Motor Fluctuations Research Articles

Home-based monitoring of persons with advanced Parkinson’s disease using smartwatch-smartphone technology

Movement deterioration is the hallmark of Parkinson’s disease (PD), characterized by levodopa-induced motor-fluctuations (i.e., symptoms’ variability related to the medication cycle) in advanced stages. However, motor symptoms are typically too sporadically and/or subjectively assessed, ultimately preventing the effective monitoring of their progression, and thus leading to suboptimal treatment/therapeutic choices. Smartwatches (SW) enable a quantitative-oriented approach to motor-symptoms evaluation, namely home-based monitoring (HBM) using an embedded inertial measurement unit. Studies validated such approach against in-clinic evaluations. In this work, we aimed at delineating personalized motor-fluctuations’ profiles, thus capturing individual differences. 21 advanced PD patients with motor fluctuations were monitored for 2 weeks using a SW and a smartphone-dedicated app (Intel Pharma Analytics Platform). The SW continuously collected passive data (tremor, dyskinesia, level of activity using dedicated algorithms) and active data, i.e., time-up-and-go, finger tapping, hand tremor and hand rotation carried out daily, once in OFF and once in ON levodopa periods. We observed overall high compliance with the protocol. Furthermore, we observed striking differences among the individual patterns of symptoms’ levodopa-related variations across the HBM, allowing to divide our participants among four data-driven, motor-fluctuations’ profiles. This highlights the potential of HBM using SW technology for revolutionizing clinical practices.

Intercultural Translation and Application of the German Version of King’s Parkinson’s Disease Pain Questionnaire in Fluctuating Parkinson’s Disease

Background. Pain is common in Parkinson’s disease (PD) and impairs quality of life. The King’s PD pain questionnaire (KPPQ) is a standardized, reliable, and valid self‐administered questionnaire for screening of pain in PD. We developed a linguistically validated German version of the KPPQ and applied it to a cohort with fluctuating PD. Methods. The interculturally adapted German translation was performed according to internationally accepted procedures in coordination with the authors of the original publication but without further psychometric validation. After final approval by all translators and original authors, the German version was then tested for feasibility and comprehension in 30 PD patients. After final adaption, the German KPPQ together with the German quantitative KPPS were applied to an independent cohort of fluctuating PD patients within the VALIDATE‐PD study. Results. The use of the German version of the KPPQ in clinical practice or in the VALIDATE‐PD study revealed no significant problems of understanding. Sufficient datasets were available from 47 patients with motor fluctuations (24 (51%) males, 23 (49%) females; median (interquartile range (IQR)) age: 65 (58‐73) years; median (IQR) Hoehn and Yahr stage: 2.5 [2‐3]). Total pain was reported by 43 (92%) of participants with a median number of 4 (IQR: 2‐5) pain subtypes. We did not observe any associations of total pain frequency, neither with gender nor with other demographic or clinical parameters. Conclusions. The German version of the KPPQ is recommended as a questionnaire for assessing the frequency of pain and its subtypes in PD in clinical studies and/or routine care.

Inhaled levodopa: from evidence to experience

Most patients with Parkinson's disease experience motor fluctuations or 'off' periods, which impact on their daily activities, increase their disability and diminish their quality of life. They suffer from these fluctuations despite multiple adjustments to the schedules, doses and intake of medication. In this context, on-demand or rescue treatments are necessary to attempt to improve 'off' periods, with drugs that have the pharmacokinetic advantage of a much faster onset of action because their routes of administration are not oral. There are currently three on-demand therapies for the treatment of fluctuations: subcutaneous apomorphine, inhaled levodopa and sublingual apomorphine. Of the three alternatives, subcutaneous apomorphine generally has the fastest onset of action, sublingual apomorphine provides the longest clinical effect, and inhaled levodopa has the most favourable side effect profile. Each of these drugs has its own characteristics: the time before onset of action, the duration of action and different side effect profiles. The choice for each patient will depend on their individual needs and circumstances. To mark the first year of the introduction of inhaled levodopa, we review these therapies, focusing on the experience with this new dosage form of levodopa.

Levodopa use in Australia: an analysis of Pharmaceutical Benefits Scheme 10% data

BackgroundLevodopa remains the mainstay of treatment of Parkinson’s disease, however, over time motor fluctuations and levodopa-induced dyskinesia develop, requiring add-on therapies to control emerging symptoms. To date, however, there is...

