Motor Fluctuations Research Articles

Tremor in Parkinson’s Disease: From Pathophysiology to Advanced Therapies

Background:Tremor is one of the most prevalent symptoms in Parkinson’s Disease (PD). The progression and management of tremor in PD can be challenging, as response to dopaminergic agents might be relatively poor, particularly in patients with tremor-dominant PD compared to the akinetic/rigid subtype. In this review, we aim to highlight recent advances in the underlying pathogenesis and treatment modalities for tremor in PD.Methods:A structured literature search through Embase was conducted using the terms “Parkinson’s Disease” AND “tremor” OR “etiology” OR “management” OR “drug resistance” OR “therapy” OR “rehabilitation” OR “surgery.” After initial screening, eligible articles were selected with a focus on published literature in the last 10 years.Discussion:The underlying pathophysiology of tremor in PD remains complex and incompletely understood. Neurodegeneration of dopaminergic neurons in the retrorubral area, in addition to high-power neural oscillations in the cerebello-thalamo-cortical circuit and the basal ganglia, play a major role. Levodopa is the first-line therapeutic option for all motor symptoms, including tremor. The addition of dopamine agonists or anticholinergics can lead to further tremor reduction. Botulinum toxin injection is an effective alternative for patients with pharmacological-resistant tremor who are not seeking advanced therapies. Deep brain stimulation is the most well-established advanced therapy owing to its long-term efficacy, reversibility, and effectiveness in other motor symptoms and fluctuations. Magnetic resonance-guided focused ultrasound is a promising modality, which has the advantage of being incisionless. Cortical and peripheral electrical stimulation are non-invasive innovatory techniques that have demonstrated good efficacy in suppressing intractable tremor.

The Efficacy of Safinamide in the Management of Parkinson's Disease: A Systematic Review.

Parkinson's disease (PD) is a chronic neurodegenerative disease that is challenging to treat due to its progressive nature and its weaning response to therapy. Safinamide, a monoamine oxidase type-B inhibitor (MAOB-I), has shown promise in managing dyskinesias caused by levodopa (L-dopa), carbidopa, and PD features such as pain and depression. This systematic review aimed to evaluate safinamide's efficacy as a monotherapy and an add-on in tackling these issues. We composed this systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Our group searched the following databases: Manchester University Library, ScienceDirect, Google Scholar, PubMed, PubMed Central, and MedLine for articles produced in the last ten years using various search terms and criteria, which we outlined in the search strategy and eligibility criteria sections. We excluded 722 out of the initially screened 730 records for multiple reasons, such as titles and abstracts being irrelevant to the topic, articles without free full access, articles originally not in the English language, and articles that did not score 70% or above on their respective quality assessment tools. The studies explored supported safinamide's use in managing motor fluctuations, pain, depression, and improving patients' quality of life.

Non-motor symptoms burden in motor-fluctuating patients with Parkinson’s disease may be alleviated by safinamide: the VALE-SAFI study

Parkinson’s disease (PD) is characterized by motor symptoms often experienced in concomitance with non-motor symptoms (NMS), such as depression, apathy, pain, sleep disorders, and urinary dysfunction. The present study aimed to explore the effect of safinamide treatment on NMS and quality of life in motor-fluctuating PD patients. VALE-SAFI is an observational single-centre study performed in fluctuating PD patients starting safinamide treatment and followed for 6 months. The effects of safinamide on NMS, sleep, fatigue, depression and pain were assessed through validated sales. Changes in the scales from baseline to the 6-month follow-up visit were analysed. 60 PD patients (66.67% males) were enrolled at baseline, and 45 patients completed the 6-month follow-up. PD patients improved motor symptoms at follow-up, with the significant reduction of motor fluctuations. The global score of the NMS Scale significantly decreased between baseline and the follow-up. Regarding pain domains, patients reported a significant improvement in discolouration and oedema/swelling. Further, a significant improvement was observed from baseline to follow-up in sleep quality measured through the Pittsburgh Sleep Quality Index, while no changes were documented in daytime sleepiness. No differences were found in depression and fatigue between baseline and follow-up. Finally, the patient’s perception of the impact of PD on functioning and well-being decreased from baseline to follow-up. The present findings confirmed the beneficial effect of safinamide on both motor and non-motor symptoms, also improving the quality of life of PD patients. Furthermore, these data support the positive effects of safinamide on pain and mood, as well as on sleep quality and continuity.

