Wearing-off Phenomenon Research Articles

Exploring the impact of wearing-off phenomenon in ocrelizumab-treated multiple sclerosis patients: Insights from a comprehensive study

BackgroundOcrelizumab (OCR) effectively modifies the disease course in multiple sclerosis (MS) patients but may cause a preinfusion "wearing-off phenomenon" (WoP). This study explored the prevalence, timing, and severity of this phenomenon in MS patients using the OCR, as well as the associated symptoms and treatment satisfaction. MethodsWe conducted a prospective multicenter study across 11 MS centers involving MS patients aged 18-70 years who had received at least two OCR doses. The study employed a questionnaire addressing demographic, clinical, and radiological data; symptom progression; and treatment satisfaction. ResultsOf the 409 patients included in the study, 406 participated. A significant portion experienced varying degrees of WoP: 39.2% sometimes, 25.9% usually, and 14.3% always, with 55.9% noting symptom onset over four weeks prior to their next dose. Common symptoms included fatigue, walking difficulties, and pain. Subgroup analysis of 334 patients revealed that 78.1% of patients experienced these effects, which correlated with shorter disease durations, a longer delay between the two doses before the last dose, and a greater rate of relapse (P>0.05). ConclusionThe WoP of the OCR is prevalent and significant among MS patients and is influenced by the dosing interval, disease duration, and relapse rate. These insights underscore the need for personalized treatment schedules and more research into factors affecting MS management.

Opicapone for the treatment of early wearing-off in levodopa-treated Parkinson’s disease: pooled analysis of patient level data from two randomized open-label studies

BackgroundThe wearing-off phenomenon is a key driver of medication change for patients with Parkinson’s disease (PD) treated with levodopa. Common first-line options include increasing the levodopa dose or adding a catechol-O-methyltransferase (COMT) inhibitor, but there are no trials comparing the efficacy of these approaches. We evaluated the effectiveness of adjunct opicapone versus an additional 100 mg levodopa dose in PD patients with early wearing-off using pooled data from 2 randomized studies.MethodsThe ADOPTION study program included two similarly designed 4-week, open-label studies conducted in South Korea (NCT04821687) and Europe (NCT04990284). Patients with PD, treated with 3–4 daily doses of levodopa therapy and with signs of early wearing-off were randomized (1:1) to adjunct opicapone 50 mg or an additional dose of levodopa 100 mg. Patient-level data from the two studies were pooled.ResultsThe adjusted mean [SE] change from baseline to week 4 in absolute OFF time (key endpoint) was − 62.8 min [8.8] in the opicapone group and − 33.8 min [9.0] in the levodopa 100 mg group, the difference significantly favoring opicapone (− 29.0 [− 53.8, − 4.2] min, p = 0.02). Significant differences in the Movement Disorder Society—Unified Parkinson’s Disease Rating Scale Part III subscore (− 4.1 with opicapone vs − 2.5 with levodopa 100 mg), also favored opicapone (− 1.7 [− 3.3, − 0.04], p < 0.05). Dyskinesia was the most frequently reported adverse event (opicapone 7.2% vs. levodopa 100 mg 4.2%).ConclusionsIn these short-term trials, introducing adjunct opicapone was more effective at reducing OFF time than adding another 100 mg levodopa dose in PD patients with early signs of wearing-off.

Insight into motor fatigue mechanisms in natalizumab treated multiple sclerosis patients with wearing off

