Consistent skin α-synuclein positivity in REM sleep behavior disorder - A two center two-to-four-year follow-up study.

OBJECTIVE/METHODS: Phosphorylated alpha-synuclein (p-syn) in dermal nerves of patients with isolated REM sleep behavior disorder (iRBD) is detectable by immunofluorescence-labeling. Skin-biopsy-p-syn-positivity was recently postulated to be a prodromal marker of Parkinson's disease (PD) or related synucleinopathies. Here, we provide two-to four-year clinical and skin biopsy follow-up data of 33 iRBD patients, whose skin biopsy findings at baseline were reported in 2017. RESULTS: Follow-up biopsies were available from 25 patients (18 positive at baseline) and showed consistent findings over time in 24 patients. One patient converted from skin-biopsy-negativity to -positivity. P-syn-positivity was observed in iRBD patients who still had a normal FP-CIT-SPECT two years later. Clinically, five of the 23 at baseline skin-biopsy-positive patients (21.7%) had converted to PD or dementia with Lewy bodies at follow-up, but none of the skin-biopsy-negative patients. CONCLUSIONS: Dermal p-syn in iRBD is most probably an early consistent marker of synucleinopathy and may support other indicators of conversion to manifest disease state.

Plant Extracts for Sleep Disturbances: A Systematic Review.

BACKGROUND: Sleep complaints are common health issues in the general population. These conditions are associated with poorer physical and psychological activity, and they may have important social, economic, and personal consequences. In the last years, several food supplements with different plant extracts have been developed and are currently taken for improving sleep. Study Objectives. The aim of this study is to systematically review recent literature on oral plant extracts acting on sleep disorders distinguishing their action on the different symptoms of sleep complaints: difficulty in initiating or maintaining sleep, waking up too early, and quality of sleep. METHODS: We searched the PubMed database up to 05/03/2020 based on data from randomized, double-blind, placebo-controlled trials, noncontrolled trials, and cohort studies conducted in children and adult subjects. The search words used contained the following terms: oral food supplement and sleep disorders and the like. The most studied compounds were further analyzed with a second search using the following terms: name of the compound and sleep disorders. We selected 7 emerging compounds and 38 relevant reports. RESULTS: Although nutraceutical natural products have been used for sleep empirically, there is a scarcity of evidence on the efficacy of each product in clinical studies. Valerian and lavender were the most frequently studied plant extracts, and their use has been associated (with conflicting results) with anxiolytic effects and improvements in quality and duration of sleep. CONCLUSIONS: Sleep aids based on plant extracts are generally safe and well tolerated by the population. More high-quality research is needed to confirm the effectiveness of food supplements containing plant extracts in sleep complaints; in particular, it would be interesting to evaluate the association between plant extracts and sleep hygiene guidelines and to identify the optimal products to be used in a specific symptom of sleep complaint, giving more appropriate tools to the medical doctor.

EAN/ERS/ESO/ESRS statement on the impact of sleep disorders on risk and outcome of stroke.

BACKGROUND: Sleep disorders are highly prevalent in the general population and may be linked in a bidirectional fashion to stroke, which is one of the leading causes of morbidity and mortality. AIM: Four major scientific societies established a task force of experts in neurology, stroke, respiratory medicine, sleep medicine and methodology to critically evaluate the evidence regarding potential links and the impact of therapy. MATERIALS AND METHODS: Thirteen research questions were evaluated in a systematic literature search using a stepwise hierarchical approach: first, systematic reviews and meta-analyses; second, primary studies post-dating the systematic reviews/meta-analyses. A total of 445 studies were evaluated and 88 were included. Statements were generated regarding current evidence and clinical practice. RESULTS: Severe obstructive sleep apnoea (OSA) doubles the risk for incident stroke, especially in young to middle-aged patients. Continuous positive airway pressure (CPAP) may reduce stroke risk, especially in treatment-compliant patients. The prevalence of OSA is high in stroke patients and can be assessed by polygraphy. Severe OSA is a risk factor for recurrence of stroke and may be associated with stroke mortality, whilst CPAP may improve stroke outcome. It is not clear if insomnia increases stroke risk, whilst the pharmacotherapy of insomnia may increase it. Periodic limb movements in sleep (PLMS), but not restless limb syndrome (RLS), may be associated with an increased risk of stroke. Preliminary data suggest a high frequency of post-stroke insomnia and RLS and their association with a less favourable stroke outcome, whilst treatment data are scarce. DISCUSSION/CONCLUSION: Overall, the evidence base is best for OSA relationship with stroke and supports active diagnosis and therapy. Research gaps remain especially regarding insomnia and RLS/PLMS relationships with stroke.

