Setting the clinical context to non-motor symptoms reflected by Park-pain, Park-sleep, and Park-autonomic subtypes of Parkinson's disease.

Non-motor symptoms (NMS) of Parkinson's disease (PD) are well described in both clinical practice and the literature, enabling their management and enhancing our understanding of PD. NMS can dominate the clinical pictures and NMS subtypes have recently been proposed, initially based on clinical observations, and later confirmed in data driven analyses of large datasets and in biomarker-based studies. In this chapter, we provide an update on what is known about three common subtypes of NMS in PD. The pain (Park-pain), sleep dysfunction (Park-sleep), and autonomic dysfunction (Park-autonomic), providing an overview of their individual classification, clinical manifestation, pathophysiology, diagnosis, and potential treatments.

Musculoskeletal pain in Parkinson's disease: Association with dopaminergic deficiency in the caudate nucleus.

BACKGROUND: Musculoskeletal (MSK) pain affects over 80% of People with Parkinson's (PD, PwP) and may, in part, be dopaminergic in origin, as dopaminergic medication often leads to its relief. METHODS: PwP who underwent striatal dopamine transporter visualization with a radiopharmaceutical DaTscan™ (123 I-Ioflupane Injection) using a single-photon emission computed tomography (SPECT) as a part of their clinical-diagnostic work up were enrolled in the "Non-motor International Longitudinal Study" (NILS; UK National Institute for Health Research Clinical Research Network Number 10084) and included in this cross-sectional analysis. The association between specific DaTscan binding ratios for each striatum, the caudate nucleus and putamen and clinical ratings for MSK pain (assessed using the King's Parkinson's Disease Pain Scale (KPPS)) were analysed. RESULTS: 53 PwP (30.2% female; age: 63.79 ± 11.31 years; disease duration (DD): 3.32 (0.31-14.41) years; Hoehn & Yahr stage (H&Y): 2 (1-4); Levodopa Equivalent Daily Dose (LEDD): 543.08 ± 308.94 mg) were assessed and included in this analysis. MSK pain was highly prevalent (71.7% of all participants, mean KPPS Item 1 score 5.34 ± 4.76) and did not correlate with the motor symptoms burden (SCOPA-Motor total score; p = 0.783) but showed a significant correlation with quality of life (PDQ-8, rs = 0.290, p = 0.035). z-scores for the caudate nucleus (Exp (B) = 0.367, 95% CI for Exp (B) 0.148-0.910, p = 0.031) and striatum (Exp (B) = 0.338, 95% CI for Exp (B) 0.123-0.931, p = 0.036), adjusted for DD, H&Y and LEDD, were significant determinants of MSK pain. CONCLUSIONS: Our findings suggest an association between MSK pain in PwP and the severity of dopaminergic deficiency in the caudate nucleus. SIGNIFICANCE: In People with Parkinson's, musculoskeletal pain does not arise simply as a direct sequel to motor symptoms-instead, it is linked to the severity of dopaminergic depletion in the caudate nucleus.

Advances in the Pharmacological and Non-pharmacological Management of Non-motor Symptoms in Parkinson's Disease: An Update Since 2017.

BACKGROUND: Non-motor symptoms (NMS) are an important and ubiquitous determinant of quality of life in Parkinson's disease (PD). However, robust evidence for their treatment is still a major unmet need. OBJECTIVE: This study aimed to provide an updated review on advances in pharmacological, nonpharmacological, and exercise-based interventions for NMS in PD, covering the period since the publication of the MDS Task Force Recommendations. METHODS: We performed a literature search to identify pharmacological, non-pharmacological, and exercise-based interventions for NMS in PD. As there are recent reviews on the subject, we have only included studies from the 1st of January 2017 to the 1st of December 2021 and limited our search to randomised and non-randomised (including open-label) clinical trials. RESULTS: We discuss new strategies to manage NMS based on data that have become available since 2017, for instance, on the treatment of orthostatic hypotension with droxidopa, several dopaminergic treatment options for insomnia, and a range of non-pharmacological and exercise-based interventions for cognitive and neuropsychiatric symptoms, pain, and insomnia and excessive sleepiness. CONCLUSION: Recent evidence suggests that targeted non-pharmacological treatments, as well as some other NMS management options, may have a significant beneficial effect on the quality of life and need to be considered in the pathways of treatment of PD.

