Search

Jordan Dubow,1 Alon Y Avidan,2 Bruce Corser,3 Amod Athavale,4 David Seiden,1 Clete Kushida5 1Avadel Pharmaceuticals, Chesterfield, MO, USA; 2Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 3Sleep Management Institute, Cincinnati, OH, USA; 4Trinity Life Sciences, Waltham, MA, USA; 5Department of Psychiatry and Behavioral Sciences, Stanford University Medical Center, Stanford Sleep Medicine Center, Redwood City, CA, USACorrespondence: David Seiden, Tel +1 954 600-4625, Fax +1 636-449-1850, Email dseiden@avadel.comPurpose: Current US FDA-approved treatments for narcolepsy include sodium oxybate (SXB) and calcium, magnesium, potassium, and sodium oxybates (mixed-salt oxybates), which require 2 nightly doses, 1 at bedtime and another 2.5 to 4 hours later. Once-nightly SXB (ON-SXB; FT218) is under FDA review to treat adults with narcolepsy. This study quantitatively characterized attributes of SXB treatment preferred by individuals with narcolepsy via a discrete choice experiment (DCE) and evaluated preferences for the product profiles of once-nightly vs twice-nightly SXB treatment.Patients and Methods: Adults with self-reported physician-diagnosed narcolepsy for ≥ 1 year and current or prior twice-nightly SXB treatment were eligible for this 30-minute, web-based study capturing patient experiences and a DCE. Participants responded to a survey instrument using 9-point scales; higher scores indicated greater severity/preference/satisfaction. In the DCE, hundreds of profiles were generated, each combining attributes of twice-nightly SXB and ON-SXB based on clinical trial data. The DCE was analyzed using a hierarchical Bayesian model.Results: Seventy-five participants were surveyed (50 current and 25 past twice-nightly SXB users). Dosing frequency was the most important attribute of SXB treatment; once nightly was significantly preferred vs twice nightly. The most common reasons for overall product preference were lack of need to wake up in the middle of the night for a second dose (48%), fewer side effects (46%), and ease of administration (32%). Number of nightly doses was the most important driver of taking the medication exactly as directed and reduced anxiety/stress. Participants were significantly more likely to prefer the blinded product profile of once-nightly SXB over twice-nightly SXB (mean rating, 7.5 vs 4.3; P< 0.05).Conclusion: Among the choices presented, dosing frequency was the most important attribute for overall product choice, likelihood to take medication exactly as directed, and reducing anxiety/stress. The ON-SXB blinded profile was significantly preferred over twice-nightly SXB.Keywords: narcolepsy, patient preference, adherence, sodium oxybate, discrete choice experiment, once-nightly

Insomnia in the geriatric patient is unique and complex, requiring a comprehensive and careful evaluation. Insomnia is the most common sleep complaint reported by persons > 60 years. It is defined as the inability to initiate or maintain sleep, and the etiology can be multifactorial. Insomnia in the geriatric patient may be due to a primary sleep disorder, such as obstructive sleep apnea, periodic limb movements in sleep, circadian rhythm disorders, or restless legs syndrome, or it may be secondary to underlying medical or psychiatric conditions, medication effects, or psychosocial factors. When insomnia becomes chronic, it may exacerbate medical and psychiatric illnesses. Insomnia can lead to excessive daytime sleepiness, which may result in disturbed intellect, impaired cognition, confusion, psychomotor retardation, or increased risk of injury, any of which can compromise the patient's quality of life and create social and economic burdens for caregivers. This article discusses the recommended diagnostic and treatment approaches that may be used by the clinician in treating the geriatric patient. Case studies are presented to illustrate diagnoses of insomnia and therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background and Objectives: Idiopathic/isolated REM sleep behavior disorder (iRBD) has been strongly linked to neurodegenerative synucleinopathies such as Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. However, there have been increasing reports of RBD as a presenting feature of serious and treatable autoimmune syndromes, particularly IGLON5. This study's objective was to investigate the frequency of autoantibodies in a large cohort of participants with iRBD., Methods: Participants were enrolled in the North American Prodromal Synucleinopathy cohort with polysomnography-confirmed iRBD, free of parkinsonism and dementia. Plasma samples were systematically screened for the autoantibodies IGLON5, DPPX, LGI1, and CASPR2 using plasma IgG cell-based assay. Positive or equivocal results were confirmed by repeat testing, plus tissue-based indirect immunofluorescence assay for IGLON5., Results: Of 339 samples analyzed, 3 participants (0.9%) had confirmed positive IGLON5 autoantibodies in the cell-based assay, which were confirmed by the tissue-based assay. An additional participant was positive for CASPR2 with low titer by cell-based assay only (of lower clinical certainty). These cases exhibited a variety of symptoms including dream enactment, cognitive decline, autonomic dysfunction, and motor symptoms. In 1 IGLON5 case and the CASPR2 case, evolution was suggestive of typical synucleinopathy, suggesting the possibility that findings were incidental. However, 2 participants with IGLON5 died before diagnosis was clinically suspected, with a final clinical picture highly suggestive of autoimmune disease., Discussion: Our finding that nearly 1% of a large iRBD cohort may have a serious but potentially treatable autoantibody syndrome has important clinical implications. In particular, it raises the question of whether autoantibody testing for IGLON-5-IgG should be widely implemented for participants with iRBD, considering the difficulty in diagnosis of autoimmune diseases, their response to treatment, and the potential for rapid disease progression. However, any routine testing protocol will also have to consider costs and potential adverse effects of false-positive findings., Trial Registration Information: NCT03623672.