In-vivo signatures of neurodegeneration in isolated rapid eye movement sleep behaviour disorder.

BACKGROUND AND PURPOSE: Isolated rapid eye movement sleep behaviour disorder (iRBD) is a parasomnia, recently recognized as a risk factor for progression to Parkinson's disease, dementia with Lewy body and multiple system atrophy. Biomarker studies in iRBD are relevant due to lack of evidence in this condition. The identification of biomarkers able to predict progression to synucleinopathy diseases is critical for iRBD. Fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging might provide information about ongoing neurodegenerative processes. In the present study, we tested for presence of brain hypometabolism patterns as biomarkers of neurodegeneration in single iRBD individuals. METHODS: We recruited 37 subjects with polysomnography-confirmed iRBD, with neuropsychological assessment and available FDG-PET scan. Images were analysed with a validated statistical parametric mapping procedure, providing individual hypometabolism maps. RESULTS: According to the neuropsychological evaluation, 22 subjects with iRBD had normal cognition and 15 subjects showed impairments, particularly in visuoperceptive/visuospatial and memory domains. One-fifth of the cases were impaired on the Qualitative Scoring of Pentagon Test. In 32 iRBD cases, FDG-PET statistical parametric maps revealed significant cerebral hypometabolism, namely in the occipital lobes (n = 5), occipital and cerebellar regions (n = 13), occipitoparietal regions (n = 13) and a selective cerebellar hypometabolism (n = 1). Five cases had normal FDG-PET scans. CONCLUSIONS: These imaging findings indicate that brain neurodegenerative processes are present and already detectable in iRBD. The different hypometabolism patterns in the single individuals may reflect specific early pathophysiological events due to the underlying synucleinopathy, with a specific neural vulnerability for the occipital cortex that might pre-date a risk of progression towards dementia with Lewy body.

Sleep-related disorders and their relationship with MRI findings in multiple sclerosis.

Sleep-related disorders have been reported to have a higher prevalence in multiple sclerosis (MS) than in the general population. They are often undervalued for the presence of more severe physical problems and the occurrence at night, without a direct observation in common clinical practice, but if not recognized and treated they can negatively affect the quality of life causing daytime drowsiness and worsening fatigue. Sleep related disorders most commonly reported in MS are as follows: insomnia, sleep-related breathing disorders (SRBD), restless legs syndrome (RLS) and periodic limb movement disorders (PLMD). Secondary narcolepsy, REM sleep behavior disorder (RBD) and propriospinal myoclonus have been also described in some case reports or series. The purpose of this review is to correlate the more common sleep disturbances in MS patients to the involvement of specific brain regions, analyzing their relationship with MRI findings. While insomnia is usually secondary to other disabling symptoms such as nocturia or pain, SRBD, RLS, narcolepsy, RBD and propriospinal myoclonus in MS patients can be the consequence of an injury of specific central nervous system (CNS) areas. Lesions in the pontine tegmentum and the dorsal medulla have been associated with SRBD, spinal cord lesions or atrophy with RLS, bilateral lesions in the lateral hypothalamus with narcolepsy-like symptoms, lesions in the dorsal pontine tegmentum with RBD and intramedullary demyelinating plaques in spinal cord with propriospinal myoclonus. MS specialists and general neurologists should be aware of these comorbidities since neuroimaging, which is routinely performed in MS, could provide helpful clinical indications on patients with secondary sleep-related disorders and to categorize symptomatic patients who need to underdo more in-depth sleep studies.

Preliminary evidence that vortioxetine may improve sleep quality in depressed patients with insomnia: a retrospective questionnaire analysis.

