Sleep apnea syndrome comorbid with and without restless legs syndrome: differences in insomnia specific symptoms.

OBJECTIVE: Sleep Apnea Syndrome (SAS) is frequently comorbid with Restless Legs Syndrome (RLS). Both disorders are associated with disturbed sleep. However, data about insomnia specific symptoms in patients suffering from both sleep disorders (SAS-RLS) are rare. METHODS: In a restrospective design, we investigated 202 patients suffering from SAS and SAS-RLS. All patients underwent polysomnography, performed a vigilance test (Quatember-Maly), and completed the Regensburg Insomnia Scale (RIS), Epworth Sleepiness Scale (ESS), Beck Depression Inventory-II (BDI-II), and a Morning Questionnaire (FZN). Differences in insomnia specific symptoms between SAS and SAS-RLS were calculated using ANOVA. In a secondary analysis, the differences in daytime sleepiness and depression were analyzed. RESULTS: Of 202 patients, 42 (21%) had SAS-RLS. The proportion of women (60%) with SASRLS was higher than for men (40%) while men had had a higher proportion (71%) of SAS alone compared to women (29%), p < 0.0005. The RIS score was higher in SAS-RLS than in SAS. No differences were found in PSG data, ESS, BDI-II, or vigilance tests. CONCLUSIONS: Patients with both disorders SAS and RLS show a higher degree of insomnia-specific symptoms than for SAS alone and may profit from additional insomnia specific treatment.

Normal-Incidence PEEM Imaging of Propagating Modes in a Plasmonic Nanocircuit.

The design of noble-metal plasmonic devices and nanocircuitry requires a fundamental understanding and control of the interference of plasmonic modes. Here we report the first visualization of the propagation and interference of guided modes in a showcase plasmonic nanocircuit using normal-incidence nonlinear two-photon photoemission electron microscopy (PEEM). We demonstrate that in contrast to the commonly used grazing-incidence illumination scheme, normal-incidence PEEM provides a direct image of the structure's near-field intensity distribution due to the absence of beating patterns and despite the transverse character of the plasmonic modes. Based on a simple heuristic numerical model for the photoemission yield, we are able to model all experimental findings if global plane wave illumination and coupling to multiple input/output ports, and the resulting interference effects are accounted for.

The European Narcolepsy Network (EU-NN) database.

Narcolepsy with cataplexy is a rare disease with an estimated prevalence of 0.02% in European populations. Narcolepsy shares many features of rare disorders, in particular the lack of awareness of the disease with serious consequences for healthcare supply. Similar to other rare diseases, only a few European countries have registered narcolepsy cases in databases of the International Classification of Diseases or in registries of the European health authorities. A promising approach to identify disease-specific adverse health effects and needs in healthcare delivery in the field of rare diseases is to establish a distributed expert network. A first and important step is to create a database that allows collection, storage and dissemination of data on narcolepsy in a comprehensive and systematic way. Here, the first prospective web-based European narcolepsy database hosted by the European Narcolepsy Network is introduced. The database structure, standardization of data acquisition and quality control procedures are described, and an overview provided of the first 1079 patients from 18 European specialized centres. Due to its standardization this continuously increasing data pool is most promising to provide a better insight into many unsolved aspects of narcolepsy and related disorders, including clear phenotype characterization of subtypes of narcolepsy, more precise epidemiological data and knowledge on the natural history of narcolepsy, expectations about treatment effects, identification of post-marketing medication side-effects, and will contribute to improve clinical trial designs and provide facilities to further develop phase III trials.

The effect of partial sleep deprivation on computer-based measures of fitness to drive.