Type-B monoamine oxidase inhibitors in neurological diseases: clinical applications based on preclinical findings.

Type-B monoamine oxidase inhibitors, encompassing selegiline, rasagiline, and safinamide, are available to treat Parkinson's disease. These drugs ameliorate motor symptoms and improve motor fluctuation in the advanced stages of the disease. There is also evidence supporting the benefit of type-B monoamine oxidase inhibitors on non-motor symptoms of Parkinson's disease, such as mood deflection, cognitive impairment, sleep disturbances, and fatigue. Preclinical studies indicate that type-B monoamine oxidase inhibitors hold a strong neuroprotective potential in Parkinson's disease and other neurodegenerative diseases for reducing oxidative stress and stimulating the production and release of neurotrophic factors, particularly glial cell line-derived neurotrophic factor, which support dopaminergic neurons. Besides, safinamide may interfere with neurodegenerative mechanisms, counteracting excessive glutamate overdrive in basal ganglia motor circuit and reducing death from excitotoxicity. Due to the dual mechanism of action, the new generation of type-B monoamine oxidase inhibitors, including safinamide, is gaining interest in other neurological pathologies, and many supporting preclinical studies are now available. The potential fields of application concern epilepsy, Duchenne muscular dystrophy, multiple sclerosis, and above all, ischemic brain injury. The purpose of this review is to investigate the preclinical and clinical pharmacology of selegiline, rasagiline, and safinamide in Parkinson's disease and beyond, focusing on possible future therapeutic applications.

Parkinson's disease: neurological manifestations and possibilities for neurosurgery

Parkinson's disease is caused by the progressive degeneration of nerve cells that produce dopamine, a neurotransmitter essential for motor coordination. The most common symptoms of Parkinson's disease are resting tremors, muscle rigidity, slow voluntary movements and postural instability. Furthermore, the disease can cause cognitive, emotional, sensory and autonomic changes. There are two main types of neurosurgery for Parkinson's disease: ablative surgery and deep brain stimulation (DBS). Objective: to evaluate the impact of neurosurgery for Parkinson's disease in improving motor symptoms, reducing medication side effects, preserving cognitive functions and improving patients' quality of life. Methodology: followed the PRISMA checklist. The databases used were PubMed, Scielo, Web of Science and Google Scholar. The descriptors used were: “Parkinson's disease”, “neurosurgery”, “ablation”, “deep brain stimulation” and “outcome”. The inclusion criteria were: articles that compared the two types of neurosurgery for Parkinson's disease (ablative surgery and deep brain stimulation), that evaluated clinical outcomes (motor symptoms, medication side effects, cognitive functions and quality of life) and that used standardized scales to measure these outcomes. The exclusion criteria were: articles that did not compare the two types of neurosurgery for Parkinson's disease, that did not evaluate the clinical outcomes of interest, that used non-validated or inadequate scales to measure these outcomes. Results: 15 studies were selected. Both types of neurosurgery for Parkinson's disease have been effective in improving patients' motor symptoms, especially tremors, rigidity, and bradykinesia. However, deep brain stimulation had an advantage over ablative surgery in terms of reducing medication side effects, such as motor fluctuations and dyskinesias. Deep brain stimulation was also safer and less invasive than ablative surgery, presenting fewer complications such as hemorrhage, infection, neurological deficits, and cognitive or psychiatric changes. However, deep brain stimulation showed greater improvement than ablative surgery, especially in physical, emotional and social aspects of quality of life. Conclusion: neurosurgery for Parkinson's disease is a valid therapeutic option for patients who do not respond adequately to drug treatment or who have intolerable side effects. Among the two main types of neurosurgery for Parkinson's disease, deep brain stimulation appears to be superior to ablative surgery in terms of efficacy, safety, and impact on patients' quality of life.

Correlation of slow-wave sleep with motor and nonmotor progression in Parkinson's disease.

