Opicapone in UK clinical practice: effectiveness, safety and cost analysis in patients with Parkinson's disease.

Aim: This subanalysis of the OPTIPARK study aimed to confirm the effectiveness and safety of opicapone in patients with Parkinson's disease and motor fluctuations in clinical practice specifically in the UK and to assess the impact of opicapone on treatment costs. Methods: Patients received opicapone added to levodopa for 6 months. Clinical outcomes were assessed at 3 and 6 months and treatment costs at 6 months. Results: Most patients' general condition improved at 3 months, with sustained improvements reported at 6 months. Opicapone improved motor and non-motor symptoms at both timepoints, was generally well tolerated and reduced total treatment costs by GBP 3719. Conclusion: Opicapone added to levodopa resulted in clinical improvements and reduced treatment costs across UK clinical practice.

Patients with Parkinson's disease (PD) often experience motor fluctuations (reduced and variable response to medication) following prolonged treatment with levodopa, which is currently the most effective treatment for the symptoms of PD. Opicapone has been developed for use in combination with levodopa to reduce the occurrence of motor fluctuations and was shown to be effective in two large clinical trials. This study describes the effectiveness, safety and cost-saving impact of opicapone when used to treat patients with PD and motor fluctuations across everyday clinical practice in the UK. Six months' treatment with opicapone was generally well tolerated, resulted in an improvement of the patients' overall PD condition and reduced treatment costs. Clinical trial registration: Registered in July 2016 at NCT02847442 (ClinicalTrial.gov).

Assessment of real life eating difficulties in Parkinson's disease patients by measuring plate to mouth movement elongation with inertial sensors.

Parkinson's disease (PD) is a neurodegenerative disorder with both motor and non-motor symptoms. Despite the progressive nature of PD, early diagnosis, tracking the disease's natural history and measuring the drug response are factors that play a major role in determining the quality of life of the affected individual. Apart from the common motor symptoms, i.e., tremor at rest, rigidity and bradykinesia, studies suggest that PD is associated with disturbances in eating behavior and energy intake. Specifically, PD is associated with drug-induced impulsive eating disorders such as binge eating, appetite-related non-motor issues such as weight loss and/or gain as well as dysphagia-factors that correlate with difficulties in completing day-to-day eating-related tasks. In this work we introduce Plate-to-Mouth (PtM), an indicator that relates with the time spent for the hand operating the utensil to transfer a quantity of food from the plate into the mouth during the course of a meal. We propose a two-step approach towards the objective calculation of PtM. Initially, we use the 3D acceleration and orientation velocity signals from an off-the-shelf smartwatch to detect the bite moments and upwards wrist micromovements that occur during a meal session. Afterwards, we process the upwards hand micromovements that appear prior to every detected bite during the meal in order to estimate the bite's PtM duration. Finally, we use a density-based scheme to estimate the PtM durations distribution and form the in-meal eating behavior profile of the subject. In the results section, we provide validation for every step of the process independently, as well as showcase our findings using a total of three datasets, one collected in a controlled clinical setting using standardized meals (with a total of 28 meal sessions from 7 Healthy Controls (HC) and 21 PD patients) and two collected in-the-wild under free living conditions (37 meals from 4 HC/10 PD patients and 629 meals from 3 HC/3 PD patients, respectively). Experimental results reveal an Area Under the Curve (AUC) of 0.748 for the clinical dataset and 0.775/1.000 for the in-the-wild datasets towards the classification of in-meal eating behavior profiles to the PD or HC group. This is the first work that attempts to use wearable Inertial Measurement Unit (IMU) sensor data, collected both in clinical and in-the-wild settings, towards the extraction of an objective eating behavior indicator for PD.

Assessment of cutaneous axon-reflex responses to evaluate functional integrity of autonomic small nerve fibers.