Insomnia is a frequent symptom in depressed patients. It can present with difficulty in initiating and/or maintaining sleep. We retrospectively evaluated a group of 15 patients affected by major depressive disorder and complaining of insomnia, who started vortioxetine (VOR) treatment for their depressive symptoms. The following questionnaires were captured at baseline and follow-up: Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Beck Depression Inventory. Pittsburgh Sleep Quality Index total score significantly decreased between follow-up and baseline (P < 0.01), and in several subitems related to sleep quality and continuity. Moreover, Epworth Sleepiness Scale decreased between follow-up and baseline (P < 0.01). Finally, Beck Depression Inventory reduction was also evident between follow-up and baseline (P < 0.01). This retrospective analysis showing the significant effect of VOR on both depressive symptoms and insomnia in patients showing comorbid major depressive disorder and insomnia invites further research in order to confirm this preliminary evidence. We hypothesize that the VOR mechanism of action may explain the improvement of subjective sleep, other than depressive symptoms.

Red Flags for early referral of people with symptoms suggestive of narcolepsy: a report from a national multidisciplinary panel.

OBJECTIVE: Narcolepsy is a lifelong disease, manifesting with excessive daytime sleepiness and cataplexy, arising between childhood and young adulthood. The diagnosis is typically made after a long delay that burdens the disease severity. The aim of the project, promoted by the "Associazione Italiana Narcolettici e Ipersonni" is to develop Red Flags to detect symptoms for early referral, targeting non-sleep medicine specialists, general practitioners, and pediatricians. MATERIALS AND METHODS: A multidisciplinary panel, including patients, public institutions, and representatives of national scientific societies of specialties possibly involved in the diagnostic process of suspected narcolepsy, was convened. The project was accomplished in three phases. Phase 1: Sleep experts shaped clinical pictures of narcolepsy in pediatric and adult patients. On the basis of these pictures, Red Flags were drafted. Phase 2: Representatives of the scientific societies and patients filled in a form to identify barriers to the diagnosis of narcolepsy. Phase 3: The panel produced suggestions for the implementation of Red Flags. RESULTS: Red Flags were produced representing three clinical pictures of narcolepsy in pediatric patients ((1) usual sleep symptoms, (2) unusual sleep symptoms, (3) endocrinological signs) and two in adult patients ((1) usual sleep symptoms, (2) unusual sleep symptoms). Inadequate knowledge of symptoms at onset by medical doctors turned out to be the main reported barrier to diagnosis. CONCLUSIONS: This report will hopefully enhance knowledge and awareness of narcolepsy among non-specialists in sleep medicine in order to reduce the diagnostic delay that burdens patients in Italy. Similar initiatives could be promoted across Europe.

World Association of Sleep Medicine (WASM) 2016 standards for recording and scoring leg movements in polysomnograms developed by a joint task force from the International and the European Restless Legs Syndrome Study Groups (IRLSSG and EURLSSG).

This report presents the results of the work by a joint task force of the International and European Restless Legs Syndrome Study Groups and World Association of Sleep Medicine that revised and updated the current standards for recording and scoring leg movements (LM) in polysomnographic recordings (PSG). First, the background of the decisions made and the explanations of the new rules are reported and then specific standard rules are presented for recording, detecting, scoring and reporting LM activity in PSG. Each standard rule has been classified with a level of evidence. At the end of the paper, Appendix 1 provides algorithms to aid implementation of these new standards in software tools. There are two main changes introduced by these new rules: 1) Candidate LM (CLM), are any monolateral LM 0.5-10 s long or bilateral LM 0.5-15 s long; 2) periodic LM (PLM) are now defined by runs of at least four consecutive CLM with an intermovement interval ≥10 and ≤ 90 s without any CLM preceded by an interval <10 s interrupting the PLM series. There are also new options defining CLM associated with respiratory events. The PLM rate may now first be determined for all CLM not excluding any related to respiration (providing a consistent number across studies regardless of the rules used to define association with respiration) and, subsequently, the PLM rate should also be calculated without considering the respiratory related events. Finally, special considerations for pediatric studies are provided. The expert visual scoringof LM has only been altered by the new standards to require accepting all LM > 0.5 s regardless of duration, otherwise the technician scores the LM as for the old standards. There is a new criterion for the morphology of LM that applies only to computerized LM detection to better match expert visual detection. Available automatic scoring programs will incorporate all the new rules so that the new standards should reduce technician burden for scoring PLMS.

