing PwP regarding the unique but common challenges facing PwP with advanced disease. A brief narrative review summarizing the suggested management of symptoms common to hospitalized PwP near EOL is provided.

A Randomized Clinical Trial to Evaluate a Digital Therapeutic to Enhance Gait Function in Individuals With Parkinson's Disease.

BACKGROUND: Postural instability and gait dysfunction (PIGD) is a cardinal symptom of Parkinson's disease (PD) and is exacerbated under dual-task conditions. Dual-task training (DTT), enhances gait performance, however it is time and cost intensive. Digitizing DTT via the Dual-task Augmented Reality Treatment (DART) platform can expand the availability of an effective intervention to address PIGD. OBJECTIVE: The aim of this project was to evaluate DART in the treatment of PIGD in people with PD compared to a Traditional DTT intervention. It was hypothesized that both groups would exhibit significant improvements in gait, and the improvements for the DART group would be non-inferior to Traditional DTT. METHODS: A single-blind randomized controlled trial was conducted with 47 PD participants with PIGD. Both groups completed 16 therapeutic sessions over 8 weeks; the DART platform delivered DTT via the Microsoft HoloLens2. Primary outcomes included clinical ratings and single- and dual-task gait biomechanical outcomes. RESULTS: Clinical measures of PD symptoms remained stable for DART and Traditional DTT groups. However, both groups exhibited a significant increase in gait velocity, cadence, and step length during single- and multiple dual-task conditions following the interventions. Improvements in gait velocity in the DART group were non-inferior to Traditional DTT under the majority of conditions. CONCLUSION: Non-inferior improvements in gait parameters across groups provides evidence of the DART platform being an effective digital therapeutic capable of improving PIGD. Effective digital delivery of DTT has the potential to increase use and accessibility to a promising, yet underutilized and difficult to administer, intervention for PIGD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Dual-task Augmented Reality Treatment for Parkinson's Disease (DART) NCT04634331; posted November 18, 2020.

Establishing a framework for quality of inpatient care for Parkinson's disease: A study on inpatient medication administration.

BACKGROUND: The complexity of antiparkinsonian medications makes patients vulnerable to medication deviations. This study examines the frequency and outcomes of deviations between outpatient and inpatient medication administrations in patients with Parkinson's disease (PD). METHODS: We included hospital admissions of patients with PD during a 12-month period at the Cleveland Clinic Main and Fairview campuses. Outpatient regimens were compared with hospital medication administration records to establish rates of deviations in terms of levodopa equivalent daily dose (LEDD) difference, timing deviations/omissions of time-critical medications, substitution of levodopa compounds, and administration of antidopaminergic medications. Logistic regression analyses were used to investigate associations with length of stay (LOS), readmission rates, and mortality. RESULTS: The study included 492 patients with 725 admissions. Of those on time-critical medications, 43% had a LEDD deviation and 19% had levodopa formulation substitutions. Of the admission days with known outpatient timing regimens, 47% had an average deviation of more than 30 min and 22% had at least one missed levodopa dose. LOS was longer with each additional day of over-dose (4%), under-dose (14%), missed dose (21%), timing deviation (15%) and substitution (19%), (all p < 0.0001). Administration of antidopaminergic medications (9.9% of admissions) was associated with increased 30-day readmission/death (OR 1.85, p = 0.041), 90-day mortality (OR 2.2, p = 0.018), and LOS (7.6 vs. 3.8 days, p < 0.0001). LEDD underdose was associated with 30-day readmission/death (OR 1.78, p = 0.025) and 90-day mortality (OR 1.14, CI 1.05-1.24, p = 0.002). CONCLUSIONS: Deviations between outpatient and hospital regimens, and administration of antidopaminergic medications, were associated with poor outcomes.

Interim Safety Profile From the Feasibility Study of the BrainGate Neural Interface System.

BACKGROUND AND OBJECTIVES: Brain-computer interfaces (BCIs) are being developed to restore mobility, communication, and functional independence to people with paralysis. Though supported by decades of preclinical data, the safety of chronically implanted microelectrode array BCIs in humans is unknown. We report safety results from the prospective, open-label, nonrandomized BrainGate feasibility study (NCT00912041), the largest and longest-running clinical trial of an implanted BCI. METHODS: Adults aged 18-75 years with quadriparesis from spinal cord injury, brainstem stroke, or motor neuron disease were enrolled through 7 clinical sites in the United States. Participants underwent surgical implantation of 1 or 2 microelectrode arrays in the motor cortex of the dominant cerebral hemisphere. The primary safety outcome was device-related serious adverse events (SAEs) requiring device explantation or resulting in death or permanently increased disability during the 1-year postimplant evaluation period. The secondary outcomes included the type and frequency of other adverse events and the feasibility of the BrainGate system for controlling a computer or other assistive technologies. RESULTS: From 2004 to 2021, 14 adults enrolled in the BrainGate trial had devices surgically implanted. The average duration of device implantation was 872 days, yielding 12,203 days of safety experience. There were 68 device-related adverse events, including 6 device-related SAEs. The most common device-related adverse event was skin irritation around the percutaneous pedestal. There were no safety events that required device explantation, no unanticipated adverse device events, no intracranial infections, and no participant deaths or adverse events resulting in permanently increased disability related to the investigational device. DISCUSSION: The BrainGate Neural Interface system has a safety record comparable with other chronically implanted medical devices. Given rapid recent advances in this technology and continued performance gains, these data suggest a favorable risk/benefit ratio in appropriately selected individuals to support ongoing research and development. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT00912041. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that the neurosurgically placed BrainGate Neural Interface system is associated with a low rate of SAEs defined as those requiring device explantation, resulting in death, or resulting in permanently increased disability during the 1-year postimplant period.