Study Objectives: Rapid eye movement sleep behavior disorder (RBD) is strongly associated with phenoconversion to an overt synucleinopathy, e.g. Parkinson's disease (PD), Lewy body dementia, and related disorders. Comorbid traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD)-henceforth "neurotrauma" (NT)-increase the odds of RBD by ~2.5-fold and are associated with an increased rate of service-connected PD in Veterans. Thus, RBD and NT are both independently associated with PD; however, it is unclear how NT influences neurological function in patients with RBD., Methods: Participants ≥18 years with overnight polysomnogram-confirmed RBD were enrolled between 8/2018 to 4/2021 through the North American Prodromal Synucleinopathy Consortium. Standardized assessments for RBD, TBI, and PTSD history, as well as cognitive, motor, sensory, and autonomic function, were completed. This cross-sectional analysis compared cases (n = 24; RBD + NT) to controls (n = 96; RBD), matched for age (~60 years), sex (15% female), and years of education (~15 years)., Results: RBD + NT reported earlier RBD symptom onset (37.5 ± 11.9 vs. 52.2 ± 15.1 years of age) and a more severe RBD phenotype. Similarly, RBD + NT reported more severe anxiety and depression, greater frequency of hypertension, and significantly worse cognitive, motor, and autonomic function compared to RBD. No differences in olfaction or color vision were observed., Conclusions: This cross-sectional, matched case:control study shows individuals with RBD + NT have significantly worse neurological measures related to common features of an overt synucleinopathy. Confirmatory longitudinal studies are ongoing; however, these results suggest RBD + NT may be associated with more advanced neurological symptoms related to an evolving neurodegenerative process., (Published by Oxford University Press on behalf of Sleep Research Society (SRS) 2024.)

Parasomnias are defined as abnormal movements or behaviors that occur in sleep or during arousals from sleep. Parasomnias vary in frequency from episodic events that arise from incomplete sleep state transition. The framework by which parasomnias are categorized and diagnosed is based on the International Classification of Sleep Disorders-Third Edition, Text Revision (ICSD-3-TR), published by the American Academy of Sleep Medicine. The recent Third Edition, Text Revision (ICSD-3-TR) of the ICSD provides an expert consensus of the diagnostic requirements for sleep disorders, including parasomnias, based on an extensive review of the current literature., Competing Interests: Disclosure Dr A.Y. Avidan has received consultant fees from Avadel, Merck, Takeda, and Idorsia and speaker honoraria from Avadel and Idorsia. This work was funded by NIH-NIA National Institute on Aging, United States, U19 AG071754 and the Karen Toffler Charitable Trust, United States., (Copyright © 2023 Elsevier Inc. All rights reserved.)

This article serves to help reduce patient burden in searching for credible information about parasomnias-abnormal behaviors during sleep-including sleepwalking, night terrors, and rapid eye movement sleep behavior disorder. It exhibits a compiled list of accessible online resources about parasomnias as well as detailed descriptions about each resource. By increasing patient accessibility to clinically validated resources, patients are more empowered to take an active role in managing their conditions, collaborating with their health-care practitioners in clinical management, enrolling in registries, and joining newsletters sponsored by these resources., Competing Interests: Disclosure Dr Avidan has received consultant fees from Avadel, Merck, Takeda, Idorsia and speaker honoraria from Avadel and Idorsia., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background and Objectives: REM sleep behavior disorder (RBD) is a parasomnia characterized by dream enactment. The International RBD Study Group developed the RBD Symptom Severity Scale (RBDSSS) to assess symptom severity for clinical or research use. We assessed the psychometric and clinimetric properties of the RBDSSS in participants enrolled in the North American Prodromal Synucleinopathy (NAPS) Consortium for RBD., Methods: NAPS participants, who have polysomnogram-confirmed RBD, and their bedpartners completed the RBDSSS (participant and bedpartner versions). The RBDSSS contains 8 questions to assess the frequency and severity/impact of (1) dream content, (2) vocalizations, (3) movements, and (4) injuries associated with RBD. Total scores for participant (maximum score = 54) and bedpartner (maximum score = 38) questionnaires were derived by multiplying frequency and severity scores for each question. The Clinical Global Impression Scale of Severity (CGI-S) and RBD symptom frequency were assessed by a physician during a semistructured clinical interview with participants and, if available, bedpartners. Descriptive analyses, correlations between overall scores, and subitems were assessed, and item response analysis was performed to determine the scale's validity., Results: Among 261 study participants, the median (interquartile range) score for the RBDSSS-PT (participant) was 10 (4-18) and that for the RBDSSS-BP (bedpartner) was 8 (4-15). The median CGI-S was 3 (3-4), indicating moderate severity. RBDSSS-BP scores were significantly lower in women with RBD (6 vs 9, p = 0.02), while there were no sex differences in RBDSSS-PT scores (8 vs 10.5, p = 0.615). Positive correlations were found between RBDSSS-PT vs RBDSSS-BP (Spearman r s = 0.561), RBDSSS-PT vs CGI-S ( r s = 0.556), and RBDSSS-BP vs CGI-S ( r s = 0.491, all p < 0.0001). Item response analysis showed a high discriminatory value (range 1.40-2.12) for the RBDSSS-PT and RBDSSS-BP (1.29-3.47)., Discussion: We describe the RBDSSS with adequate psychometric and clinimetric properties to quantify RBD symptom severity and good concordance between participant and bedpartner questionnaires and between RBDSSS scores and clinician-assessed global severity.

Background and Objectives: Although orthostatic hypotension (OH) can be an early feature of autonomic dysfunction in isolated REM sleep behavior disorder (iRBD), no large-scale studies have examined the frequency of OH in iRBD. In this study, we prospectively evaluated the frequency of OH in a large multicenter iRBD cohort., Methods: Participants 18 years or older with video polysomnogram-confirmed iRBD were enrolled through the North American Prodromal Synucleinopathy consortium. All participants underwent 3-minute orthostatic stand testing to assess the frequency of OH, and a Δ heart rate/Δ systolic blood pressure (ΔHR/ΔSBP) ratio <0.5 was used to define reduced HR augmentation, suggestive of neurogenic OH. All participants completed a battery of assessments, including the Scales for Outcomes in Parkinson Disease-Autonomic Dysfunction (SCOPA-AUT) and others assessing cognitive, motor, psychiatric, and sensory domains., Results: Of 340 iRBD participants (65 ± 10 years, 82% male), 93 (27%) met criteria for OH (ΔHR/ΔSBP 0.37 ± 0.28; range 0.0-1.57), and of these, 72 (77%) met criteria for OH with reduced HR augmentation (ΔHR/ΔSBP 0.28 ± 0.21; range 0.0-0.5). Supine hypertension (sHTN) was present in 72% of those with OH. Compared with iRBD participants without OH, those with OH were older, reported older age of RBD symptom onset, and had worse olfaction. There was no difference in autonomic symptom scores as measured by SCOPA-AUT., Discussion: OH and sHTN are common in iRBD. However, as patients may have reduced autonomic symptom awareness, orthostatic stand testing should be considered in clinical evaluations. Longitudinal studies are needed to clarify the relationship between OH and phenoconversion risk in iRBD., Trial Registration Information: ClinicalTrials.gov: NCT03623672; North American Prodromal Synucleinopathy Consortium.