This study aimed to explore the association between slow-wave sleep and the progression of motor and nonmotor symptoms in patients with PD. Data were collected from the Parkinson's Progression Markers Initiative study. Slow-wave sleep, also known as deep non-rapid eye movement (DNREM) sleep, was objectively assessed using the Verily Study Watch. Motor function was assessed using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale Part III score, Hoehn and Yahr stage, freezing of gait, motor fluctuations, and dyskinesia severity. Comprehensive assessments were conducted on nonmotor symptoms, including depression, anxiety, global cognitive function, and autonomic dysfunction. Statistical analyses involved repeated-measures analysis of variance and linear regression. A total of 102 patients with PD were included in the study, with a median follow-up duration of 3.4 years. In the long DNREM sleep duration group (n = 55), better motor function (DNREM × time interaction: F(1,100) = 4.866, p = 0.030), less severe sexual dysfunction (p = 0.026), and improved activities of daily living (p = 0.033) were observed at the last follow-up visit compared with the short DNREM sleep duration group (n = 47). Reduced DNREM sleep duration is a risk factor for motor progression (β = -0.251, p = 0.021; 95% confidence interval = -0.465 to -0.038). The findings suggest an association between longer DNREM sleep duration and slower motor and nonmotor progression in patients with PD.

Objective assessment of the effects of opicapone in Parkinson’s disease through kinematic analysis

BackgroundOpicapone (OPC) is a third-generation, selective peripheral COMT inhibitor that improves peripheral L-DOPA bioavailability and reduces OFF time and end-of-dose motor fluctuations in Parkinson’s disease (PD) patients.ObjectivesIn this study, we objectively assessed the effects of adding OPC to L-DOPA on bradykinesia in PD through kinematic analysis of finger movements.MethodsWe enrolled 20 treated patients with PD and motor fluctuations. Patients underwent two experimental sessions (L-DOPA, L-DOPA + OPC), separated by at least 1 week. In each session, patients were clinically evaluated and underwent kinematic movement analysis of repetitive finger movements at four time points: (i) before their usual morning dose of L-DOPA (T0), (ii) 30 min (T1), (iii) 1 h and 30 min (T2), and (iv) 3 h and 30 min after the L-DOPA intake (T3).ResultsMovement velocity and amplitude of finger movements were higher in PD patients during the session with OPC compared to the session without OPC at all the time points tested. Importantly, the variability of finger movement velocity and amplitude across T0–T3 was significantly lower in the L-DOPA + OPC than L-DOPA session.ConclusionsThis study is the first objective assessment of the effects of adding OPC to L-DOPA on bradykinesia in patients with PD and motor fluctuations. OPC, in addition to the standard dopaminergic therapy, leads to significant improvements in bradykinesia during clinically relevant periods associated with peripheral L-DOPA dynamics, i.e., the OFF state in the morning, delayed-ON, and wearing-OFF periods.

Scale-invariant changes in corticospinal excitability reflect multiplexed oscillations in the motor output.

In the absence of disease, humans produce smooth and accurate movement trajectories. Despite such 'macroscopic' aspect, the 'microscopic' structure of movements reveals recurrent (quasi-rhythmic) discontinuities. To date, it is unclear how the sensorimotor system contributes to the macroscopic and microscopic architecture of movement. Here, we investigated how corticospinal excitability changes in relation to microscopic fluctuations that are naturally embedded within larger macroscopic variations in motor output. Participants performed a visuomotor tracking task. In addition to the 0.25Hz modulation that is required for task fulfilment (macroscopic scale), the motor output shows tiny but systematic fluctuations at ∼2 and 8Hz (microscopic scales). We show that motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) during task performance are consistently modulated at all (time) scales. Surprisingly, MEP modulation covers a similar range at both micro- and macroscopic scales, even though the motor output differs by several orders of magnitude. Thus, corticospinal excitability finely maps the multiscale temporal patterning of the motor output, but it does so according to a principle of scale invariance. These results suggest that corticospinal excitability indexes a relatively abstract level of movement encoding that may reflect the hierarchical organisation of sensorimotor processes. KEY POINTS: Motor behaviour is organised on multiple (time)scales. Small but systematic ('microscopic') fluctuations are engrained in larger and slower ('macroscopic') variations in motor output, which are instrumental in deploying the desired motor plan. Corticospinal excitability is modulated in relation to motor fluctuations on both macroscopic and microscopic (time)scales. Corticospinal excitability obeys a principle of scale invariance, that is, it is modulated similarly at all (time)scales, possibly reflecting hierarchical mechanisms that optimise motor encoding.

