Patients with advanced Parkinson's disease (PD) often need to continue with device-aided therapies (DAT), such as intestinal and subcutaneous infusion therapies. Recently, continuous subcutaneous administration of foslevodopa/foscarbidopa (LDp/CDp) has emerged as a new therapeutic method. Two years after its approval in Germany, a large amount of real-world experience has been collected. Based on this, we present important practical recommendations to help clinicians optimise treatment. Key topics include identifying suitable patients, approaches to initiation and dose determination as well as strategies for balancing LDp/CDp with concomitant oral dopaminergic therapies. Practical challenges, particularly infusion site reactions and neuropsychiatric vulnerability in older or cognitively impaired patients, are discussed, and recommendations are presented on how to prevent and manage these adverse effects during routine management. The review also addresses reasons for discontinuation, organisational factors relevant to real-world implementation and future directions in pump technology. Overall, LDp/CDp is effective in managing motor fluctuations and provides sustained benefits with an overall favourable tolerability profile. Dermatological reactions are common but manageable, and careful adjustment of oral medication rather than rapid pursuit of monotherapy is advisable. The rate of early discontinuation has decreased with growing clinical experience.

In addition to response fluctuations caused by the pharmacokinetics of dopamine replacement medication, temporal variation in the expression and severity of motor and non-motor symptoms, which is not or only partially attributable to the effects of the medication, are also common in Parkinson's disease (PD). The spectrum of transient changes of motor symptom expression unrelated to the classical ON-OFF fluctuations ranges from brief episodes of gait freezing or tremor breakthroughs to severe akinetic crisis and non-motor phenomena include discontinuous changes in cognition and vigilance. Disease-related factors such as dementia or orthostatic dysregulation or disturbances of the circadian rhythm may also contribute to these non-pharmacological symptom fluctuations. Additionally, external factors including infections or surgery and general anaesthesia can lead to transient changes of PD symptom severity and drug responsiveness. Accurately classifying these symptom oscillations and distinguishing them from drug-induced ON-OFF fluctuations is essential for their appropriate management.

BACKGROUND:Foslevodopa/foscarbidopa (LDp/CDp) significantly reduced motor fluctuations in people with Parkinson's disease (PwP) in clinical trials, but its real-world tolerability and optimal dosing remain unclear. OBJECTIVES:To assess tolerability, dosing patterns, and modifications to concomitant medication with LDp/CDp in clinical practice. METHODS:A single-center retrospective cross-sectional analysis. RESULTS:The LDp/CDp was initiated in 53 PwP (41% women, mean age 66 ± 11.3 years, mean disease duration 14.1 ± 5.7 years, median H&Y 4 (3-5); history of cognitive impairment: 40%, history of psychosis: 62%, previous device aided therapies failure: 39%). After an optimization period (18.4 ± 6.8 days), the mean Base hourly infusion rate was significantly higher than recommended (0.39 ± 0.18 vs. 0.32 ± 0.13 ml/h, p < 0.001) and the LDp/CDp was co-administered with MAO-B-inhibitors (50%), COMT-inhibitors (44%), and dopamine agonists (12%). Adverse events occurred in 40%: skin reactions (31%), psychosis (8%), falls (2%), and nausea (2%). Thirteen patients discontinued therapy. CONCLUSIONS:LDp/CDp may be an effective and well-tolerated non-surgical option for managing motor fluctuations in PD, though higher dosing and combination therapy are often required.

Parkinson's disease is characterized by a large inter-individual variability of symptom constellations and courses. In routine clinical practice, standard treatment strategies are often used, but outcomes differ considerably from patient to patient. The definition of different Parkinson's subtypes may help to better predict the individual course of the disease and to find the most suitable treatment options for different patient groups.

BACKGROUND:Motor fluctuations are routinely documented using the Parkinson's disease (PD) home diary. However, the validity of this diary when compared to clinical observers is limited. OBJECTIVE:This study disassembled the effects of nonmotor symptoms (NMS) on inter-method agreement between the PD home motor diary and clinical observers (outside validity criterion). METHODS:A prospective observational VALIDATE-PD cohort study in advanced PD assessing symptom severity by simultaneous hourly ratings using the home diary (Off, On, dyskinetic state) and a nonmotor diary (11 key NMSs) was performed. Test validity measures (accuracy and Cohen's κ) were compared between hours with and without co-occurring NMS. RESULTS:Four hundred eighty-seven hourly time periods from 47 participants were analyzed. Inter-method agreement (accuracy, Cohen's κ) of the motor diary was independent of co-occurring NMSs, but simultaneous NMSs inversely influence false ratings of motor Off and On states. CONCLUSIONS:Simultaneously occurring NMSs do not affect general validity but the interpretation of the PD home motor diary.