Introduction: This guideline establishes clinical practice recommendations for the management of rapid eye movement sleep behavior disorder (RBD) in adults., Methods: The American Academy of Sleep Medicine (AASM) commissioned a task force of experts in sleep medicine to develop recommendations and assign strengths based on a systematic review of the literature and an assessment of the evidence using Grading of Recommendations, Assessment, Development and Evaluation methodology. The task force provided a summary of the relevant literature and the certainty of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations that support the recommendations. The AASM Board of Directors approved the final recommendations., Good Practice Statement: The following good practice statement is based on expert consensus, and its implementation is necessary for the appropriate and effective management of patients with RBD: It is critically important to help patients maintain a safe sleeping environment to prevent potentially injurious nocturnal behaviors. In particular, the removal of bedside weapons, or objects that could inflict injury if thrown or wielded against a bed partner, is of paramount importance. Sharp furniture like nightstands should be moved away or their edges and headboard should be padded. To reduce the risk of injurious falls, a soft carpet, rug, or mat should be placed next to the bed. Patients with severe, uncontrolled RBD should be recommended to sleep separately from their partners, or at the minimum, to place a pillow between themselves and their partners., Recommendations: The following recommendations, with medications listed in alphabetical order, are a guide for clinicians in choosing a specific treatment for RBD in adults. Each recommendation statement is assigned a strength ("strong" or "conditional"). A "strong" recommendation (ie, "We recommend…") is one that clinicians should follow under most circumstances. A "conditional" recommendation (ie, "We suggest…") is one that requires that the clinician use clinical knowledge and experience and strongly consider the patient's values and preferences to determine the best course of action., Adult patients with isolated RBD ., 1. The AASM suggests that clinicians use clonazepam (vs no treatment) for the treatment of isolated RBD in adults. (CONDITIONAL)., 2. * The AASM suggests that clinicians use immediate-release melatonin (vs no treatment) for the treatment of isolated RBD in adults. (CONDITIONAL)., 3. * The AASM suggests that clinicians use pramipexole (vs no treatment) for the treatment of isolated RBD in adults. (CONDITIONAL)., 4. The AASM suggests that clinicians use transdermal rivastigmine (vs no treatment) for the treatment of isolated RBD in adults with mild cognitive impairment. (CONDITIONAL)., Adult patients with secondary RBD due to medical condition ., 5. * The AASM suggests that clinicians use clonazepam (vs no treatment) for the treatment of secondary RBD due to medical condition in adults. (CONDITIONAL)., 6. * The AASM suggests that clinicians use immediate-release melatonin (vs no treatment) for the treatment of secondary RBD due to medical condition in adults. (CONDITIONAL)., 7. The AASM suggests that clinicians use transdermal rivastigmine (vs no treatment) for the treatment of secondary RBD due to medical condition (Parkinson disease) in adults. (CONDITIONAL)., 8. * The AASM suggests that clinicians not use deep brain stimulation (DBS; vs no treatment) for the treatment of secondary RBD due to medical condition in adults. (CONDITIONAL)., Adult patients with drug-induced RBD ., 9. * The AASM suggests that clinicians use drug discontinuation (vs drug continuation) for the treatment of drug-induced RBD in adults. (CONDITIONAL)., * The Recommendations section of this paper includes remarks that provide additional context to guide clinicians with implementation of this recommendation., Citation: Howell M, Avidan AY, Foldvary-Schaefer N, et al. Management of REM sleep behavior disorder: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2023;19(4):759-768., (© 2023 American Academy of Sleep Medicine.)

This systematic review provides supporting evidence for a clinical practice guideline for the management of rapid eye movement (REM) sleep behavior disorder in adults and children. The American Academy of Sleep Medicine commissioned a task force of 7 experts in sleep medicine. A systematic review was conducted to identify randomized controlled trials and observational studies that addressed interventions for the management of REM sleep behavior disorder in adults and children. Statistical analyses were performed to determine the clinical significance of critical and important outcomes. Finally, the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) process was used to assess the evidence for making recommendations. The literature search identified 4,690 studies; 148 studies provided data suitable for statistical analyses; evidence for 45 interventions is presented. The task force provided a detailed summary of the evidence assessing the certainty of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations., Citation: Howell M, Avidan AY, Foldvary-Schaefer N, et al. Management of REM sleep behavior disorder: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med . 2023;19(4):769-810., (© 2023 American Academy of Sleep Medicine.)