PURPOSE: Using a partial sleep deprivation paradigm, the aim of the study was to investigate the sensitivity of a computer-based test battery of fitness to drive to detect impairments related to sleepiness. METHODS: Forty-seven healthy subjects (34 females, mean age 26.0 ± 6.8 years) participated in a counterbalanced within-subject design of two conditions: (i) normal night sleep and (ii) partial sleep deprivation (PSD) with 4 h time in bed. For the assessment of fitness to drive, we used a validated traffic psychological test battery. Moreover, well-established measures of sleepiness highly responsive to sleep deprivation were applied: the Karolinska Sleepiness Scale (KSS), pupillography (Pupil Unrest Index (PUI) as physiological sleepiness indicator) and two sustained attention tasks (psychomotor Vigilance Task and Mackworth Clock Test). RESULTS: Subjective and physiological sleepiness were significantly increased after PSD, accompanied by large (d > 1.50 for KSS) and medium (d = 0.55 for PUI) effect sizes. Sleepiness-related performance decrements were found in both sustained attention tasks (d = 0.59-0.77). Assessing driving-related ability, PSD induced decrements only in the test domain Reaction Test (reaction time d = 0.54 and motor time d = 0.45). All other subtests-as well as the overall judgement of fitness to drive-were not significantly affected by PSD. CONCLUSION: In contrast to established tests of sustained attention and subjective sleepiness, computer-based test batteries of fitness to drive might lack sensitivity to core aspects of sleepiness as they mainly consist of short and stimulating subtests. Therefore, tasks that require sustained attention should be an essential part of traffic psychological test batteries when sleepiness is a potential issue.

ImmunoChip study implicates antigen presentation to T cells in narcolepsy.

Recent advances in the identification of susceptibility genes and environmental exposures provide broad support for a post-infectious autoimmune basis for narcolepsy/hypocretin (orexin) deficiency. We genotyped loci associated with other autoimmune and inflammatory diseases in 1,886 individuals with hypocretin-deficient narcolepsy and 10,421 controls, all of European ancestry, using a custom genotyping array (ImmunoChip). Three loci located outside the Human Leukocyte Antigen (HLA) region on chromosome 6 were significantly associated with disease risk. In addition to a strong signal in the T cell receptor alpha (TRA@), variants in two additional narcolepsy loci, Cathepsin H (CTSH) and Tumor necrosis factor (ligand) superfamily member 4 (TNFSF4, also called OX40L), attained genome-wide significance. These findings underline the importance of antigen presentation by HLA Class II to T cells in the pathophysiology of this autoimmune disease.

Shaping and spatiotemporal characterization of sub-10-fs pulses focused by a high-NA objective.

We describe a setup consisting of a 4f pulse shaper and a microscope with a high-NA objective lens and discuss the aspects most relevant for an undistorted spatiotemporal profile of the focused beam. We demonstrate shaper-assisted pulse compression in focus to a sub-10-fs duration using phase-resolved interferometric spectral modulation (PRISM). We introduce a nanostructure-based method for sub-diffraction spatiotemporal characterization of strongly focused pulses. The distortions caused by optical aberrations and space-time coupling from the shaper can be reduced by careful setup design and alignment to about 10 nm in space and 1 fs in time.

Multimode plasmon excitation and in situ analysis in top-down fabricated nanocircuits.

We experimentally demonstrate synthesis and in situ analysis of multimode plasmonic excitations in two-wire transmission lines supporting a symmetric and an antisymmetric eigenmode. To this end we irradiate an incoupling antenna with a diffraction-limited excitation spot exploiting a polarization- and position-dependent excitation efficiency. Modal analysis is performed by recording the far-field emission of two mode-specific spatially separated emission spots at the far end of the transmission line. To illustrate the power of the approach we selectively determine the group velocities of symmetric and antisymmetric contributions of a multimode ultrafast plasmon pulse.

Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study.