Neurology and psychiatry: waking up to opportunities of sleep. : State of the art and clinical/research priorities for the next decade.

In recent years, evidence has emerged for a bidirectional relationship between sleep and neurological and psychiatric disorders. First, sleep-wake disorders (SWDs) are very common and may be the first/main manifestation of underlying neurological and psychiatric disorders. Secondly, SWDs may represent an independent risk factor for neuropsychiatric morbidities. Thirdly, sleep-wake function (SWF) may influence the course and outcome of neurological and psychiatric disorders. This review summarizes the most important research and clinical findings in the fields of neuropsychiatric sleep and circadian research and medicine, and discusses the promise they bear for the next decade. The findings herein summarize discussions conducted in a workshop with 26 European experts in these fields, and formulate specific future priorities for clinical practice and translational research. More generally, the conclusion emerging from this workshop is the recognition of a tremendous opportunity offered by our knowledge of SWF and SWDs that has unfortunately not yet entered as an important key factor in clinical practice, particularly in Europe. Strengthening pre-graduate and postgraduate teaching, creating academic multidisciplinary sleep-wake centres and simplifying diagnostic approaches of SWDs coupled with targeted treatment strategies yield enormous clinical benefits for these diseases.

REM Sleep Behavior Disorder (RBD) as a marker of neurodegenerative disorders.

Rapid eye movement (REM) sleep behavior disorder (RBD) can occur in the absence of any other obvious associated neurologic disorder or in association with a neurodegenerative disease, in which case it is considered as symptomatic RBD. RBD is frequently associated with Parkinson's disease (PD), Lewy body dementia or multiple system atrophy (MSA), and in several cases may even antedate the occurrence of motor symptoms by decades. When no neurologic disorder is obvious, RBD can be considered as idiopathic (iRBD). Several studies have looked at neurophysiologic and neuropsychological functions in iRBD and have found evidence of CNS dysfunction during both wakefulness and sleep in a variable proportion of these patients, challenging the concept of iRBD. Identifying subjects with a high risk of developing a neurodegenerative process may be crucial in order to develop early intervention strategies. Some prospective results in iRBD showed that potential markers of neurodegeneration are the following: 1) marked EEG slowing on spectral analysis; 2) decreased striatal 123I-FPCIT; 3) impaired color vision.

Rapid eye movement sleep behavior disorder: devising controlled active treatment studies for symptomatic and neuroprotective therapy--a consensus statement from the International Rapid Eye Movement Sleep Behavior Disorder Study Group.

OBJECTIVES: We aimed to provide a consensus statement by the International Rapid Eye Movement Sleep Behavior Disorder Study Group (IRBD-SG) on devising controlled active treatment studies in rapid eye movement sleep behavior disorder (RBD) and devising studies of neuroprotection against Parkinson disease (PD) and related neurodegeneration in RBD. METHODS: The consensus statement was generated during the fourth IRBD-SG symposium in Marburg, Germany in 2011. The IRBD-SG identified essential methodologic components for a randomized trial in RBD, including potential screening and diagnostic criteria, inclusion and exclusion criteria, primary and secondary outcomes for symptomatic therapy trials (particularly for melatonin and clonazepam), and potential primary and secondary outcomes for eventual trials with disease-modifying and neuroprotective agents. The latter trials are considered urgent, given the high conversion rate from idiopathic RBD (iRBD) to Parkinsonian disorders (i.e., PD, dementia with Lewy bodies [DLB], multiple system atrophy [MSA]). RESULTS: Six inclusion criteria were identified for symptomatic therapy and neuroprotective trials: (1) diagnosis of RBD needs to satisfy the International Classification of Sleep Disorders, second edition, (ICSD-2) criteria; (2) minimum frequency of RBD episodes should preferably be ⩾2 times weekly to allow for assessment of change; (3) if the PD-RBD target population is included, it should be in the early stages of PD defined as Hoehn and Yahr stages 1-3 in Off (untreated); (4) iRBD patients with soft neurologic dysfunction and with operational criteria established by the consensus of study investigators; (5) patients with mild cognitive impairment (MCI); and (6) optimally treated comorbid OSA. Twenty-four exclusion criteria were identified. The primary outcome measure for RBD treatment trials was determined to be the Clinical Global Impression (CGI) efficacy index, consisting of a four-point scale with a four-point side-effect scale. Assessment of video-polysomnographic (vPSG) changes holds promise but is costly and needs further elaboration. Secondary outcome measures include sleep diaries; sleepiness scales; PD sleep scale 2 (PDSS-2); serial motor examinations; cognitive indices; mood and anxiety indices; assessment of frequency of falls, gait impairment, and apathy; fatigue severity scale; and actigraphy and customized bed alarm systems. Consensus also was established for evaluating the clinical and vPSG aspects of RBD. End points for neuroprotective trials in RBD, taking lessons from research in PD, should be focused on the ultimate goal of determining the performance of disease-modifying agents. To date no compound with convincing evidence of disease-modifying or neuroprotective efficacy has been identified in PD. Nevertheless, iRBD patients are considered ideal candidates for neuroprotective studies. CONCLUSIONS: The IRBD-SG provides an important platform for developing multinational collaborative studies on RBD such as on environmental risk factors for iRBD, as recently reported in a peer-reviewed journal article, and on controlled active treatment studies for symptomatic and neuroprotective therapy that emerged during the 2011 consensus conference in Marburg, Germany, as described in our report.

