The Melanocortin and Endorphin Neuropeptides in Patients with Restless Legs Syndrome.

OBJECTIVE: Based upon similarities between the urge to move and sensory discomfort of restless legs syndrome (RLS) and properties of melanocortin hormones, including their incitement of movement and hyperalgesia, we assessed plasma and cerebrospinal fluid (CSF) α-melanocyte-stimulating hormone (α-MSH) and ß-endorphin in RLS patients and controls. METHODS: Forty-two untreated moderate-to-severe RLS patients and 44 matched controls underwent venipuncture at 19:00, 20:30, and 22:00; 37 RLS and 36 controls had lumbar puncture at 21:30. CSF and plasma were analyzed for pro-opiomelanocortin (POMC), adrenocorticotropin hormone (ACTH), α-MSH, ß-MSH, and ß-endorphin by immunoassay. RLS severity was assessed by International RLS Study Group Severity Scale. RESULTS: RLS participants were 52.7 ± 12.0 years old, 61.9% were women, 21.4% had painful RLS, and RLS severity was 24.8 ± 9.0. Controls had similar age and sex. Plasma ACTH, α-MSH, and ß-endorphin were similar between groups. Plasma POMC was significantly greater in RLS than controls (17.0 ± 11.5 vs 12.7 ± 6.1fmol/ml, p = 0.048). CSF ACTH was similar between groups. CSF ß-MSH was significantly higher in painful than nonpainful RLS or controls (48.2 ± 24.8 vs 32.1 ± 14.8 vs 32.6 ± 15.2pg/ml, analysis of variance [ANOVA] p = 0.03). CSF α-MSH was higher in RLS than controls (34.2 ± 40.9 vs 20.3 ± 11.0pg/ml, p = 0.062). CSF ß-EDP was lowest in painful RLS, intermediate in nonpainful RLS, and highest in controls (8.0 ± 3.4 vs 10.8 ± 3.1 vs 12.3 ± 5.0pg/ml, ANOVA p = 0.049). The ratio of the sum of CSF α- and ß-MSH to CSF ß-endorphin was highest, intermediate, and lowest in painful RLS, nonpainful RLS, and controls (p = 0.007). INTERPRETATION: CSF ß-MSH is increased and CSF ß-endorphin decreased in RLS patients with painful symptoms. ANN NEUROL 2024;95:688-699.

Review of the role of the endogenous opioid and melanocortin systems in the restless legs syndrome.

Restless legs syndrome (RLS) is responsive to opioid, dopaminergic and iron-based treatments. Receptor blocker studies in RLS patients suggest that the therapeutic efficacy of opioids is specific to the opioid receptor and mediated indirectly through the dopaminergic system. An RLS autopsy study reveals decreases in endogenous opioids, ß-endorphin and perhaps Met-enkephalin in the thalamus of RLS patients. A total opioid receptor knock-out (mu, delta and kappa) and a mu-opioid receptor knock-out mouse model of RLS show circadian motor changes akin to RLS and, although both models show sensory changes, the mu-opioid receptor knock mouse shows circadian sensory changes closest to those seen in idiopathic RLS. Both models show changes in striatal dopamine, anaemia and low serum iron. However, only in the total receptor knock-out mouse do we see the decreases in serum ferritin that are normally found in RLS. There are also decreases in serum iron when wild-type mice are administered a mu-opioid receptor blocker. In addition, the mu-opioid receptor knock-out mouse also shows increases in striatal zinc paralleling similar changes in RLS. Adrenocorticotropic hormone and α-melanocyte stimulating hormone are derived from pro-opiomelanocortin as is ß-endorphin. However, they cause RLS-like symptoms and periodic limb movements when injected intraventricularly into rats. These results collectively suggest that an endogenous opioid deficiency is pathogenetic to RLS and that an altered melanocortin system may be causal to RLS as well.

Differential impact of resilience on demoralization and depression in Parkinson disease.

