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.

Development and validation of a model predicting mild stroke severity on admission using electronic health record data.

OBJECTIVE: Initial stroke severity is a potent modifier of stroke outcomes but this information is difficult to obtain from electronic health record (EHR) data. This limits the ability to risk-adjust for evaluations of stroke care and outcomes at a population level. The purpose of this analysis was to develop and validate a predictive model of initial stroke severity using EHR data elements. METHODS: This observational cohort included individuals admitted to a US Department of Veterans Affairs hospital with an ischemic stroke. We extracted 65 independent predictors from the EHR. The primary analysis modeled mild (NIHSS score 0-3) versus moderate/severe stroke (NIHSS score ≥4) using multiple logistic regression. Model validation included: (1) splitting the cohort into derivation (65%) and validation (35%) samples and (2) evaluating how the predicted stroke severity performed in regard to 30-day mortality risk stratification. RESULTS: The sample comprised 15,346 individuals with ischemic stroke (n = 10,000 derivation; n = 5,346 validation). The final model included 15 variables and correctly classified 70.4% derivation sample patients and 69.4% validation sample patients. The areas under the curve (AUC) were 0.76 (derivation) and 0.76 (validation). In the validation sample, the model performed similarly to the observed NIHSS in terms of the association with 30-day mortality (AUC: 0.72 observed NIHSS, 0.70 predicted NIHSS). CONCLUSIONS: EHR data can be used to construct a surrogate measure of initial stroke severity. Further research is needed to better differentiate moderate and severe strokes, enhance stroke severity classification, and how to incorporate these measures in evaluations of stroke care and outcomes.

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.

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.

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.

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.

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.

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.

Association of novel measures of sleep disturbances with blood pressure: the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Mechanisms underlying blood pressure (BP) changes in obstructive sleep apnoea (OSA) are incompletely understood. We assessed the associations between BP and selected polysomnography (PSG) traits: sleep depth, airflow limitation measurements and OSA-specific hypoxic burden. METHODS: This cross-sectional analysis included 2055 participants from the Multi-Ethnic Study of Atherosclerosis who underwent PSG and BP measurements in 2010-2013. Sleep depth was assessed using the 'OR product', a continuous measure of arousability. Airflow limitation was assessed by duty cycle (Ti/Tt) and % of breaths with flow limitation, and hypoxia by 'hypoxic burden'. Primary outcomes were medication-adjusted systolic BP (SBP) and diastolic BP (DBP). We used generalised linear models adjusted for age, sex, race/ethnicity, smoking, education, body mass index, alcohol use, periodic limb movements and alternative physiological disturbances. RESULTS: The sample had a mean age of 68.4 years and apnoea-hypopnoea index of 14.8 events/hour. Sleep depth was not significantly associated with BP. Every 1 SD increment in log-transformed non-rapid eye movement duty cycle was associated with 0.9% decrease in SBP (95% CI: 0.1% to 1.6%), even after adjusting for sleep depth and hypoxic burden. Every 1 SD increment in log-transformed hypoxic burden was associated with a 1.1% increase in SBP (95% CI: 0.1% to 2.1%) and 1.9% increase in DBP (95% CI: 1.0% to 2.8%) among those not using hypertension medications. CONCLUSIONS: Higher duty cycle was associated with lower SBP overall and hypoxic burden with higher SBP and DBP among non-BP medication users. These findings suggest changes in both respiratory effort and oxygenation during sleep influence BP.

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.

Associations Between Sleep Apnea and Subclinical Carotid Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis.

