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Objective Information on borderline personality disorder (BPD) and its comorbidities is often limited to concentrate on a few diagnoses. The aim of the study was to use national register data to investigate all diagnostic co-occurring mental health disorders and somatic diseases 3 years before and after initial BPD diagnosis compared with a matched control group. Method The study was a register-based cohort of 2756 patients with incident BPD (ICD F60.3) and 11,024 matched controls, during 2002–2016. Comorbidity data were classified into main disease groups, in accordance with the World Health Organization ICD-10 criteria. Results Almost half the patients had been diagnosed with mental and behavioral disorders before the BPD diagnosis as compared to 3% in the control group. Further, the co-occurrence of diseases due to external causes of morbidity, including injury, self-harm, and poisoning were more represented in the BPD group before diagnosis as compared to the control group. In addition, co-occurring morbidity related to diseases in the circulatory, the respiratory, the digestive, the musculoskeletal, and the genitourinary system was more represented in the BPD group. After diagnosis, the proportion of patients with co-occurring morbidity increased further in all main disease groups in the BPD group. As many as 87% of patients had mental and behavioral co-occurring morbidity and 15% nervous diseases as compared with 3% and 4%, respectively, in the control group. Also, comorbidities related to external causes of morbidity, including for example, injury and self-harm were more represented in the BPD group. The BPD group had more somatic co-occurring morbidity, especially digestive, respiratory, circulatory, and endocrine diseases. Finally, the mortality over 12 years was statistically significantly higher in people with BPD than in the control group. Conclusion Patients with BPD have higher odds for multiple physical healt, Objective: Information on borderline personality disorder (BPD) and its comorbidities is often limited to concentrate on a few diagnoses. The aim of the study was to use national register data to investigate all diagnostic co-occurring mental health disorders and somatic diseases 3 years before and after initial BPD diagnosis compared with a matched control group. Method: The study was a register-based cohort of 2756 patients with incident BPD (ICD F60.3) and 11,024 matched controls, during 2002–2016. Comorbidity data were classified into main disease groups, in accordance with the World Health Organization ICD-10 criteria. Results: Almost half the patients had been diagnosed with mental and behavioral disorders before the BPD diagnosis as compared to 3% in the control group. Further, the co-occurrence of diseases due to external causes of morbidity, including injury, self-harm, and poisoning were more represented in the BPD group before diagnosis as compared to the control group. In addition, co-occurring morbidity related to diseases in the circulatory, the respiratory, the digestive, the musculoskeletal, and the genitourinary system was more represented in the BPD group. After diagnosis, the proportion of patients with co-occurring morbidity increased further in all main disease groups in the BPD group. As many as 87% of patients had mental and behavioral co-occurring morbidity and 15% nervous diseases as compared with 3% and 4%, respectively, in the control group. Also, comorbidities related to external causes of morbidity, including for example, injury and self-harm were more represented in the BPD group. The BPD group had more somatic co-occurring morbidity, especially digestive, respiratory, circulatory, and endocrine diseases. Finally, the mortality over 12 years was statistically significantly higher in people with BPD than in the control group. Conclusion: Patients with BPD have higher odds for multiple physical health conditions and co-occurrence of me

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

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

Objective: To assess whether the polygenic risk score (PRS) for migraine is associated with acute and/or prophylactic migraine treatment response. Methods: We interviewed 2,219 unrelated patients at the Danish Headache Center using a semistructured interview to diagnose migraine and assess acute and prophylactic drug response. All patients were genotyped. A PRS was calculated with the linkage disequilibrium pred algorithm using summary statistics from the most recent migraine genome-wide association study comprising ∼375,000 cases and controls. The PRS was scaled to a unit corresponding to a twofold increase in migraine risk, using 929 unrelated Danish controls as reference. The association of the PRS with treatment response was assessed by logistic regression, and the predictive power of the model by area under the curve using a case-control design with treatment response as outcome. Results: A twofold increase in migraine risk associates with positive response to migraine-specific acute treatment (odds ratio [OR] = 1.25 [95% confidence interval (CI) = 1.05–1.49]). The association between migraine risk and migraine-specific acute treatment was replicated in an independent cohort consisting of 5,616 triptan users with prescription history (OR = 3.20 [95% CI = 1.26–8.14]). No association was found for acute treatment with non–migraine-specific weak analgesics and prophylactic treatment response. Conclusions: The migraine PRS can significantly identify subgroups of patients with a higher-than-average likelihood of a positive response to triptans, which provides a first step toward genetics-based precision medicine in migraine.