Objective: Rapid eye movement (REM) sleep behavior disorder (RBD) is widely considered a prodromal synucleinopathy, as most with RBD develop overt synucleinopathy within ~10 years. Accordingly, RBD offers an opportunity to test potential treatments at the earliest stages of synucleinopathy. The North American Prodromal Synucleinopathy (NAPS) Consortium has created a multisite RBD participant, primarily clinic-based cohort to better understand characteristics at diagnosis, and in future work, identify predictors of phenoconversion, develop synucleinopathy biomarkers, and enable early stage clinical trial enrollment., Methods: Participants ≥18 years of age with overnight polysomnogram-confirmed RBD without Parkinson's disease, dementia, multiple system atrophy, or narcolepsy were enrolled from nine sites across North America (8/2018 to 4/2021). Data collection included family/personal history of RBD and standardized assessments of cognitive, motor, sensory, and autonomic function., Results: Outcomes are primarily reported based on sex (361 total: n = 295 male, n = 66 female), and secondarily based on history of antidepressant use (n = 200 with, n = 154 without; with correction for sex differences) and based on extent of synucleinopathy burden (n = 56 defined as isolated RBD, n = 305 defined as RBD+ [i.e., exhibiting ≥1 abnormality]). Overall, these participants commonly demonstrated abnormalities in global cognition (MoCA; 38%), motor function (alternate tap test; 48%), sensory (BSIT; 57%), autonomic function (orthostatic hypotension, 38.8%), and anxiety/depression (BAI and PHQ-9; 39.3% and 31%, respectively)., Interpretation: These RBD participants, assessed with extensive history, demographic, cognitive, motor, sensory, and autonomic function demonstrated a lack of sex differences and high frequency of concomitant neurological abnormalities. These participants will be valuable for future longitudinal study and neuroprotective clinical trials., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Summary: Central disorders of hypersomnolence include a spectrum of conditions, such as narcolepsy, idiopathic hypersomnia, and Kleine-Levin syndrome, in which excessive daytime sleepiness is the primary feature. Subjective testing with tools, such as sleep logs and sleepiness scales, are often helpful in the evaluation of these disorders but do not necessarily correlate well with objective testing, such as polysomnography and multiple sleep latency test and maintenance of wakefulness test. The most recent International Classification of Sleep Disorders-Third Edition has incorporated biomarkers, such as cerebrospinal fluid hypocretin level, into the diagnostic criteria and have restructured the classification of conditions based on our evolved understanding of their underlying pathophysiologic mechanisms. Therapeutic approaches largely consist of behavioral therapy, with a focus on optimizing sleep hygiene, optimizing opportunity for sleep, and strategic napping, along with judicious use of analeptic and anticataleptic agents when necessary. Emerging therapy has revolved around hypocretin-replacement therapy, immunotherapy, and nonhypocretin agents, with the goal of better targeting the underlying pathophysiology of these disorders rather than addressing symptoms. The most novel treatments have targeted the histaminergic system (pitolisant), dopamine reuptake transmission (solriamfetol), and gamma-aminobutyric acid modulation (flumazenil and clarithromycin) to promote wakefulness. Continued research is required for a more solid understanding of the biology of these conditions to develop a more robust armamentarium of therapeutic options., Competing Interests: A. Y. Avidan: consultant with Balance Therapeutics, Eisai Inc, and Merck; served on Speakers' Bureau for Harmony Pharmaceuticals and has received stipend for educational services from UpToDate, Elsevier, and LWW. The remaining author has no conflicts of interest to disclose., (Copyright © 2020 by the American Clinical Neurophysiology Society.)

What Is This Summary About?: Sodium oxybate is a medicine for narcolepsy symptoms. It contains a high level of sodium. Should people taking sodium oxybate and their doctors worry about the sodium increasing their risk of heart or cardiovascular problems? This is a summary of an article that reviewed 20 years of published data to answer that question., What Were the Results?: We found that sodium oxybate was not linked to cardiovascular risks, such as heart attacks or strokes., What Do the Results Mean?: This suggests that the sodium in sodium oxybate may not add cardiovascular risk for people with narcolepsy. People currently taking sodium oxybate should talk to their doctor to ask if they need to be concerned about the sodium in their medicine. People who take sodium oxybate are unlikely to need to change their sodium oxybate medicine because of the sodium.

This article updates the American Academy of Sleep Medicine protocols for the administration of the Multiple Sleep Latency Test and the Maintenance of Wakefulness Test. The American Academy of Sleep Medicine commissioned a task force of clinical experts in sleep medicine to review published literature on the performance of these tests since the publication of the 2005 American Academy of Sleep Medicine practice parameter paper. Although no evidence-based changes to the protocols were warranted, the task force made several changes based on consensus. These changes included guidance on patient preparation, medication and substance use, sleep before testing, test scheduling, optimum test conditions, and documentation. This article provides guidance to providers who order and administer the Multiple Sleep Latency Test and the Maintenance of Wakefulness Test., Citation: Krahn LE, Arand DL, Avidan AY, et al. Recommended protocols for the Multiple Sleep Latency Test and the Maintenance of Wakefulness Test in adults: guidance from the American Academy of Sleep Medicine. J Clin Sleep Med. 2021;17(12):2489-2498., (© 2021 American Academy of Sleep Medicine.)