Standardizing default electronic health record tools to improve safety for hospitalized patients with Parkinson's disease.

Electronic Health Record (EHR) systems are often configured to address challenges and improve patient safety for persons with Parkinson's disease (PWP). For example, EHR systems can help identify Parkinson's disease (PD) patients across the hospital by flagging a patient's diagnosis in their chart, preventing errors in medication and dosing through the use of clinical decision support, and supplementing staff education through care plans that provide step-by-step road maps for disease-based care of a specific patient population. However, most EHR-based solutions are locally developed and, thus, difficult to scale widely or apply uniformly across hospital systems. In 2020, the Parkinson's Foundation, a national and international leader in PD research, education, and advocacy, and Epic, a leading EHR vendor with more than 35% market share in the United States, launched a partnership to reduce risks to hospitalized PWP using standardized EHR-based solutions. This article discusses that project which included leadership from physician informaticists, movement disorders specialists, hospital quality officers, the Parkinson's Foundation and members of the Parkinson's community. We describe the best practice solutions developed through this project. We highlight those that are currently available as standard defaults or options within the Epic EHR, discuss the successes and limitations of these solutions, and consider opportunities for scalability in environments beyond a single EHR vendor. The Parkinson's Foundation and Epic launched a partnership to develop best practice solutions in the Epic EHR system to improve safety for PWP in the hospital. The goal of the partnership was to create the EHR tools that will have the greatest impact on outcomes for hospitalized PWP.

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.

Digitizing a Therapeutic: Development of an Augmented Reality Dual-Task Training Platform for Parkinson's Disease.

Augmented reality (AR) may be a useful tool for the delivery of dual-task training. This manuscript details the development of the Dual-task Augmented Reality Treatment (DART) platform for individuals with Parkinson's disease (PD) and reports initial feasibility, usability, and efficacy of the DART platform in provoking dual-task interference in individuals with PD. The DART platform utilizes the head-mounted Microsoft HoloLens2 AR device to deliver concurrent motor and cognitive tasks. Biomechanical metrics of gait and cognitive responses are automatically computed and provided to the supervising clinician. To assess feasibility, individuals with PD (N = 48) completed a bout of single-task and dual-task walking using the DART platform. Usability was assessed by the System Usability Scale (SUS). Dual-task interference was assessed by comparing single-task walking and walking during an obstacle course while performing a cognitive task. Average gait velocity decreased from 1.06 to 0.82 m/s from single- to dual-task conditions. Mean SUS scores were 81.3 (11.3), which placed the DART in the "good" to "excellent" category. To our knowledge, the DART platform is the first to use a head-mounted AR system to deliver a dual-task paradigm and simultaneously provide biomechanical data that characterize cognitive and motor performance. Individuals with PD were able to successfully use the DART platform with satisfaction, and dual-task interference was provoked. The DART platform should be investigated as a platform to treat dual-task declines associated with PD.

Directional Stimulation in Parkinson's Disease and Essential Tremor: The Cleveland Clinic Experience.

OBJECTIVE: To assess use of directional stimulation in Parkinson's disease and essential tremor patients programmed in routine clinical care. MATERIALS AND METHODS: Patients with Parkinson's disease or essential tremor implanted at Cleveland Clinic with a directional deep brain stimulation (DBS) system from November 2017 to October 2019 were included in this retrospective case series. Omnidirectional was compared against directional stimulation using therapeutic current strength, therapeutic window percentage, and total electrical energy delivered as outcome variables. RESULTS: Fifty-seven Parkinson's disease patients (36 males) were implanted in the subthalamic nucleus (105 leads) and 33 essential tremor patients (19 males) were implanted in the ventral intermediate nucleus of the thalamus (52 leads). Seventy-four percent of patients with subthalamic stimulation (65% of leads) and 79% of patients with thalamic stimulation (79% of leads) were programmed with directional stimulation for their stable settings. Forty-six percent of subthalamic leads and 69% of thalamic leads were programmed on single segment activation. There was no correlation between the length of microelectrode trajectory through the STN and use of directional stimulation. CONCLUSIONS: Directional programming was more common than omnidirectional programming. Substantial gains in therapeutic current strength, therapeutic window, and total electrical energy were found in subthalamic and thalamic leads programmed on directional stimulation.

