A general clinical overview of the non-motor symptoms in Parkinson's disease: Neuropsychiatric symptoms.

The heterogeneity of non-motor features observed in people with Parkinson's disease (PD) is often dominated by one or more symptoms belonging to the neuropsychiatric spectrum, such as cognitive impairment, psychosis, depression, anxiety, and apathy. Due to their high prevalence in people with PD (PwP) and their occurrence in every stage of the disease, from the prodromal to the advanced stage, it is not surprising that PD can be conceptualised as a complex neuropsychiatric disorder. Despite progress in understanding the pathophysiological mechanisms underlying the neuropsychiatric signs and symptoms in PD, and better identification and diagnosis of these symptoms, effective treatments are still a major unmet need. The impact of these symptoms on the quality of life of PwP and caregivers, as well as their contribution to the overall non-motor symptom burden can be greater than that of motor symptoms and require a personalised, holistic approach. In this chapter, we provide a general clinical overview of the major neuropsychiatric symptoms of PD.

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

PURPOSE OF REVIEW: 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). RECENT FINDINGS: 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. SUMMARY: 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'.

Wellness, sexual health, and nonmotor Parkinson's.

Nonmotor symptoms of Parkinson's disease (PD) range from neuropsychiatric and cognitive to sleep, sensory, and genito-urinary disorders, and occur as a result of the disease process as well as due to side effects of drug treatment for PD. Sexual dysfunction is an important aspect of the nonmotor profile of Parkinson's but is rarely discussed. Sexual health is considered an integral element of holistic health, thus sexual dysfunction can also significantly impact quality of life in people with Parkinson's. The effect of sexual dysfunction of PD, both disease related and drug induced, on the concept of "wellness" of patients and their intimate partners is poorly understood, inadequately researched and a key unmet need in care and support. In this chapter we discuss the concept of "wellness" as applied to the treatment of PD, the ways in which nonmotor symptoms and other aspects of living may affect wellness in PD, and strategies for addressing sexual health utilizing a wellness model.

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.

Can therapeutic strategies prevent and manage dyskinesia in Parkinson's disease? An update.

Introduction: Dyskinesia is a motor complication of Parkinson's disease (PD) characterized by clinical heterogeneity and complex pathogenesis and associated with long-term levodopa therapy. Recent and controversial views on the management of PD patients have suggested that overall dyskinesia rates, and particularly troublesome dyskinesia, may be declining due to more conservative levodopa dosing regimens, widespread availability and early introduction of deep brain stimulation, and use of continuous drug delivery strategies. Nevertheless, anti-dyskinetic agents continue to be evaluated in clinical trials and recent efforts have focused on non-dopaminergic drugs.Areas covered: In this review, the authors discuss the clinical phenomenology and current understanding of dyskinesia in PD with a focus on up-to-date therapeutic strategies to prevent and manage these drug-related involuntary movements.Expert opinion: The way dyskinesia in PD is currently managed should be changed and attention should be focused toward a more personalized medicine rather than a one-fits-all-approach. The correct identification of dyskinesia types and tailored treatments are crucial for a better management of these involuntary movements together with a holistic approach which considers additional influencing factors. The future for dyskinesia treatment is likely to be found in non-dopaminergic approaches, first set into motion by the introduction of amantadine.

Advanced Parkinson's or "complex phase" Parkinson's disease? Re-evaluation is needed.

Holistic management of Parkinson's disease, now recognised as a combined motor and nonmotor disorder, remains a key unmet need. Such management needs relatively accurate definition of the various stages of Parkinson's from early untreated to late palliative as each stage calls for personalised therapies. Management also needs to have a robust knowledge of the progression pattern and clinical heterogeneity of the presentation of Parkinson's which may manifest in a motor dominant or nonmotor dominant manner. The "advanced" stages of Parkinson's disease qualify for advanced treatments such as with continuous infusion or stereotactic surgery yet the concept of "advanced Parkinson's disease" (APD) remains controversial in spite of growing knowledge of the natural history of the motor syndrome of PD. Advanced PD is currently largely defined on the basis of consensus opinion and thus with several caveats. Nonmotor aspects of PD may also reflect advancing course of the disorder, so far not reflected in usual scale based assessments which are largely focussed on motor symptoms. In this paper, we discuss the problems with current definitions of "advanced" PD and also propose the term "complex phase" Parkinson's disease as an alternative which takes into account a multimodal symptoms and biomarker based approach in addition to patient preference.

Palliative Care and Nonmotor Symptoms in Parkinson's Disease and Parkinsonism.