Cutaneous autonomic small nerve fibers encompass unmyelinated C-fibers and thinly myelinated Aδ-fibers, which innervate dermal vessels (vasomotor fibers), sweat glands (sudomotor fibers), and hair follicles (pilomotor fibers). Analysis of their integrity can capture early pathology in autonomic neuropathies such as diabetic autonomic neuropathy or peripheral nerve inflammation due to infectious and autoimmune diseases. Furthermore, intraneural deposition of alpha-synuclein in synucleinopathies such as Parkinson's disease can lead to small fiber damage. Research indicated that detection and quantitative analysis of small fiber pathology might facilitate early diagnosis and initiation of treatment. While autonomic neuropathies show substantial etiopathogenetic heterogeneity, they have in common impaired functional integrity of small nerve fibers. This impairment can be evaluated by quantitative analysis of axonal responses to iontophoretic application of adrenergic or cholinergic agonists to the skin. The axon-reflex can be elicited in cholinergic sudomotor fibers to induce sweating and in cholinergic vasomotor fibers to induce vasodilation. Currently, only few techniques are available to quantify axon-reflex responses, the majority of which is limited by technical demands or lack of validated analysis protocols. Function of vasomotor small fibers can be analyzed using laser Doppler flowmetry, laser Doppler imaging, and laser speckle contrast imaging. Sudomotor function can be assessed using quantitative sudomotor axon-reflex test, silicone imprints, and quantitative direct and indirect testing of sudomotor function. More recent advancements include analysis of piloerection (goose bumps) following stimulation of adrenergic small fibers using pilomotor axon-reflex test. We provide a review of the current literature on axon-reflex tests in cutaneous autonomic small fibers.

Restless legs syndrome - the under-recognised non-motor burden: a questionnaire-based cohort study.

Objectives: Non-motor symptoms (NMS) range from neuropsychiatric to pain and are an important but underexplored feature of restless legs syndrome (RLS). There are currently no tools available which enable the holistic assessment of NMS in RLS in clinical practice. The primary aim of this study was to systematically assess NMS prevalence and burden in patients with RLS using the NMS Questionnaire (NMSQuest) validated for Parkinson's disease. Methods: Patients with idiopathic RLS according to the criteria of the international RLS study group (IRLSSG) were included. Patients underwent a physical examination and clinical interview as well as completed the NMS Questionnaire and the international restless legs syndrome study group (IRLSSG) rating scale. Results: Seventy-four patients with primary RLS were included (mean age 64.6 ± 14.4 years, 62.2% female, mean disease duration 23.5 ± 17.8 years, mean Levodopa equivalent daily dose 63.3 ± 67.4 mg). On average patients reported an IRLSSG rating scale score of 24.8 ± 8.2 (maximum 40) and NMSQuest score of 9.9 ± 5.0 (maximum 30). Patients reported a minimum of two NMS with the majority (39.2%) reporting a moderate NMS burden, followed by severe (28.4%) and very severe (17.6%) burden. The most frequent NMS were insomnia (89.2%) followed by nocturia (70.3%), feeling sad (59.5%), forgetfulness (54.1%), urgency (47.3%), feeling anxious (43.2%), unexplained pain (41.9%), difficulty concentrating (40.5%) and dizziness (40.5%). There were no significant differences in NMSQuest total scores according to disease duration and gender (p = 0.739, p = 0.849). Conclusion: In conclusion, this study is one of the first to address NMS in RLS systematically and the data underlines the need to holistically assess NMS in RLS in order to deliver true value-based healthcare for these patients.

Profiling individual clinical responses by high-frequency serum neurofilament assessment in MS.

Objective: To evaluate individual neurofilament light chain (NfL) variation over the time of disease course and the potential of NfL measurement to predict treatment response in patients with MS. Methods: We investigated 15 patients with MS after immune reconstitution treatment with alemtuzumab (ATZ). Monthly serum NfL (sNFL) measurements were correlated with Expanded Disability Status Scale (EDSS), MRI, and relapse activity over an observational period of up to 102 months. Results: Before ATZ, sNfL was significantly increased in correlation with previous relapse/MRI activity. After ATZ, sNfL decreased quickly within the first 6 months. In patients classified as NEDA-3, sNfL declined and persisted at an individual low steady-state level of <8 pg/mL. During follow-up, 34 sNfL peaks with a >20 fold increase could be detected, which were associated with clinical or MRI disease activity. Even patient-reported relapse-suspicious symptoms, which have not been confirmed because relapses were accompanied by sNfL, increase, proposing sNfL assessment as a marker for relapse activity. sNfL started to increase earliest 5 months before, peaked at clinical onset, and recovered within 4-5 months. sNfL presented at higher levels in active patients requiring ATZ retreatment compared with responder patients. During 2 documented pregnancies, sNfL was at a low level, whereas a postpartum transient sNfL increase was seen without any signs of activity. Conclusions: This study applied a long-term high-frequency sNfL assessment in an ATZ-treated cohort, allowing a holistic profiling on the individual level and highlighted that sNfL can eminently complement the individual clinical and MRI monitoring in clinical practice.

Correlation of Quantitative Motor State Assessment Using a Kinetograph and Patient Diaries in Advanced PD: Data from an Observational Study.