Electroencephalogram (EEG) recording is essential in the evaluation of complex movement and behaviors during sleep, but in particular for differentiating epileptic versus nonepileptic events. In general, epileptiform discharges occur with greater density in the first few nonerapid eye movement cycles, and approximately 12% to 20% of seizures occur exclusively at night. This review examines the epilepsy types and syndromes whose presentation is strongly influenced by the sleep state, with an appraisal about the role that sleep plays in facilitating seizures, while deleaneatign EEG findings and clinical manifestation. The review will summarize the typical semiology of sleep-related hypermotor seizures and contrasted with those occurring during none/rapid eye movement parasomnias and sleep-related movement disorders., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Sodium oxybate (SO), the sodium salt of γ-hydroxybutyric acid, is one of the primary pharmacologic agents used to treat excessive sleepiness, disturbed nighttime sleep, and cataplexy in narcolepsy. The sodium content of SO ranges from 550 to 1640 mg at 3-9 g, given in two equal nightly doses. Clinicians are advised to consider daily sodium intake in patients with narcolepsy who are treated with SO and have comorbid disorders associated with increased cardiovascular (CV) risk, in whom sodium intake may be a concern. It remains unclear whether all patients with narcolepsy treated with SO should modify or restrict their sodium intake. No data are currently available specific to the sodium content or threshold of SO at which patients might experience increased CV risk. To appraise attributable risk, critical evaluation of the literature was conducted to examine the relationship between CV risk and sodium intake, narcolepsy, and SO exposure. The findings suggest that increased CV risk is associated with extremes of daily sodium intake, and that narcolepsy is associated with comorbidities that may increase CV risk in some patients. However, data from studies regarding SO use in patients with narcolepsy have shown a very low frequency of CV side effects (eg, hypertension) and no overall association with CV risk. In the absence of data that specifically address CV risk with SO based on its sodium content, the clinical evidence to date suggests that SO treatment does not confer additional CV risk in patients with narcolepsy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To present (1) justification for earmarking sleep medicine education as an essential component of all medical school curricula and (2) various avenues to incorporate sleep medicine exposure into medical school curricula through (primarily) neuroscience and neurology courses., Methods: Per consensus of a team of leading neurology and sleep medicine educators, an evidence-based rationale for including sleep medicine across a 4-year medical school curriculum is presented along with suggested content, available/vetted resources, and formats for delivering sleep medicine education at various points and through various formats., Results: Growing evidence has linked sleep disorders (e.g., sleep-disordered breathing, chronic insufficient sleep) as risk factors for several neurologic disorders. Medical educators in neurology/neuroscience are now strongly advocating for sleep medicine education in the context of neurology/neuroscience pre and post graduate medical education. Sleep medicine education is also a critical component of a proactive strategy to address physician wellness and burnout. The suggested curriculum proposes a sleep educational exposure time of 2-4 hours per year in the form of lectures, flipped-classroom sessions, clinical opportunities, and online educational tools that would result in a 200%-400% increase in the amount of sleep medicine exposure that US medical schools currently provide. The guidelines are accompanied by the recommendation for use of technological education, to facilitate more seamless curricular incorporation., Conclusion: Even in this era with limited flexibility to add content to an already packed medical school curriculum, incorporating sleep medicine exposure into the current medical school curriculum is both justified and feasible., (© 2018 American Academy of Neurology.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Purpose of Review: Neurologists, along with all health care providers, commonly encounter patients with insomnia, which is a condition that impacts patients' underlying neurologic conditions in a bidirectional manner. While chronic insomnia is one of the most common sleep disturbances, only a small proportion of individuals with this condition discuss their sleep problems with their providers. When insomnia is described, it is more often in relationship to another medical problem, as opposed to an independent condition. In neurology practice, multiple factors including pain, movement disorders, sleep apnea, and medications that act on the central nervous system often contribute to insomnia. An all-inclusive approach is necessary when evaluating sleep problems in patients with insomnia., Recent Findings: The US Food and Drug Administration (FDA) has approved several medications for the treatment of insomnia that target specific receptor systems in the brain and incorporate several unique pharmacodynamic and pharmacokinetic profiles that can represent customized therapy for specific insomnia phenotypes. FDA-approved medications for insomnia include γ-aminobutyric acid (GABA)-modulating benzodiazepine receptor agonists, a melatonin receptor agonist, a histamine receptor antagonist, and the newest approved option, a hypocretin (orexin) receptor antagonist., Summary: This article provides an evidence-based multidisciplinary approach to the treatment of insomnia, highlighting the rationale and utility of cognitive-behavioral therapy and pharmacologic interventions. Neurologists should be proactive in assessing the impact of underlying comorbidities on insomnia, particularly in the setting of psychiatric conditions such as depression, sleep disorders such as circadian rhythm disorders, and medical problems such as nocturia.

Sleep disorders are common in neurology practice, but are often undiagnosed and untreated. Specific patient cohorts, such as older adults, patients residing in nursing homes, and patients with underlying chronic neurologic and psychiatric disorders, are at particular risk. If these sleep problems are not properly evaluated and managed the patient may experience exacerbation of the underlying neurologic disorder. This article highlights some of the key sleep disorders relevant to practicing neurologists, emphasizing hypersomnolence, insomnia, and sleep-related movement disorders in the setting of neurologic disorders to enhance the tools available for evaluation, and discusses management strategies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: The aim was to assess gabapentin enacarbil (GEn) treatment effects on quality of life (QOL) and mood in adults with moderate-to-severe primary restless legs syndrome (RLS)., Methods: Data were pooled from three placebo-controlled, randomized, double-blind, 12-week trials for adults receiving GEn (600 mg or 1200 mg) or placebo once daily. QOL was assessed with the RLS QOL questionnaire in two studies. Mood was examined with the Profile of Mood States Brief Form (POMS-B), and as an exploratory analysis with International Restless Legs Scale (IRLS) item 9 (daily affairs) and item 10 (mood disturbance) across all three studies. Mood and QOL were secondary endpoints in the individual clinical trials. No adjustments for multiplicity were applied., Results: The QOL analysis modified intent-to-treat (MITT) population included 541 adults (placebo, n = 204; GEn 600 mg, n = 114; GEn 1200 mg, n = 223). Both GEn doses significantly improved QOL versus placebo (week 12; p < 0.01). The mood analysis MITT population included 671 adults (placebo, n = 244; GEn 600 mg, n = 161; GEn 1200 mg, n = 266). GEn 600 mg significantly improved POMS vigor-activity versus placebo (week 12; p < 0.05); other POMS criteria were not significantly affected. GEn 1200 mg significantly improved POMS scores for total mood disturbance, depression-dejection, fatigue-inertia, vigor-activity, and confusion-bewilderment versus placebo at week 12 (p < 0.05); tension-anxiety and anger-hostility were not significantly affected. Both GEn doses significantly improved IRLS item 9 and item 10 versus placebo at week 12 (p < 0.05). The most frequent treatment-emergent adverse events with GEn were somnolence and dizziness., Conclusions: GEn (600 mg and 1200 mg) once daily significantly improved QOL in adults with moderate-to-severe primary RLS at all time points examined. While the only POMS item significantly improved by GEn 600 mg versus placebo at week 12 was vigor-activity, GEn 1200 mg significantly improved total mood disturbance and several other POMS items versus placebo at week 12. Both QOL and mood improvements were numerically greater with GEn 1200 mg versus 600 mg., Trial Registrations: Clinicaltrials.gov identifiers NCT00298623, NCT00365352, NCT01332305.