The term palliative care (PC) is defined as a collection of interventions and strategies that helps to improve and sustain the quality of life of patients and caregivers in situations and scenarios associated with life-threatening illness. This is usually implemented by means of early identification and treatment of relevant motor and nonmotor issues such as pain, sleep, and autonomic dysfunction, dementia, and depression. In addition, a holistic PC program also includes delivery of physical, psychosocial, and spiritual support. PC as a specific discipline, as well as a treatment strategy for long-term neurological conditions such as Parkinson's disease (PD), is relatively new, but very important as neurodegenerative disorders in the United Kingdom alone affects approximately 10 million people and there are over 130,000 people with PD. With longer life expectancy, the burden of long duration and late stage PD is even more evident, bringing in focus the need for PC. However, the concept of PC in PD is still poorly defined and although there are pockets of excellence, the strategy is poorly implemented into routine clinical practice. The variable progressive nature of the disease, the heterogeneity of clinical subtypes, and also the burden of nonmotor symptoms create challenges for effective PC delivery in PD, but recent clinical trials have started addressing PC in PD and are to be welcomed.

Personalized Medicine and Nonmotor Symptoms in Parkinson's Disease.

Parkinson's disease (PD) is a multineurotransmitter dysfunction related disorder resulting in a range of motor and nonmotor symptoms. Phenotypic heterogeneity is pronounced in PD and nonmotor symptoms dominant subtypes have been described. These endophenotypes may be underpinned by considerable nondopaminergic dysfunction; however, conventional treatment of PD continues to be mostly reliant on dopamine replacement strategy or manipulation of brain dopaminergic pathways. Consequently, treatment of many nondopaminergic nonmotor and some motor symptoms remains a key unmet need. It is also recognized that treatment strategies for PD are influenced by a number of nondrug-related issues. These include factors such as age, personality, and preferences for treatment, cultural beliefs, lifestyle, pharmacoeconomics, pharmacogenetics as well as comorbidity. Therefore, the success of clinical therapy will rest on how much these factors are considered to develop a truly holistic treatment plan. Personalized medicine is the modern way of delivering this holistic strategy for treatment of PD. Personalized medicine thus encompasses several strands of treatment. From the pharmaceutical point of view, it should involve dopaminergic and nondopaminergic strategies. In addition, there are substrategies involving precision and tailored medicine to suit the needs and requirements of individual patients. Precision medicine would be relevant for patients who may be at risk of developing the clinical syndrome of Parkinson's as identified by specific gene mutations. Precision medicine in this scenario will attempt to be preventive. Tailored medicine would address the "single multifactorial" complex nature of PD and address symptoms as well subtype-specific strategies. Personalized medicine is now practiced for other conditions such as oncology as well as diabetes. In this chapter, we discuss the rationale and the need to develop strategies for personalized medicine for PD.

Nonmotor Parkinson's and Future Directions.

Nonmotor symptoms (NMS) of Parkinson's disease (PD) are integral to the condition largely regarded as a motor syndrome. A range of NMS underpin the prodromal stage of Parkinson's and are present with variable frequency, range, and nature across the whole journey of a patient with Parkinson's from the onset of the motor disease to palliative stage. These symptoms also are key determinants of quality of life of the patient as well as the carer. Despite this, recognition management and focused treatment of NMS of PD remain poor. Future would, therefore, need to focus on better definition and management of NMS of PD. This would include development of robust animal models of specific NMS such as cognitive, sleep, and autonomic dysfunctions as well as pain to understand the mechanistic pathways of these symptoms. In turn this will lead to better drug development using a bench to bedside model. Nonmotor clinical subtypes of PD have also been described and, in future, proper biomarkers will consolidate these findings in addition to defining the natural history of the subtypes. Revised versions of established scales and questionnaires will enable the adoption of good clinical practice with recognition of these subtypes in clinic. This will enhance the delivery of true subtype-specific therapies. Drug development should also include nondopaminergic and cell replacement restorative therapies with a nonmotor focus. An additional key area of future research would be the formalizing of true personalized medicine for PD. Personalized medicine pathways should concentrate on the role of exercise, complementary medicine as well as age, body weight, ethnicity on various NMS of PD. Genetics and pharmacogenetic developments in PD will add to the precision of the individualized approach.

The Nonmotor Features of Parkinson's Disease.

Nonmotor symptoms (NMS) of Parkinson's disease (PD) were recognized by the great James Parkinson himself who mentioned symptoms such as sleep dysfunction, delirium, dementia, and dysautonomia, in his seminal 1817 essay, "An Essay on the Shaking Palsy" (Parkinson, 1817). In spite of the key impact of PD NMS on quality of life, there was little holistic research and awareness till the validation and use of comprehensive tools such as the NMS questionnaire, scale, and the revised version of the unified PD rating scale. Research studies using these tools highlighted the key impact of the burden of NMS on quality of life of PD patients and the need for NMS to be routinely assessed in clinic. We now define PD as a motor and nonmotor disorder, and the natural history includes a long prodromal phase of PD dominated by a range of NMS. The prodromal phase is the subject of much research particularly in relation to neuroprotection and identifying subjects at risk. Use of NMS tools has also validated burden grading of NMS with cutoff values, which can be used as outcome measure in clinical trials. Finally, the complex multineurotransmitter dysfunction that is seen in PD has been shown to manifest clinically as nonmotor subtypes. Recognition of such subtypes is likely to lead to the emergence of personalized and precision medicine in PD.