The aim of this study was to describe the clinical and PSG characteristics of narcolepsy with cataplexy and their genetic predisposition by using the retrospective patient database of the European Narcolepsy Network (EU-NN). We have analysed retrospective data of 1099 patients with narcolepsy diagnosed according to International Classification of Sleep Disorders-2. Demographic and clinical characteristics, polysomnography and multiple sleep latency test data, hypocretin-1 levels, and genome-wide genotypes were available. We found a significantly lower age at sleepiness onset (men versus women: 23.74 ± 12.43 versus 21.49 ± 11.83, P = 0.003) and longer diagnostic delay in women (men versus women: 13.82 ± 13.79 versus 15.62 ± 14.94, P = 0.044). The mean diagnostic delay was 14.63 ± 14.31 years, and longer delay was associated with higher body mass index. The best predictors of short diagnostic delay were young age at diagnosis, cataplexy as the first symptom and higher frequency of cataplexy attacks. The mean multiple sleep latency negatively correlated with Epworth Sleepiness Scale (ESS) and with the number of sleep-onset rapid eye movement periods (SOREMPs), but none of the polysomnographic variables was associated with subjective or objective measures of sleepiness. Variant rs2859998 in UBXN2B gene showed a strong association (P = 1.28E-07) with the age at onset of excessive daytime sleepiness, and rs12425451 near the transcription factor TEAD4 (P = 1.97E-07) with the age at onset of cataplexy. Altogether, our results indicate that the diagnostic delay remains extremely long, age and gender substantially affect symptoms, and that a genetic predisposition affects the age at onset of symptoms.

Narcolepsy and pregnancy: a retrospective European evaluation of 249 pregnancies.

In a retrospective cohort study undertaken in 12 European countries, 249 female narcoleptic patients with cataplexy (n = 216) and without cataplexy (n = 33) completed a self-administrated questionnaire regarding pregnancy and childbirth. The cohort was divided further into patients whose symptoms of narcolepsy started before or during pregnancy (308 pregnancies) and those in whom the first symptoms of narcolepsy appeared after delivery (106 pregnancies). Patients with narcolepsy during pregnancy were older during their first pregnancy (P < 0.001) and had a higher body mass index (BMI) prior to pregnancy (P < 0.01). Weight gain during pregnancy was higher in narcoleptic patients with cataplexy (P < 0.01). More patients with narcolepsy-cataplexy during pregnancy had impaired glucose metabolism and anaemia. Three patients experienced cataplexy during delivery. The rate of caesarean sections was higher in the narcolepsy-cataplexy group compared to the narcolepsy group (P < 0.05). The mean birth weight and gestational age of neonates were within the normal range and did not differ across groups. Neonatal care was affected adversely by symptoms of narcolepsy in 60.1% of those with narcolepsy during pregnancy. This study reports more obstetric complications in patients with narcolepsy-cataplexy during pregnancy; however, these were not severe. This group also had a higher BMI and higher incidence of impaired glucose metabolism during pregnancy. Caesarian section was conducted more frequently in narcolepsy-cataplexy patients, despite cataplexy being a rare event during delivery. Furthermore, symptoms of narcolepsy may render care of the infant more difficult.

Regensburg Insomnia Scale (RIS): a new short rating scale for the assessment of psychological symptoms and sleep in insomnia; study design: development and validation of a new short self-rating scale in a sample of 218 patients suffering from insomnia and 94 healthy controls.

BACKGROUND: The Regensburg Insomnia Scale (RIS) is a new self-rating scale to assess cognitive, emotional and behavioural aspects of psychophysiological insomnia (PI) with only ten items. A specific purpose of the new scale is the evaluation of the outcome of insomnia- specific cognitive behaviour therapy (CBT-I). METHODS: Internal consistency of the RIS has been validated in 218 patients with PI. For determining sensitivity and specificity, this sample has been compared to 94 healthy controls. Sensitivity to change and pre-post cross-validation with the Pittsburgh Sleep Quality Index (PSQI) has been tested in a separate sample of 38 patients with PI undergoing CBT-I. RESULTS: RIS distinguishes well between controls and patients with PI. Internal consistency was within a good range (Cronbach alpha = .890). RIS was sensitive for detecting improvements after CBT-I in sleep parameters and target symptoms such as sleep-related thinking. CONCLUSION: The RIS is a valid and feasible instrument for assessing psychological PI-symptoms and sleep parameters.

Insomnia symptoms influence CPAP compliance.