A Review on Response to Device-Aided Therapies Used in Monogenic Parkinsonism and GBA Variants Carriers: A Need for Guidelines and Comparative Studies.

Parkinson’s disease (PD) is in some cases predisposed-or-caused by genetic variants, contributing to the expression of different phenotypes. Regardless of etiology, as the disease progresses, motor fluctuations and/or levodopa-induced dyskinesias limit the benefit of pharmacotherapy. Device-aided therapies are good alternatives in advanced disease, including deep brain stimulation (DBS), levodopa-carbidopa intestinal gel, and continuous subcutaneous infusion of apomorphine. Candidate selection and timing are critical for the success of such therapies. Genetic screening in DBS cohorts has shown a higher proportion of mutation carriers than in general cohorts, suggesting that genetic factors may influence candidacy for advanced therapies. The response of monogenic PD to device therapies is not well established, and the contribution of genetic information to decision-making is still a matter of debate. The limited evidence regarding gene-dependent response to device-aided therapies is reviewed here. An accurate understanding of the adequacy and responses of different mutation carriers to device-aided therapies requires the development of specific studies with long-term monitoring.

Effect of Opicapone on Levodopa Pharmacokinetics in Patients with Fluctuating Parkinson's Disease.

Inhibiting catechol-O-methyltransferase extends the plasma half-life of levodopa, potentially allowing physicians to optimize the levodopa regimen in patients with Parkinson's disease (PD) experiencing motor fluctuations. To evaluate the effects of once-daily opicapone on levodopa plasma pharmacokinetics and motor response when added to two different levodopa dosing regimens. A total of 24 patients with PD and motor fluctuations were enrolled in an exploratory, open-label, modified cross-over trial. Participants first received levodopa/carbidopa 500/125 mg (five intakes) for 2 weeks and were then randomly assigned (1:1) to levodopa/carbidopa 400/100 mg given over either four or five daily intakes plus opicapone 50 mg for an additional 2 weeks. Levodopa 12-hour pharmacokinetics was the primary outcome (ie, excluding the effect of last/evening levodopa/carbidopa intake), with motor complications evaluated as secondary outcomes. Over 12-hour pharmacokinetics and compared with five-intake levodopa/carbidopa 500/125 mg without opicapone, maximal levodopa concentrations were similar or nonsignificantly higher on both levodopa/carbidopa 400/100 mg regimens plus opicapone. Despite a 100 mg lower total levodopa/carbidopa daily dose, adding opicapone 50 mg at least doubled the levodopa plasma half-life and minimal concentrations, with a significant ≈30% increase in total exposure. The levodopa fluctuation index was only significantly lower for the five intakes plus opicapone regimen (difference of -71.8%; P< 0.0001). Modifications to levodopa pharmacokinetics were associated with decreased off time and increased on time. Combining opicapone 50 mg with a 100 mg lower daily dose of levodopa provides higher levodopa bioavailability with avoidance of trough levels. Despite the lower levodopa dose, modifying the levodopa pharmacokinetic profile with opicapone was associated with decreased off time and increased on time. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Rasagiline as Adjunct to Levodopa for Treatment of Parkinson’s Disease: A Systematic Review and Meta-Analysis