BACKGROUND AND PURPOSE: Cluster headache (CH) is characterized by severe, unilateral attacks of pain and a high nocturnal attack burden. It remains unknown whether perturbations of sleep are solely present during the CH bout. Therefore, we aimed to investigate differences in sleep between the bout and remission period in patients with episodic CH and, secondly, to compare patients in the two phases with controls.METHODS: Patients with episodic CH (aged 18-65 years), diagnosed according to the International Classification of Headache Disorders 2nd edition, were admitted for polysomnography at the Danish Center for Sleep Medicine in bout and in remission. The macrostructure of sleep, including arousals, breathing parameters, limb movements and periodic limb movements, was compared with 25 age-, sex- and body mass index-matched healthy controls.RESULTS: There were no differences in any of the sleep parameters for patients in bout (n = 32) compared with patients in remission (n = 23). Attacks were unrelated to sleep stages, presence of apnea episodes, periodic limb movements, limb movements and arousals. In bout, patients had longer sleep latency (18.8 vs. 11.7 min, P < 0.05) and rapid eye movement sleep latency (1.7 vs. 1.2 h, P < 0.05) than controls and sleep efficiency was lower (82.5% vs. 86.5%, P < 0.05). Patients in remission only had a longer sleep latency compared with controls (17.5 vs. 11.7 min, P < 0.01).CONCLUSIONS: The results support the presence of a continuing or slowly recovering disturbance of sleep outside the bout rather than a disturbance occurring secondary to attacks. Further, we confirm that there is no relation between CH attacks and specific sleep stages or between CH and breathing parameters.

Objectives/Introduction:Patients with idiopathic rapid eye move-ment (REM) sleep behaviour disorder (iRBD) have a high risk of con-verting into α‐synucleinopathies due to an early neurodegenerative process involving lower brain stem areas. Eye movements (EMs) are controlled by neurons located in the lower brain stem, midbrain, and frontal areas, and are therefore vulnerable to be affected by an early neurodegeneration. Several studies have reported impairment of the oculomotor function in patients with Parkinson's disease (PD) during wakefulness, but no studies have investigated how neurodegeneration affects EMs during sleep. We aimed to evaluate nocturnal EMsin iRBD and PD hypothesizing that these patients present abnormalEMs during sleep.Methods:A total of 28 patients with periodic leg movement disor-der (PLMD; 15 males; 60.3 ± 11.9 years), 24 with iRBD (17 males;63.0 ± 10.1 years), 23 with PD without RBD (PD‐RBD; 14 males;61.4 ± 5.4 years), 29 with PD and RBD (PD+RBD; 19 males;63.3 ± 5.1 years), and 24 controls (11 males; 56.7 ± 9.9 years) were included. A previous validated EM detector was used to automatically detect periods with any kind of EMs in artefact‐free epochs between lights off and on. The EM coverage was computed as the percentage of time containing EMs, during stages of wakefulness,N1, N2, N3, and REM sleep. Between‐group comparisons were performed using Wilcoxon‐Ranksum tests, and the Benjamini‐Hoch-berg procedure with a false discovery rate of 0.1 was used to con-trol for multiple testing.Results:We found that PD+RBD had significant less EM coverage during wakefulness compared to controls (p<0.001), and signifi-cantly higher EM coverage during N2 compared to controls(p= 0.003) and PLMD (p= 0.004). Furthermore, PD‐RBD showed significantly higher EM coverage during N2 compared to controls(p<0.001) and PLMD (p= 0.001). Same trends were observed between iRBD and controls in wakefulness and N2, but were not significant after correction for multip