Background and Purpose- Many health effects of sleep apnea (SA) may be mediated through accelerated atherosclerosis. We examined the associations of snoring and several measurements of SA with subclinical carotid atherosclerosis in a large multiethnic population sample. Methods- This analysis included 1615 participants (mean age, 68 years) from examination 5 (2010-2013) of the MESA study (Multi-Ethnic Study of Atherosclerosis). Sleep measures including SA (apnea-hypopnea index [4%], ≥15 events/hour) were derived from full in-home polysomnography. Carotid atherosclerosis was measured using high-resolution B-mode ultrasound. Multivariable linear and logistic regression models were used to evaluate the associations between sleep exposures with carotid intima-media thickness and the presence of carotid plaque, respectively. Effect modification by age, sex, and race/ethnicity was examined. Results- In multivariable analysis, SA was associated with an increased odds of carotid plaque presence in individuals aged <68 years (odds ratio, 1.47; 95% CI, 1.05-2.06) but not in older individuals (odds ratio, 0.95; 95% CI, 0.67-1.37; P interaction=0.078). Greater hypoxemia (sleep time <90% saturation) was associated with increasing carotid intima-media thickness in younger (0.028±0.014 mm) but not in older individuals (-0.001±0.013 mm; P interaction=0.106). Self-reported snoring was not associated with carotid atherosclerosis. In assessing race-specific outcomes, greater hypoxemia was associated with increased carotid intima-media thickness in blacks (0.049±0.017 mm; P interaction=0.033). Conclusions- In this large multiethnic population-based sample, sleep disturbances are associated with subclinical carotid atherosclerosis in both men and women, particularly in those <68 years of age. The mechanisms underlying the association between SA and carotid atherosclerosis may differ for carotid plaque and carotid intima-media thickness.

Polysomnography Utilization in Veterans Presenting Acutely with Ischemic Stroke or Transient Ischemic Attack.

INTRODUCTION: Obstructive sleep apnea (OSA) is an independent cerebrovascular risk factor and highly prevalent in patients with ischemic stroke and transient ischemic attack (TIA). Timely diagnosis and treatment of OSA is important as clinical data suggest that treatment of OSA in the setting of acute ischemic stroke improves functional outcomes. We aimed to assess polysomnography (PSG) utilization in US. Veterans with acute stroke or TIA over a 2-year period. METHODS: Veterans with acute ischemic stroke or TIA presenting to a Veterans Administration Medical Center (VAMC) between October 1, 2015, and June 30, 2017, were included. Demographic, clinical data, and PSG within 12 months of hospital discharge were obtained from the VA Corporate Data Warehouse to determine the rate of PSG testing among those with acute ischemic stroke or TIA. Fisher's exact test and two-sample t tests were used to compare demographic and clinical characteristics for those receiving and not receiving PSG. Mixed effect logistic regression was used to model the association of clinical and demographic characteristics with PSG receipt. RESULTS: In fiscal years (FYs) 2016 and 2017, 9,200 Veterans were admitted to a VAMC with ischemic stroke (6,011) or TIA (3,089). Veterans were elderly (70.5 ± 11.1 years), predominantly male (95.7%), and largely Caucasian (68.0% Caucasian, 26.3% African-American). Just 6.0% of Veterans underwent PSG within 1 year of acute ischemic stroke or TIA in FY 2016, compared to 6.2% in FY 2017 (p = 0.72). Compared to Veterans ≥80 years, those <60 had adjusted OR of 6.73 (4.10-11.05), those 60-69 had OR 4.29 (2.73-6.74), and those 70-79 had OR 2.63 (1.66-4.18) of having PSG. Veterans with diabetes or heart failure had significantly higher odds, whereas those with dementia had significantly lower odds of receiving PSG. CONCLUSION: PSG utilization among US Veterans is low and stable over time, despite recent guidelines recommending PSG among those having stroke or TIA. Older Veterans and those with dementia were unlikely to get PSG, representing especially vulnerable populations.

Polysomnographic phenotypes and their cardiovascular implications in obstructive sleep apnoea.