Aim: Assess efficacy and tolerability of gabapentin enacarbil (GEn) in adults with severe primary restless legs syndrome (RLS)., Methods: We pooled data from three 12-week, double-blind, placebo-controlled, randomized trials (NCT00298623, NCT00365352, NCT01332305) across GEn 600-mg, GEn 1200-mg, and placebo treatment groups for severe primary RLS (baseline International Restless Legs Scale (IRLS) total score ≥24). Co-primary end points at week 12 were mean change from baseline in IRLS total score and proportion of responders ("much"/very much" improved) on the investigator-rated Clinical Global Impression - Improvement (CGI-I) Scale. Outcomes for individual IRLS items (eg, sleep, mood, quality of life, pain, safety) were assessed., Results: A total of 309 patients had severe primary RLS (placebo, n = 110; GEn 600 mg, n = 80; GEn 1200 mg, n = 119). GEn 600 mg and 1200 mg significantly improved least-squares mean IRLS total scores versus placebo at week 12 (placebo, -12.3; GEn 600 mg, -16.3; GEn 1200 mg, -18.0; treatment difference vs. placebo, both p <0.01). Significantly more patients with severe primary RLS treated with GEn 600 mg (64%) and 1200 mg (74%) were CGI-I responders at week 12 versus placebo (42%; p <0.01 for both GEn doses). Both GEn doses led to significant improvements in the other outcomes explored versus placebo at week 12. The most frequent treatment-emergent adverse events (TEAEs) were somnolence (GEn, 21-24%; placebo, 3%) and dizziness (GEn, 14-19%; placebo, 3%)., Conclusions: GEn (600 mg or 1200 mg) once daily significantly improved RLS symptoms and consequences of these symptoms in severe primary RLS. The most frequent TEAEs were somnolence and dizziness., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The older patient population is growing rapidly around the world and in the USA. Almost half of seniors over age 65 who live at home are dissatisfied with their sleep, and nearly two-thirds of those residing in nursing home facilities suffer from sleep disorders. Chronic and pervasive sleep complaints and disturbances are frequently associated with excessive daytime sleepiness and may result in impaired cognition, diminished intellect, poor memory, confusion, and psychomotor retardation all of which may be misinterpreted as dementia. The key sleep disorders impacting patients with dementia include insomnia, hypersomnolence, circadian rhythm misalignment, sleep disordered breathing, motor disturbances of sleep such as periodic leg movement disorder of sleep and restless leg syndrome, and parasomnias, mostly in the form of rapid eye movement (REM) sleep behavior disorder (RBD). RBD is a pre-clinical marker for a class of neurodegenerative diseases, the "synucleinopathies", and requires formal polysomnographic evaluation. Untreated sleep disorders may exacerbate cognitive and behavioral symptoms in patients with dementia and are a source of considerable stress for bed partners and family members. When left untreated, sleep disturbances may also increase the risk of injury at night, compromise health-related quality of life, and precipitate and accelerate social and economic burdens for caregivers.

We report a case of a 53-year-old man presenting with depressed alertness and severe excessive sleepiness in the setting of neurosarcoidosis. Neuroimaging demonstrated hypothalamic destruction due to sarcoidosis with a CSF hypocretin level of 0 pg/mL. The patient also experienced respiratory depression that presumably resulted from hypocretin-mediated hypothalamic dysfunction as a result of extensive diencephalic injury. This is a novel case, demonstrating both hypocretin deficiency syndrome, as well as respiratory dysfunction from destruction of hypocretin neurons and extensive destruction of key diencephalic structures secondary to the underlying neurosarcoidosis., (© 2015 American Academy of Sleep Medicine.)

Sleep is disrupted in most patients hospitalized in the intensive care unit and the disturbances are even more profound in patients impacted by epilepsy. Nocturnal seizures must be differentiated from other common nocturnal events, such as delirium, parasomnias, and sedation. Many antiepileptic drugs produce undesirable side effects on sleep architecture that may further predispose patients to insomnia during the night and excessive sedation and hypersomnolence during the day. Failure to recognize, correctly diagnose, and adequately manage these disturbances may lead to more prolonged hospitalization, increased risk for nosocomial infections, poorer health-related qualify of life, and greater health care financial burden., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Sleep disturbances are common among patients with cancer for many reasons. Sleep problems can be present at any stage during treatment for cancer and in some patients, sleep disturbance may be the presenting symptoms that lead to the diagnosis of some types of cancer. Poor sleep impairs quality of life In people with cancer, but most do not specifically complain of sleep problems unless they are explicitly asked. Insomnia and fatigue are most common sleep disorders in this cohort, although primary sleep disorders, including obstructive sleep apnea and restless legs syndrome, which are common in the general population, have not been carefully studied in the oncology setting despite significant impairment to their quality of life., (©2015 Frontline Medical Communications.)

Objective: To evaluate the current state of sleep medicine educational resources and training offered by US neurology residency programs., Methods: In 2010, a 20-item peer reviewed Sleep Education Survey (SES) was sent to neurology residency program directors surveying them about sleep medicine educational resources used in teaching residents. Pearson product momentum correlation was used to determine correlation of program attributes with resident interest in pursuing a career in sleep medicine., Results: Of the programs completing the survey, 81% listed a formal sleep rotation and 24% included a forum for sleep research. A variety of innovative approaches for teaching sleep medicine were noted. Program directors noted that 5.7% residents entered sleep medicine fellowship training programs in the preceding 5 years. Programs that had a more substantial investment in sleep medicine teaching resources were more likely to report residents entering a sleep medicine training program., Conclusion: This is the first report providing an analysis of the current state of sleep medicine training in US Neurology Residency Programs. Our data provide evidence that investment by the residency program in sleep education may enhance the ultimate decision by the neurology trainee to pursue a career in sleep medicine.

Purpose of Review: Fragmented sleep, prolonged work hours, misalignment of sleep-wake cycles, and an expectation to make medical decisions when alertness levels are reduced are pervasive in neurology residency training. Sleep loss in residency training can lead to cognitive and psychosocial impairment and accidents, compromise patient care, and reduce the trainee's quality of life. Neurology residents experience levels of hypersomnolence similar to residents in surgical specialties and have comparable subjective levels of sleepiness as persons with pathologic sleep disorders such as narcolepsy and obstructive sleep apnea. Over the past 2 decades, work-hour limitations were established to alleviate fatigue and sleepiness. However, the implementation of work-hour limitations alone does not guarantee alleviation of fatigue and may be insufficient without additional key measures to prevent, counteract, and control sleepiness when it strikes. This article provides effective strategies to combat sleepiness, such as modification of the on-call structure (night float), power naps, and caffeine, in neurologists in training and those who are at risk for excessive sleepiness., Recent Findings: Despite two specific work-hour restrictions set by the Accreditation Council for Graduate Medical Education, the most recent in July 2011, little data exist about the efficacy of work-hour restrictions alone in improving fatigue and sleepiness. Curtailed work hours, while appearing attractive on the surface, have important financial, educational, and patient care imperfections and fail to address the core issue--sleepiness., Summary: Historically, sleepiness and fatigue place both residents and patients at risk. Excessive sleepiness in residency training occurs because of sleep deprivation and a spectrum of other factors, such as mood disorders or even the anxiety of anticipating being woken up. An effective model to counteract sleep deprivation and its consequences is a multiplayer approach that uniquely targets and addresses the needs of all the stakeholders. A sleep medicine perspective is proposed along with other interventions to prevent adverse consequences.