INTRODUCTION: Effective management and development of new treatment strategies for response fluctuations in advanced Parkinson's disease (PD) largely depends on clinical rating instruments such as the PD home diary. The Parkinson's kinetigraph (PKG) measures movement accelerations and analyzes the spectral power of the low frequencies of the accelerometer data. New algorithms convert each hour of continuous PKG data into one of the three motor categories used in the PD home diary, namely motor Off state and On state with and without dyskinesia. OBJECTIVE: To compare quantitative motor state assessment in fluctuating PD patients using the PKG with motor state ratings from PD home diaries. METHODS: Observational cohort study on 24 in-patients with documented motor fluctuations who completed diaries by rating motor Off, On without dyskinesia, On with dyskinesia, and asleep for every hour for 5 consecutive days. Simultaneously collected PKG data (recorded between 6 am and 10 pm) were analyzed and calibrated to the patient's individual thresholds for Off and dyskinetic state by novel algorithms classifying the continuous accelerometer data into these motor states for every hour between 6 am and 10 pm. RESULTS: From a total of 2,040 hours, 1,752 hours (87.4%) were available for analyses from calibrated PKG data (7.5% sleeping time and 5.1% unclassified motor state time were excluded from analyses). Distributions of total motor state hours per day measured by PKG showed moderate-to-strong correlation to those assessed by diaries for the different motor states (Pearson's correlations coefficients: 0.404-0.658), but inter-rating method agreements on the single-hour-level were only low-to-moderate (Cohen's κ: 0.215-0.324). CONCLUSION: The PKG has been shown to capture motor fluctuations in patients with advanced PD. The limited correlation of hour-to-hour diary and PKG recordings should be addressed in further studies.

Quantitative assessment of non-motor fluctuations in Parkinson's disease using the Non-Motor Symptoms Scale (NMSS).

Data on frequency, severity and correlations of NMS with motor complications are only available for a limited number of NMS. The NMS Scale (NMSS) is a validated tool to assess a broad range of NMS, which has not been used in NMS fluctuations. We assessed fluctuations of a broad range of non-motor symptom (NMS) for a 1-month time period in fluctuating Parkinson's disease (PD) in a multicenter cross-sectional study using the NMSS assessing NMS in motor On (NMSSOn) and Off state (NMSSOff) combined with clinical NMS and motor function scoring in 100 fluctuating PD patients. ΔNMSSOn/Off was defined as the differences of NMSS scores between On and Off. Complete NMSS datasets were available from 73 patients (53 % men; age: 68.2 ± 9.7 years) with mean total NMSS score in On state of 41.5 ± 37.6 and in Off state of 75.6 ± 42.3 (P < 0.001). Scores were higher in Off compared to On state for all domains except for domain "perceptual problems/hallucinations" (P = 0.608). Clinimetric properties of the NMSS were similar to those reported previously for NMS assessments independent of motor oscillations. NMSSOn, NMSSOff and ΔNMSSOn/Off showed weak to moderate correlations with demographics, indicators of motor symptom severity as well as with other measures of NMS, depression and quality of life. Correlations of NMSS items/domains with independent measures of related constructs were weak to moderate. In conclusion, when assessed with the NMSS, a broad range of NMS fluctuate with motor oscillations, but these fluctuations do neither correlate with motor function nor with measures of disease progression.

Improving the assessment of everyday cognitive functioning in patients with epilepsy by means of proxy reports.

OBJECTIVES: The self-report of cognitive deficits by of patients with epilepsy is often poorly correlated with objective test performances but highly related to mood and personality. The aim of this study was to evaluate whether information obtained by close relatives of the patient shows higher correlations with the patients' objective test scores and thereby can be a complementary measure for ensuring a reliable basis for diagnostic decision-making. METHODS: Thirty-four patients and 29 relatives were asked to fill in a questionnaire about everyday cognitive deficits of the patient. All patients completed a neuropsychological test battery comprising measures of memory, attention, and executive functioning and questionnaires on anxiety, depression, and the personality trait neuroticism. RESULTS: Correlations between relatives' reports and patients' test performances were highly significant across all examined domains. By contrast, self-reports of the patients significantly correlated with none of the neuropsychological measures of memory and with only a subset of the objective measures of attention and executive functioning. Regression analyses additionally revealed a strong dependency of the patients' self-assessment on depression, anxiety, and neuroticism (R(2)=0.42). CONCLUSIONS: These results point out the risk of self-reports distorting reality and additionally recommend consulting a close relative of the patient to ensure reliable information about the patient's everyday cognitive functioning.

Cost-of-illness in multiple system atrophy and progressive supranuclear palsy.