Objectives: The objective of this study was to study the interrelations of demoralization, depression, and resilience in patients with Parkinson disease, and, more specifically, to determine if higher resilience in patients with Parkinson disease is associated with lower demoralization, lower depression, or both. Methods: Outpatients with Parkinson disease (N = 95) were assessed for demoralization, depression, and resilience, as well as sociodemographic, clinical, and treatment-related variables. Bivariable associations, standard regressions, linear regression with copula correction, and correspondence analysis were used to analyze the data. Results: Although the bivariable association between resilience and depression was statistically significant, the association ceased to be significant when demoralization was taken into consideration in both standard regressions and linear regression with copula correction. By contrast, the association between resilience and demoralization was significant when depression was not taken into consideration and continued to be significant when depression was taken into consideration. Correspondence analysis revealed that low resilience was strongly related to demoralization combined with depression, whereas normal resilience was closely correlated with depression without demoralization. Conclusion: These results expand our understanding of resilience by suggesting that it is a mechanism evolved to reduce or prevent demoralization and not just depression. Reducing demoralization and strengthening resilience as part of a comprehensive treatment plan are likely to improve the prognosis of Parkinson disease.

Impact of the coronavirus disease-2019 pandemic on Veterans Health Administration Sleep Services.

Objectives: To understand the impact of the coronavirus disease-2019 pandemic on sleep services within the United States Department of Veterans Affairs using separate surveys from "pre-COVID" and pandemic periods. Methods: Data from a pre-pandemic survey (September to November 2019) were combined with data from a pandemic-period survey (August to November 2020) to Veterans Affairs sleep medicine providers about their local sleep services within 140 Veterans Affairs facilities). Results: A total of 67 (47.9%) facilities responded to the pandemic online survey. In-lab diagnostic and titration sleep studies were stopped at 91.1% of facilities during the pandemic; 76.5% of facilities resumed diagnostic studies and 60.8% resumed titration studies by the time of the second survey. Half of the facilities suspended home sleep testing; all facilities resumed these services. In-person positive airway pressure clinics were stopped at 76.3% of facilities; 46.7% resumed these clinics. Video telehealth was either available or in development at 86.6% of facilities and was considered a lasting addition to sleep services. Coronavirus disease-2019 transmission precautions occurred at high rates. Sleep personnel experienced high levels of stress, anxiety, fear, and burnout because of the pandemic and in response to unexpected changes in sleep medicine care delivery. Conclusions: Sleep medicine services within the Veterans Affairs evolved during the pandemic with many key services being interrupted, including in-lab studies and in-person positive airway pressure clinics. Expansion and initiation of telehealth sleep services occurred commonly. The pandemic adversely affected sleep medicine personnel as they sought to maintain access to care.

Urges to Move and Other Motivation States for Physical Activity in Clinical and Healthy Populations: A Scoping Review Protocol.

Motivation for bodily movement, physical activity and exercise varies from moment to moment. These motivation states may be "affectively-charged," ranging from instances of lower tension (e.g., desires, wants) to higher tension (e.g., cravings and urges). Currently, it is not known how often these states have been investigated in clinical populations (e.g., eating disorders, exercise dependence/addiction, Restless Legs Syndrome, diabetes, obesity) vs. healthy populations (e.g., in studies of motor control; groove in music psychology). The objective of this scoping review protocol is to quantify the literature on motivation states, to determine what topical areas are represented in investigations of clinical and healthy populations, and to discover pertinent details, such as instrumentation, terminology, theories, and conceptual models, correlates and mechanisms of action. Iterative searches of scholarly databases will take place to determine which combination of search terms (e.g., "motivation states" and "physical activity"; "desire to be physically active," etc.) captures the greatest number of relevant results. Studies will be included if motivation states for movement (e.g., desires, urges) are specifically measured or addressed. Studies will be excluded if referring to motivation as a trait. A charting data form was developed to scan all relevant documents for later data extraction. The primary outcome is simply the extent of the literature on the topic. Results will be stratified by population/condition. This scoping review will unify a diverse literature, which may result in the creation of unique models or paradigms that can be utilized to better understand motivation for bodily movement and exercise.

From Perceived Stress to Demoralization in Parkinson Disease: A Path Analysis.