Motor activity in healthy young humans displays intrinsic fluctuations that are scale-invariant over a wide range of time scales (from minutes to hours). Human postmortem and animal lesion studies showed that the intact function of the suprachiasmatic nucleus (SCN) is required to maintain such scale-invariant patterns. We therefore hypothesized that scale invariance is degraded in patients treated for suprasellar tumors that compress the SCN. To test the hypothesis, we investigated 68 patients with nonfunctioning pituitary macroadenoma and 22 patients with craniopharyngioma, as well as 72 age-matched healthy controls (age range 21.0–70.6 years). Spontaneous wrist locomotor activity was measured for 7 days with actigraphy, and detrended fluctuation analysis was applied to assess correlations over a range of time scales from minutes to 24 h. For all the subjects, complex scale-invariant correlations were only present for time scales smaller than 1.5 h, and became more random at time scales 1.5–10 h. Patients with suprasellar tumors showed a larger decrease in correlations at 1.5–10 h as compared to healthy controls. Within healthy subject, gender and age >33 year were associated with attenuated scale invariance. Conversely, activity patterns at time scales between 10 and 24 h were significantly more regular than all other time scales, and this was mostly associated with age. In conclusion, scale invariance is degraded in healthy subjects at the ages of >33 year as characterized by attenuation of correlations at time scales 1.5–10 h. In addition, scale invariance was more degraded in patients with suprasellar tumors as compared to healthy subjects.

BACKGROUND: Idiopathic REM sleep behaviour disorder (iRBD) has been recognised as a significant biomarker for developing a neurodegenerative alpha-synucleinopathy, which is why iRBD is considered to be a prodromal state for alpha-synucleinopathies including Parkinson's disease (PD). Many patients with PD suffer from complaints of pain and present impaired somatosensory function. We hypothesized that pain perception and somatosensory function could be altered already in a preclinical stage of PD including iRBD. Hence, the objective of this study was to investigate pain perception and somatosensory function in patients with iRBD.METHODS: Quantitative sensory testing (QST), laser evoked potentials (LEPs), and conditioned pain modulation (CPM) testing were performed in 13 iRBD patients without any clinical signs of PD or narcolepsy (11 males, 2 females, mean age 65.2 years) and 15 gender- and age-matched healthy control subjects (12 males, 3 females, mean age 65.8 years).RESULTS: Thermal detection thresholds were higher in the iRBD group compared with the control group (cold detection threshold (CDT) p = 0.020, thermal sensory limen (TSL) p = 0.001), indicating an impaired temperature sensation in iRBD patients. The N2/P2 LEPs amplitude was smaller in iRBD patients than controls, but not statistically significant (p = 0.053).CONCLUSIONS: This study found an impaired somatosensory function in iRBD patients, suggesting that somatosensory impairment might be an early feature in the neurodegenerative process of PD.

BACKGROUND: Idiopathic REM sleep behaviour disorder (iRBD) has been recognised as a significant biomarker for developing a neurodegenerative alpha-synucleinopathy, which is why iRBD is considered to be a prodromal state for alpha-synucleinopathies including Parkinson's disease (PD). Many patients with PD suffer from complaints of pain and present impaired somatosensory function. We hypothesized that pain perception and somatosensory function could be altered already in a preclinical stage of PD including iRBD. Hence, the objective of this study was to investigate pain perception and somatosensory function in patients with iRBD.METHODS: Quantitative sensory testing (QST), laser evoked potentials (LEPs), and conditioned pain modulation (CPM) testing were performed in 13 iRBD patients without any clinical signs of PD or narcolepsy (11 males, 2 females, mean age 65.2 years) and 15 gender- and age-matched healthy control subjects (12 males, 3 females, mean age 65.8 years).RESULTS: Thermal detection thresholds were higher in the iRBD group compared with the control group (cold detection threshold (CDT) p = 0.020, thermal sensory limen (TSL) p = 0.001), indicating an impaired temperature sensation in iRBD patients. The N2/P2 LEPs amplitude was smaller in iRBD patients than controls, but not statistically significant (p = 0.053).CONCLUSIONS: This study found an impaired somatosensory function in iRBD patients, suggesting that somatosensory impairment might be an early feature in the neurodegenerative process of PD.