Multiple system atrophy and progressive supranuclear palsy are disabling neurodegenerative disorders, also known as atypical parkinsonian syndromes. Currently, no health economic evaluations of these diseases are available. The objective of this study was to evaluate disease-related costs in German patients with multiple system atrophy and progressive supranuclear palsy and to identify cost-driving factors. We recruited 101 consecutive patients with multiple system atrophy (n = 54) and progressive supranuclear palsy (n = 47) in four German specialised movement disorder clinics. The health economic data were collected using comprehensive health economic questionnaires ("bottom-up" approach). Costs were calculated from the societal perspective in 2010 Euros. Independent cost-driving factors were identified in multiple regression analysis. The total semi-annual costs of atypical parkinsonian syndromes were EUR 16,670 (95% CI: 13,470-21,850). Direct costs accounted for 73% (inpatient care 31%, special equipment 24%, copayments of patients 21%, others 24%) and indirect costs for 27% of total costs. The economic burden imposed on patients by atypical parkinsonian syndromes accounted for 36% of their income. Independent cost-driving factors were younger age, disease severity, living without a partner and depression. The disease-related costs of atypical parkinsonian syndromes in Germany are high and above the costs reported for idiopathic Parkinson's disease. Disease-specific patterns of cost distributions in atypical parkinsonian syndromes and independent cost-drivers should be considered in future health economic evaluations and healthcare programs. The early diagnosis and treatment of depression in patients with atypical parkinsonian syndromes as well as programs aimed to improve social support will reduce disease-related costs.

Comprehensive autonomic assessment does not differentiate between Parkinson's disease, multiple system atrophy and progressive supranuclear palsy.

Differential diagnosis of parkinsonian syndromes is a major challenge in movement disorders. Dysautonomia is a common feature but may vary in clinical severity and onset. The study attempted to find a pattern of autonomic abnormalities discriminative for patients with different parkinsonian syndromes. The cross-sectional study included 38 patients with multiple system atrophy (MSA), 32 patients with progressive supranuclear palsy (PSP), 26 patients with idiopathic Parkinson's disease (IPD) and 27 age-matched healthy controls. Autonomic symptoms were evaluated by a standardized questionnaire. The performance of patients and controls was compared on five autonomic function tests: deep breathing, Valsalva manoeuvre, tilt-table testing, sympathetic skin response, pupillography, and 24-h ambulatory blood pressure monitoring (ABPM). Disease severity was significantly lower in IPD than PSP and MSA. Except for pupillography, none of the laboratory autonomic tests distinguished one patient group from the other alone or in combination. The same was observed on the questionnaire. Receiver operating characteristic curve revealed discriminating performance of pupil diameter in darkness and nocturnal blood pressure change. The composite score of urogenital and vasomotor domains significantly distinguished MSA from IPD patients but not from PSP. Our study supports the observation that even mild IPD is frequently indistinguishable from more severe MSA and PSP. Thus, clinical combination of motor and non-motor symptoms does not exclusively point at MSA. Pupillography, ABPM and the questionnaire may assist in delineating the three syndromes when applied in combination.

Adherence to antiparkinson medication in a multicenter European study.

Two small studies reported suboptimal therapy adherence in Parkinson's disease. We conducted a larger multicenter European study to assess medicine-taking behavior. Parkinson's disease patients taking dopaminergic therapy were enrolled in 8 centers in 5 countries, and disease severity and demographics recorded. Antiparkinson drug adherence was measured for 4 weeks using electronic monitoring bottles which record the date and time of cap opening (Aardex, Switzerland). One hundred twelve patients, mean age 65 years (standard deviation (SD) 10), with Parkinson's disease for 7.7 (SD 8.2) years completed the study. Total median adherence (doses taken/doses prescribed) was 97.7% (interquartile range [IQ] 90.6-100), days adherence (correct dose days) was 86.2% (IQ 61.1-96.2) and timing adherence (doses taken at correct time intervals) was 24.4% (IQ 5.3-56.5). Fourteen patients (12.5%) took less than 80% of prescribed doses, which was defined as suboptimal adherence. Patients with satisfactory adherence took a median of 8 mg/day (IQ 0-33) less than their prescribed dose of levodopa (P = NS), while suboptimal adherence patients took a median of 481 mg/day (IQ 205-670) less than their prescribed dose (P = 0.0006). The Parkinson motor score was significantly higher in patients with suboptimal adherence at 29 (IQ 20-40), versus those with satisfactory adherence at 19 (IQ 13-26), P = 0.005. Once daily drugs had significantly better adherence when compared with drugs prescribed more frequently (P < 0.0001). Suboptimal therapy adherence is associated with significant deviation from prescribed levodopa doses, despite greater Parkinson's motor severity. Optimizing oral medication intake has a potential role in maximizing the therapy response in Parkinson's disease.