Background Rasagiline is a selective, irreversible monoamine oxidase type B inhibitor used as monotherapy in early Parkinson's disease and as an adjunct therapy to levodopa in Parkinson's disease with motor fluctuations. Objectives This meta-analysis aimed to provide updated evidence on the efficacy for motor and nonmotor symptoms and the safety of rasagiline/levodopa versus levodopa in patients with Parkinson's disease experiencing motor fluctuations. Methods A systematic literature search was conducted (January 18-19, 2021) using PubMed, Cochrane Library, EMBASE, Web of Science, and Google Scholar to identify randomized controlled trials comparing rasagiline/levodopa versus placebo/levodopa in patients with Parkinson's disease experiencing motor fluctuations. Outcomes included change in wearing-off time, Unified Parkinson's Disease Rating Scale (UPDRS)/Movement Disorder Society-UPDRS (MDS-UPDRS) II and III scores, treatment-emergent adverse events (TEAEs), and Parkinson's Disease Questionnaire (PDQ-39) summary index score. A random effect model was used to estimate the treatment effects. Results Six studies were included (1912 patients). Significant improvements in wearing-off time (standardized mean difference [SMD]: −0.50, 95% confidence interval [CI]: –0.92 to –0.09, p = 0.002), levodopa dosage (SMD: −0.18, 95% CI: −0.35 to –0.01, p = 0.041), UPDRS/MDS-UPDRS II (SMD: −0.39, 95% CI: −0.52 to –0.25, p < 0.0001), UPDRS/MDS-UPDRS III (SMD: −0.30, 95% CI: −0.44 to –0.16, p < 0.0001), and PDQ-39 summary index score (SMD: –0.21, 95% CI: –0.37 to –0.04, p = 0.013) were observed with rasagiline/levodopa versus placebo/levodopa. The incidence of TEAEs did not differ between treatments (risk ratio: 1.13, 95% CI: 0.98–1.30, p = 0.093). Conclusions This meta-analysis further indicated the superiority of rasagiline/levodopa in improving motor and nonmotor symptoms of Parkinson's disease, with a similar safety profile to that of levodopa in Parkinson's disease with motor fluctuations.

Do we start too late? Insights from the real-world non-interventional BALANCE study on the present use of levodopa/carbidopa intestinal gel in advanced Parkinson's disease in Germany and Switzerland

IntroductionAdvanced Parkinson's disease is characterized by motor and non-motor fluctuations to oral dopamine replacement therapy. The BALANCE study evaluated the clinical practice in Germany and Switzerland, when patients eligible for levodopa/carbidopa intestinal gel (LCIG) therapy decided to either switch to LCIG or to stay on optimized standard of care (SoC) oral therapy as a non-randomized regular clinical decision. MethodsIn this non-interventional, multicenter, prospective observational study, patients were recruited between 2015 and 2020. We obtained comprehensive baseline characteristics in both groups. As primary endpoint, we evaluated whether LCIG led to higher quality-of-life (QoL) improvement than SoC after 12 months. As secondary endpoints, we studied several motor and non-motor outcomes. ResultsAbout half of the 137 patients decided for LCIG treatment (n = 73, 53.5%). Those were aged >70 years more often, had more advanced disease stage, higher burden of motor and neuropsychiatric symptoms, and cognitive impairment including dementia compared to SoC. QoL change after 12 months did not differ between groups (P = 0.286). The LCIG group improved in secondary outcomes, including the UPDRS III in ON, UPDRS IV, Unified Dyskinesia Rating Scale, and Non-Motor Symptoms Scale. Clinical Global Impression-Improvement scale improved in 78.0% and 19.5% of patients receiving LCIG and SoC, respectively. Caregiver burden remained stable in LCIG but worsened with SoC. ConclusionIn current practice, patients and physicians delayed LCIG treatment and started substantially beyond the established indication criteria. This practice bears the risk to produce inferior results compared to the results from existing high-level evidence.

The safety/tolerability of opicapone when used early in Parkinson's disease patients with levodopa-induced motor fluctuations: A post-hoc analysis of BIPARK-I and II