Motor activity in healthy young humans displays intrinsic fluctuations that are scale-invariant over a wide range of time scales (from minutes to hours). Human postmortem and animal lesion studies showed that the intact function of the suprachiasmatic nucleus (SCN) is required to maintain such scale-invariant patterns. We therefore hypothesized that scale invariance is degraded in patients treated for suprasellar tumors that compress the SCN. To test the hypothesis, we investigated 68 patients with nonfunctioning pituitary macroadenoma and 22 patients with craniopharyngioma, as well as 72 age-matched healthy controls (age range 21.0–70.6 years). Spontaneous wrist locomotor activity was measured for 7 days with actigraphy, and detrended fluctuation analysis was applied to assess correlations over a range of time scales from minutes to 24 h. For all the subjects, complex scale-invariant correlations were only present for time scales smaller than 1.5 h, and became more random at time scales 1.5–10 h. Patients with suprasellar tumors showed a larger decrease in correlations at 1.5–10 h as compared to healthy controls. Within healthy subject, gender and age >33 year were associated with attenuated scale invariance. Conversely, activity patterns at time scales between 10 and 24 h were significantly more regular than all other time scales, and this was mostly associated with age. In conclusion, scale invariance is degraded in healthy subjects at the ages of >33 year as characterized by attenuation of correlations at time scales 1.5–10 h. In addition, scale invariance was more degraded in patients with suprasellar tumors as compared to healthy subjects.

Objectives/Introduction:REM sleep behaviour disorder (RBD) isa parasomnia characterized by lack of atonia during REM sleep. Gold standard methods for RBD diagnosis require manual REM sleep without atonia (RSWA) scoring, which is time‐consuming and subjective. We propose and validate a new data‐driven algorithm and com-pare it to other automatic methods based on RSWA detection for identifying RBD patients.Methods:We included 27 control subjects (C), 29 idiopathic RBDpatients and 36 patients with periodic limb movement disorder(PLMD). After artefact removal, mean absolute amplitude values of1‐s windows of chin, tibialis left and right EMG signals during REMfrom 9 randomly selected controls were used to define a probabilistic model delineating atonia. For the remaining subjects, each 1‐s window was labelled as movementif its probability of being atonia was lower than an optimized threshold. For each EMG signal, we calculated the percentages of 1‐s windows with movements and themedian intra‐movement distance during REM and NREM. Usingthese indices, a classification algorithm was trained and tested (5‐fold cross‐validation) to distinguish the three subject groups. For comparison, the REM atonia index (RAI), Frandsen index (FRI) and Kempfner index (KEI) were calculated for the same cohort and ananalogous classification algorithm was applied to each of them. The overall test accuracies, sensitivities and specificities for C, RBD and PLMD were calculated for each method.Results:The following test performances were achieved (mean and standard deviation across the five folds in %): Overall accuracy:79.58±9.16 (this work), 44.56±6.27 (RAI) 46.73±5.40 (FRI),49.08±11.82 (KEI); RBD sensitivity: 81.67±17.08 (this work),53.67±13.03 (RAI), 58.71±10.94 (FRI), 58.81±28.37 (KEI); RBD speci-ficity: 83.98±5.09 (this method), 83.59±4.12 (RAI), 85.48±4.18 (FRI),77.80±5.54 (KEI). Further, the proposed method achieved higher sen-sitivity and specificity for identifying C and PLMD than the ot