Objectives: The objective of this study was to determine whether depression and anxiety are mediators between perceived stress and demoralization via a loss of the cognitive map to get out of the predicament manifesting as subjective incompetence. Methods: Ninety-five consecutive outpatients with Parkinson's disease were evaluated for perceived stress, depression, anxiety, subjective incompetence, and demoralization using reliable and valid scales. Inclusion criteria were ages 40-90, intact cognition, and no current history of substance use. The setting was a Movement Disorders Clinic at a university-affiliated hospital. The outcome variable was demoralization, selected a priori. Mediators between perceived stress and demoralization were examined using path analysis. Results: Depression, anxiety, and subjective incompetence were mediators between perceived stress and demoralization. Among all variables, subjective incompetence was the largest contributor to demoralization. Depression connected to demoralization indirectly via subjective incompetence (ß = 0.25, p < 0.001), whereas anxiety bypassed subjective incompetence (ß = -0.01, p = 0.882), connecting directly to demoralization (ß = 0.37, p = 0.008). Conclusion: Early treatment and reversal of subjective incompetence and anxiety could potentially prevent the escalation of demoralization and the associated disruption in health-related quality of life and eventual suicide.

Diagnostic and Treatment Considerations in Restless Legs Syndrome Complicated by Diabetic Neuropathy.

PURPOSE OF REVIEW: Diabetic neuropathy from type I diabetes (DMI), type II diabetes (DMII), or gestational diabetes commonly occurs concurrently with restless legs syndrome (RLS) with an estimated prevalence in DMII specifically of 17.7 to 45%. The diagnosis of RLS can be obscured by symptoms of peripheral neuropathy, which may be similar to those of RLS, but also by other RLS mimics, including nocturnal leg cramps or akathisia. The purpose of this review is to outline a framework for considering comorbid diabetic neuropathy and RLS by discussing RLS and its association with peripheral nerve disease, diabetes, and sleep disruption. Treatment for patients with both diabetic neuropathy and RLS may differ from treatment of persons with solely RLS or diabetic neuropathy; key points in this difference are discussed. Finally, a treatment algorithm is provided to guide the approach to treating patients with comorbid RLS and diabetic neuropathy. RECENT FINDINGS: There have been several revisions of the RLS diagnostic criteria which in addition to the main four essential criteria of having (1) an urge to move the legs which is (2) exacerbated by rest, (3) relieved temporarily by movement, and (4) occurs in the evening or night time, now includes a consideration for RLS mimics, requiring that (5) symptoms not be explained by any other symptoms. Additionally, the treatment of both diabetic neuropathy and RLS has evolved to focus first on controlling the blood glucose, avoiding exacerbating medications, supplementing with iron if serum ferritin is low, and starting pharmacotherapy with alpha-2-delta ligands such as gabapentin or pregabalin. Knowledge of the prevalence of peripheral neuropathy with RLS, revised RLS diagnostic criteria, and a general treatment algorithm for the combination of peripheral neuropathy and RLS is critical to providing appropriate care to patients suffering from these two diseases.

Cluster Headache: Clinical Characteristics and Opportunities to Enhance Quality of Life.

PURPOSE OF REVIEW: Cluster headache is a highly disabling primary headache disorder characterized by severe pain and autonomic features. We present the existing body of literature on psychological factors associated with cluster headache and recommendations to address gaps in current clinical care with regards to psychological treatments for cluster headache. RECENT FINDINGS: People with cluster headache often endorse depressive symptoms, are more likely than the general population to report suicidal ideation and behaviors, and experience significantly decreased quality of life. Psychological treatments such as Acceptance and Commitment Therapy may be particularly valuable for patients with cluster headache given that they are transdiagnostic in nature and can therefore simultaneously address the disease burden and common psychiatric comorbidities that present. Greater understanding of the debilitating nature of cluster headache and behavioral interventions that seek to reduce the burden of the disease and improve the quality of life of people with cluster headache is paramount.

The Management of Restless Legs Syndrome: An Updated Algorithm.