IntroductionPost-hoc analyses of the BIPARK-I and II trials previously demonstrated that opicapone (OPC) 50 mg was efficacious over the whole trajectory of motor fluctuation evolution in patients with Parkinson's disease (PD) and end-of-dose motor fluctuations, with enhanced efficacy in patients who were earlier vs. later in their disease course and levodopa treatment pathway. Complementary post-hoc analyses were performed to evaluate the safety/tolerability of OPC following the same pre-defined segmentation of the wide spectrum of duration of both PD and levodopa therapy, as well as of motor fluctuation history, in this patient population.Materials and methodsData from matching treatment arms in BIPARK-I and II were combined for the placebo (PLC) and OPC 50 mg groups and exploratory post-hoc analyses were performed to investigate the safety/tolerability of OPC 50 mg and PLC in 22 subgroups of patients who were in “earlier” vs. “later” stages of both their disease course (e.g., duration of PD <6 years vs. ≥6 years) and levodopa treatment pathway (e.g., levodopa treatment duration <4 vs. ≥4 years). Safety/tolerability assessments included evaluation of treatment-emergent adverse events (TEAEs).ResultsThe Safety Set included 522 patients (PLC, n = 257; OPC 50 mg, n = 265). For OPC 50 mg, incidences of TEAEs, related TEAEs, related serious TEAEs, and related TEAEs leading to discontinuation were lower for patients in earlier vs. later stages of their disease course and levodopa treatment pathway in 86.4, 86.4, 63.6, and 68.2% of the 22 pairwise comparisons conducted, respectively (compared with 63.6, 77.3, 18.2, and 45.5%, respectively, in the 22 corresponding PLC comparisons).ConclusionOPC 50 mg was generally well-tolerated when used to treat patients with PD with end-of-dose fluctuations, with an even more favorable tolerability profile in patients who were earlier, as opposed to later, in their disease course and levodopa treatment pathway, further supporting its use as an early adjunct to levodopa in PD.

Characterization of Non-Motor Fluctuations Using the Movement Disorder Society Non-Motor Rating Scale.

BackgroundNon‐motor fluctuations (NMF) in people with Parkinson's disease (PwP) are clinically important yet understudied.ObjectiveTo study NMF in PwP using both the Movement Disorder Society Non‐Motor Rating Scale (MDS‐NMS) NMF subscale and wearable sensors.MethodsWe evaluated differences in overall burden of NMF and of specific NMF across disease durations: <2 years (n = 33), 2–5 years (n = 35), 5–10 years (n = 33), and > 10 years (n = 31). In addition, wearable triaxial sensor output was used as an exploratory outcome for early morning “off” periods.ResultsSignificant between‐group differences were observed for MDS‐NMS NMF total scores (P < 0.001), and specifically for depression, anxiety, fatigue and cognition, with both NMF prevalence and burden increasing in those with longer disease duration. Whereas only 9.1% with a short disease duration had NMF (none of whom had dyskinesia), in PwP with a disease duration of >10 years this was 71.0% (P < 0.001). From a motor perspective, dyskinesia severity increased evenly with increasing disease duration, while NMF scores in affected individuals showed an initial increase with largest differences between 2–5 years disease duration (P < 0.001), with plateauing afterwards. Finally, we observed that the most common NMF symptoms in patients with sensor‐confirmed early morning “off” periods were fluctuations in cognitive capabilities, restlessness, and excessive sweating.ConclusionsNon‐motor fluctuations prevalence in PwP increases with disease duration, but in a pattern different from motor fluctuations. Moreover, NMF can occur in PwP without dyskinesia, and in those with NMF the severity of NMF increases most during years 2–5 after diagnosis.

Evaluating Opicapone as Add-on Treatment to Levodopa/DDCI in Patients with Parkinson's Disease.

COMT (catechol-O-methyltransferase) inhibitors are key therapeutic agents in the management of motor fluctuations (MF) in patients with Parkinson’s disease (PD). As levodopa/DDCI add-on therapy, their main benefit lies in increasing ON-time and reducing OFF-time for PD patients in the middle stages of the disease. Two of the three available COMT inhibitors, tolcapone and entacapone, have been approved for over two decades.Opicapone, a third-generation COMT inhibitor approved in 2016, was designed with the aim of overcoming specific challenges of the earlier generation compounds, specifically hepatotoxicity and short effect duration. This review aims at highlighting the specific properties and characteristics of opicapone, namely combining efficacy with good tolerability as demonstrated in the registration studies and since then confirmed under real-world conditions. Opicapone has been shown to be effective in patients with early, as well as late motor fluctuations. Whilst patients in the earlier Hoehn and Yahr stages benefit more than patients in later stages, the incidence of dyskinesia in patients with recent onset MF is around half that of patients with more established fluctuations. With the added advantage of a once-daily administration, this particular COMT inhibitor provides a simple, yet effective therapy for patients with Parkinson’s disease and MF.