Parkinson's disease and Covid-19: Is there an impact of ethnicity and the need for palliative care.

Under the traditional models of care for People with Parkinson's Disease (PD, PwP), many of their needs remain unmet and a substantial burden of motor and non-motor symptoms they experience may not be tackled sufficiently. An introduction of palliative care (PC) interventions early in the course of PD offers profound benefits: it may improve quality of life of patients, their families and caregivers through the prevention and relief of medical symptoms, while, at the same time, emphasizing their emotional needs and spiritual wellbeing, establishing goals of care, and engaging in the advance care planning (ACP). The ongoing Coronavirus Disease 2019 (Covid-19) pandemic poses an unprecedented set of challenges for PwP and has in many ways (both directly and indirectly) magnified their suffering, thus rapidly raising the demand for PC interventions. Covid-19, as well as the repercussions of prolonged mobility restrictions and limited health-care access might exacerbate the severity of PD motor symptoms and interact negatively with a range of non-motor symptoms, with a detrimental effect on quality of life. Greater motor disability, higher amount of levodopa-induced motor fluctuations with an increased daily off-time, fatigue, anxiety, depression, sleep disturbances, pain and worsening of cognitive complaints might dominate the clinical presentation in PwP during the Covid-19 pandemic, alongside raising psychological and spiritual concerns and anticipatory grief. Here, we aim to provide a foundation for pragmatic and clinically orientated PC approach to improve quality of life and relieve suffering of PwP in the context of the current, ongoing Covid-19 pandemic.

Tolerability of overnight rotigotine transdermal patch combined with intrajejunal levodopa infusion at 1 year: a 24-h treatment option in Parkinson's disease.

BACKGROUND: Twenty-four-hour treatment options could provide a continuous drug delivery strategy in advanced Parkinson's disease and can ameliorate motor and non-motor complications. Use of levodopa infusion is often limited to 12-16 h/day due to its cost. Adjunctive overnight rotigotine transdermal patch is a continuous drug delivery option successfully used in clinical practice coupled with apomorphine infusion. However, real-life data addressing the tolerability of transdermal dopamine agonist therapy with concomitant use of intrajejunal levodopa infusion in advanced Parkinson's disease are not available. OBJECTIVE: To evaluate the tolerability and beneficial effects of combined therapy with overnight rotigotine transdermal patch and intrajejunal levodopa infusion over a follow-up period of 12 months in advanced Parkinson's disease. METHOD: In this retrospective data analysis, data before and after the initiation of the continuous drug delivery combined therapy using overnight rotigotine transdermal patch and intrajejunal levodopa infusion were collected from the ongoing non-motor-international-longitudinal study (NILS) and local clinical practice at King's College Hospital (London, United Kingdom). 12 advanced Parkinson's disease patients on intrajejunal levodopa therapy who were additionally treated with overnight rotigotine transdermal patch (mean dose 5.67 ± 4.19 mg) are included. Tolerability over a 12-month period was assessed. In addition, changes in motor symptoms (SCales for Outcomes in Parkinson's disease, SCOPA-Motor), non-motor symptoms (Non-Motor Symptoms Scale, NMSS) and quality of life (Parkinson's disease Questionnaire-8, PDQ-8) before and 12-month after continuous drug delivery combined therapy initiation are evaluated. RESULTS: Tolerability was 100% irrespective of age, disease duration, stages of disease. (Treatment with overnight rotigotine transdermal patch that was maintained for a minimum of 6 months was considered "tolerated", primary tolerability). In addition, we noted a significant reduction of the NMSS total score (p = 0.009) and the NMSS domain 3 score (mood and apathy domain) (p = 0.028), although the latter did not remain statistically significant after correction for multiple testing (p2 = 0.252) at 12 months. CONCLUSION: Combination of intrajejunal levodopa infusion with overnight rotigotine transdermal patch is well tolerated and extend the beneficial effects of infusion with excellent tolerability; and also improved aspects of mood and apathy sustained at 12 months in advanced Parkinson's disease.

Ethnic Disparities in Treatment of Chronic Pain in Individuals with Parkinson's Disease Living in the United Kingdom.