Objectives/Introduction:Disrupted sleep is a contributing factor to cognitive aging, while also being associated with major neurode-generative disorders. Little is known, however, about the relation of sleep and the gradual positive or negative cognitive changes over the adult life course. Patterns in the sleep electroencephalogram(EEG) are potential markers of the cognitive progress.Methods:To test this hypothesis, we assessed the sleep architecture and sleep EEG of 167 men born in the Copenhagen Metropolitan Area in 1953, who–based on individual cognitive testing from early(~18 years) to late adulthood (~58 years)–were divided in 85 subjects with negative and 82 with positive cognitive change over their adultage span. As part of a Center for Healthy Aging (University of Copenhagen) study, participants underwent standard polysomnography including manual sleep scoring between 2009 and 2013. Features ofsleep stage distribution were combined with a number of EEG features to distinguish between the two groups: EEG rhythmicity was assessed by spectral power analysis in frontal, central and occipital scalp sites.Functional connectivity was measured by inter‐hemispheric EEG coherence. Group‐differences were assessed by analysis of covariance (p<0.05) including completed level of formal education as covariate.Significant features were combined in a machine learning approach toestimate their discriminative usability.Results:Subjects with cognitive decline exhibited lower sleep efficiency, reduced inter‐hemispheric functional connectivity duringrapid eye movement (REM) sleep, and slower EEG rhythms during stage 2 non‐REM sleep. While none of these measures passed as stand‐alone features, the combined effects discriminated the two groups with an accuracy of 72% (sensitivity 75%, specificity 67%).Conclusions:In conclusion, the study demonstrates the potential of combined sleep and electrophysiological measures as signs of cognitive changes. Ongoing medical screenings of the

Sleep apnea is a common sleep disorder, which involves cessation of breathing due to obstruction of the upper airway (obstructive) or due to suspension of ventilatory effort (central) during sleep. Currently, sleep apnea is diagnosed using polysomnography (PSG). Breathing events are manually scored by trained sleep technicians, however this is time-consuming, expensive, and prone to subjective interpretation. Thus, the aim of this study was to develop a fully automatic algorithm to detect respiratory events in sleep. Methods: Oxygen saturation, nasal pressure (transducer), oral airflow (thermistor), respiratory effort (RIP belts), and snoring signals were extracted from 2,366 PSGs from the Wisconsin Sleep Cohort (age: 59.7 ± 8.4, BMI: 31.6 ± 7.2 (mean±SD)). After filtering, sixteen features (time and frequency domain) were extracted from each signal using a sliding window of ten seconds with eight seconds overlap. Two models were developed based on bidirectional long short-term memory (bLSTM) neural networks: 1)a two-class model for classification of windows as “normal” or “event”, and 2)a four-class model for classification as “normal”, “obstructive”, “central”, or “mixed”. 1882 subjects were used for training; 249 subjects were used for validation. Preliminary results were obtained for a test set of 235 subjects. Results: With respect to the total number of events, the two-class model obtained precision of 0.740 and recall of 0.769. The four-class model obtained precision of 0.787, 0.205, and 0.100, and recall of 0.685, 0.190, and 0.0985, for obstructive, central, and mixed events, respectively. The Pearson correlation coefficient between annotated and predicted apnea hypopnea index (AHI) were 0.844 and 0.861 for the two-class and the four-class model, respectively. Conclusion: These results indicate that obstructive events can be reliably detected with a bLSTM network. However, the models had difficulties detecting central and mixed events

Cortical arousals are transient events that occur during sleep. Although they can occur naturally, arousals are often used to evaluate sleep-wake dysfunction. The gold standard for detecting arousals is visual inspection of polysomnography recordings. Manual annotation of arousals is time consuming and has been shown to have a high inter- and intra-scorer variation. This study proposes a method to fully automate detection of arousals using recent advances in machine learning. Methods: The proposed method in this study extracted features from electroencephalography (EEG), electrooculography (EOG) and chin electromyography (EMG) to compute a probability of arousals through a bi-directional long short-term memory neural network. The study used a dataset of 233 nocturnal PSGs of population-based samples from Wisconsin Sleep Cohort (WSC) and 30 nocturnal PSGs of clinical samples from the Stanford Sleep Cohort (SSC). The model was trained on 186 recordings from WSC and annotations from two scorers. The model was tested on 47 recordings from WSC and then compared to a set of 3 annotations from 9 independent scorers on 30 recordings from both cohorts by measure of Fleiss’ Kappa (level of agreement greater than chance). Results: The model obtained a precision of 0.79, a recall of 0.8 and F1-score of 0.79 on the 47 recordings from WSC. The model was robust to different sleep stages showing an F1-score of 0.71 ± 0.19, 0.8 ± 0.13, 0.89 ± 0.18 and 0.8 ± 0.17 (mean ± SD) for N1, N2, N3 and REM sleep, respectively. Preliminary results comparing the scorers show a Fleiss’ Kappa of 0.38 ± 0.12, while including the model predictions result in a Fleiss’ Kappa of 0.4 ± 0.1. Conclusion: Cortical arousals were detected automatically with the proposed algorithm with a high performance and robustness to different sleep stages. Preliminary results comparing nine independent scorers demonstrates a low inter-scorer reliability with a similar agreement to the model pred