PURPOSE: The aim of this study is to determine parameters which influence 6-month compliance of continuous positive airway pressure therapy (CPAP) in patients with obstructive sleep apnea syndrome (OSAS). METHODS: This prospective study investigated 73 patients (24 females) with OSAS and medical indication for CPAP therapy: age 55.1 ± 11.5 years, body mass index (BMI) 30.8 ± 5.0 kg/m2, Apnea-Hypopnea Index (AHI) 39.2 ± 26.7/h, Oxygen Desaturation Index (ODI) 33.2 ± 25.4/h, minimum O(2) saturation 78.9 ± 7.6%. The influence of baseline parameters (demographic and polysomnographic data, sleeping medication intakes, BMI, psychometrics [Epworth Sleepiness Scale, Regensburg Insomnia Scale, Vigilance test and Beck Depression Inventory]) on 6-month compliance was evaluated with a correlation and a linear regression analysis. RESULTS: The baseline value of the Regensburg Insomnia Scale (RIS) predicts 6-month CPAP compliance (r = -0.376, R (2) = 0.14, p < 0.001), although no other baseline parameter correlates. Patients with a compliance of <4 h/night show higher RIS scores, i.e., more insomnia symptoms (17.6 ± 8.8) compared to those with ≥4 h/night (12.6 ± 6.9; p < 0.05). CONCLUSIONS: Insomnia symptoms prior to the beginning of CPAP treatment show a negative influence on CPAP compliance. Further studies should clarify, if a treatment of insomnia symptoms leads to a benefit in compliance.

Ultrafast plasmon propagation in nanowires characterized by far-field spectral interferometry.

Spectral interferometry is employed to fully characterize amplitude and phase of propagating plasmons that are transmitted through silver nanowires in the form of ultrashort pulses. For nanowire diameters below 100 nm, the plasmon group velocity is found to decrease drastically in accordance with the theory of adiabatic focusing. Furthermore, the dependence of the plasmon group velocity on the local nanowire environment is demonstrated. Our findings are of relevance for the design and implementation of nanoplasmonic signal processing and in view of coherent control applications.

Single sessions of transcranial direct current stimulation and transcranial random noise stimulation exert no effect on sleepiness in patients with narcolepsy and idiopathic hypersomnia.

Background: Hypersomnia poses major challenges to treatment providers given the limitations of available treatment options. In this context, the application of non-invasive brain stimulation techniques such as transcranial electrical stimulation (tES) may open up new avenues to effective treatment. Preliminary evidence suggests both acute and longer-lasting positive effects of transcranial direct current stimulation (tDCS) on vigilance and sleepiness in hypersomniac patients. Based on these findings, the present study sought to investigate short-term effects of single sessions of tDCS and transcranial random noise stimulation (tRNS) on sleepiness in persons suffering from hypersomnia. Methods: A sample of 29 patients suffering from narcolepsy or idiopathic hypersomnia (IH) was recruited from the Regensburg Sleep Disorder Center and underwent single sessions of tES (anodal tDCS, tRNS, sham) over the left and right dorsolateral prefrontal cortex on three consecutive days in a double-blind, sham-controlled, pseudorandomized crossover trial. The primary study endpoint was the mean reaction time measured by the Psychomotor Vigilance Task (PVT) before and directly after the daily tES sessions. Secondary endpoints were additional PVT outcome metrics as well as subjective outcome parameters (e.g., Karolinska Sleepiness Scale; KSS). Results: There were no significant treatment effects neither on objective (i.e., PVT) nor on subjective indicators of sleepiness. Conclusion: We could not demonstrate any clinically relevant effects of single sessions of tDCS or tRNS on objective or subjective measures of sleepiness in patients with hypersomnia. However, we cannot exclude that repeated sessions of tES may affect vigilance or sleepiness in hypersomniac patients.

Narcolepsy risk loci outline role of T cell autoimmunity and infectious triggers in narcolepsy.

Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin transmission. Risk factors include pandemic 2009 H1N1 influenza A infection and immunization with Pandemrix®. Here, we dissect disease mechanisms and interactions with environmental triggers in a multi-ethnic sample of 6,073 cases and 84,856 controls. We fine-mapped GWAS signals within HLA (DQ0602, DQB1*03:01 and DPB1*04:02) and discovered seven novel associations (CD207, NAB1, IKZF4-ERBB3, CTSC, DENND1B, SIRPG, PRF1). Significant signals at TRA and DQB1*06:02 loci were found in 245 vaccination-related cases, who also shared polygenic risk. T cell receptor associations in NT1 modulated TRAJ*24, TRAJ*28 and TRBV*4-2 chain-usage. Partitioned heritability and immune cell enrichment analyses found genetic signals to be driven by dendritic and helper T cells. Lastly comorbidity analysis using data from FinnGen, suggests shared effects between NT1 and other autoimmune diseases. NT1 genetic variants shape autoimmunity and response to environmental triggers, including influenza A infection and immunization with Pandemrix®.

Spectral-interference microscopy for characterization of functional plasmonic elements.

Plasmonic modes supported by noble-metal nanostructures offer strong subwavelength electric-field confinement and promise the realization of nanometer-scale integrated optical circuits with well-defined functionality. In order to measure the spectral and spatial response functions of such plasmonic elements, we combine a confocal microscope setup with spectral interferometry detection. The setup, data acquisition, and data evaluation are discussed in detail by means of exemplary experiments involving propagating plasmons transmitted through silver nanowires. By considering and experimentally calibrating any setup-inherent signal delay with an accuracy of 1 fs, we are able to extract correct timing information of propagating plasmons. The method can be applied, e.g., to determine the dispersion and group velocity of propagating plasmons in nanostructures, and can be extended towards the investigation of nonlinear phenomena.

Sleep deprivation in chronic somatoform pain-effects on mood and pain regulation.

Sleep deprivation was found to exert complex effects on affective dimensions and modalities of pain perception both in healthy volunteers and patients with major depression. Considering multifaceted links between mood and pain regulation in patients with chronic somatoform pain, it is intriguing to study sleep deprivation effects for the first time in this group of patients. Twenty patients with a somatoform pain disorder according to ICD-10 diagnostic criteria were sleep-deprived for one night, followed by one recovery night. Clinical pain complaints (visual analog scale), detection- and pain thresholds (temperature and pressure) as well as mood states (Profile of Mood States) were assessed on the day prior to the experiment, on the day after sleep deprivation and on the day after recovery sleep. We found a discrepancy between significantly increased clinical pain complaints and unaltered experimental pain perception after sleep deprivation. Only the clinical pain complaints, but not the experimental pain thresholds were correlated with tiredness-associated symptoms. Total mood disturbances decreased and feelings of depression and anger improved significantly after sleep deprivation. However, these changes were not correlated with a change in clinical pain perception. We conclude that sleep deprivation may generally change the reagibility of the limbic system, but mood processing and pain processing may be affected in an opposite way reflecting neurobiological differences between emotional regulation and interoceptive pain processing.

Polysomnography reveals unexpectedly high rates of organic sleep disorders in patients with prediagnosed primary insomnia.

OBJECTIVE: It is a matter of debate whether patients with primary insomnia require a polysomnographic examination in order to exclude specific sleep disorders such as sleep apnea syndrome (SAS) or periodic limb movements (PLM). Using a prospective design, we investigated the prevalence of organic sleep disorders by means of polysomnography (PSG) in a series of patients who were previously diagnosed with primary insomnia. This diagnosis was based on a clinical exam and an ambulatory monitoring device or previous PSG. METHODS: Seventy-seven women and 16 men (mean age 55.12 ± 13.21 years) who were admitted for cognitive behavioral therapy for insomnia were evaluated by PSG including cardiorespiratory parameters and tibialis EMG. Among them, 50 patients had undergone a clinical exam by a sleep specialist; in 18 patients, actigraphy or portable monitoring had been performed to exclude SAS or PLM; 25 patients had undergone PSG in another sleep lab previously. RESULTS: In 32 patients (34% of the sample), a PSG revealed a specific sleep disorder (SAS 16; PLMD 11; both 5), resulting in therapeutic consequences for 21 patients (SAS 10; PLMD 9; both 2). SAS and PLM patients were older and SAS patients had a higher body mass index than insomnia patients without additional findings. CONCLUSION: Indications for a PSG should be handled less restrictively in the diagnostic workup of older insomnia patients since they have a higher risk of comorbid sleep disorders even in the absence of the clinical signs of SAS or PLM.