Motor fatigue in Multiple Sclerosis (MS) is due to reduced motor cortex (M1) output and altered sensorimotor network (SMN) modulation. Natalizumab, a disease-modifying therapy, reduces neuroinflammation and improves fatigue. However, some patients treated with natalizumab experience fatigue recurrence (‘wearing-off’) before subsequent infusions. Wearing-off provides a valuable window into MS-related motor fatigue mechanisms in a controlled, clinically stable, setting. This study investigates whether wearing-off is associated with worsening motor fatigue and its neurophysiological mechanisms and assesses natalizumab’s effect on MS-related fatigue. Forty-five relapsing–remitting MS patients with wearing-off symptoms were evaluated pre- and post-natalizumab infusion. Assessments included evaluating disability levels, depressive symptoms, and the impact of fatigue symptoms on cognitive, physical, and psychosocial functioning. The motor fatigue index was computed through the number of blocks completed during a fatiguing task and peripheral, central, and supraspinal fatigue (M1 output) were evaluated by measuring the superimposed twitches evoked by peripheral nerve and transcranial magnetic stimulation of M1. Transcranial magnetic stimulation-electroencephalography assessed M1 effective connectivity by measuring TMS-evoked potentials (TEPs) within the SMN before- and after the task. We found that wearing-off was associated with increased motor fatigue index, increased central and supraspinal fatigue, and diminished task-related modulation of TEPs compared to post-natalizumab infusion. Wearing-off was also associated with worsened fatigue impact and depression symptom scores. We conclude that the wearing-off phenomenon is associated with worsening motor fatigue due to altered M1 output and modulation of the SMN. Motor fatigue in MS may reflect reversible, inflammation-related changes in the SMN that natalizumab can modulate. Our findings apply primarily to MS patients receiving natalizumab, emphasizing the need for further research on other treatments with wearing-off.

The influence of sex on non-motor wearing-off in Parkinson’s disease: A WORK-PD post-hoc study

IntroductionThe wearing-off phenomenon is characterized by the recurrence of motor and non-motor symptoms of Parkinsonism during a period free from levodopa. It is a pivotal aspect marking the end of the pharmacological “honeymoon” period in Parkinson’s disease (PD). A growing body of literature is connecting sex with the likelihood of developing fluctuations. We investigated such an association in a post-hoc analysis of the large WORK-PD study. MethodsWORK-PD analyzed the usability of the wearing-off questionnaire 19 (WOQ19) in clinical practice and included cross-sectional data on age, disease duration, time on levodopa, Hoehn and Yahr stage, and WOQ19 scores of 532 PD patients. In the present study, we selected patients with an exposure time to levodopa of at least 1 year. ResultsA total of 380 patients were included. Women reported a higher number of wearing-off symptoms than men (6.09 ± 3.39 vs 4.96 ± 3.11, p = 0.0006). Sex groups also differed in non-motor symptoms (2 ± 1.9 vs 1.5 ± 1.5, p = 0.021), particularly behavioral wearing-off scores being higher in women (p < 0.001). The latter were primarily featured by anxiety-related phenomena. Finally, there was a significant interaction between behavioral symptoms, sex, and age at onset (df = 2, F = 9.79, p < 0.0001), whereas no such interaction was observed with levodopa exposure and motor impairment, unlike motor symptoms. DiscussionWomen showed a greater propensity than men to experience wearing-off, particularly non-motor fluctuations on the anxiety spectrum. The latter may demonstrate a lesser reliance on dopamine compared to motor symptoms. This observation could be underpinned by biological variances between genders at the neurotransmitter level.

Treating Idiopathic Parkinson’s Disease with Bonoesikpungjigyeong-tang : A Case Study on “Delayed On” and “Wearing Off” Phenomena after Long-term Levodopa Intake

A 69-year-old female diagnosed with idiopathic Parkinson’s disease and treated with anti-Parkinsonian medications, including levodopa, for 7 years presented with complaints of wearing-off phenomenon and delayed onset of medication efficacy, resulting in postural instability and feeling of severe exhaustion. The patient underwent a 50-day course of treatment with Bonoesikpungjigyeong-tang formula. The effects of the treatment were evaluated by recording the average time to onset of medication efficacy, the average time to medication wearing-off, and discomfort due to wearing-off phenomenon. Postural instability was assessed using the Numeric Rating Scale (NRS). The patient’s overall quality of life was assessed using the EQ-5D-3L. After 50 days of treatment, the average time to onset of medication efficacy decreased, and the average time to medication wearing-off increased. Discomfort due to wearing-off phenomenon and postural instability decreased. This case suggests that Bonoesikpungjigyeong-tang might be an alternative for improving discomfort caused by long-term levodopa intake.