Harnessing the neuroprotective effect of oral administration of benfotiamine in MPTP induced Parkinson's disease in rats

The study was performed to evaluate the neuroprotective effects of Benfotiamine (BFT) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) in rats. The rats were given daily doses of BFT (100 mg/kg, 200 mg/kg) through oral administration for 42 days. The rats were given a single bilateral dosage of MPTP (0.1 mg/nostril) intranasally once before the drug treatment to induce PD. On day 42, the animals were subjected to various behavioral paradigms. Post-treatment with BFT for 42 days significantly improved the motor and nonmotor fluctuations of MPTP. The results demonstrated that treatment with BFT ameliorated MPTP-induced disorders in behavior, body balance, and dopamine levels in the mid-brain. Among the post-treated groups, a high dose of BFT was the most effective treatment. Mean values are indicated in ±SEM, n = 5***(p < 0.001) when compared with the vehicle control, n = 5 ### (p < 0.001) when compared with the disease control; (p < 0.001) when compared with the BFT per se; (p < 0.001) when compared with the low dose of BFT; (p < 0.001) when compared with the high dose of BFT. Our finding suggests that BFT contributed to superior antioxidant, and anti-inflammatory and could be a novel therapeutic method for PD management. In conclusion, BFT could be a potential drug candidate for curbing and preventing PD.

Management of OFF condition in Parkinson disease.

Parkinson disease (PD) impacts nearly 1 million individuals in the United States. Nearly every patient with PD will require therapy with dopamine in the form of levodopa as the disease progresses. In more advanced stages of the disease, patients will experience motor fluctuations and require adjustment to their medication regimens to maintain good control of their symptoms. During the last 10 years, several new therapeutic treatment options have come to the market to treat motor fluctuations and improve patient quality of life. Some of these agents represent additional options to previously available drug classes, such as the catechol-O-methyl transferase (COMT) inhibitor, opicapone, and monoamine-oxidase B-inhibitor (MAO-B inhibitor), safinamide, as well as new dosage forms for available therapeutics. One new agent, istradefylline, has a novel mechanism in the treatment of PD. The place in therapy for these newer therapeutic options will be explored through a series of patient cases. This article focuses on evidence-based recommendations for the use of these newer options in the management of patients experiencing OFF episodes.

The effects of safinamide according to gender in Chinese parkinsonian patients

The incidence and prevalence of Parkinson’s disease (PD) is expected to raise dramatically over the next decades. Gender-related differences are not yet widely recognized, particularly regarding the response to dopaminergic medications. To analyse gender differences in the clinical effects of safinamide, compared to placebo, in Chinese PD patients of the pivotal XINDI trial. The XINDI study was a phase III, randomized, double-blind, placebo-controlled, multicenter trial. Patients were followed for 16 weeks receiving safinamide or placebo as add-on to levodopa. The primary efficacy endpoint was the change in the mean total daily OFF time. Secondary efficacy endpoints included total daily ON time, ON time with no/non-troublesome dyskinesia, Unified Parkinson’s Disease Rating Scale and Parkinson's Disease Questionnaire-39 items. A post-hoc analysis was performed to describe the efficacy of safinamide in both genders on motor symptoms, motor fluctuations and quality of life. 128 (42%) out of 305 patients enrolled were women and 177 (58%) men. Our additional analyses of the XINDI study have shown that safinamide, compared to placebo, was associated with improvements in motor symptoms, motor fluctuations and quality of life in both genders, with some differences in the response that did not reach statistical significance, possibly due to sample size limitation and post-hoc design of the study. The changes from baseline at week 16 were > 50% higher in the females compared to males for the total daily OFF time (− 1.149 h vs − 0.764 h in males), the total daily ON time (1.283 h vs 0.441 h in males), the UPDRS total score (− 8.300 points vs − 5.253 points in males) and the UPDRS part II score (− 2.574 points vs − 1.016 points in males). The changes from baseline at week 16 were higher in the females compared to males in the “ADL” domain (− 6.965 points vs − 5.772 points in males), the “Emotional well-being” domain (− 6.243 points vs − 4.203 in males), the “Stigma” domain (− 6.185 points vs − 4.913 points in males) and the “Bodily discomfort” domain (− 5.196 points vs 1.099 points in males), while were higher in males in the “Mobility” score (− 6.523 points vs − 4.961 points in females) and the “Communication” score (− 3.863 points vs − 1.564 points in females). Safinamide was shown to improve PD symptoms and quality of life in both male and female Chinese patients. Possible differences in the response between genders need to be further studied in larger and different ethnic populations.