BACKGROUND: Obstructive sleep apnoea (OSA) is a heterogeneous disorder, and improved understanding of physiologic phenotypes and their clinical implications is needed. We aimed to determine whether routine polysomnographic data can be used to identify OSA phenotypes (clusters) and to assess the associations between the phenotypes and cardiovascular outcomes. METHODS: Cross-sectional and longitudinal analyses of a multisite, observational US Veteran (n=1247) cohort were performed. Principal components-based clustering was used to identify polysomnographic features in OSA's four pathophysiological domains (sleep architecture disturbance, autonomic dysregulation, breathing disturbance and hypoxia). Using these features, OSA phenotypes were identified by cluster analysis (K-means). Cox survival analysis was used to evaluate longitudinal relationships between clusters and the combined outcome of incident transient ischaemic attack, stroke, acute coronary syndrome or death. RESULTS: Seven patient clusters were identified based on distinguishing polysomnographic features: 'mild', 'periodic limb movements of sleep (PLMS)', 'NREM and arousal', 'REM and hypoxia', 'hypopnoea and hypoxia', 'arousal and poor sleep' and 'combined severe'. In adjusted analyses, the risk (compared with 'mild') of the combined outcome (HR (95% CI)) was significantly increased for 'PLMS', (2.02 (1.32 to 3.08)), 'hypopnoea and hypoxia' (1.74 (1.02 to 2.99)) and 'combined severe' (1.69 (1.09 to 2.62)). Conventional apnoea-hypopnoea index (AHI) severity categories of moderate (15≤AHI<30) and severe (AHI ≥30), compared with mild/none category (AHI <15), were not associated with increased risk. CONCLUSIONS: Among patients referred for OSA evaluation, routine polysomnographic data can identify physiological phenotypes that capture risk of adverse cardiovascular outcomes otherwise missed by conventional OSA severity classification.

Mood Symptoms and Restless Legs Syndrome Without Periodic Limb Movements During Sleep: Is it a Clinical Subtype?

Frequently co-occurring restless legs syndrome (RLS) and periodic limb movements during sleep (PLMS) are postulated to share common pathophysiology. The authors compared clinical characteristics and polysomnography (PSG) parameters among 155 idiopathic, untreated RLS patients who were stratified into three groups based on periodic limb movement index (PLMI). The authors found that RLS patients without PLMS (PLMI <5) had higher depression and anxiety scores, a lower total arousal index, longer latency to REM, and a higher spontaneous arousal frequency on PSG than RLS patients with PLMS. RLS severity was associated with PLMI in RLS patients with PLMS but not without PLMS. RLS without PLMS seems to be a phenotypically distinct clinical subtype of RLS. Future study should examine whether RLS without PLMS has a different clinical course, treatment response, and pathophysiology than RLS with PLMS.

Restless Legs Syndrome and Depression: Effect Mediation by Disturbed Sleep and Periodic Limb Movements.

OBJECTIVE: To investigate an association between restless legs syndrome (RLS) and depression and to what extent sleep disturbance, periodic limb movements during sleep (PLMS), and antidepressant medication mediate this relationship. METHODS: A cross-sectional analysis was conducted of the Osteoporotic Fractures in Older Men Study data in 982 men assessed for RLS (International RLS Study Group scale [IRLSS]) and depression (Geriatric Depression Scale [GDS]), who underwent actigraphy (for sleep latency/efficiency) and polysomnography (for PLMS). Men were split into three groups: no RLS (N = 815), mild RLS (IRLSS ≤ 12, N = 85), moderate-to-severe RLS (IRLSS > 12, N = 82). Depression was defined as GDS score ≥ 6. Logistic and linear regression assessed associations of RLS and depression or number depressive symptoms, respectively. Models were adjusted for age, site, race, education, body mass index, personal habits, benzodiazepine/dopaminergic medication, physical activity, cardiovascular risk factors, and apnea-hypopnea index. RESULTS: Of 982 men, 167 (17.0%) had RLS. Depression was significantly associated with moderate-to-severe RLS after adjustment (versus no RLS: OR [95% CI] 2.85 [1.23, 6.64]). Further adjustment for potential mediators attenuated effect size modestly, most for sleep efficiency (OR: 2.85-2.55). Compared with no RLS, moderate-to-severe RLS was associated with the number of depressive symptoms after adjustment (adjusted means [95% CI]; no RLS: 1.14 [1.05, 1.24] versus IRLSS > 12: 1.69 [1.32, 2.11]). Further adjustment for potential mediators did not alter effect size. For men with PLMS index at least median, number of depressive symptoms significantly increased as RLS category became more severe. CONCLUSION: Depression is more common as RLS severity worsens. The RLS-depression relationship is modestly explained by sleep disturbance and PLMS.

Observational Study of Obstructive Sleep Apnea in Wake-Up Stroke: The SLEEP TIGHT Study.