The ocrelizumab wearing-off phenomenon is associated with reduced immunomodulatory response and increased neuroaxonal damage in multiple sclerosis

ObjectiveThe wearing-off phenomenon is common in people with multiple sclerosis (MS) treated with ocrelizumab. We aim to evaluate the presence and severity of wearing-off to ocrelizumab in relation to demographic and MS clinical variables, immune profiling, and a marker of neuroaxonal damage (plasma neurofilament light chain (pNfl)).MethodsThis cross-sectional study included MS patients treated with ocrelizumab from at least 1 year. Wearing-off questionnaire and blood samples were collected between 21 and 23 weeks after the previous ocrelizumab infusion. Lymphocyte subpopulations were evaluated on peripheral blood using flow cytometry. PNfl was evaluated using fully automated chemiluminescent enzyme immunoassay.ResultsWe included 106 people with MS (age 49.5 ± 11.6 years; females 42.3%; wearing-off 57.6%). On regression models, wearing-off was associated with higher pNfl, CD8, CD3, and CD3CD27 lymphocytes. Most frequent wearing-off symptoms were cognitive, sensory, and balance problems; wearing-off started < 1 week (9.4%), 1–4 weeks (10.7%) or > 4 weeks (10.7%) before infusion; 44.8% of the complaints were moderate to severe. Severity of wearing-off was associated with higher pNfl and CD8 lymphocytes.ConclusionsWearing-off is common in people with MS treated with ocrelizumab, and is associated with reduced immunomodulation (higher T lymphocytes) and increased neuroaxonal damage, suggesting reduced treatment response.

The patient-reported wearing-off phenomenon with monoclonal antibody treatments for multiple sclerosis

Background Many patients report a wearing-off phenomenon with monoclonal antibody treatment for multiple sclerosis in which perceived benefits wear off before the next dose is due. Objectives To determine prevalence of the wearing-off effect, symptoms experienced, impact on treatment satisfaction, and associated patient characteristics. Methods Patients receiving natalizumab, ocrelizumab, ofatumumab, or rituximab at a tertiary multiple sclerosis center were invited to take an online survey interrogating their monoclonal antibody experience. Additional history and patient characteristic data were collected. Logistic regression was used to determine if patient characteristics predicted the wearing-off effect and linear regression to evaluate the impact of the wearing-off effect on treatment satisfaction. The models were adjusted for age, disease duration, race, sex, body mass index, education, and depression as measured by the Patient Health Questionnaire-9. Results We received 258 qualifying responses and 141 (54.7%) patients reported the wearing-off phenomenon. The most common symptom was fatigue (47.7%). Higher Patient Health Questionnaire-9 scores were significantly associated with the wearing-off phenomenon (OR = 1.02, p = 0.005). The wearing-off effect (β = −0.52, p = 0.04) and higher Patient Health Questionnaire-9 (β = −0.09, p &lt; 0.01) scores were associated with significantly reduced treatment satisfaction. Conclusion The wearing-off phenomenon is common, associated with depression, and reduces treatment satisfaction. Research addressing mitigation strategies is needed.

Validity and Reliability of the Korean Versions of the 9- and 19-Item Wearing-Off Questionnaires in Parkinson's Disease.