The Increasing Prevalence of REM Sleep Behavior Disorder with Parkinson's Disease Progression: A Polysomnography-Supported Study.

Rapid eye movement (REM) sleep behavior disorder (RBD) is proposed as an early diagnostic marker in Parkinson's disease (PD). We investigated the frequency of RBD during the progression of PD in the advanced stages and identified potential risk factors for developing RBD earlier or later. We performed a retrospective analysis and determined the frequency of RBD in all PD in-patients (Hoehn and Yahr stages ≥3) with motor fluctuations who had undergone video-polysomnography (vPSG) for a sleep complaint or daytime sleepiness. To correct for selection bias, we analyzed the prevalence of RBD in PD patients from the DeNoPa cohort. PD patients with RBD were compared with PD without RBD. To identify potential risk factors, we performed multiple regression modeling. A total of 504 PD patients had vPSG. 37 were excluded due to missing REM or artifacts during REM. RBD was present in 406/467 (86.9%) PD patients. PD + RBD patients were older than PDnonRBD (69 ± 7.7 vs. 64 ± 9.2 years, P < 0.01), were more likely to have postural instability [234 (59.1%) vs. 19 (33.9%), P < 0.01], and were treated more often with antidepressants (other than SSRIs) [141 (34.7%) vs. 7 (13%), P < 0.01]. Multiple regression modeling identified predictors of RBD with an AUC of 0.78. The prevalence of RBD in patients with advanced PD is high and increases with disease severity, motor deficits, postural instability, orthostatic symptoms, and age. This suggests RBD is a progression marker of PD in patients with sleep complaints.

Safety and tolerability of long-term apomorphine infusion in advanced Parkinson's disease: an Indian multi-center (APO-IND) experience

Advanced Parkinson’s Disease (APD) is complicated by the emergence of motor and non-motor fluctuations, which are initially predictable and eventually become unpredictable, in part due to erratic gastric absorption and short half of oral levodopa. Attempts to manage such fluctuations with oral dopaminergic drugs often lead to disabling dyskinesias. Continuous Subcutaneous Apomorphine Infusion (CSAI), despite being approved for the treatment of APD since 1993, was approved in India only in 2019. We studied the safety, tolerability and efficacy of CSAI in Indian patients with APD in a registry design to raise local awareness of this important treatment. We conducted a prospective registry-based observational audit at 10 centers across different states of India. Patients with APD, not responding to or with significant side effects from oral dopaminergic therapy, were assessed at baseline and at month 6 and 12 following CSAI infusion. Fifty-one patients completed the study, CSAI significantly reduced the functional impact of dyskinesia (p < 0.01 at 6 months and p < 0.001 at 12 months). There was a significant improvement in the OFF-state from baseline (p < 0.01 at 6 months and p < 0.001 at 12 months) No discernible side effects were observed apart from mild site reaction (n = 7), nausea (n = 7) skin nodules (n = 2). CSAI demonstrated safety, efficacy, tolerability and improved quality of life in patients with APD, as shown in previous studies. Our study highlighted current existing inequalities in treatment availability, lack of awareness, knowledge gap, affordability and cost remains a concern regarding apomorphine use in Indian PD population.

Cost-Effectiveness of Carbidopa-Levodopa Enteral Suspension for Advanced Parkinson's Disease in the United States.