BACKGROUND: Wake-up stroke (WUS) accounts for a quarter of all ischemic strokes. Its conspicuous occurrence during sleep suggests that WUS may be associated with obstructive sleep apnea (OSA). We investigated the potential association among WUS, OSA, and measures of sympathetic hyperactivity. METHODS: This is a cross-sectional analysis of data from the Sleep Apnea in Transient Ischemic Attack and Stroke (SLEEP TIGHT) study. Ischemic stroke patients were divided into WUS and non-WUS groups. Participants underwent polysomnography and ambulatory blood pressure monitoring. Collected data included demographic, medical, stroke characteristics (including severity by National Institutes of Health Stroke Scale), cholesterol, serum catecholamines, C-reactive protein, interleukin-6, B-type natriuretic peptide, blood pressure, and polysomnographic (apnea-hypopnea index (AHI); measures of hypoxia). Because both stroke and OSA affect men and women to varying degrees, the cohort was considered as a whole and by gender stratification. RESULTS: Among 164 participants, 30.3% had WUS. The mean age was 62.0 ± 11.3 and the mean body mass index was 30.2 ± 7.9 kg/m2. One-hundred-and-five participants (63.6%) were males and 92 participants (56.8%) were Caucasian. Neither AHI nor OSA (AHI ≥5) frequency differed between WUS and non-WUS groups. Men tended to be more likely than women to have WUS (74.0 vs. 59.6%; p = 0.08), but this was not statistically significant. In gender-stratified analyses, men with WUS compared to men with non-WUS had significantly higher rates of severe OSA (AHI >30: 45.0 vs. 17.6%; p = 0.03) and tended toward more 3% oxygen desaturation events (57.0 ± 63.9 vs. 31.8 ± 22.9; p = 0.06). These differences were not seen in women. WUS patients tended to be of the male gender (74.0 vs. 59.6%; p = 0.08). History of stroke, hypertension, diabetes, dyslipidemia, or atrial fibrillation, serum catecholamines, and inflammatory biomarkers was no different between the groups. Low-density lipoprotein (LDL) was significantly higher in WUS (114.5 ± 36.3 vs. 101.4 ± 37.6; p = 0.04). Baseline diastolic blood pressure (DBP) was significantly greater in the WUS group. There was no difference in systolic or ambulatory blood pressure (including nighttime blood pressure) between WUS and non-WUS groups. CONCLUSIONS: WUS may be associated with severe OSA with more oxygen desaturation in men but not in women. WUS may be associated with high DBP and increased LDL cholesterol.

The Determining Risk of Vascular Events by Apnea Monitoring (DREAM) study: design, rationale, and methods.

PURPOSE: The goal of the Determining Risk of Vascular Events by Apnea Monitoring (DREAM) study is to develop a prognostic model for cardiovascular outcomes, based on physiologic variables-related to breathing, sleep architecture, and oxygenation-measured during polysomnography in US veterans. METHODS: The DREAM study is a multi-site, retrospective observational cohort study conducted at three Veterans Affairs (VA) centers (West Haven, CT; Indianapolis, IN; Cleveland, OH). Veterans undergoing polysomnography between January 1, 2000 and December 31, 2004 were included based on referral for evaluation of sleep-disordered breathing, documented history and physical prior to sleep testing, and ≥2-h sleep monitoring. Demographic, anthropomorphic, medical, medication, and social history factors were recorded. Measures to determine sleep apnea, sleep architecture, and oxygenation were recorded from polysomnography. VA Patient Treatment File, VA-Medicare Data, Vista Computerized Patient Record System, and VA Vital Status File were reviewed on dates subsequent to polysomnography, ranging from 0.06 to 8.8 years (5.5 ± 1.3 years; mean ± SD). RESULTS: The study population includes 1840 predominantly male, middle-aged veterans. As designed, the main primary outcome is the composite endpoint of acute coronary syndrome, stroke, transient ischemic attack, or death. Secondary outcomes include incidents of neoplasm, congestive heart failure, cardiac arrhythmia, diabetes, depression, and post-traumatic stress disorder. Laboratory outcomes include measures of glycemic control, cholesterol, and kidney function. (Actual results are pending.) CONCLUSIONS: This manuscript provides the rationale for the inclusion of veterans in a study to determine the association between physiologic sleep measures and cardiovascular outcomes and specifically the development of a corresponding outcome-based prognostic model.