The wearing-off (WO) phenomenon is the most common motor complication in advanced Parkinson's disease (PD), but its identification remains challenging. The 9- and 19-item Wearing-off Questionnaires (WOQ-9 and WOQ-19) are self-assessment tools for motor and nonmotor symptoms that are widely used for WO screening. We produced Korean versions of the WOQ-19 and WOQ-9 (K-WOQ-19 and K-WOQ-9) and investigated their validity and reliability. We used the translation-back translation method to produce K-WOQ-19 and K-WOQ-9, which were self-administered by 124 patients with PD. We conducted in-depth 10-minute interviews for confirming the presence of the WO phenomenon, and then stratified the participants into groups with and without WO. Diagnostic accuracy was assessed byanalyzing receiver operating characteristic curves. Concurrent validity was assessed using the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) andthe Hoehn and Yahr stage with Spearman's rank correlation analysis. Reliability was assessedbased on test-retest Cohen's kappa (κ) values and intraclass correlation coefficients (ICCs). The optimal cutoff scores on the K-WOQ-19 and K-WOQ-9 for WO screening were 4 and 2, respectively. The test-retest ICCs of K-WOQ-19 and K-WOQ-9 were 0.943 and 0.938, respectively. Nineteen of the combined 20 items in K-WOQ-19 and K-WOQ-9 showed moderate-to-substantial agreement (κ=0.412-0.771, p<0.001). The scores on the translated scales were significantly correlated with MDS-UPDRS IV scores. K-WOQ-19 and K-WOQ-9 are reliable and valid tools for detecting WO, with optimal cutoff scores of 4 and 2, respectively.

Integrity of the nucleus basalis of meynert and self-reported cognitive dysfunction during wearing-off periods in parkinson's disease.

Cognition in Parkinson's Disease can be impacted by the wearing-off phenomenon which results from changes in dopaminergic tone throughout the day. Given the well-established role of the cholinergic basal forebrain in cognition, we hypothesized that the Nucleus Basalis of Meynert may support cognitive processes during wearing-off periods. Specifically, we evaluated whether worsening of cognitive symptoms during wearing-off is more likely to occur with structural degeneration of the Nucleus Basalis of Meynert. Cognitive wearing-off was evaluated via the Movement Disorders Society Non-Motor Fluctuation Assessment Questionnaire in 33 Parkinson's Disease participants undergoing evaluation for deep brain stimulation. Pre-operative diffusion MRIs were used to measure brain diffusion metrics of the Nucleus Basalis of Meynert and control regions (caudate and putamen). The number of cognitive symptoms which worsened during OFF periods positively correlated with mean diffusivity (ρ = 0.561, p = 0.0007) and generalized fractional anisotropy (ρ=-0.447, p = 0.009) within the Nucleus Basalis of Meynert but not in the caudate or putamen. Meanwhile, stable cognitive symptoms, and ON-state cognitive performance as measured by the DRS-2 did not correlate with Nucleus Basalis of Meynert metrics. Correlations were corrected for age, sex, scanner type, disease duration, education and LEDD. Our study suggests that reduced structural integrity of the Nucleus Basalis of Meynert is associated with worsening of participant-reported cognitive deficits during OFF periods, but not overall cognitive functioning in the ON-state. These findings support the hypothesis that structural integrity of the cholinergic Nucleus Basalis of Meynert may provide resilience to cognitive worsening during dopamine-related wearing-off.

Parkinson’s disease in a patient with GBA and LRRK2 covariants after acute hypoxic insult: a case report

BackgroundThe glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 (LRRK2) genes are associated with the risk of sporadic Parkinson’s disease (PD). As an environmental factor, hypoxic insults may impair dopamine neurons in the substantia nigra and exacerbate PD symptoms. However, covariants of GBA and LRRK2 combined with hypoxic insults in clinical cases of Parkinsonism have not yet been reported.Case presentationA 69-year-old male patient with PD and his relatives were clinically characterized and sequenced using the whole-exome technique. A novel covariant, c.1448 T > C (p. L483P, rs421016) on GBA and c.691 T > C (p. S231P, rs201332859) on LRRK2 were identified in this patient who first developed bradykinesia and rigidity in the neck at one month after an acute hypoxic insult during mountaineering. The patient presented with a mask-like face, festinating gait, asymmetric bradykinesia, and moderate rigidity. These symptoms were treated with levodopa and pramipexole, resulting in a 65% improvement in the Unified Parkinson’s Disease Rating Scale (UPDRS) motor score. These parkinsonian symptoms persisted and developed with hallucinations, constipation, and rapid eye movement sleep behavior disorder. After 4 years, the patient exhibited a wearing-off phenomenon and died from pulmonary infection 8 years after disease onset. His parents, wife, and siblings were not diagnosed with PD, and his son carried p. L483P without Parkinsonism-like symptoms.ConclusionsThis is a case report of PD after hypoxic insult in a patient carrying a covariant of GBA and LRRK2. This study may help us understand the interaction between genetic and environmental factors in clinical PD.