Carbidopa/levodopa enteral suspension (CLES) is indicated for the treatment of advanced Parkinson's disease (aPD) with severe motor fluctuations. To determine the cost, quality-adjusted life years (QALY), and cost-effectiveness of CLES compared to the standard-of-care (SoC) for aPD patients in the United States (US), using real-world data. A published Markov model, comprising of 25 health states and a death state, (defined by a combination of the Hoehn and Yahr scale and waking time spent in OFF-time) was adapted to estimate the benefits for CLES versus oral SoC over a patient's lifetime in the US healthcare setting. Clinical inputs were based on a clinical trial and a registry study; utility inputs were sourced from the Adelphi-Disease Specific Programmes. CLES compared to SoC was associated with incremental costs ($1,031,791 vs. $1,025,180) and QALY gain (4.61 vs. 3.76), resulting in an incremental cost-effectiveness ratio of $7711/QALY. CLES is a cost-effective treatment for aPD patients with medication resistant motor fluctuations. © 2023 AbbVie, Inc and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Comparative efficacy and safety of adjunctive drugs to levodopa for fluctuating Parkinson’s disease - network meta-analysis

It remains unclear which adjunctive drug for Parkinson’s disease (PD) in combination with levodopa is more effective, tolerable, and safe. We aimed to compare the efficacy, tolerability, and safety among anti-PD drugs from several classes in patients with fluctuating PD who received levodopa through network meta-analysis (NMA). Twelve anti-PD drugs belonging to 4 different drug classes (dopamine agonists, monoamine oxidase type B inhibitors, catechol-O-methyl transferase inhibitors, and an adenosine A2A receptor antagonist) were selected. We systematically searched PubMed, Embase, and the Cochrane Library for eligible randomized controlled trials (RCTs) comparing placebo with anti-PD drug or among anti-PD drugs in patients with PD who experienced motor fluctuations or wearing-off and received levodopa. We included 54 RCTs in the analysis. The NMA was performed under a frequentist framework using a random-effects model. The efficacy outcome was change in daily off-time, and the tolerability outcome was discontinuation due to all causes. Safety outcomes included discontinuation due to adverse events (AEs) and the incidence of AEs, dyskinesia, hallucination, and orthostatic hypotension. According to the surface under the cumulative ranking curve (SUCRA) in the NMA, ropinirole transdermal patch (SUCRA, 0.861) ranked the highest in efficacy, followed by pramipexole (0.762), ropinirole extended release (ER) (0.750), and safinamide (0.691). In terms of tolerability, ropinirole (0.954) ranked the highest, followed by pramipexole (0.857), safinamide (0.717), and ropinirole ER (0.708). Each anti-PD drug had different SUCRA ranking profiles for the safety outcomes. These findings suggest that ropinirole, pramipexole, and safinamide are well-balanced anti-PD drugs that satisfy both efficacy and tolerability outcomes.

Application of single wrist-wearable accelerometry for objective motor diary assessment in fluctuating Parkinson’s disease

Advanced Parkinson’s disease (PD) is characterized by motor fluctuations including unpredictable oscillations remarkably impairing quality of life. Effective management and development of novel therapies for these response fluctuations largely depend on clinical rating instruments such as the widely-used PD home diary, which are associated with biases and errors. Recent advancements in digital health technologies provide user-friendly wearables that can be tailored for continuous monitoring of motor fluctuations. Their criterion validity under real-world conditions using clinical examination as the gold standard remains to be determined. We prospectively examined this validity of a wearable accelerometer-based digital Parkinson’s Motor Diary (adPMD) using the Parkinson’s Kinetigraph (PKG®) in an alternative application by converting its continuous data into one of the three motor categories of the PD home diary (Off, On and Dyskinetic state). Sixty-three out of 91 eligible participants with fluctuating PD (46% men, average age 66) had predefined sufficient adPMD datasets (>70% of half-hour periods) from 2 consecutive days. 92% of per-protocol assessments were completed. adPMD monitoring of daily times in motor states showed moderate validity for Off and Dyskinetic state (ICC = 0.43–0.51), while inter-rating methods agreements on half-hour-level can be characterized as poor (median Cohen’s κ = 0.13–0.21). Individualization of adPMD thresholds for transferring accelerometer data into diary categories improved temporal agreements up to moderate level for Dyskinetic state detection (median Cohen’s κ = 0.25–0.41). Here we report that adPMD real-world-monitoring captures daily times in Off and Dyskinetic state in advanced PD with moderate validities, while temporal agreement of adPMD and clinical observer diary data is limited.

Catechol-O-methyltransferase inhibition with entacapone: Evidence from controlled clinical trials in Parkinson's disease.