Deep learning has seen significant progress over the last few years, especially in computer vision, where competitions such as the ImageNet challenge have been the driving factor behind many new model architectures far superior to humans in image recognition. We propose a novel method for automatic sleep staging, which relies on current advances in computer vision models eliminating the need for feature engineering or other transformations of input data. By exploiting the high capacity for complex learning in a state of the art object recognition model, we can effectively use raw PSG signals to detect and classify sleep stages in a robust and reliable way. Methods: A total of 2322 PSG studies from the Wisconsin Sleep Cohort were used in this study. Central and occipital EEG, left and right EOG, and chin EMG signals were extracted from all PSGs and subjected to initial pre-processing of zero-phase Butterworth bandpass filters with AASM-specified cutoffs. The raw signals were then segmented into 30 s epochs and fed as inputs to a novel deep neural network model based on the ResNet-50 architecture. The model was optimized over cross-entropy loss with respect to annotated scorings using the Adam optimizing algorithm and trained on a subset of 1858 PSGs. Hyperparameters were tuned using 40 iterations of random search in relevant hyperparameter intervals. Best performing model was selected based on performance measured by overall accuracy on a hold-out validation set of 232 PSGs. Results: Training accuracy, precision and recall were 84.93%, 97.42% and 97.02%, respectively. Evaluating on the validation set yielded an overall accuracy of 85.07% and overall precision/recall of 98.54% and 95.72%, respectively. Conclusion: Preliminary results indicate that state of the art deep learning models can effectively be used to classify sleep stages using untransformed PSG signals. We will perform further testing on independent datasets to enhance the model’s u

The complexity of central breathing disturbances during sleep has become increasingly obvious. They present as central sleep apnoeas (CSAs) and hypopnoeas, periodic breathing with apnoeas, or irregular breathing in patients with cardiovascular, other internal or neurological disorders, and can emerge under positive airway pressure treatment or opioid use, or at high altitude. As yet, there is insufficient knowledge on the clinical features, pathophysiological background and consecutive algorithms for stepped-care treatment. Most recently, it has been discussed intensively if CSA in heart failure is a "marker" of disease severity or a "mediator" of disease progression, and if and which type of positive airway pressure therapy is indicated. In addition, disturbances of respiratory drive or the translation of central impulses may result in hypoventilation, associated with cerebral or neuromuscular diseases, or severe diseases of lung or thorax. These statements report the results of an European Respiratory Society Task Force addressing actual diagnostic and therapeutic standards. The statements are based on a systematic review of the literature and a systematic two-step decision process. Although the Task Force does not make recommendations, it describes its current practice of treatment of CSA in heart failure and hypoventilation.

BACKGROUND AND PURPOSE: In the world today 10-20 million people are still living with late effects of poliomyelitis (PM), but the long-term consequences of the disease are not well known. The aim of this study was to describe lifelong morbidity and mortality among Danes who survived PM.METHODS: Data from official registers for a cohort of 3606 Danes hospitalized for PM in the period 1940-1954 were compared with 13 762 age- and gender-matched controls.RESULTS: Compared with controls, mortality was moderately increased for both paralytic as well as non-paralytic PM cases; Hazard Ratio, 1.31 (95% confidence interval, 1.18-1.44) and 1.09 (95% confidence interval, 1.00-1.19), respectively. Hospitalization rates were approximately 1.5 times higher among both paralytic and non-paralytic PM cases as compared with controls. Discharge diagnoses showed a broad spectrum of diseases. There were no major differences in morbidities between paralytic and non-paralytic PM cases.CONCLUSIONS: Poliomyelitis has significant long-term consequences on morbidity and mortality of both paralytic and non-paralytic cases.