Current Pharmacological Treatment for Parkinson's Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder and its global incidence is on the rise. A well-established dopamine replacement therapy for PD is based on dopamine deficiency, primarily due to dopaminergic neuronal loss in the substantia nigra. Current dopaminergic pharmacotherapy for PD consists of levodopa and other dopaminergic drugs, such as a dopamine agonist (DA) and monoamine oxidase B (MAOB) inhibitor, and patients with PD are administered these mainly according to age, disability of parkinsonism, and tolerance of the drugs. In the advanced stage, patients with PD usually experience motor complications, mainly the wearing-off phenomenon and dyskinesias, resulting in disabled activities of daily life. Many pharmacological options are available against motor fluctuations in patients with advanced PD, including long-acting DAs, MAOB inhibitors, and catechol-O-methyltransferase inhibitors, as adjunct alternatives for dopamine-replacement therapy. Non-dopaminergic pharmacological approaches, including zonisamide and istradefylline, which have been mainly developed in Japan, are also available. Amantadine and anticholinergic drugs may be useful in specific situations. Device-aided therapies, such as deep brain stimulation and levodopa-carbidopa intestinal gel infusion therapy, can be performed at the advanced stage. In this article, we provide an overview of recent pharmacological treatments for PD.

Management for the patients with severe Parkinson's disease during dental treatments and tooth extractions: A retrospective observational study

Background/purposeWhen Parkinson's disease (PD) progresses, oral and swallowing functions decline, and special care is necessary when performing dental treatments. This study aimed to retrospectively investigate the records of patients with PD and analyze dental and general problems to establish countermeasures during dental treatments. Materials and methodsWe retrospectively examined the medical records of patients with PD to obtain data on dental treatments and management methods. ResultsOf the 27 patients, 40% had severe grade IV or higher Hoehn–Yale (HY) scores, and the wearing-off phenomenon was observed in those with grade III or higher. Additionally, 19% of the patients were receiving levodopa 500 mg/day or more. Intravenous sedation was administered 21 times (three patients) and general anesthesia eight times (three patients). Discontinuation of tooth extraction was observed in four patients: two with difficulty in opening the mouth, one with respiratory failure caused by the wearing-off phenomenon, and one with excessively elevated blood pressure due to the interaction between adrenaline in local anesthesia and the catechol-O-methyltransferase inhibitor. Tooth extraction was performed by adjusting the time of levodopa administration in two patients, under general anesthesia in one patient, and using adrenaline-free local anesthetics under intravenous sedation in one patient. ConclusionWhen PD progresses, oral and swallowing functions decline and body motor function deteriorates. Thus, the respiratory and circulatory conditions and the wearing-off phenomenon during dental treatments should be properly managed in patients with severe PD.

Impact of Istradefylline on Levodopa Dose Escalation in Parkinson’s Disease: Results of the ISTRA ADJUST PD Randomized, Controlled Study (P13-11.015)