Effects of continuous positive airway pressure on cognitition and neuroimaging data in sleep apnea.

Obstructive sleep apnea (OSA) has been associated with a broad range of neurocognitive difficulties. The current view is that the neurocognitive impairment in OSA is due to the adverse effects of sleep fragmentation and/or intermittent hypoxia. The overall picture of cognitive deficits in OSA is complex. On balance, there appears to be negative effects of OSA on cognition, most likely in the domains of attention/vigilance, verbal and visual delayed long-term memory, visuospatial/constructional abilities, and executive dysfunction. Continuous positive airway pressure (CPAP) is the most effective and widely used treatment of OSA. In the majority of studies of OSA patients treated with CPAP, attention/vigilance improved, but changes in global functioning, executive functioning, and memory improved in about half of the studies. This may be due, in part, to variability in study design and sampling methodology across studies. Structural volume changes have been demonstrated in brain regions of OSA patients including areas that regulate memory and executive function (e.g., frontal cortex, anterior cingulate, and hippocampus). Growing evidence suggests that the OSA-related changes in brain morphology may improve with CPAP treatment. Neuroimaging studies performed during cognitive testing have provided insight into CPAP's effect on function of neuroanatomical circuits in the brain. Although neuroimaging can provide important insights into the structural and functional differences associated with OSA, one of the challenges is to interpret the findings in light of comorbid conditions that also cause neural injury. The purpose of this article is to provide a narrative review of the publications on cognition and neuroimaging in OSA before and after CPAP treatment.

Environmental risk factors for REM sleep behavior disorder: a multicenter case-control study.

OBJECTIVE: Idiopathic REM sleep behavior disorder is a parasomnia characterized by dream enactment and is commonly a prediagnostic sign of parkinsonism and dementia. Since risk factors have not been defined, we initiated a multicenter case-control study to assess environmental and lifestyle risk factors for REM sleep behavior disorder. METHODS: Cases were patients with idiopathic REM sleep behavior disorder who were free of dementia and parkinsonism, recruited from 13 International REM Sleep Behavior Disorder Study Group centers. Controls were matched according to age and sex. Potential environmental and lifestyle risk factors were assessed via standardized questionnaire. Unconditional logistic regression adjusting for age, sex, and center was conducted to investigate the environmental factors. RESULTS: A total of 694 participants (347 patients, 347 controls) were recruited. Among cases, mean age was 67.7 ± 9.6 years and 81.0% were male. Cases were more likely to smoke (ever smokers = 64.0% vs 55.5%, adjusted odds ratio [OR] = 1.43, p = 0.028). Caffeine and alcohol use were not different between cases and controls. Cases were more likely to report previous head injury (19.3% vs 12.7%, OR = 1.59, p = 0.037). Cases had fewer years of formal schooling (11.1 ± 4.4 years vs 12.7 ± 4.3, p < 0.001), and were more likely to report having worked as farmers (19.7% vs 12.5% OR = 1.67, p = 0.022) with borderline increase in welding (17.8% vs 12.1%, OR = 1.53, p = 0.063). Previous occupational pesticide exposure was more prevalent in cases than controls (11.8% vs 6.1%, OR = 2.16, p = 0.008). CONCLUSIONS: Smoking, head injury, pesticide exposure, and farming are potential risk factors for idiopathic REM sleep behavior disorder.