BACKGROUND:Dysphagia remains a major clinical concern in multiple system atrophy (MSA), and so far, lacks relevant treatment options. OBJECTIVE:To systematically assess levodopa-responsiveness of dysphagia in MSA. METHODS:19 MSA-patients underwent endoscopic swallowing evaluation in Off- and On-state, following an adapted FEES-levodopa-test-protocol. Findings were compared between states and correlated to disease-specific and demographic factors. RESULTS:All 19 MSA-patients 70 [66-72] years, 15/4 MSA-P/ C, 10 women exhibited dysphagia. Levodopa-responsiveness of motor-impairment was poor (UPDRS-3 Off 46 [34-52] vs On 43 [40-48], P = 0.31). Dysphagia severity varied greatly. Sum-scores ranged between 9-21 in Off and 6-20 in On. MSA-P-patients were more likely to have higher sum-scores (rpb 0.41, P = 0.01). Sum-scores otherwise were independent of disease-specific and demographic factors. 3/19 MSA-patients showed marked score-improvement by ≥30% through reduced leaking and aspiration but remained unchanged for the majority. Scores worsened in 2/19 patients. In the group analysis, the median dysphagia-score remained unchanged (2 [1, 2], P = 0.28). The occurrence of leaking, pharyngeal residue, penetration, and aspiration was not changed (P = 0.13-0.19). Severity of leaking was reduced (3 [2-4] vs. 0[0.5-1], P < 0.0001), while severity of pharyngeal residue, penetration, and aspiration remained unchanged (P = 0.29-0.53). Liquids were more often associated with leaking (P < 0.05) and aspiration (P < 0.005). All patients exhibited laryngeal movement disorders, with irregular arytenoid cartilage movements (iACM) being observed in all patients, regardless of levodopa-state. CONCLUSION:The levodopa-response in MSA-related dysphagia varies greatly. Some patients might improve markedly, necessitating individual assessments to tailor patient-specific therapies. Non-pharmacological measures should be investigated to address dysphagia in MSA. IACM again proved to be highly prevalent in MSA.

BACKGROUND:With the introduction of sensing-enabled deep brain stimulation devices, characterization of long-term biomarker dynamics is of growing importance for treatment optimization. The microlesion effect is a well-known phenomenon of transient clinical improvement in the acute post-operative phase. While beta band activity is confirmed as a reliable biomarker for bradykinesia using chronic recordings, little is known about the ideal time point for initial electrophysiology-based programming. OBJECTIVE:To investigate the microlesion effect impact in chronic biomarker recordings. METHODS:Subthalamic peak biomarker power was continuously recorded during the first 40 post-operative days in 12 Parkinson's disease patients implanted with a sensing-enabled neurostimulator. Daily change in mean peak power and complexity was analyzed. Additionally, power spectral density at rest was compared between immediate postoperative period and three-months-follow-up. We additionally present continuous pallidal recordings in 2 dystonia patients. RESULTS:Mean peak power increased postoperatively, and the rate of change stabilized at 22-29 days. Peak power complexity showed a decrease in the number of recurrence states and laminarity, stabilizing around the same time point. Biomarker activity showed a significant increase at 3-month-follow up compared to the early post-operative phase. The microlesion effect was clinically reflected as a decrease in pre-vs. postoperative medication before setting of chronic stimulation parameters. CONCLUSIONS:The transient postoperative microlesional effect is characterized by reduced beta band power and reduced neural signal complexity that gradually stabilize towards the end of the first month after surgery and most likely reflect local neuronal adaptation. These findings are important for the timing of electrophysiology-supported DBS programming, such as contact selection or adaptive algorithms.