Background: Over 80% people with Parkinson's disease (PD; PwP) live with chronic pain. Objective: Whether ethnic disparities in receipt of appropriate analgesia exist among PwP with chronic pain living in the United Kingdom (UK). Methods: A retrospective datamining of an existing King's PD Pain Questionnaire validation study dataset enrolling 300 PwP. Results: 69 PwP: 23 Black (57% female), 23 Asian (57% female) and 23 White (65% female) had similar pain burden on the King's PD Pain Scale. Significantly more White PwP (83%) received pain relief compared to Black (48%) and Asian (43%) PwP (p = 0.016). The difference was most evident for opioid analgesics (White 43% vs. Black 4% vs. Asian 4%, p ≤ 0.001). Conclusions: Ethnic disparities in the analgesic use among PwP with chronic pain living in the UK are evident in this retrospective analysis, prompting large-scale studies and reinforcement of interventions to tackle the impact ethnicity might have on the successful analgesia.

Management strategies of sexual dysfunctions in Parkinson's disease.

Sexual dysfunctions (SD) are frequent and highly disabling nonmotor manifestations of Parkinson's disease (PD) but are also potentially treatable. Neurologists should actively discuss, recognize and treat sexual health issues as an integral part of the management of the disease. In this chapter, we provide recommendations for managing and treating both primary and secondary SD in PD. Many sexual problems can be, at least partially, improved by adjusting the treatment of motor, nonmotor symptoms and comorbidities. Although some treatments of primary SD are evidence-based, many therapeutic options have not been yet systematically studied in patients with PD. The development of new treatments and repurposing of existing remedies in patients with PD remain an unmet need.

New approaches to treatments for sleep, pain and autonomic failure in Parkinson's disease - Pharmacological therapies.

Non-motor symptoms (NMSs) are highly prevalent throughout the course of Parkinson's disease (PD). Pain, autonomic dysfunction and sleep disturbances remain at the forefront of the most common NMSs; their treatment is challenging and their effect on the quality of life of both patients and caregivers detrimental. Yet, the landscape of clinical trials in PD is still dominated by therapeutic strategies seeking to ameliorate motor symptoms; subsequently, effective strategies to successfully treat NMSs remain a huge unmet need. Wider awareness among industry and researchers is thus essential to give rise to development and delivery of high-quality, large-scale clinical trials in enriched populations of patients with PD-related pain, autonomic dysfunction and sleep. In this review, we discuss recent developments in the field of pharmacological treatment strategies designed or re-purposed to target three key NMSs: pain, autonomic dysfunction and sleep disturbances. We focus on emerging evidence from recent clinical trials and outline some exciting and intriguing findings that call for further investigations. This article is part of the Special Issue on 'New therapeutic approaches to Parkinson's disease'.

Effects of safinamide on pain in patients with fluctuating Parkinson's disease.

BACKGROUND: Non-motor symptoms (NMS) are integral to Parkinson's Disease (PD) and management remains a challenge. Safinamide is a novel molecule in relation to addressing NMS due to its multifocal mechanism of action with both dopaminergic and non-dopaminergic properties. OBJECTIVE: To investigate the efficacy of safinamide on NMS and its burden in PD patients with motor fluctuations after 6 months of treatment. METHODS: This observational, multicenter, open-label, pilot study assessed a wide range of NMS using the following rating scales, NMSS (non-motor symptom scale), KPPS (King's PD pain scale), HADS (hospital anxiety and depression scale), PDQ-8 (Parkinson's disease quality of life questionnaire), and PDSS-2 (Parkinson's disease sleep scale), EuroQol-5D 3 level version (EQ-5D-3L), CGI-I (clinical global impression of improvement), and PGI-C (patient global impression of change). Motor examination using UPDRS part III (Unified Parkinson's disease rating scale, motor examination), UPDRS IV (complications of therapy) and Hoehn and Yahr staging were also obtained. RESULTS: 27 patients were included in the analysis and were evaluated at baseline and ≥ 6 months after safinamide treatment. 26 patients had a daily maintenance dose of 100 mg and 1 patient a daily dose of 50 mg. Significant improvements in UPDRS IV, KPPS item 5 (region-specific "off" dystonia), KPPS domain 3 (items 4-6, fluctuation related pain) and KPPS total score were observed after treatment with safinamide, while maintaining stable dopaminergic medication. No statistically significant differences were found in NMSS, HADS, PDSS-2, EQ-5D-3L, and PDQ-8 after treatment. CONCLUSIONS: Our results suggest that safinamide may have a beneficial effect on pain, a key unmet need in fluctuating PD patients.

