European guideline for the diagnosis and treatment of insomnia.

This European guideline for the diagnosis and treatment of insomnia was developed by a task force of the European Sleep Research Society, with the aim of providing clinical recommendations for the management of adult patients with insomnia. The guideline is based on a systematic review of relevant meta-analyses published till June 2016. The target audience for this guideline includes all clinicians involved in the management of insomnia, and the target patient population includes adults with chronic insomnia disorder. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) system was used to grade the evidence and guide recommendations. The diagnostic procedure for insomnia, and its co-morbidities, should include a clinical interview consisting of a sleep history (sleep habits, sleep environment, work schedules, circadian factors), the use of sleep questionnaires and sleep diaries, questions about somatic and mental health, a physical examination and additional measures if indicated (i.e. blood tests, electrocardiogram, electroencephalogram; strong recommendation, moderate- to high-quality evidence). Polysomnography can be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep-related breathing disorders), in treatment-resistant insomnia, for professional at-risk populations and when substantial sleep state misperception is suspected (strong recommendation, high-quality evidence). Cognitive behavioural therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (strong recommendation, high-quality evidence). A pharmacological intervention can be offered if cognitive behavioural therapy for insomnia is not sufficiently effective or not available. Benzodiazepines, benzodiazepine receptor agonists and some antidepressants are effective in the short-term treatment of insomnia (≤4 weeks; weak recommendation, moderate-quality evidence). Antihistamines, antipsychotics, melatonin and phytotherapeutics are not recommended for insomnia treatment (strong to weak recommendations, low- to very-low-quality evidence). Light therapy and exercise need to be further evaluated to judge their usefulness in the treatment of insomnia (weak recommendation, low-quality evidence). Complementary and alternative treatments (e.g. homeopathy, acupuncture) are not recommended for insomnia treatment (weak recommendation, very-low-quality evidence).

Analysis of automated quantification of motor activity in REM sleep behaviour disorder.

Rapid eye movement (REM) sleep behaviour disorder (RBD) is characterized by dream enactment and REM sleep without atonia. Atonia is evaluated on the basis of visual criteria, but there is a need for more objective, quantitative measurements. We aimed to define and optimize a method for establishing baseline and all other parameters in automatic quantifying submental motor activity during REM sleep. We analysed the electromyographic activity of the submental muscle in polysomnographs of 29 patients with idiopathic RBD (iRBD), 29 controls and 43 Parkinson's (PD) patients. Six adjustable parameters for motor activity were defined. Motor activity was detected and quantified automatically. The optimal parameters for separating RBD patients from controls were investigated by identifying the greatest area under the receiver operating curve from a total of 648 possible combinations. The optimal parameters were validated on PD patients. Automatic baseline estimation improved characterization of atonia during REM sleep, as it eliminates inter/intra-observer variability and can be standardized across diagnostic centres. We found an optimized method for quantifying motor activity during REM sleep. The method was stable and can be used to differentiate RBD from controls and to quantify motor activity during REM sleep in patients with neurodegeneration. No control had more than 30% of REM sleep with increased motor activity; patients with known RBD had as low activity as 4.5%. We developed and applied a sensitive, quantitative, automatic algorithm to evaluate loss of atonia in RBD patients.

Attenuated heart rate response in REM sleep behavior disorder and Parkinson's disease.

The objective of this study was to determine whether patients with Parkinson's disease with and without rapid-eye-movement sleep behavior disorder and patients with idiopathic rapid-eye-movement sleep behavior disorder have an attenuated heart rate response to arousals or to leg movements during sleep compared with healthy controls. Fourteen and 16 Parkinson's patients with and without rapid-eye-movement sleep behavior disorder, respectively, 11 idiopathic rapid-eye-movement sleep behavior disorder patients, and 17 control subjects underwent 1 night of polysomnography. The heart rate response associated with arousal or leg movement from all sleep stages was analyzed from 10 heartbeats before the onset of the sleep event to 15 heartbeats following onset of the sleep event. The heart rate reponse to arousals was significantly lower in both parkinsonian groups compared with the control group and the idiopathic rapid-eye-movement sleep behavior disorder group. The heart rate response to leg movement was significantly lower in both Parkinson's groups and in the idiopathic rapid-eye-movement sleep behavior disorder group compared with the control group. The heart rate response for the idiopathic rapid-eye-movement sleep behavior disorder group was intermediate with respect to the control and the parkinsonian groups. The attenuated heart rate response may be a manifestation of the autonomic deficits experienced in Parkinson's disease. The idiopathic rapid-eye-movement sleep behavior disorder patients not only exhibited impaired motor symptoms but also incipient autonomic dysfunction, as revealed by the attenuated heart rate response.