Practice guideline summary: Treatment of restless legs syndrome in adults: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology.

OBJECTIVE: To make evidence-based recommendations regarding restless legs syndrome (RLS) management in adults. METHODS: Articles were classified per the 2004 American Academy of Neurology evidence rating scheme. Recommendations were tied to evidence strength. RESULTS AND RECOMMENDATIONS: In moderate to severe primary RLS, clinicians should consider prescribing medication to reduce RLS symptoms. Strong evidence supports pramipexole, rotigotine, cabergoline, and gabapentin enacarbil use (Level A); moderate evidence supports ropinirole, pregabalin, and IV ferric carboxymaltose use (Level B). Clinicians may consider prescribing levodopa (Level C). Few head-to-head comparisons exist to suggest agents preferentially. Cabergoline is rarely used (cardiac valvulopathy risks). Augmentation risks with dopaminergic agents should be considered. When treating periodic limb movements of sleep, clinicians should consider prescribing ropinirole (Level A) or pramipexole, rotigotine, cabergoline, or pregabalin (Level B). For subjective sleep measures, clinicians should consider prescribing cabergoline or gabapentin enacarbil (Level A), or ropinirole, pramipexole, rotigotine, or pregabalin (Level B). For patients failing other treatments for RLS symptoms, clinicians may consider prescribing prolonged-release oxycodone/naloxone where available (Level C). In patients with RLS with ferritin ≤75 µg/L, clinicians should consider prescribing ferrous sulfate with vitamin C (Level B). When nonpharmacologic approaches are desired, clinicians should consider prescribing pneumatic compression (Level B) and may consider prescribing near-infrared spectroscopy or transcranial magnetic stimulation (Level C). Clinicians may consider prescribing vibrating pads to improve subjective sleep (Level C). In patients on hemodialysis with secondary RLS, clinicians should consider prescribing vitamin C and E supplementation (Level B) and may consider prescribing ropinirole, levodopa, or exercise (Level C).

The impact of non-motor symptoms on health-related quality of life of patients with Parkinson's disease.

BACKGROUND: Non-motor symptoms are detrimental to health-related quality of life (HRQoL) of Parkinson's disease patients. In this study, the Non-Motor Symptoms Scale (NMSS) was used to assess the impact of the non-motor symptoms on HRQoL of Parkinson's disease patients. METHODS: In a multicenter, international, cross sectional study on 411 Parkinson's disease patients, the NMSS was applied along with clinical (Hoehn and Yahr staging and SCOPA-Motor) and HRQoL measures (PDQ-39, and EQ-5D). Prevalence of non-motor symptoms was determined also through the NMSS. The association of NMSS and SCOPA-Motor with HRQoL measures and the differences in HRQoL scores between patients with and without non-motor symptoms in each NMSS domain were estimated by non-parametric statistics. Predictors of HRQoL were sought through multiple linear regression analyses. RESULTS: Nocturia (68.4% of the sample), fatigue (65.9%), and dribbling saliva (56.7%), were the most frequent complaints. Total NMSS score: (1) showed a higher correlation coefficient (r(S) = 0.70) with the PDQ-39 Summary Index (SI) than SCOPA-Motor (r(S) = 0.58); (2) showed high-moderate correlation (r(S) = 0.60 - 0.38) with all PDQ-39 domains; and (3) was the best predictor of HRQoL as measured by the PDQ-39 SI. For each NMSS domain, patients with symptoms had significantly worse HRQoL scores than patients without symptoms. DISCUSSION: To our knowledge, this is the first study to determine in a holistic manner the impact of the non-motor symptoms on HRQoL of Parkinson's disease patients. The results show that non-motor symptoms have, as a whole, a greater impact on HRQoL than motor symptoms and non-motor symptoms progression contributes importantly to HRQoL decline in patients with Parkinson's disease.

Clinical significance of RLS.

While the restless legs syndrome (RLS) may have been known in antiquity, it has only recently come to medical attention. Individuals with RLS fall along a spectrum from mild, infrequent symptoms to those with severe daily life-impairing discomforts and sleep disruption. These problems can cause impaired mood, daytime fatigue, cognitive difficulties, and inability to participate in a variety of quiet activities. This leads to a general reduction in quality of life similar to other significant psychiatric and medical disorders. Recent studies suggest that RLS may be a risk factor for developing both psychiatric disorders (such as major depression and anxiety) and somatic diseases (such as hypertension and cardiovascular disease). In dialysis patients, RLS has been found to be a risk factor for mortality. Therefore, those with RLS who have clinically significant symptoms suffer increased morbidity and are at risk for impaired long-term medical outcomes.