High-dose versus low-dose inhaled levodopa (CVT-301) in patients with Parkinson disease for the treatment of OFF episodes: a meta-analysis of randomized controlled trials.

Levodopa is the most commonly used first-line drug for Parkinson's disease. However, during the period of medication, the generation of motor fluctuations affects the life quality of patients. CVT-301, as an inhaled levodopa for the treatment of OFF episodes, rose in response to this condition. We systematically searched Medline, EMBASE, Cochrane Library, and Clinicaltrials.gov for relevant randomized controlled trials, from the earliest available date to February 12, 2022, to evaluate the efficacy of high and low dose of inhaled levodopa in patients with Parkinson's disease. A total of six multicenter, randomized controlled trials with 1166 patients were included. Compared with placebo, CVT-301 has a statistically significant effect on the treatment of Parkinson's patients with OFF episodes of medication interval. The UPDRS Part III score decreased more significantly in the high-dose group 30minutes after administration than the low-dose group (WMD = - 4.51; 95% CI, - 7.34 to - 1.68; p = 0.002). More patients in the high-dose group achieved and maintained an on state up to 60min after receiving study medication (RR = 1.17; 95% CI, 1.08 to 1.27; p < 0.001). And more patients were proved with improved PGIC scores in the high-dose group (RR = 1.13; 95% CI, 1.05 to 1.21; p = 0.001). High doses CVT-301 can improve the motor function of the patient to some extent. There seems no risk of increasing adverse reactions.

Frequency of adverse events in Levodopa‐carbidopa intestinal gel treatment: A retrospective real life study.

• Levodopa‐Carbidopa Intestinal Gel infusion (LCIG) in advanced stages of Parkinson's Disease is proven to significantly reduce motor fluctuations and dyskinesia compared to oral levodopa. • It is a very complex therapy requiring a lot of effort from the healthcare staff and a close collaboration between neurologists and gastroenterologists. • Complications with the procedure and with the device are common, presenting in more than 60% of patients. • A lot of complications will be solved improving the devices used for the endoscopic procedures, the better maintenance of the skin around the stoma and greater interaction among patients, caregivers and healthcare professionals.

Long‐term efficacy of bilateral subthalamic deep brain stimulation in the parkinsonism of SCA 3: A rare case report

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant inherited disorder that manifests as a mixture of cerebellar ataxia, parkinsonism, and polyneuropathy; in type IV SCA3, pure parkinsonism is the only symptom. Currently, no disease-modifying treatment is available, but variable responses to antiparkinsonism agents have been reported. However, the benefits of deep brain stimulation (DBS) for treating parkinsonism in this subtype of SCA3remain unclear. A 39-year-old male patient with a rare disorder of type IV SCA3 presented with pure parkinsonism including unilateral resting tremor, rigidity, and bradykinesia at the age of 30 years. Young-onset Parkinson disease was diagnosed at the age of 32 years. His family history revealed a mild ataxia in his father since the age of 55 years. Genetic testing confirmed an expanded CAG repeated number, with 66 in this case and 63 in his father for SCA3mutation. Excellent response to levodopa and dopamine agonists in the first 3years was noted, but wearing-off phenomena, levodopa-induced dyskinesia, and severe impulse control disorders later developed. To alleviate drug-induced complications, he received bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in the absence of cerebellar signs, depression, and cognitive impairment. As of 2019, no impulsive control disorders, motor fluctuations, or DBS-related complications were observed during a 4-year follow-up, with 66% Unified Parkinson's Disease Rating Scale Part III reduction at medication OFF state noted, whereas levodopa equivalent daily dosage decreased by almost half. STN-DBS may be considered as adjunct treatment for severe dopa-related motor/nonmotor complications in patients with parkinsonian phenotype of SCA 3.