Neurophysiological basis of rapid eye movement sleep behavior disorder: informing future drug development.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by a history of recurrent nocturnal dream enactment behavior and loss of skeletal muscle atonia and increased phasic muscle activity during REM sleep: REM sleep without atonia. RBD and associated comorbidities have recently been identified as one of the most specific and potentially sensitive risk factors for later development of any of the alpha-synucleinopathies: Parkinson's disease, dementia with Lewy bodies, and other atypical parkinsonian syndromes. Several other sleep-related abnormalities have recently been identified in patients with RBD/Parkinson's disease who experience abnormalities in sleep electroencephalographic frequencies, sleep-wake transitions, wake and sleep stability, occurrence and morphology of sleep spindles, and electrooculography measures. These findings suggest a gradual involvement of the brainstem and other structures, which is in line with the gradual involvement known in these disorders. We propose that these findings may help identify biomarkers of individuals at high risk of subsequent conversion to parkinsonism.

Increased Motor Activity During REM Sleep Is Linked with Dopamine Function in Idiopathic REM Sleep Behavior Disorder and Parkinson Disease.

STUDY OBJECTIVES: Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by impaired motor inhibition during REM sleep, and dream-enacting behavior. RBD is especially associated with α-synucleinopathies, such as Parkinson disease (PD). Follow-up studies have shown that patients with idiopathic RBD (iRBD) have an increased risk of developing an α-synucleinopathy in later life. Although abundant studies have shown that degeneration of the nigrostriatal dopaminergic system is associated with daytime motor function in Parkinson disease, only few studies have investigated the relation between this system and electromyographic (EMG) activity during sleep. The objective of this study was to investigate the relationship between the nigrostriatal dopamine system and muscle activity during sleep in iRBD and PD. METHODS: 10 iRBD patients, 10 PD patients with PD, 10 PD patients without RBD, and 10 healthy controls were included and assessed with (123)I-N-omega-fluoropropyl-2-beta-carboxymethoxy-3beta-(4-iodophenyl) nortropane ((123)I-FP-CIT) Single-photon emission computed tomography (SPECT) scanning ((123)I-FP-CIT SPECT), neurological examination, and polysomnography. RESULTS: iRBD patients and PD patients with RBD had increased EMG-activity compared to healthy controls. (123)I-FP-CIT uptake in the putamen-region was highest in controls, followed by iRBD patients, and lowest in PD patients. In iRBD patients, EMG-activity in the mentalis muscle was correlated to (123)I-FP-CIT uptake in the putamen. In PD patients, EMG-activity was correlated to anti-Parkinson medication. CONCLUSIONS: Our results support the hypothesis that increased EMG-activity during REM sleep is at least partly linked to the nigrostriatal dopamine system in iRBD, and with dopamine function in PD.

Sleep stability and transitions in patients with idiopathic REM sleep behavior disorder and patients with Parkinson's disease.