Determinants of depressive symptoms in narcoleptic patients with and without cataplexy.

The present prospective study assesses depressive symptoms in narcoleptic patients with (NC+) and without (NC-) cataplexy (46 women, 40 men) and age- and sex- matched healthy controls. Seventy patients were under treatment with stimulants and/or anticataplectics. All subjects completed the Beck Depression Inventory (BDI), the Zung Self-Rating Depression Scale (SDS), the Global Impression of Severity of Depression (GSD), the Profile of Mood States (POMS) and Epworth Sleepiness Scale. Patients with narcolepsy were more depressed than controls (higher scores in BDI, GSD, SDS, and POMS [in the total score and in all subscale scores]); however, between the NC+ and NC- patient groups, no differences were found. Our study shows that the women and the patients using antidepressants and stimulants (combination) have a higher probability for depressive symptoms independent of the presence of cataplexy. The lack of difference between NC+ and NC- in the level of depression supports the assumption that the major psychosocial burden in narcolepsy is not necessarily associated with the presence of cataplexy.

Mode imaging and selection in strongly coupled nanoantennas.

The number of eigenmodes in plasmonic nanostructures increases with complexity due to mode hybridization, raising the need for efficient mode characterization and selection. Here we experimentally demonstrate direct imaging and selective excitation of the "bonding" and "antibonding" plasmon mode in symmetric dipole nanoantennas using confocal two-photon photoluminescence mapping. Excitation of a high-quality-factor antibonding resonance manifests itself as a two-lobed pattern instead of the single spot observed for the broad "bonding" resonance in accordance with numerical simulations. The two-lobed pattern is observed due to the fact that excitation of the antibonding mode is forbidden for symmetric excitation at the feedgap, while concomitantly the mode energy splitting is large enough to suppress excitation of the "bonding" mode. The controlled excitation of modes in strongly coupled plasmonic nanostructures is mandatory for efficient sensors, in coherent control as well as for implementing well-defined functionalities in complex plasmonic devices.

Treatment of moderate to severe restless legs syndrome: 2-year safety and efficacy of rotigotine transdermal patch.

BACKGROUND: Rotigotine is a unique dopamine agonist with activity across D1 through D5 receptors as well as select adrenergic and serotonergic sites. This study reports the 2-year follow-up safety and efficacy data of an ongoing open-label multicenter extension study (NCT00498186) of transdermal rotigotine in patients with moderate to severe restless legs syndrome (RLS). METHODS: Patients received a once-daily patch application of an individually optimized dose of rotigotine between 0.5 mg/24 h to 4 mg/24 h. Safety assessments included adverse events (AEs) and efficacy was measured by the International RLS Study Group Severity Rating Scale (IRLS), RLS-6 scales and Clinical Global Impression (CGI). Quality of life (QoL) was measured by QoL-RLS. RESULTS: Of 310 patients who completed a 6-week placebo-controlled trial (SP709), 295 (mean age 58 ± 10 years, 66% females) were included in the open-label trial SP710. 64.7% (190/295 patients) completed the 2-year follow-up; 29 patients discontinued during the second year. Mean daily rotigotine dose after 2 years was 2.93 ± 1.14 mg/24 h with a 2.9% dose increase from year 1. Rotigotine was generally well tolerated. The rate of typical dopaminergic side effects, nausea and fatigue, was low (0.9% and 2.3%, respectively) during the second year; application site reactions were frequent but lower than in year 1 (16.4% vs. 34.5%). The IRLS total score improved from baseline of SP709 (27.8 ± 5.9) by 17.2 ± 9.2 in year 2 completers. Similar improvements were observed in RLS-6 scales, CGI scores and QoL-RLS. The responder rate in the CGI change item 2 ("much" and "very much" improved) was 95% after year 2. CONCLUSIONS: Transdermal rotigotine is an efficacious and well-tolerated long-term treatment option for patients with moderate to severe RLS with a high retention rate during 2 years of therapy. TRIAL REGISTRATION: NCT00498186.