Restless legs syndrome (RLS) is a common disorder. The population prevalence is 1.5% to 2.7% in a subgroup of patients having more severe RLS with symptoms occurring 2 or more times a week and causing at least moderate distress. It is important for primary care physicians to be familiar with the disorder and its management. Much has changed in the management of RLS since our previous revised algorithm was published in 2013. This updated algorithm was written by members of the Scientific and Medical Advisory Board of the RLS Foundation based on scientific evidence and expert opinion. A literature search was performed using PubMed identifying all articles on RLS from 2012 to 2020. The management of RLS is considered under the following headings: General Considerations; Intermittent RLS; Chronic Persistent RLS; Refractory RLS; Special Circumstances; and Alternative, Investigative, and Potential Future Therapies. Nonpharmacologic approaches, including mental alerting activities, avoidance of substances or medications that may exacerbate RLS, and oral and intravenous iron supplementation, are outlined. The choice of an alpha2-delta ligand as first-line therapy for chronic persistent RLS with dopamine agonists as a second-line option is explained. We discuss the available drugs, the factors determining which to use, and their adverse effects. We define refractory RLS and describe management approaches, including combination therapy and the use of high-potency opioids. Treatment of RLS in pregnancy and childhood is discussed.

Demoralization predicts suicidality in patients with cluster headache.

OBJECTIVE: To determine the frequency of suicidal ideation and assess suicide risk in cluster headache (CH) patients compared to matched controls without CH in this observational case-control study. BACKGROUND: CH is characterized by recurrent intolerable attacks of unilateral retro-orbital pain, which can cause disability, depression, and desperation. CH has been linked to suicide since its early descriptions by B.T. Horton; however, there is relatively little empiric data showing the association between suicidality and CH, especially in the context of other psychological phenomena, such as depression and demoralization. METHODS: CH and control participants were recruited through community and CH patient group advertisements. CH diagnosis was confirmed using the International Classification of Headache Disorders, 3rd edition diagnostic criteria for CH. Lifetime suicidal ideation and suicide risk were assessed using the Suicidal Behavior Questionnaire-revised and the Columbia Suicide Severity Rating Scale. The Brief Lifetime Depression Scale evaluated lifetime depression. Demoralization was assessed using the Diagnostic Criteria for use in Psychosomatic Research - Demoralization and the Kissane Demoralization Scale. Forward stepwise logistic regression determined the odds of suicidal ideation. RESULTS: One hundred CH and 135 control participants were comparable for age, sex, race, income, and marital status. Significantly more CH than control participants had lifetime active suicidal ideation (47.0% vs. 26.7%; p = 0.001), high suicide risk (38.0% vs. 18.5%; p = 0.0009), lifetime depression history (67.0%% vs. 32.6%; p < 0.00001), and demoralization (28.0% vs. 15.6%; p = 0.02). The odds of lifetime suicidal ideation were higher in those with CH (odds [95% confidence interval]; 2.04 [1.08,3.85]), even after accounting for depression and demoralization. In CH, suicidal ideation was associated with demoralization (6.66 [1.56,28.49]) but not depression (1.89 [0.66,5.46]). CONCLUSIONS: Lifetime suicidal ideation and high suicide risk are prevalent in CH sufferers, and its likelihood is dependent on the presence of demoralization.

Demoralization and Quality of Life of Patients with Parkinson Disease.

INTRODUCTION: Demoralization is quite prevalent in patients with Parkinson disease (PD). Unrecognized or untreated, demoralization may progress, at times, to demands for euthanasia and the desire for suicide. Typically, patients with PD do not complain of being "demoralized"; rather, they report disruptions in the quality of their lives. Hence, early identification of disruptions in health-related quality of life (HRQoL) specifically associated with demoralization may prompt earlier recognition and treatment. Published data on such associations, however, could not be found. Alleviation of demoralization in PD is likely to improve treatment outcomes. OBJECTIVE: This research aimed at identifying the disruptions of HRQoL specifically associated with the demoralization of patients with PD. METHODS: Consecutive general hospital outpatients with PD (n = 95) were assessed for: demoralization, with the Diagnostic Criteria for Psychosomatic Research Demoralization Scale (DCPR-D) and the Demoralization Scale (DS); depression, with the Patient Health Questionnaire-9 (PHQ-9); HRQoL, with the Parkinson Disease Questionnaire-Short Form (PDQ-8); sociodemographic variables; medical comorbidities; PD severity; and types of treatment. RESULTS: The prevalence of demoralization was 19%. Regression analyses showed that demoralization was significantly more likely to be experienced by participants who had difficulty with mobility and felt embarrassed in public due to having PD. Demoralization explained HRQoL over and above depression. CONCLUSIONS: Stigma and perceived difficulty with mobility are associated with demoralization of PD patients, and they may signal the need for psychotherapeutic and behavioral interventions to prevent the progression to helplessness, hopelessness, demands for euthanasia, and desire for suicide.