OBJECTIVE: Patients with idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) are at high risk of developing Parkinson's disease (PD). As wake/sleep-regulation is thought to involve neurons located in the brainstem and hypothalamic areas, we hypothesize that the neurodegeneration in iRBD/PD is likely to affect wake/sleep and REM/non-REM (NREM) sleep transitions. METHODS: We determined the frequency of wake/sleep and REM/NREM sleep transitions and the stability of wake (W), REM and NREM sleep as measured by polysomnography (PSG) in 27 patients with PD, 23 patients with iRBD, 25 patients with periodic leg movement disorder (PLMD) and 23 controls. Measures were computed based on manual scorings and data-driven labeled sleep staging. RESULTS: Patients with PD showed significantly lower REM stability than controls and patients with PLMD. Patients with iRBD had significantly lower REM stability compared with controls. Patients with PD and RBD showed significantly lower NREM stability and significantly more REM/NREM transitions than controls. CONCLUSIONS: We conclude that W, NREM and REM stability and transitions are progressively affected in iRBD and PD, probably reflecting the successive involvement of brain stem areas from early on in the disease. SIGNIFICANCE: Sleep stability and transitions determined by a data-driven approach could support the evaluation of iRBD and PD patients.

Quantification of muscle activity during sleep for patients with neurodegenerative diseases.

Idiopathic REM sleep behavior disorder (iRBD) is a very strong predictor for later development of Parkinson's disease (PD), and is characterized by REM sleep without atonia (RSWA), resulting in increased muscle activity during REM sleep. Abundant studies have shown the loss of atonia during REM sleep, but our aim was to investigate whether iRBD and PD patients have increased muscle activity in both REM and NREM sleep compared to healthy controls. This was achieved by developing a semi-automatic algorithm for quantification of mean muscle activity per second during all sleep stages for the enrolled patients. The three groups examined included patients suffering from iRBD, PD and healthy control subjects (CO). To determine muscle activity, a baseline and threshold were established after pre-processing of the raw surface electromyography (sEMG) signal. The signal was then segmented according to the different sleep stages and muscle activity beyond the threshold was counted. The results were evaluated statistically using the two-sided Mann-Whitney U-test. The results suggested that iRBD patients also exhibit distinctive muscle activity characteristics in NREM sleep, however not as evident as in REM sleep, leading to the conclusion that RSWA still is the most distinct characteristic of RBD. Furthermore, the muscle activity of PD patients was comparable to that of controls with only slightly elevated amplitudes.

Sleep spindle alterations in patients with Parkinson's disease.

UNLABELLED: The aim of this study was to identify changes of sleep spindles (SS) in the EEG of patients with Parkinson's disease (PD). Five sleep experts manually identified SS at a central scalp location (C3-A2) in 15 PD and 15 age- and sex-matched control subjects. Each SS was given a confidence score, and by using a group consensus rule, 901 SS were identified and characterized by their (1) duration, (2) oscillation frequency, (3) maximum peak-to-peak amplitude, (4) percent-to-peak amplitude, and (5) density. Between-group comparisons were made for all SS characteristics computed, and significant changes for PD patients vs. control subjects were found for duration, oscillation frequency, maximum peak-to-peak amplitude and density. Specifically, SS density was lower, duration was longer, oscillation frequency slower and maximum peak-to-peak amplitude higher in patients vs. CONTROLS: We also computed inter-expert reliability in SS scoring and found a significantly lower reliability in scoring definite SS in patients when compared to controls. How neurodegeneration in PD could influence SS characteristics is discussed. We also note that the SS morphological changes observed here may affect automatic detection of SS in patients with PD or other neurodegenerative disorders (NDDs).

Sensorimotor gating deficits in multiple system atrophy: comparison with Parkinson's disease and idiopathic REM sleep behavior disorder.