Objective Observer vs. Patient Motor State Assessments Using the PD Home Diary in Advanced Parkinson's Disease.

BackgroundThe Parkinson Disease (PD) Home Diary (HD) is a commonly used clinical outcome measure, but it has not been extensively compared to direct assessments by experienced observers.ObjectiveValidation of patient-reported HD by investigating the agreement between motor state assessments by patients and observers.MethodsThis observational study included patients with PD and motor fluctuations. Observers were physicians or research nurses. Patients completed a screening visit, one day of diary ratings at home, and then two days of ratings on-site during which patients and observers simultaneously judged the participants' motor state.ResultsObservers and 40 patients completed 1,288 pairs of half-hourly blinded motor state assessments. There were significant differences between observer and patient ratings (P < 0.001) and the temporal agreement was poor (Cohen's κ = 0.358). The agreement between patient and observer ratings was 71.1% for observed “On without dyskinesia”, 57.3% for observed “Off”, and 49.4% for observed “On with dyskinesia”. Daily times spent in the three motor states as aggregated diary data showed fair to excellent reliability with intraclass coefficient values ranging from 0.45 to 0.52 for “On” and 0.77 for “Off”.ConclusionThere were significant differences between observer and patient ratings. Patients and observers generally agreed on when the patients was in the “On” state (with or without dyskinesia). Patient ratings on the hour level seem to be influenced by other aspects of the patients' experience than the observed motor state, but assessment of daily time spent in the different motor state provides reasonable reliability.

Movement disorders in COVID-19 times: impact on care in movement disorders and Parkinson disease.

The purpose of this review is to outline the impact of the COVID-19 pandemic on movement disorder holistic care, particularly in the care of people with Parkinson disease (PWP). As the pandemic unfolds, a flurry of literature was published regarding the impact of COVID-19 on people with Parkinson disease including the direct impact of infection, availability of ambulatory care, loss of community-based team care, and acceptability of telemedicine. COVID-19 has impacted the care of PWP in numerous ways. Recognizing infection in PWP poses challenges. Specific long-term complications, including emerging reports of long COVID syndrome is a growing concern. Caregivers and PWP have also been impacted by COVID-19 social isolation restrictions, with radical changes to the structure of social networks and support systems globally. In a matter of weeks, the global community saw an incredible uptake in telemedicine, which brought benefits and pitfalls. As PWP adapted to virtual platforms and the changing architecture of care delivery, the pandemic amplified many preexisting inequities amongst populations and countries, exposing a new 'digital divide'.

Newly Approved and InvestigationalDrugsfor Motor Symptom Control in Parkinson's Disease.

Motor symptoms are a core feature of Parkinson’s disease (PD) and cause a significant burden on patients’ quality of life. Oral levodopa is still the most effective treatment, however, the motor benefits are countered by inherent pharmacologic limitations of the drug. Additionally, with disease progression, chronic levodopa leads to the appearance of motor complications including motor fluctuations and dyskinesia. Furthermore, several motor abnormalities of posture, balance, and gait may become less responsive to levodopa. With these unmet needs and our evolving understanding of the neuroanatomic and pathophysiologic underpinnings of PD, several advances have been made in defining new therapies for motor symptoms. These include newer levodopa formulations and drug delivery systems, refinements in adjunctive medications, and non-dopaminergic treatment strategies. Although some are in early stages of development, these novel treatments potentially widen the available options for the management of motor symptoms allowing clinicians to provide an individually tailored care for PD patients. Here, we review the existing and emerging interventions for PD with focus on newly approved and investigational drugs for motor symptoms, motor fluctuations, dyskinesia, and balance and gait dysfunction.

Istradefylline for OFF Episodes in Parkinson's Disease: A US Perspective of Common Clinical Scenarios.