<h3>Objective:</h3> To evaluate the effect of istradefylline (IST), an adenosine A_2A receptor antagonist, on levodopa dose escalation in patients with Parkinson’s disease (PD) and wearing-off phenomena. <h3>Background:</h3> Clinical data suggest that the lowest possible levodopa dose should be used to balance treatment benefits against the risk of motor complications. IST is approved in Japan and the US as an adjunct to levodopa/decarboxylase inhibitors in patients with PD and wearing-off phenomena/off episodes. Robust data on the impact of IST on levodopa dose titration are lacking. <h3>Design/Methods:</h3> In this multicenter, randomized, open-label, parallel-group controlled study, 114 patients with PD and wearing-off phenomena receiving 300–400 mg/day levodopa were randomly assigned (1:1) to the IST or control group. Levodopa dose escalation was based on the clinical impression of severity. The primary endpoint was the cumulative additional levodopa dose throughout the 37-week treatment period. Changes in symptom rating scales, motor activity using a wearable device, and safety outcomes were evaluated as secondary endpoints. <h3>Results:</h3> In total, 105 patients (IST, n = 52; control, n = 53) were included in the efficacy and safety analyses. The cumulative additional levodopa dose as area under the curve was 5-fold significantly lower in the IST group than in the control group. Changes in symptom rating scales from baseline were comparable between the groups. Device-evaluated motor activities significantly improved from baseline to week 36 only in the IST group. Incidences of adverse drug reactions (ADRs) were 28.8% in the IST group and 13.2% in the control group. No serious ADRs occurred in either group. <h3>Conclusions:</h3> IST treatment effectively prevented the need for levodopa dose escalation, resulting in a lower cumulative levodopa dose during the study. Data from the wearable device suggest that more objective improvement in motor function may be achieved with IST than with levodopa dose escalation. <b>Disclosure:</b> Dr. Hatano has nothing to disclose. Dr. Kano has nothing to disclose. Dr. Sengoku has nothing to disclose. Mr. Yanagisawa has nothing to disclose. Prof. Nagayama has nothing to disclose.

Switching from Rasagiline to Safinamide as an Add-On Therapy Regimen in Patients with Levodopa: A Literature Review.

Parkinson's disease (PD) is a complex disease, and the treatment is focused on the patient's clinical symptoms. Levodopa continues to be the most effective drug for symptomatic PD treatment. However, chronic levodopa treatment is associated with the development of motor complications in most patients. Add-on therapeutic drugs, such as dopamine agonists and monoamine oxidase B (MAO-B) inhibitors, for example, safinamide and rasagiline, may be a desirable addition to continuously increase the levodopa dose for the optimization of motor control in PD. The scientific literature shows that safinamide significantly alleviated motor fluctuations with no increase in troublesome dyskinesia, thanks to its unique double mechanism, providing further benefits to fluctuating PD patients when compared to a placebo or other drugs. Switching from rasagiline to safinamide has been shown to improve the wearing-off phenomena, which is defined as the recurrent, predictable worsening of symptoms of parkinsonism at the end of the levodopa dose until the next dose reaches a clinical effect. In this situation, safinamide may be helpful for reducing the total daily dose of levodopa, improving the OFF time and ON time without troublesome dyskinesias, and being more effective than other MAO-B inhibitors. In this narrative review, we explore the switch from rasagiline to safinamide in patients with motor complications as a feasible and effective alternative to optimize antiparkinsonian treatment.

A Perspective of the Wearing-off Phenomenon in a Patient with Parkinson’s Disease: A Case Report

A Perspective of the Wearing-off Phenomenon in a Patient with Parkinson’s Disease: A Case Report

Treatment Reconciliation in Parkinson’s Disease Patients with Particular Reference to Wearing-off and Motor fluctuations: A Registry-based, Prospective, Observational Study