Parasomnias are classified into nonrapid eye movement and rapid eye movement sleep parasomnias. It is important for the clinician to consider other parasomnia mimics that present to the sleep disorders clinic. These conditions can be differentiated by taking a detailed sleep history and conducting nocturnal polysomnograms to evaluate for potential comorbidities and better characterize the disorder. Mainstays of treatment include treating any underlying primary sleep disorders that induce sleep fragmentation and could trigger the parasomnia, as well as implementing safety precautions to protect patients and their household. Pharmacologic treatment of many parasomnias is also available if needed and clinically indicated., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Opinion Statement: Patients with cerebral degenerative conditions commonly suffer from a variety of sleep disorders, including sleep-disordered breathing, insomnia, parasomnias (REM sleep behavior disorder), circadian rhythm disturbances, and restless legs syndrome. When these sleep disorders go unrecognized and untreated, they can lead to decreased quality of life and worsening neurological symptoms related to the underlying condition. Appropriate management initially requires taking a careful history from the patient and bed partner regarding their sleep. In addition, polysomnography may be required to aid in the diagnosis of sleep-disordered breathing or parasomnias. Occasionally, adjusting the dosages of sedating or sleep disrupting medications and improving sleep hygiene may improve sleep complaints. However, in most cases restoring quality nighttime sleep requires specific therapeutic intervention. In patients that suffer from sleep apnea, this usually means treatment with continuous positive airway pressure (CPAP), positional therapy, dental appliances, upper airway surgery, or weight loss. Pharmacological treatment of insomnia in patients with cerebral degenerative conditions can be difficult due to side effects (worsening balance, cognition) and lack of data in this patient population. Behavioral strategies such as cognitive-behavioral therapy have been effective and are considered safer than hypnotic therapy, but can be limited due to access to trained providers (distance and number of providers) and limited cognitive functioning of the patient. Parasomnias, namely REM sleep behavior disorder, are managed by looking for any underlying cause of arousals (sleep apnea, periodic leg movements of sleep), implementing safety precautions, and pharmacologically with either benzodiazepines or melatonin. Restless legs syndrome may improve with iron replacement or dopamine agonist therapy, as it does in other patient populations. Light therapy may be beneficial in patients suffering from circadian rhythm disorders such as advanced sleep phase syndrome.

Background/aims: Evidence suggests that patients with dementia with Lewy bodies (DLB) may have more nocturnal sleep disturbance than patients with Alzheimer's disease (AD). We sought to confirm such observations using a large, prospectively collected, standardized, multicenter-derived database, i.e. the National Alzheimer's Coordinating Center Uniform Data Set., Methods: Nocturnal sleep disturbance (NSD) data, as characterized by the Neuropsychiatric Inventory Questionnaire (NPI-Q), were derived from 4,531 patients collected between September 2005 and November 2008 from 32 National Institute on Aging participating AD centers. Patient and informant characteristics were compared between those with and without NSD by dementia diagnosis (DLB and probable AD). Finally, a logistic regression model was created to quantify the association between NSD status and diagnosis while adjusting for these patient/informant characteristics, as well as center., Results: NSD was more frequent in clinically diagnosed DLB relative to clinically diagnosed AD (odds ratio = 2.93, 95% confidence interval = 2.22-3.86). These results were independent from the gender of the patient or informant, whether the informant lived with the patient, and other patient characteristics, such as dementia severity, depressive symptoms, and NPI-Q-derived measures of hallucinations, delusions, agitation and apathy. In AD, but not DLB, patients, NSD was associated with more advanced disease. Comorbidity of NSD with hallucinations, agitation and apathy was higher in DLB than in AD. There was also evidence that the percentage of DLB cases with NSD showed wide variation across centers., Conclusion: As defined by the NPI-Q, endorsement of the nocturnal behavior item by informants is more likely in patients with DLB when compared to AD, even after the adjustment of key patient/informant characteristics., (Copyright © 2011 S. Karger AG, Basel.)

The circadian system regulates the cyclical occurrence of wakefulness and sleep through a series of oscillatory networks that comprise two different theoretical processes. The suprachiasmatic nucleus (SCN) of the hypothalamus contains the master oscillatory network necessary for coordinating these daily rhythms, and in addition to its ability to robustly generate rhythms, it can also synchronize to environmental light cues. During jet lag, abrupt shifts in the environmental light-dark cycle temporarily desynchronize the SCN and downstream oscillatory networks from each other, resulting in increased sleepiness and impaired daytime functioning. Polysomnographic data show that not only does jet lag result in changes of sleep-wake timing, but also in different aspects of sleep architecture. This type of circadian misalignment can further lead to a cluster of symptoms including major metabolic, cardiovascular, psychiatric, and neurological impairments. There are a number of treatment options for jet lag involving bright light exposure, melatonin, and use of hypnotics, but their efficacy greatly depends on their time of use, the length of time in the new time zone, and the specific circadian disturbance involved. The aim of this review is to provide mechanistic links between the fields of sleep and circadian rhythms to understand the biological basis of jet lag and to apply this information to clinical management strategies.

Parasomnias are a group of disorders exclusive to sleep and wake-to-sleep transition that encompass arousals with abnormal motor, behavioral, or sensory experiences. Sensory experiences often involve but are not limited to perceptions, dreamlike hallucinatory experiences, and autonomic symptoms. When accompanied with excessive motoric activity and other complex motor behaviors, these parasomnnias can be disruptive to the patient and bed partners. Motor behaviors may or may not be restricted to bed but can become dangerous when the subject ambulates or is agitated. The behaviors are inappropriate for the time of occurrence but may seem purposeful or goal directed. Most parasomnias are more common in children and decrease in frequency as they get older. Parasomnias have been reported in approximately 4% of the adult population., (Copyright 2010 Elsevier Inc. All rights reserved.)