The impact of COVID-19 on palliative care for people with Parkinson's and response to future pandemics.

Introduction: Although in some countries, palliative care (PC) still remains poorly implemented, its importance throughout the course of Parkinson's disease (PD) is increasingly being acknowledged. With an emergence of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic, growing emphasis has been placed on the palliative needs of people with Parkinson's (PwP), particularly elderly, frail, and with comorbidities.Areas covered: The ongoing COVID-19 pandemic poses an enormous challenge on aspects of daily living in PwP and might interact negatively with a range of motor and non-motor symptoms (NMS), both directly and indirectly - as a consequence of pandemic-related social and health care restrictions. Here, the authors outline some of the motor and NMS relevant to PC, and propose a pragmatic and rapidly deployable, consensus-based PC approach for PwP during the ongoing COVID-19 pandemic, potentially relevant also for future pandemics.Expert opinion: The ongoing COVID-19 pandemic poses a considerable impact on PwP and their caregivers, ranging from mental health issues to worsening of physical symptoms - both in the short- and long-term, (Long-COVID) and calls for specific, personalized PC strategies relevant in a lockdown setting globally. Validated assessment tools should be applied remotely to flag up particular motor or NMS that require special attention, both in short- and long-term.

Pain in Parkinson's disease: Mechanism-based treatment strategies.

PURPOSE OF REVIEW: Chronic pain, highly prevalent throughout the course of Parkinson's disease (PD), has been ranked as one of the top ten most bothersome symptoms people with Parkinson's (PwP) are experiencing. Yet, robust evidence-based treatment strategies are lacking. This unmet need is partly attributable to the multifaceted nature of PD-related pain, which results in part from a complex and poorly understood interplay involving a range of neurotransmitter pathways. Degeneration of nigrostriatal dopaminergic pathways and alterations of central nervous system extra-striatal dopaminergic, noradrenergic, serotoninergic, glutamatergic, opioidergic and endocannabinoid circuits may all promote a heightened experience of pain in PwP. Thus, the potential targets for mechanism-based pain-relieving strategies in PwP are several. These targets are discussed herein. RECENT FINDINGS: An increasing number of clinical trials and experimental studies in animal models of PD are being designed with the aim of addressing the pathophysiological mechanism(s) underlying PD-related pain. Overall, recent research findings highlight the analgesic effects of dopaminergic and opioidergic medication for certain subtypes of pain in PwP, whereas proposing novel strategies that involve targeting other neurotransmitter pathways. SUMMARY: The origin of pain in PwP remains under investigation. Although our understanding of the mechanisms underpinning persistent pain in PD has improved in recent years, this has not yet translated to clinical alleviation of this most troublesome nonmotor symptom. Patient stratification linked with evidence-based personalized pain-treatment plans for optimal analgesic relief will rely on advances in our understanding of the dopaminergic and nondopaminergic targets outlined in this review.

Nonmotor symptom burden grading as predictor of cognitive impairment in Parkinson's disease.

BACKGROUND: Identifying predictors of incident cognitive impairment (CI), one of the most problematic long-term outcomes, in Parkinson's disease (PD) is highly relevant for personalized medicine and prognostic counseling. The Nonmotor Symptoms Scale (NMSS) provides a global clinical assessment of a range of NMS, reflecting NMS burden (NMSB), and thus may assist in the identification of an "at-risk" CI group based on overall NMSB cutoff scores. METHODS: To investigate whether specific patterns of PD NMS profiles predict incident CI, we performed a retrospective longitudinal study on a convenience sample of 541 nondemented PD patients taking part in the Nonmotor Longitudinal International Study (NILS) cohort, with Mini-Mental State Examination (MMSE), NMSS, and Scales for Outcomes in PD Motor Scale (SCOPA Motor) scores at baseline and last follow-up (mean 3.2 years) being available. RESULTS: PD patients with incident CI (i.e., MMSE score ≤ 25) at last follow-up (n = 107) had severe overall NMSB level, significantly worse NMSS hallucinations/perceptual problems and higher NMSS attention/memory scores at baseline. Patients with CI also were older and with more advanced disease, but with no differences in disease duration, dopamine replacement therapy, sex, and comorbid depression, anxiety, and sleep disorders. CONCLUSIONS: Our findings suggest that a comprehensive baseline measure of NMS and in particular hallucinations and perceptual problems assessed with a validated single instrument can be used to predict incident CI in PD. This approach provides a simple, holistic strategy to predict future CI in this population.