Introduction: Parkinson’s Disease (PD) is the second most frequent neurodegenerative disease and dopaminergic agents are frequently used as a treatment while ‘end of dose deterioration’ or ‘Wearing-Off (WO)’ phenomenon is common with these agents. Treatment reconciliation may be helpful in this situation and there is dearth of studies especially in India. Aim: To study the WO effects in patients of PD, their pharmacotherapy and outcome. Materials and Methods: This registry-based, prospective, observational, outcomes-based study was conducted in the Department of Clinical and Experimental Pharmacology, School of Tropical Medicine, Kolkata, West Bengal, India, in collaboration with Department of Neuromedicine of Kolkata Medical College and private clinics of a Neurologist from January 2020 to December 2021. An attempt was also undertaken to make a registry of Idiopathic Parkinson’s Disease (IPD) patients. WO Questionnaire 19-items (WOQ19), Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS Scale), The 39-items Parkinson’s Disease Questionnaire (PDQ-39 questionnaire), The 8-items Morisky Medication Adherence Scale (MMAS scale), suspected Adverse Drug Reaction (ADR) Reporting Form of Indian Pharmacoepia commission (version 1.3), World Health Organisation- Uppsala Monitoring Centre (WHO-UMC) Scale, Naranjo causality assessment scale, Hartwig and Seigel’s Severity Assessment Scale were used in the present study. The study was commenced after obtaining approval from institutional ethics committee. The data was then analysed with parametric or non parametric tests using (mean±Standard Deviation (SD), median, Fisher’s-exact test, Friedman’s Analysis of Variance (ANOVA) test, Wilcoxon matched pair signedrank test). Data collected and then statistically analysed by using WPS Excel version 2021 and GraphPad Prism version 9 software. Results: Total IPD patients were found to be 111 in the present study with a mean age of IPD patients as 61.85±7.20 years. Incidence of WO in the present study was found to be 40.5% among IPD patients. Most common characteristic of WO was found to be tremor in 104 (28.8%) patients followed by slowness of movement in 63 (17.5%) patients. WHO-UMC scale and Naranjo causality assesment scale both revealed 36.4% ADRs were probable category and 63.6% were possible category. MDS-UPDRS Score, PDQ-39 Score, MMAS-8 score significantly (p-value&lt;0.05) improved during the course of treatment. Conclusion: Dose adjustment of syndopa was mostly used in the management of WO phenomenon and significant improvement in the quality of life of the patients was seen.

Chronic Pain And Levodopa Therapy in Parkinson’s Disease Patients

Background: Pain is a frequent non-motor symptom in patients with Parkinson’s disease (PD) and appears to be related to low levels of dopamine. This study describes the characteristics of chronic pain in a group of PD patients undergoing levodopa therapy. Methods: This was a cross-sectional study. The pain was assessed in 21 selected PD patients with chronic pain using several scales and instruments. Changes in pain response from levodopa use (wearing-off phenomenon) were monitored. Results: The most prevalent type of pain was nociceptive (71.4%), musculoskeletal and dystonic, but neuropathic pain accounted for the highest pain score according to the Parkinson’s Disease Pain Classification System (45.5±30.08). Patients with neuropathic, nociplastic, or nociceptive pain upon wearing-off were those who responded to levodopa (p=0.999). According to the McGill questionnaire, patients with pain upon wearing-off had higher scores in the affective/motivational dimension (p=0.022). Conclusion: Using a new pain classification and scoring tool, this study corroborates a good response to levodopa in PD-related pain.

A Digital Architecture for the Real-Time Tracking of Wearing off Phenomenon in Parkinson’s Disease

Levodopa administration is currently the most common treatment to alleviate Parkinson's Disease (PD) symptoms. Nevertheless, prolonged use of Levodopa leads to a wearing-off (WO) phenomenon, causing symptoms to reappear. To build a personalized treatment plan aiming to manage PD and its symptoms effectively, there is a need for a technological system able to continuously and objectively assess the WO phenomenon during daily life. In this context, this paper proposes a WO tracker able to exploit neuromuscular data acquired by a dedicated wireless sensor network to discriminate between a Levodopa benefit phase and the reappearance of symptoms. The proposed architecture has been implemented on a heterogeneous computing platform, that statistically analyzes neural and muscular features to identify the best set of features to train the classifier model. Eight models among shallow and deep learning approaches are analyzed in terms of performance, timing and complexity metrics to identify the best inference engine. Experimental results on five subjects experiencing WO, showed that, in the best case, the proposed WO tracker can achieve an accuracy of ~84%, providing the inference in less than 41 ms. It is possible by employing a simple fully-connected neural network with 1 hidden layer and 32 units.