Objective: This study examined the risk of accidental events in older adults prescribed a sedating antidepressant, long-acting benzodiazepine, short-acting benzodiazepine, and nonbenzodiazepine, relative to a reference group (selective melatonin receptor agonist)., Methods: This was a retrospective cohort analysis of older adults (≥65 years) with newly initiated pharmacological treatment of insomnia. Data were collected from the Thomson MarketScan(®) Medicare Supplemental and Coordination of Benefits databases (January 1, 2000, through June 30, 2006). Probit models were used to evaluate the probability of an accidental event., Results: Data were analyzed for 445,329 patients. Patients taking a long-acting benzodiazepine (1.21 odds ratio [OR]), short-acting benzodiazepine (1.16 OR), or nonbenzodiazepine (1.12 OR) had a significantly higher probability of experiencing an accidental event during the first month following treatment initiation compared with patients taking the reference medication (P < 0.05 for all). A significantly higher probability of experiencing an accidental event was also observed during the 3-month period following the initiation of treatment (1.62 long-acting benzodiazepine, 1.60 short-acting benzodiazepine, 1.48 nonbenzodiazepine, and 1.56 sedating antidepressant; P < 0.05)., Conclusions: Older adults taking an SAD or any of the benzodiazepine receptor agonists appear to have a greater risk of an accidental event compared with a reference group taking an MR.

Neurologists are often enlisted to help diagnose, evaluate, and manage a spectrum of abnormal spells during the night ranging from parasomnias to motor disturbance that span the sleep-wake cycle. Parasomnias are undesirable emotional or physical events that accompany sleep. These events typically occur during entry into sleep from wakefulness, or during arousals from sleep, and are often augmented by the sleep state. Some parasomnias, such as the rapid eye movement (REM) sleep behavior disorder may be extremely undesirable, while others such as somniloquy are often of little concern. The parasomnias include a spectrum of abnormal emotions, movements, behaviors, sensory perceptions, dream mentation, and autonomic activity. Basic physiologic drives, such as sex, hunger, and aggression, may manifest as sleep-related eating, sleep-related sexual behaviors, and sleep-related violence. Parasomnias have a very bizarre nature, but are readily explainable, diagnosable, and treatable. They are hypothesized to be due to changes in brain organization across multiple states of being, and are particularly apt to occur during the incomplete transition or oscillation from one sleep state to another. Parasomnias are often explained on the basis that wakefulness and sleep are not mutually exclusive states, and abnormal intrusion of wakefulness into non-REM (NREM) sleep produces arousal disorders, and intrusion of wakefulness into REM sleep produces REM sleep parasomnias and REM sleep behavior disorder (RBD). Restless legs syndrome (RLS) and periodic limb movement disorder (PLMD), two closely related conditions that often result in disturbed sleep onset and sleep maintenance, are also reviewed in this article. Although the mechanisms that underlie idiopathic RLS or PLMD are not fully understood, there is currently substantial evidence that dopaminergic dysfunction is likely involved in both conditions. The discussion will conclude with the "other parasomnias" and sleep-related movement disorders of clinical interest to the neurologist., (Thieme Medical Publishers.)

Sleep disorders are common and may result in significant morbidity. Examples of the major sleep disturbances in primary care practice include insomnia; sleep-disordered breathing, such as obstructive sleep apnea; central nervous system hypersomnias, including narcolepsy; circadian rhythm sleep disturbances; parasomnias, such as REM sleep behavior disorder; and sleep-related movement disorders, including restless legs syndrome. Diagnosis is based on meticulous inventory of the clinical history and careful physical examination. In some cases referral to a sleep laboratory for further evaluation with polysomnography, a sleep study, is indicated.

Sleep and stroke have an important and fascinating interaction. Patients with sleep-disordered breathing present with cardiovascular heart disease, cognitive decline, and increased risk of stroke. Stroke adversely affects sleep and factors such as prolonged immobilization, chronic pain, nocturnal hypoxia, and depression, which can also adversely impact sleep quality. Obstructive sleep apnea (OSA), one of the most common and serious sleep disturbances, manifests itself in almost 50% of all stroke patients. Sleep apnea patients who experience a stroke may be at a greater impairment in their rehabilitation potential and have increased risk of secondary stroke and mortality. Given these factors, the practicing neurologist should possess the skills to appropriately recognize, rapidly diagnose, and properly manage stroke patients with OSA.

Complaints of insomnia are prevalent in neurodegenerative and neurological disorders. Neurologists therefore must be aware of the underlying causes, pathophysiologic mechanisms, and potential interventions when encountering a patient with underlying neurological disorders who is also complaining of poor sleep and insomnia. This article describes the underlying pathophysiology, diagnostic approaches, and potential interventions for insomnia in the neurological patient. Clinicians need to recognize that insomnia in older patients with underlying neurological disorders is not only unique, but also complex, demanding comprehensive and careful evaluation and management. Treatment of insomnia should start by addressing nonpharmacologic options, including improvements in sleep hygiene, improving sunlight exposure during the day, and searching for underlying reversible causes, such as sleep apnea, restless legs syndrome, periodic leg movements, and circadian rhythm disturbances, all of which can precipitate insomnia when left untreated. Some patients may benefit from targeted and carefully tailored pharmacologic treatment. Successful amelioration of insomnia can ultimately be a very rewarding experience for the patient, family members, and the practitioner.

Objective: Sleep-related material in medical textbooks may be the only method by which physicians educate themselves about sleep. In the last decade significant progress in sleep research has been made, but how textbooks in relevant fields reflect it has not been examined. Our purpose was to review and compare (2005 with 1998) sleep content in representative medical textbooks., Methods: Sleep content of the latest edition of textbooks in four specialties was evaluated. Present sleep content in seven textbooks was compared with that found in 1998. Numbers of pages devoted to sleep were counted and reported for the subjects covered and for the specialty of the textbook., Results: Thirty-one textbooks were examined for current content and seven textbooks for content comparison. Sleep coverage in medical textbooks uniformly received less than 2% of the text volume. Focus of topics covered varied with specialty. Compared with 1998, the proportion of pages devoted to sleep remained the same or decreased. Coverage of new topics remained minimal., Conclusions: Major medical textbooks present small amounts of sleep content and few provide a comprehensive overview of sleep medicine. In comparison to textbook editions from the 1990s, current editions still devote little attention to sleep, and the diversity of topics has not improved.