Adjunct therapy with the catechol-O-methyltransferase inhibitor entacapone is a first-line approach to treat wearing-off type motor fluctuations in levodopa-treated Parkinson's disease (PD) patients. Five randomized placebo-controlled trials including a total of >1000 patients have established its efficacy, showing increases in ON time between 0.7 and 1.6 h, with corresponding OFF-time reductions. These and other trials also found improvements in ON motor function and quality of life. Additional trials have tested the efficacy of adjunct entacapone in patients either without or with early and mild motor fluctuations and also found enhanced motor control and improved activities of daily living function and quality of life, whereas the STRIDE-PD trial failed to show efficacy of early entacapone use in delaying the onset of dyskinesias. Adjunct entacapone enhances dopaminergic activity and may increase levodopa-induced adverse events like dyskinesias, which can usually be controlled by modest levodopa dose reductions. There is no formal requirement to monitor liver function during entacapone treatment. Entacapone can be a rare cause of lymphocytic colitis with severe diarrhoea and need for treatment discontinuation. In 2003, a triple-combination pill of levodopa, carbidopa, and entacapone (LCE) was first introduced onto the market, and since then proprietary LCE (Stalevo® ) is indicated on the basis of those trials for patients with idiopathic PD to (i) substitute for immediate-release carbidopa/levodopa and entacapone previously administered as individual products or (ii) replace immediate-release carbidopa/levodopa therapy (without entacapone) when patients taking a total daily dose of levodopa of ≤600 mg and not experiencing dyskinesias experience signs and symptoms of end-of-dose wearing off.

Clinical assessment of a new wearable tool for continuous and objective recording of motor fluctuations and ON/OFF states in patients with Parkinson's disease.

Clinical rating scales typically includes subjective evaluations, and their time-limited duration may fail to capture daily fluctuations in motor symptoms resulting from Parkinson's disease (PD). Recently, a new tool (i.e. the PD-Watch) has been proposed for the objective and continuous assessment of PD motor manifestations based on evaluating frequency data from a wrist-worn tri-axial accelerometer and identifying specific movement patterns typically associated with disorders. This reduces the probability of confusing physiological or pathological movements occurring at the same frequency. In this work, we present a new method for assessing motor fluctuations through a wrist-worn accelerometer. We also explore the agreement between the continuous data generated by the proposed method and data reported in the patient diaries. In this study, twelve PD patients were recruited with an overall recording duration of 528 hours. Results of this preliminary study show that the proposed tool has suitable and adequate performances for analysing the motor signs of PD patients, and the estimated sensitivity, specificity, and accuracy of the tool are 85%, 94%, and 91%, respectively.

Response to levodopa in Parkinson's disease over time. A 4-year follow-up study

Background and objectiveA good response to levodopa is a key factor to indicate device-aided therapies in people with Parkinson's disease (PwPD). The aim of the present study was to analyze the response to levodopa in PwPD with motor fluctuations followed for 4 years. Patients and methodsPwPD with motor fluctuations recruited from January 2016 to November 2017 from the COPPADIS cohort and assessed annually (from baseline to 4-year follow-up) during the OFF and ON states were included in this analysis. At each visit, the Unified Parkinson's Disease Rating Scale – part III (UPDRS-III) was applied during the OFF state (without medication during the last 12 h) and during the ON state. General linear model repeated measures were used to test for changes in the mean UPDRS–III–OFF, UPDRS–III–ON, and ΔUPDRS-III (UPDRS–III–OFF – UPDRS–III–ON) between visits. Levodopa equivalent daily dose (LEDD) was included as covariate. ResultsSixty-three patients (63.94 ± 8.42 years old; 68.3% males) were included. Mean disease duration was 7.81 ± 3.64 years. From baseline to 4-year follow-up visit, a significant increase in both the UPDRS–III–OFF (from 27.98 ± 9.58 to 31.75 ± 12.39; p = 0.003) and the UPDRS–III–ON (from 15.92 ± 7.93 to 18.84 ± 8.17; p = 0.006) was observed despite the significant increase in the LEDD (from 896.35 ± 355.65 to 1085.51 ± 488.29; p = 0.003). However, no significant differences were detected between visits in the ΔUPDRS-III. ConclusionIn this cohort of PwPD with motor fluctuations, the response to levodopa did not weaken after a 4-year follow-up.