BackgroundLevodopa is the mainstay of Parkinson’s disease (PD) therapy, but its long-term use is often complicated by the development of motor fluctuations. While COMT inhibitors, such as opicapone, are routinely used for managing motor fluctuations, recent evidence has suggested that earlier vs. later intervention, at onset of motor fluctuations, may provide greater benefits. However, the longer-term impact of earlier intervention has not been well studied.MethodsThis pooled subgroup analysis included data from randomized, 14–15 week, double-blind, placebo-controlled trials of opicapone and their 1-year open-label extensions. Exploratory analyses included all participants who were randomized to placebo or opicapone 50 mg, who continued opicapone into the open-label extension, and had developed motor fluctuations within 2 years before double-blind screening. Motor status was assessed using 24-h patient diaries and Unified Parkinson’s Disease Rating Scale (UPDRS) scores.ResultsThis post-hoc analysis included 227 patients who had been diagnosed with motor fluctuations within the prior 2 years (opicapone n = 117, placebo n = 110). Opicapone 50 mg significantly reduced daily OFF-time compared to placebo (mean placebo-adjusted reduction: –65.6 [95%CI, −105.5, −25.6] minutes, p = 0.0014) and increased Good ON-time (mean placebo-adjusted increase of: 88.3 [95% CI, 47.0, 129.6] minutes, p < 0.0001). Participants switching from double-blind placebo to open-label opicapone demonstrated the expected reductions in motor fluctuations. However, at the end of the open-label phase, those who started opicapone earlier maintained greater numeric reductions in OFF-time (mean treatment difference of −30.0 [95%CI, −74.8, 14.8] minutes, p = 0.2) and increases in total Good ON-time over 1 year (mean treatment difference of 38.2 [95%CI, −6.6, 82.9] minutes, p = 0.09) vs. those who switched from placebo. Mean levodopa doses remained stable throughout both the double-blind and open-label phases in both groups, indicating that the symptomatic benefits of opicapone were achieved without the need for increased levodopa dosing. There was no significant increase in troublesome dyskinesia.ConclusionEarly initiation of opicapone in PD patients with recently diagnosed motor fluctuations leads to sustained reductions in OFF-time and improvements in ON-time, without increasing dyskinesia or requiring escalation of levodopa doses. These exploratory findings support revising treatment strategies to include earlier use of opicapone, maximizing long-term benefits for patients with fluctuating PD.

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.

Background: Stigma is a relevant aspect of Parkinson’s disease (PD). Specific stigma tools are needed to address the complex construct of stigma in PD comprehensively. Objective: To test the dimensionality and psychometric properties of the newly developed Parkinson’s Disease Stigma Questionnaire (PDStigmaQuest). Methods: In this multi-center, cross-sectional study including PD patients and healthy controls, the dimensionality of the PDStigmaQuest was examined through exploratory factor analysis. Acceptability and psychometric properties were investigated. PDStigmaQuest scores of patients and healthy controls were compared. Results: In total, 201 PD patients and 101 healthy controls were included in the final analysis. Results suggested high data quality of the PDStigmaQuest (0.0001% missing data for patients). The exploratory factor analysis produced four factors: felt stigma, hiding, enacted stigma: rejection, and enacted stigma: patronization, explaining 47.9% of variance. An optional work domain for employed patients was included. Moderate floor effects and skewness, but no ceiling effects were found. Cronbach’s alpha of 0.85 indicated high internal consistency. Calculated item-total correlations met standard criteria. Test-retest reliability was high ( rs = 0.83). PDStigmaQuest scores correlated significantly with other stigma measures ( rs = 0.56–0.69) and were significantly higher in patients than in healthy controls and higher in patients with depressive symptoms than in those without. Conclusions: The patient-reported 18-item PDStigmaQuest showed strong psychometric properties of validity and reliability. Our results suggest that the PDStigmaQuest can be used to assess and evaluate stigma comprehensively in PD, which will improve our understanding of the construct of PD stigma.

BACKGROUND AND OBJECTIVE:There are multiple pharmacological treatment options for motor symptoms of Parkinson's disease (PD). These comprise multiple drug classes which are approved for the condition, including levodopa, dopamine agonists, COMT inhibitors, MAO-B inhibitors, NMDA-receptor antagonists, anticholinergics, and others. Some of the drugs are approved for monotherapy and combination therapy while others are only approved as adjunctive therapy to levodopa. Furthermore, treatment for special treatment situations, e.g., rescue medication for off-phases, for tremor, treatment during pregnancy and breast feeding is discussed and recommendations are given with further details. METHODS:The recommendations were based on systematic literature reviews, drafted by expert teams, consented in online polls followed by online consensus meetings of the whole German Parkinson's Guideline Group, and publicly released in November 2023. RESULTS:In the new S2k (i.e., consensus-based) guidelines, the pharmacotherapy of the motor symptoms of PD is discussed in five chapters. These comprise "Parkinson medication", "Initial monotherapy", "Early combination therapy", "Fluctuations and dyskinesia", and "Parkinsonian tremor". Furthermore, there is a chapter for special treatment situations, including perioperative management, freezing of gait, and pregnancy and breastfeeding. CONCLUSION:The recommendations for the pharmacotherapy of motor symptoms of PD have been updated. Newly available drugs have been added, while other drugs (e.g., ergoline dopamine agonists, anticholinergics, budipine) have been removed from the recommendations.