BACKGROUND: Prepulse inhibition (PPI) of the auditory blink reflex is a measure of sensorimotor gating, which reflects an organism's ability to filter out irrelevant sensory information. PPI has never been studied in patients with multiple system atrophy (MSA), although sensorimotor deficits are frequently associated with synucleinopathies. We investigated whether alterations in PPI were more pronounced in MSA compared with Parkinson's disease (PD), idiopathic rapid eye movement sleep behavior disorder (iRBD) and healthy controls. METHODS: 10 patients with MSA, 12 patients with iRBD, 40 patients with PD, and 20 healthy controls completed the study. A passive acoustic prepulse inhibition paradigm was applied with prepulses 5 dB and 15 dB above background noise at 30-, 60-, 120- and 300-ms intervals. RESULTS: Non-parametric analyses showed that MSA patients had significantly lower prepulse inhibition, as measured with max-amplitude, than PD patients and iRBD patients on the 60 ms-85 dB and 120 ms-85 dB inter-stimulus intervals. The same relation was found when using area under the curve. No differences were found between groups for the 30 ms-85 dB and 300 ms-85 dB. Furthermore, blink reflex characteristics such as habituation did not differ between patients and controls. CONCLUSIONS: The present study showed that sensorimotor gating, as measured with PPI, is markedly reduced in MSA. This may be due to the pronounced severity of striatal and brainstem dysfunction, as well as the degeneration of other structures related to the PPI modulating pathways in MSA. PPI may be a non-invasive neurophysiological measure that can aid in the differential diagnosis between PD and MSA.

Prepulse inhibition is associated with attention, processing speed, and 123I-FP-CIT SPECT in Parkinson's disease.

BACKGROUND: Prepulse inhibition is a measure of sensorimotor gating, which reflects the ability to filter or 'gate' irrelevant information. Prepulse inhibition is dramatically altered in basal ganglia disorders associated with dysfunction in the midbrain dopaminergic system, and corresponding cognitive information processing deficits such as slowed processing speed. Parkinson's disease is characterised by the degeneration of the midbrain dopaminergic system and is associated with cognitive dysfunction, including slowed information processing. Although sensorimotor processes in Parkinson's disease have been extensively studied in relation to motor function, less is known about the potential role of sensorimotor processes in cognitive function. OBJECTIVE: We investigated the relationship between prepulse inhibition, cognition and nigrostriatal dysfunction, as measured with 123I-FP-CIT-SPECT scanning, in patients with Parkinson's disease. METHODS: 38 Parkinson patients were assessed with prepulse inhibition, neuropsychological tests, and neurological investigation. A subset of these patients underwent 123I-FP-CIT-SPECT scanning. RESULTS: Patients with a higher level of prepulse inhibition performed better on cognitive measures tapping attention and processing speed than patients with a lower level of prepulse inhibition. Furthermore, there were significant correlations between prepulse inhibition and 123I-FP-CIT uptake in the striatum. CONCLUSIONS: Our results suggest that the level of prepulse inhibition is related to the efficiency of information processing in Parkinson's disease, and to the density of dopamine transporters in the striatum.

Decreased sleep spindle density in patients with idiopathic REM sleep behavior disorder and patients with Parkinson's disease.

OBJECTIVE: To determine whether sleep spindles (SS) are potentially a biomarker for Parkinson's disease (PD). METHODS: Fifteen PD patients with REM sleep behavior disorder (PD+RBD), 15 PD patients without RBD (PD-RBD), 15 idiopathic RBD (iRBD) patients and 15 age-matched controls underwent polysomnography (PSG). SS were scored in an extract of data from control subjects. An automatic SS detector using a Matching Pursuit (MP) algorithm and a Support Vector Machine (SVM) was developed and applied to the PSG recordings. The SS densities in N1, N2, N3, all NREM combined and REM sleep were obtained and evaluated across the groups. RESULTS: The SS detector achieved a sensitivity of 84.7% and a specificity of 84.5%. At a significance level of α=1%, the iRBD and PD+RBD patients had a significantly lower SS density than the control group in N2, N3 and all NREM stages combined. At a significance level of α=5%, PD-RBD had a significantly lower SS density in N2 and all NREM stages combined. CONCLUSIONS: The lower SS density suggests involvement in pre-thalamic fibers involved in SS generation. SS density is a potential early PD biomarker. SIGNIFICANCE: It is likely that an automatic SS detector could be a supportive diagnostic tool in the evaluation of iRBD and PD patients.

Data-driven modeling of sleep EEG and EOG reveals characteristics indicative of pre-Parkinson's and Parkinson's disease.