North American survey on impact of the COVID-19 pandemic shutdown on DBS care.

BACKGROUND: The initial COVID-19 pandemic shutdown led to the canceling of elective surgeries throughout most of the USA and Canada. OBJECTIVE: This survey was carried out on behalf of the Parkinson Study Group (PSG) to understand the impact of the shutdown on deep brain stimulation (DBS) practices in North America. METHODS: A survey was distributed through RedCap® to the members of the PSG Functional Neurosurgical Working Group. Only one member from each site was asked to respond to the survey. Responses were collected from May 15 to June 6, 2020. RESULTS: Twenty-three sites participated; 19 (83%) sites were from the USA and 4 (17%) from Canada. Twenty-one sites were academic medical centers. COVID-19 associated DBS restrictions were in place from 4 to 16 weeks. One-third of sites halted preoperative evaluations, while two-thirds of the sites offered limited preoperative evaluations. Institutional policy was the main contributor for the reported practice changes, with 87% of the sites additionally reporting patient-driven surgical delays secondary to pandemic concerns. Pre-post DBS associated management changes affected preoperative assessments 96%; electrode placement 87%; new implantable pulse generator (IPG) placement 83%; IPG replacement 65%; immediate postoperative DBS programming 74%; and routine DBS programming 91%. CONCLUSION: The COVID-19 pandemic related shutdown resulted in DBS practice changes in almost all North American sites who responded to this large survey. Information learned could inform development of future contingency plans to reduce patient delays in care under similar circumstances.

The Neural Representation of Force across Grasp Types in Motor Cortex of Humans with Tetraplegia.

Intracortical brain-computer interfaces (iBCIs) have the potential to restore hand grasping and object interaction to individuals with tetraplegia. Optimal grasping and object interaction require simultaneous production of both force and grasp outputs. However, since overlapping neural populations are modulated by both parameters, grasp type could affect how well forces are decoded from motor cortex in a closed-loop force iBCI. Therefore, this work quantified the neural representation and offline decoding performance of discrete hand grasps and force levels in two human participants with tetraplegia. Participants attempted to produce three discrete forces (light, medium, hard) using up to five hand grasp configurations. A two-way Welch ANOVA was implemented on multiunit neural features to assess their modulation to force and grasp Demixed principal component analysis (dPCA) was used to assess for population-level tuning to force and grasp and to predict these parameters from neural activity. Three major findings emerged from this work: (1) force information was neurally represented and could be decoded across multiple hand grasps (and, in one participant, across attempted elbow extension as well); (2) grasp type affected force representation within multiunit neural features and offline force classification accuracy; and (3) grasp was classified more accurately and had greater population-level representation than force. These findings suggest that force and grasp have both independent and interacting representations within cortex, and that incorporating force control into real-time iBCI systems is feasible across multiple hand grasps if the decoder also accounts for grasp type.

Neural Representation of Observed, Imagined, and Attempted Grasping Force in Motor Cortex of Individuals with Chronic Tetraplegia.

Hybrid kinetic and kinematic intracortical brain-computer interfaces (iBCIs) have the potential to restore functional grasping and object interaction capabilities in individuals with tetraplegia. This requires an understanding of how kinetic information is represented in neural activity, and how this representation is affected by non-motor parameters such as volitional state (VoS), namely, whether one observes, imagines, or attempts an action. To this end, this work investigates how motor cortical neural activity changes when three human participants with tetraplegia observe, imagine, and attempt to produce three discrete hand grasping forces with the dominant hand. We show that force representation follows the same VoS-related trends as previously shown for directional arm movements; namely, that attempted force production recruits more neural activity compared to observed or imagined force production. Additionally, VoS-modulated neural activity to a greater extent than grasping force. Neural representation of forces was lower than expected, possibly due to compromised somatosensory pathways in individuals with tetraplegia, which have been shown to influence motor cortical activity. Nevertheless, attempted forces (but not always observed or imagined forces) could be decoded significantly above chance, thereby potentially providing relevant information towards the development of a hybrid kinetic and kinematic iBCI.

Tremor in chronic inflammatory demyelinating polyneuropathy: Proof of unifying network model for dystonia.

Traditional hypotheses for the pathogenesis of dystonia, the third most common movement disorder, have focused primarily on the basal ganglia. Contemporary theories have emphasized the role of the cerebellum. The modulation of peripheral proprioception also affects dystonia. We proposed a unifying network model for dystonia where the cerebellum, basal ganglia, and peripheral proprioception are connected in a circuit that forms the neural integrator network, ensuring steady position. We suggested that impairment anywhere along this circuit leads to common phenomenology-slow drifts followed by corrective movements, resembling dystonic tremor. We tested this concept in a patient with chronic inflammatory demyelinating polyneuropathy with resulting abnormal proprioception. Quantitative assessment of tremor in this patient revealed drifts in limb position followed by corrective movements and superimposed sinusoidal oscillations-consistent with neural integrator dysfunction. This unique case of chronic inflammatory demyelinating polyneuropathy describes the role of proprioception on the unifying network model for dystonia.