Hypothyroidism in restless legs syndrome.

The diurnal nature of restless legs syndrome (RLS) and its response to dopamine hint that hormones are central in RLS pathophysiology. Hypothyroidism has been linked to RLS, but studies are limited. This study's objective is to determine whether RLS is more prevalent in persons with hypothyroidism and whether hypothyroidism is more prevalent in RLS sufferers. Persons with hypothyroidism and controls were recruited through an on-line registry of potential research participants. RLS was assessed using the Cambridge-Hopkins questionnaire. RLS persons and controls were recruited through RLS Foundation and on-line registry advertisements and assessed for hypothyroidism by self-report. The International RLS Study Group Severity Scale assessed RLS severity; 266 hypothyroid subjects and 321 controls were comparable in age (52.3 ± 13.4 versus 53.9 ± 11.7 years; p = .14) and gender (91.7% versus 91.3% women; p = .85), as were 354 RLS and 313 controls (59.1 ± 13.2 versus 58.2 ± 13.6 years; p = .41; 80.8% versus 78.3% women; p = .42). Hypothyroid participants versus controls had a significantly higher prevalence of RLS (14.3% versus 8.1%; p = .02). RLS participants versus controls had a significantly higher prevalence of hypothyroidism (22.3% versus. 13.8%; p = .005). RLS severity was similar in persons with and without hypothyroidism. Among 73 persons with RLS and hypothyroidism, 14 previously were hyperthyroid versus 0 of 37 persons with hypothyroidism alone (p = .004). RLS prevalence is increased in individuals with hypothyroidism; hypothyroidism prevalence is increased in individuals with RLS. Persons with hypothyroidism and RLS are significantly more likely than those with hypothyroidism alone to have had hyperthyroidism prior to hypothyroidism. Associations between RLS and thyroid disease may shed light on complex biological mechanisms underlying RLS.

Impact of Obstructive Sleep Apnea on Cognitive and Motor Functions in Parkinson's Disease.

INTRODUCTION: Parkinson's disease (PD) is a chronic neurodegenerative disorder that presents with motor and non-motor manifestations. Amongst the non-motor features, various forms of sleep disturbances can occur, and obstructive sleep apnea (OSA) is considered to be a common comorbidity. We conducted this systematic review and meta-analysis to assess the impact of OSA on cognitive and motor functions in PD. METHODS: The information sources of for this systematic review and meta-analysis were PubMed, SCOPUS, Web of Science, and ScienceDirect. Studies meeting the following criteria were included: (1) studies including idiopathic PD patients, (2) studies using polysomnography to categorize PD patients into PD with OSA and PD without OSA, and (3) studies with observational designs (case-control, cohort, or cross-sectional). Data analysis was performed using RevMan. RESULTS: Our meta-analysis showed that OSA was associated with significantly lower scores of Montreal Cognitive Assessments (MoCA) (mean difference (MD) = -0.70, 95% confidence interval (CI) [-1.28, -0.13], P = 0.01) and Mini-Mental State Examination (MMSE) (MD = -0.69, 95% CI [-1.17, -0.21], P = 0.005). Moreover, the score of the motor part of the Unified Parkinson's Disease Rating Scale (UPDRS III) was significantly higher in PD patients with OSA as compared with those without OSA (MD = 1.63, 95% CI [0.03, 3.23], P = 0.049). CONCLUSIONS: OSA is associated with increased severity of PD-associated cognitive dysfunction and motor symptoms. However, further studies are needed to corroborate these findings, assess the underlying mechanisms by which OSA influences the motor and cognitive functions in PD, and investigate whether OSA can accelerate the neurodegenerative process of PD. © 2020 International Parkinson and Movement Disorder Society.

Implications of the Gut Microbiome in Parkinson's Disease.