Background: Visual acuity and image stability are crucial for daily activities, particularly during head motion. The vestibulo-ocular reflex (VOR) and its suppression (VORS) support stable fixation of objects of interest. The VOR drives a reflexive eye movement to counter retinal slip of a stable target during head motion. In contrast, VORS inhibits this countermovement when the target stimulus is in motion. The VORS allows for object fixation when it aligns with the direction of the head’s movement, or when an object within or outside the peripheral vision needs to be focused upon. Summary: Deficits of the VORS have been linked to age-related diseases such as balance deficits associated with an increased fall risk. Therefore, the accurate assessment of the VORS is of particular clinical relevance. However, current clinical assessment methods for VORS are mainly qualitative and not sufficiently standardised. Recent advances in digital health technology, such as smartphone-based videooculography, offer a promising alternative for assessing VORS in a more accessible, efficient, and quantitative manner. Moreover, integrating mobile eye-tracking technology with virtual reality environments allows for the implementation of controlled VORS assessments with different visual inputs. These assessment approaches allow the extraction of novel parameters with potential pathomechanistic and clinical relevance. Key Messages: We argue that researchers and clinicians can obtain a more nuanced understanding of this ocular stabilisation reflex and its associated pathologies by harnessing digital health technology for VORS assessment. Further research is warranted to explore the technologies’ full potential and utility in clinical practice.

Background:Pain fluctuations are a characteristic phenomenon in advanced Parkinson's disease (PD), but their temporal association with motor and non-motor symptom (NMS) fluctuations remains largely enigmatic. Moreover, data on their importance for disease severity perception and health-related quality-of-life (hr-QoL) is limited. Objective:To dissect pain fluctuations with respect to pain type and frequency patterns, and their association with motor and non-motor fluctuations. Methods:Prospective observational cohort study in advanced PD assessing symptom fluctuations by simultaneous hourly ratings using the PD Home diary (Off, On, Dyskinetic state), a pain diary (assessing 9 pain types) and a non-motor diary (10 key NMS) based on validated instruments. Results:Forty-seven out of 55 eligible participants with fluctuating PD (51% men, median age 65, median disease duration 10 years) had sufficient datasets (>95% of hours) from 2 consecutive days. Pain was reported in 35% of waking hours with clear circadian rhythm peaking in early morning Off periods and clustering during motor Off state (49% of Off state hours with pain). Main NMS co-fluctuating with pain were "Fatigue" and "Inner Restlessness". Simultaneous assessment of global disease severity by participants revealed that pain was associated with worse disease severity only in motor On and Dyskinetic state but not in Off state, which translated into significant correlations of daily pain times with hr-QoL only during motor On and Dyskinetic state. Conclusions:Aside from treating motor Off periods, specific recognition of pain particularly during motor On and Dyskinetic state comprises an important aspect for disease management in advanced PD.

BACKGROUND:Parkinson's disease (PD) significantly impacts the health-related quality of life of affected individuals and their relatives. In order to support the affected individuals and their families in coping with PD, it is essential to offer comprehensive information about their experiences. A comprehensive understanding of their lived experiences with the disease, the healthcare system, applied self-management strategies and their needs is considered crucial for developing a PD support program. Therefore, we aimed to explore the lived experiences and support needs of individuals with PD and their relatives in Germany.METHODS:This non-interventional, qualitative study conducted an explorative status quo and needs assessment. It generated knowledge through semi-structured focus groups and interviews with individuals with PD at various disease stages and their relatives. The interviews were digitally recorded, transcribed verbatim, and analysed using content analysis.RESULTS:Fifty-two individuals with PD and 29 relatives participated in eight focus groups and 13 paired and 13 individual interviews. Four themes with corresponding subthemes emerged: (1) experiences, revealing individuals' experiences around their diagnosis and with disease-specific care provision; (2) management support offers, clarifying who provides support and the type of support offered; (3) self-management, including comprehensibility, meaningfulness and manageability; and (4) future needs, differentiating between deficits and needs. Most participants expressed a sense of abandonment when obtaining self-management strategies and mastering their lives with PD, often referred to as 'life 2.0'. They identified the lack of structured and adequate provision of information, system orientation and social awareness.CONCLUSIONS:In Germany, there is an urgent need for a comprehensive PD care program that addresses the needs of individuals with PD and their relatives from the start of their care trajectory. It could assist individuals in gaining a comprehensive understanding of the disease, obtaining self-management strategies, building a support network, and becoming experts in self-managing their disease. Moreover, it may positively influence their care trajectory and reduce burdens, such as overburdening, fear of progression, and health anxiety.TRIAL REGISTRATION:German Clinical Studies Register ( https://www.drks.de/DRKS00030090 , No. DRKS00030090, Date of registration: 15.12.2022).