Evaluation of Simvastatin as a Disease-Modifying Treatment for Patients With Parkinson Disease

Current treatments manage symptoms of Parkinson disease (PD), but no known treatment slows disease progression. Preclinical and epidemiological studies support the potential use of statins as disease-modifying therapy. To determine whether simvastatin has potential as a disease-modifying treatment for patients with moderate PD. This randomized clinical trial, a double-blind, parallel-group, placebo-controlled futility trial, was conducted between March 2016 and May 2020 within 23 National Health Service Trusts in England. Participants aged 40 to 90 years with a diagnosis of idiopathic PD, with a modified Hoehn and Yahr stage of 3.0 or less while taking medication, and taking dopaminergic medication with wearing-off phenomenon were included. Data were analyzed from May 2020 to September 2020, with additional analysis in February 2021. Participants were allocated 1:1 to simvastatin or matched placebo via a computer-generated random sequence, stratified by site and Hoehn and Yahr stage. In the simvastatin arm, participants entered a 1-month phase of simvastatin, 40 mg daily, followed by 23 months of simvastatin, 80 mg daily, before a 2-month washout period. The prespecified primary outcome was 24-month change in Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) part III score measured while not taking medication (high scores indicate worse outcome). The primary futility analysis included participants who commenced the 80-mg phase and had valid primary outcome data. The safety analysis included all participants who commenced trial treatment and is reported by dose at time of event. Of 332 patients assessed for eligibility, 32 declined and 65 were ineligible. Of 235 recruited participants, 97 (41%) were female, 233 (99%) were White, and the mean (SD) age was 65.4 (9.4) years. A total of 216 patients progressed to the 80-mg dose. Primary outcome analysis (n = 178) indicated the simvastatin group had an additional deterioration in MDS-UPDRS III score while not taking medication at 24 months compared with the placebo group (1.52 points; 2-sided 80% CI, -0.77 to 3.80; 1-sided futility test P = .006). A total of 37 serious adverse events (AEs), including 3 deaths, and 171 AEs were reported for participants receiving 0-mg simvastatin; 37 serious AEs and 150 AEs were reported for participants taking 40 mg or 80 mg of simvastatin. Four participants withdrew from the trial because of an AE. In this randomized clinical trial, simvastatin was futile as a disease-modifying therapy in patients with PD of moderate severity, providing no evidence to support proceeding to a phase 3 trial. ISRCTN Identifier: 16108482.

Safety and effectiveness of istradefylline as add-on therapy to levodopa in patients with Parkinson's disease: Final report of a post-marketing surveillance study in Japan

IntroductionIstradefylline is approved in Japan and the US for treatment of Parkinson's disease (PD) in adult patients who experience the wearing-off phenomenon while receiving levodopa; however, safety and efficacy data for real-world clinical use are lacking. MethodsWe report the final results of a prospective, long-term, post-marketing surveillance study of istradefylline adjunct to levodopa for adults with PD experiencing the wearing-off phenomenon. Patients across 214 study sites initiating treatment with oral istradefylline once-daily 20- or 40-mg were followed-up for 1 year. We collected demographic data, disease and treatment histories, and recorded adverse events and adverse drug reactions (ADRs). The priority survey item was the occurrence of psychiatric ADRs. Effectiveness was evaluated by the physician's global and motor function assessments. ResultsCase report forms were collected for 1320 patients, and the safety and effectiveness analysis sets included 1318 and 1284 patients, respectively. The mean age was 71.5 years and 56.2% of patients were women. A total of 274 patients (20.8%) experienced an ADR, 39 patients had a serious ADR, and 7 patients had a fatal ADR that was considered not related to istradefylline. Common ADRs included dyskinesia, hallucination, and visual hallucination. Sixty-five patients (4.9%) experienced a psychiatric ADR. Istradefylline was effective (physician-rated) in 59.8% of patients, and most patients had reduced or unchanged off-time duration, improved or unchanged off-time symptoms, and improved or unchanged motor symptoms. ConclusionIstradefylline safely and effectively improves motor symptoms in PD patients experiencing the wearing-off phenomenon with levodopa therapy in the real-world setting.