The effective management of OFF episodes remains an important unmet need for patients with Parkinson’s disease (PD) who develop motor complications with long-term levodopa therapy. Istradefylline is a selective adenosine A2A receptor antagonist for the treatment of patients with PD experiencing OFF episodes while on levodopa/decarboxylase inhibitor. Originally approved in Japan, istradefylline was recently approved in the USA. In this article, we provide a specific review of the four clinical studies that the FDA included in the approval of istradefylline in the USA, and discuss common clinical scenarios, based on our experience, where treatment with istradefylline may benefit patients experiencing motor fluctuations.

Non-Oral Drug Delivery in Parkinson's Disease: Current Applications and Future.

Parkinson's disease (PD) is a type of movement disorder that affects the ability to perform daily activities. It is considered that 1 million people in the U.S. and more than 10 million people worldwide live with PD. It is a chronic and progressive disease, so symptoms worsen over the time. Patients experience motor symptoms such as tremors, stiffness and slow motion, and non-motor symptoms such as sleep problems, constipation, anxiety, depression and fatigue. Dopaminergic drugs are critical for treating motor symptoms in PD. Levodopa (L-DOPA) is the "gold standard" medication for the control of motor symptoms. Because of the progression of the disease, the effectiveness of oral L-DOPA decreases over time and motor fluctuations such as "delayed ON", "no ON" and unpredictable "ON-OFF" periods appear. These motor fluctuations affect the quality of life of the patient at a high rate and the patient has problems in fulfilling his daily morning routines. Gastrointestinal (GI) problems, as the common non-motor symptom, are the most important cause of motor fluctuations that occur because of inadequate oral treatment with the progression of PD. When oral treatments are not sufficient, non-oral treatments that are not affected by GI problems are required. In this review, the treatment strategies, developed and approved non-oral drug delivery systems in the early and advanced stages of PD are emphasized.

Opicapone as an add-on to levodopa for reducing end-of-dose motor fluctuations in Parkinson's disease: a systematic review and meta-analysis.

Aim: To assess the clinical efficacy and safety profile of opicapone (25 and 50mg once daily) versus placebo. Patients: Levodopa-treated adults with Parkinson's disease. Material & methods: A systematic review and meta-analysis were conducted. Results: Opicapone provided a greater reduction in the absolute OFF-time, increased the chances of ≥1-hreduction in the OFF-time and ≥1-hincrease in the ON-timecompared with placebo. Receiving opicapone more often facilitated levodopa dose reductionversus placebo. There were no differences in the occurrence of adverse events (severe and leading to drug discontinuation), but receiving opicapone increased the frequency of dyskinesia. Conclusion: Opicapone demonstrated superior clinical efficacy to placebo, with a comparable general safety profile.

Long-term independence and quality of life after subthalamic stimulation in Parkinson disease.

Background and purposeStudies on long‐term nonmotor outcomes of subthalamic nucleus stimulation in Parkinson disease (PD) are scarce. This study reports on very long‐term non‐motor and motor outcomes in one of the largest cohorts of people with advanced PD, treated for >10 years with subthalamic nucleus stimulation. The main outcome was to document the evolution of independence in activities of daily living. The secondary outcomes were to measure the change in quality of life, as well as non‐motor and motor outcomes.MethodsPatients were studied preoperatively, at 1 year, and beyond 10 years after subthalamic stimulation with an established protocol including motor, non‐motor, and neuropsychological assessments.ResultsEighty‐five people with PD were included. Independence scores in the off‐medication condition (measured with the Schwab & England Activities of Daily Living Scale) as well as quality of life (measured with the Parkinson's Disease Questionnaire [PDQ]‐37) remained improved at longest follow‐up compared to preoperatively (respectively, p < 0.001, p = 0.015). Cognitive scores, measured with the Mattis Dementia Rating Scale, significantly worsened compared to before and 1 year after surgery (p < 0.001), without significant change in depression, measured with the Beck Depression Inventory. Motor fluctuations, dyskinesias, and off dystonia remained improved at longest follow‐up (p < 0.001), with a significant reduction in dopaminergic treatment (45%, p < 0.001).ConclusionsThis study highlights the long‐term improvement of subthalamic stimulation on independence and quality of life, despite the progression of disease and the occurrence of levodopa‐resistant symptoms.