Observational study of sleep-related disorders in Italian patients with Parkinson's disease: usefulness of the Italian version of Parkinson's disease sleep scale.

Sleep disturbances are common in patients with Parkinson's disease (PD). We aimed to evaluate prevalence and severity of nighttime sleep disturbances in Italian PD patients and to validate the Italian version of the Parkinson's disease sleep scale. A total of 221 PD patients and 57 healthy controls participated in a cross-sectional study with retest. PDSS, Epworth Sleepiness Scale (ESS), Hamilton Depression Rating Scale, Unified Parkinson's Disease Rating Scale (UPDRS), and Hoehn and Yahr staging were applied. PDSS total and individual items scores from patients were significantly lower than those in controls. Internal consistency of PDSS scale was satisfactory and intraclass correlation coefficient for test-retest reliability was 0.96 for total PDSS score. A significant negative correlation was found between total PDSS and ESS scores, and between total PDSS and HDRS scores. PDSS scores were also related to UPDRS sections II, III and IV, and H&Y stage. PDSS and ESS scores were not related to levodopa equivalent dose. Daytime sleepiness, depressive symptoms and disease severity correlate with sleep disturbances in Italian PD patients. The PDSS is a valid and reliable tool to evaluate sleep disturbances in Italian patients.

Bruxism and nocturnal groaning.

Sleep bruxism (SB) is a sleep-related movement disorder, characterized by tooth grinding and/or clenching. The causes of SB range from psychosocial factors to an excessive sleep arousal response. Some studies showed that SB episodes during sleep are under the influences of transient activity of the brainstem arousal. Nocturnal groaning (NG) is a parasomnia characterized by an expiratory monotonous vocalization occurring during sleep, especially in REM sleep and during the second half of the night. The pathogenesis of NG remains still unclear and many hypotheses arose, ranging from the persistence of a vestigial ventilatory pattern rather than an expiratory upper airways' obstruction. Sleep microstructure fluctuation might modulate the NG, since the end of the NG episode usually is synchronized with a cortical arousal and an autonomic activation. Further studies should clarify the pathophysiology of SB and NG, especially when the two phenomena are associated.

Preferential D2 or preferential D3 dopamine agonists in restless legs syndrome.

OBJECTIVE: A comparison between equivalent low doses of the D2 preferential agonist bromocriptine and the D3 preferential agonist pramipexole was performed in order to understand which dopamine agonist receptor subtype plays the main role in the treatment of restless legs syndrome (RLS) with periodic leg movements during sleep (PLMS). METHODS: A placebo-controlled, prospective, single-blind investigation was carried out on 45 drug-naive patients with idiopathic RLS. Each patient underwent 2 consecutive full night polysomnographic studies. The first night was performed without medication. Prior to the second night, one group received a single oral dose of 0.25 mg pramipexole while a second group received a single oral dose of 2.5 mg bromocriptine, and the remaining patients received placebo. Additionally, symptoms of restlessness were assessed. RESULTS: Subjective symptoms improved with both pramipexole and bromocriptine; however, the amelioration after pramipexole was scored higher. Only pramipexole induced an improvement in sleep efficiency and a reduction in wakefulness after sleep onset. Pramipexole was more effective than bromocriptine in reducing periodic leg movements, in particular in patients with a high baseline periodic leg movements index. Typical periodic leg movements, with an interval ranging between 10 and 40 seconds, disappeared completely after pramipexole treatment but persisted, even if reduced, after bromocriptine. CONCLUSIONS: Dopamine agonists targeting the dopamine D3 receptor subtype have a higher efficacy on periodic leg movements and RLS than a drug that preferentially targets the D2 receptor subtype. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with RLS pramipexole as compared to an estimated equivalent dose of bromocriptine results in greater improvement in some measures of RLS and PLMS severity after one night of treatment.