BACKGROUND: Manual scoring of sleep relies on identifying certain characteristics in polysomnograph (PSG) signals. However, these characteristics are disrupted in patients with neurodegenerative diseases. NEW METHOD: This study evaluates sleep using a topic modeling and unsupervised learning approach to identify sleep topics directly from electroencephalography (EEG) and electrooculography (EOG). PSG data from control subjects were used to develop an EOG and an EEG topic model. The models were applied to PSG data from 23 control subjects, 25 patients with periodic leg movements (PLMs), 31 patients with idiopathic REM sleep behavior disorder (iRBD) and 36 patients with Parkinson's disease (PD). The data were divided into training and validation datasets and features reflecting EEG and EOG characteristics based on topics were computed. The most discriminative feature subset for separating iRBD/PD and PLM/controls was estimated using a Lasso-regularized regression model. RESULTS: The features with highest discriminability were the number and stability of EEG topics linked to REM and N3, respectively. Validation of the model indicated a sensitivity of 91.4% and a specificity of 68.8% when classifying iRBD/PD patients. COMPARISON WITH EXISTING METHOD: The topics showed visual accordance with the manually scored sleep stages, and the features revealed sleep characteristics containing information indicative of neurodegeneration. CONCLUSIONS: This study suggests that the amount of N3 and the ability to maintain NREM and REM sleep have potential as early PD biomarkers. Data-driven analysis of sleep may contribute to the evaluation of neurodegenerative patients.

Automatic sleep classification using a data-driven topic model reveals latent sleep states.

BACKGROUND: The golden standard for sleep classification uses manual scoring of polysomnography despite points of criticism such as oversimplification, low inter-rater reliability and the standard being designed on young and healthy subjects. NEW METHOD: To meet the criticism and reveal the latent sleep states, this study developed a general and automatic sleep classifier using a data-driven approach. Spectral EEG and EOG measures and eye correlation in 1s windows were calculated and each sleep epoch was expressed as a mixture of probabilities of latent sleep states by using the topic model Latent Dirichlet Allocation. Model application was tested on control subjects and patients with periodic leg movements (PLM) representing a non-neurodegenerative group, and patients with idiopathic REM sleep behavior disorder (iRBD) and Parkinson's Disease (PD) representing a neurodegenerative group. The model was optimized using 50 subjects and validated on 76 subjects. RESULTS: The optimized sleep model used six topics, and the topic probabilities changed smoothly during transitions. According to the manual scorings, the model scored an overall subject-specific accuracy of 68.3 ± 7.44 (% µ ± σ) and group specific accuracies of 69.0 ± 4.62 (control), 70.1 ± 5.10 (PLM), 67.2 ± 8.30 (iRBD) and 67.7 ± 9.07 (PD). COMPARISON WITH EXISTING METHOD: Statistics of the latent sleep state content showed accordances to the sleep stages defined in the golden standard. However, this study indicates that sleep contains six diverse latent sleep states and that state transitions are continuous processes. CONCLUSIONS: The model is generally applicable and may contribute to the research in neurodegenerative diseases and sleep disorders.

A computerized algorithm for arousal detection in healthy adults and patients with Parkinson disease.

Arousals occur from all sleep stages and can be identified as abrupt electroencephalogram (EEG) and electromyogram (EMG) changes. Manual scoring of arousals is time consuming with low interscore agreement. The aim of this study was to design an arousal detection algorithm capable of detecting arousals from non-rapid eye movement (REM) and REM sleep, independent of the subject's age and disease. The proposed algorithm uses features from EEG, EMG, and the manual sleep stage scoring as input to a feed-forward artificial neural network (ANN). The performance of the algorithm has been assessed using polysomnographic (PSG) recordings from a total of 24 subjects. Eight of the subjects were diagnosed with Parkinson disease (PD) and the rest (16) were healthy adults in various ages. The performance of the algorithm was validated in 3 settings: testing on the 8 patients with PD using the leave-one-out method, testing on the 16 healthy adults using the leave-one-out method, and finally testing on all 24 subjects using a 4-fold crossvalidation. For these 3 validations, the sensitivities were 89.8%, 90.3%, and 89.4%, and the positive predictive values (PPVs) were 88.8%, 89.4%, and 86.1%. These results are high compared with those of previously presented arousal detection algorithms and especially compared with the high interscore variability of manual scorings.