Non-motor complications in late stage Parkinson's disease: recognition, management and unmet needs.

Introduction: The burden of non-motor symptoms (NMS) is a major determinant of health-related quality of life in Parkinson's disease (PD), particularly at its late stage.Areas covered: The late stage is usually defined as the period from unstable advanced to the palliative stage, characterized by a combination of emerging treatment-resistant axial motor symptoms (freezing of gait, postural instability, falls and dysphagia), as well as both non-dopaminergic and dopaminergic NMS: cognitive decline, neuropsychiatric symptoms, aspects of dysautonomia, pain and sleep disturbances (insomnia and excessive day-time sleepiness). Here, the authors summarize the current knowledge on NMS dominating the late stage of PD and propose a pragmatic and clinically focused approach for their recognition and treatment.Expert opinion: The NMS progression pattern is complex and remains under-researched. While dopamine-dependent NMS may improve with dopamine replacement therapy, non-dopamine dependent NMS worsen progressively and culminate at the late stages of PD. Furthermore, some PD specific features could interact negatively with other comorbidities, multiple medication use and frailty - the evaluation of these aspects is important in the creation of personalized management plans in the late stage of PD.

Pain in neurodegenerative diseases with atypical parkinsonism: a systematic review on prevalence, clinical presentation, and findings from experimental studies.

Parkinson's disease-related pain has increasingly been investigated in research studies. Still, only a few studies have addressed the prevalence and clinical characteristics of pain in neurodegenerative disorders with atypical parkinsonism. The existing evidence, although scarce, suggests that, similarly as in Parkinson's disease, individuals with neurodegenerative diseases with atypical parkinsonism might be predisposed to the development of persistent pain. Today, as the global population is aging and we face an epidemic of neurodegenerative disorders, under-treated pain is taking a great toll on an ever-rising number of people. Here, we provide an up-to-date review of the current knowledge on the prevalence of pain, its clinical features, and findings from experimental studies that might signpost altered pain processing in the most prevalent neurodegenerative disorders with atypical parkinsonism: multiple system atrophy, progressive supranuclear palsy, corticobasal syndrome, frontotemporal dementia, and dementia with Lewy bodies. Finally, we point out the current gaps and unmet needs that future research studies should focus on. Large-scale, high-quality clinical trials, coupled with pre-clinical research, are urgently needed to reveal the exact pathophysiological mechanisms underpinning heightened pain and pave the path for mechanistically-driven analgesic interventions to be developed, ultimately leading to an improvement in the quality of life of individuals with neurodegenerative disorders.

A Dual Centre Study of Pain in Parkinson's Disease and Its Relationship with Other Non-Motor Symptoms.

BACKGROUND: Pain is a disabling and often underestimated non-motor symptom (NMS) detrimentally affecting the quality of life of patients with Parkinson's disease (PD). OBJECTIVE: Here, we conducted a cross-sectional, observational international study on 167 patients with idiopathic PD in order to analyze the potential relationship between pain and other NMS. METHODS: Subjects were assessed with the Unified Parkinson's Disease Rating Scale (UPDRS) part III, Hoehn and Yahr (H&Y) stage, King's Parkinson's Disease Pain Scale (KPPS), Brief Pain Inventory (BPI), Non-Motor Symptoms Scale (NMSS), and Beck Depression Inventory (BDI). Spearman's rank correlation coefficient, multiple regression and multiple index-based clustering algorithms were used for data analysis. RESULTS: The prevalence of pain was 88.6%, was not correlated with age, motor severity (UPDRS part III) or disease duration, whereas a weak correlation with female gender and H&Y stage >2.5 was found. Multiple NMS correlated significantly with pain. Specifically, sleep disturbance had the strongest correlation with pain, followed by depression, gastrointestinal and cardiovascular disturbances. Further analyses showed that sleep and cardiovascular disturbance were independently associated with pain, and that these symptoms clustered together in a subset of PD patients. The relationship between pain, sleep and dysautonomia persisted independently from dopamine replacement therapy. CONCLUSION: Our study suggests that sleep disruption and cardiovascular disturbance are associated with pain in PD, and possibly identifies a specific subtype within PD patients with pain. Our data also indicate that sleep disruption, pain and dysautonomia may have a common pathophysiology, possibly involving non-dopaminergic pathways.