Parkinson's disease is a common neurodegenerative disorder that presents with nonmotor and motor symptoms. The nonmotor manifestations of Parkinson's disease often begin years before the motor symptoms. Autopsy studies, including both Parkinson's disease patients and matched controls, demonstrated that α-synuclein aggregates in Parkinson's disease patients can be found in both the substantia nigra and the enteric nervous system. Therefore, it has been hypothesized that the pathological process that leads eventually to Parkinson's disease might initially take place in the enteric nervous system years before the appearance of motor features. The gut microbiome plays essential roles in the development and maintenance of different body systems. Dysbiosis of the normal gut microbiome is thought to be associated with pathophysiologic changes not only in the gastrointestinal system itself but also in the enteric and central nervous systems. These changes are thought to ultimately cause loss of dopaminergic neurons via various mechanisms including the release of neurotoxins into the systemic circulation, decreased production of neuroprotective factors, and triggering inflammatory and autoimmune responses. In this review, we review the gut microbiome changes in Parkinson's disease and discuss the mechanisms by which gut microbiome dysbiosis may be a contributing factor to the pathophysiology of Parkinson's disease. © 2020 International Parkinson and Movement Disorder Society.

Pathophysiologic mechanisms, neuroimaging and treatment in wake-up stroke.

Wake-up stroke (WUS) or ischemic stroke occurring during sleep accounts for 14%-29.6% of all ischemic strokes. Management of WUS is complicated by its narrow therapeutic time window and attributable risk factors, which can affect the safety and efficacy of administering intravenous (IV) tissue plasminogen activator (t-PA). This manuscript will review risk factors of WUS, with a focus on obstructive sleep apnea, potential mechanisms of WUS, and evaluate studies assessing safety and efficacy of IV t-PA treatment in WUS patients guided by neuroimaging to estimate time of symptom onset. The authors used PubMed (1966 to March 2018) to search for the term "Wake-Up Stroke" cross-referenced with "pathophysiology," ''pathogenesis," "pathology," "magnetic resonance imaging," "obstructive sleep apnea," or "treatment." English language Papers were reviewed. Also reviewed were pertinent papers from the reference list of the above-matched manuscripts. Studies that focused only on acute Strokes with known-onset of symptoms were not reviewed. Literature showed several potential risk factors associated with increased risk of WUS. Although the onset of WUS is unknown, a few studies investigated the potential benefit of magnetic resonance imaging (MRI) in estimating the age of onset which encouraged conducting clinical trials assessing the efficacy of MRI-guided thrombolytic therapy in WUS.

Demoralization in essential tremor: prevalence, clinical correlates, and dissociation from tremor severity.

OBJECTIVE: Essential tremor (ET) is associated with psychological difficulties, including anxiety and depression. Demoralization (feelings of helplessness, hopelessness, inability to cope), another manifestation of psychological distress, has yet to be investigated in ET. Our objectives are to (1) estimate the prevalence of demoralization in ET, (2) assess its clinical correlates, and (3) determine whether demoralization correlates with tremor severity. METHODS: We administered the Kissane Demoralization Scale (KDS-II) and several psychosocial evaluations (ie, scales assessing subjective incompetence, resilience, and depression [eg, Geriatric Depression Scale]) to 60 ET subjects. Tremor was assessed with a disability score and total tremor score. KDS-II >8 indicated demoralization. RESULTS: Among 60 ET subjects (mean age = 70.2 ± 6.8 years), the prevalence of demoralization was 13.3%, 95% confidence interval = 6.9-24.2%. Although there was overlap between demoralization and depression (10% of the sample meeting criteria for both), 54% of depressed subjects were not demoralized, and 25% of demoralized subjects were not depressed. Demoralization correlated with psychological factors, but demoralized subjects did not have significantly higher total tremor scores, tremor disability scores, or years with tremor. CONCLUSIONS: Demoralization has a prevalence of 13.3% in ET, similar to that in other chronic or terminal illnesses (eg, cancer 13-18%, Parkinson's disease 18.1%, coronary heart disease 20%). Demoralization was not a function of increased tremor severity, suggesting that it is a separable construct, which could dictate how a patient copes with his/her disease. These data further our understanding of the psychological and psychosocial correlates of ET.