The health-related, social, and economic consequences of parkinsonism: a controlled national study.

Parkinson's disease (PD) and atypical parkinsonism (AP) cause a significant socioeconomic burden, but there is insufficient information about the total disease burden at a national level. Thus, the goal of this study was to estimate the excess direct and indirect costs of PD and AP in a national sample. Using records from the Danish National Patient Registry (1997-2007), 13,400 PD and 647 AP patients were identified and compared with, respectively, 53,600 and 2,588 control cases randomly selected with respect to age, gender, civil status, and geographic location. Direct costs including frequencies of primary and sector contacts and procedures, and medication from primary and secondary sectors were obtained from the Danish Ministry of Health, the Danish Medicines Agency, and the National Health Security. Indirect costs, which included labor supply and social transfer payments, were based on income data derived from the Coherent Social Statistics. Patients with PD and AP had significantly higher rates of health-related contact and medication use and a higher socioeconomic cost. Furthermore, they had very low employment rates, and those in employment had a lower income level than employed control subjects. The annual mean excess health-related cost was 6,500 ($8,975/£5,543) and 9,771 ($13,491/£8,332) for each patient with PD and AP, respectively. In addition, the patients with PD and AP received an annual mean excess social transfer income of 324 (£276/$447) and 844 (£719/$1,165), respectively. The employment- and health-related consequences could be identified up to 8 years before the first diagnosis and increased with disease advancement. PD and AP have major socioeconomic consequences for patients and society. The health effects are present for up to more than 8 years before a diagnosis of PD/AP.

REM behaviour disorder detection associated with neurodegenerative diseases.

UNLABELLED: Abnormal skeleton muscle activity during REM sleep is characterized as REM Behaviour Disorder (RBD), and may be an early marker for different neurodegenerative diseases. Early detection of RBD is therefore highly important, and in this ongoing study a semi-automatic method for RBD detection is proposed by analyzing the motor activity during sleep. METHOD: A total number of twelve patients have been involved in this study, six normal controls and six patients diagnosed with Parkinsons Disease (PD) with RBD. All subjects underwent at least one ambulant polysomnographic (PSG) recording. The sleep recordings were scored, according to the new sleep-scoring standard from the American Academy of Sleep Medicine, by two independent sleep specialists. A follow-up analysis of the scoring consensus between the two specialists has been conducted. Based on the agreement of the two manual scorings, a computerized algorithm has been attempted implemented. By analysing the REM and non-REM EMG activity, using advanced signal processing tools combined with a statistical classifier, it is possible to discriminate normal and abnormal EMG activity. Due to the small number of patients, the overall performance of the algorithm was calculated using the leave-one-out approach and benchmarked against a previously published computerized/visual method. RESULTS: Based on the available data and using optimal settings, it was possible to correctly classify PD subjects with RBD with 100% sensitivity, 100% specificity, which is an improvement compared to previous published studies. CONCLUSION: The overall result indicates the usefulness of a computerized scoring algorithm and may be a feasible way of reducing scoring time. Further enhancement on additional data, i.e. subjects with idiopathic RBD (iRBD) and PD without RBD, is needed to validate its robustness and the overall result.

[Rapid eye movement sleep behaviour disorder--diagnosis, causes and treatment]. / Rapid eye movement sleep behavior disorder--diagnostik, årsager og behandling.

Rapid eye movement (REM) sleep behaviour disorder (RBD) is characterized by loss of REM sleep and related electromyographic atonia with marked muscular activity and dream enactment behaviour. RBD is seen in 0.5% of the population. It occurs in an idiopathic form and secondarily to medical and neurological disease. RBD is related to brainstem pathology. Furthermore, it is increasingly recognized that RBD is frequently related to Parkinsonian disorders and narcolepsy. This article reviews recent knowledge about RBD with focus on the diagnostic process and management.