AIMS AND OBJECTIVES: Based on class-I studies, sodium oxybate is regarded as a first-line treatment for both EDS and cataplexy. The cost-effectiveness of sodium oxybate is largely unknown, though. In this study, we estimate the cost-effectiveness of sodium oxybate as treatment for patients with narcolepsy as compared to standard treatment, by calculating incremental cost-effectiveness ratios (cost per quality-adjusted life year, QALY) for patients in a Swedish setting.MATERIALS AND METHODS: Calculations were performed using a Markov model with a 10-year time horizon. The study population consisted of adult patients treated for narcolepsy with cataplexy. Healthcare utilization and quality-adjusted life years (QALYs) for each treatment alternative were calculated assuming no treatment effect on survival. Sensitivity analyses were performed for treatment effectiveness and healthcare cost parameters.RESULTS: The cost per additional quality-adjusted life year was estimated at SEK 563,481. The cost-effectiveness measure was demonstrated to be particularly sensitive to the duration of the relative quality-of-life improvements accruing to patients treated with sodium oxybate.CONCLUSIONS: The estimated cost per additional QALY for the sodium oxybate treatment alternative compared with standard treatment was estimated above the informal Swedish willingness-to-pay threshold (SEK 500,000). The estimated cost per additional QALY obtained here is likely to overestimate the true cost-effectiveness ratio as potentially beneficial effects on productivity of treatment with sodium oxybate were not included (due to lack of data).

As light plays an important role in the synchronisation of the internal biological clock to the environmental day/night schedule, we compared the 24-h profiles of biological circadian markers in blind and normal sighted individuals. Salivary melatonin and cortisol concentrations were collected every two hours in eleven blind subjects, reporting no conscious light perception, and eleven age- and sex-matched normal sighted controls. Timing of melatonin onset and associated cortisol quiescence period confirm an increased incidence of abnormal circadian patterns in blindness. Additionally, blind subjects showed a greater overall melatonin concentration throughout the 24-h period. Cortisol profiles, including concentration and morning cortisol peaks, on the other hand, did not differ between blind and sighted individuals. These findings support previous reports of an increase in abnormal circadian rhythms and the absence of the entrainment properties of light in blindness.

Contains fulltext : 168186.pdf (publisher's version ) (Closed access), 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.

Summary: 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. Copyright

Contains fulltext : 168186.pdf (publisher's version ) (Closed access), 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.

Contains fulltext : 168186.pdf (publisher's version ) (Closed access), 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.

Summary: 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. Copyright

BACKGROUND: Sleep deprivation and delirium are major problems in the ICU. We aimed to assess the sleep quality by polysomnography (PSG) in relation to delirium in mechanically ventilated non-sedated ICU patients.METHODS: Interpretation of 24-h PSG and clinical sleep assessment in 14 patients. Delirium assessment was done using the confusion assessment method for the intensive care unit (CAM-ICU).RESULTS: Of four patients who were delirium free, only one had identifiable sleep on PSG. Sleep was disrupted with loss of circadian rhythm, and diminished REM sleep. In the remaining three patients the PSGs were atypical, meaning that no sleep signs were found, and sleep could not be quantified from the PSGs. Clinical total sleep time (ClinTST) ranged from 2.0-13.1 h in patients without delirium. Six patients with delirium all had atypical PSGs, so sleep could not be quantified. Short periods of REM sleep were found. ClinTST was median 8.5 h (range 0.4-13.8 h). EEG reactivity and wakefulness was found in all but one PSG. Four patients were CAM-ICU "unassessable" (unresponsive to voice). PSGs were atypical without reactivity or wakefulness, even though clinical wakefulness was documented. ClinTST was median 18.3 h (range 3.7-19.8 h). Paroxystic EEG activity was found in this subgroup.CONCLUSIONS: The objective signs of sleep were absent in all but one PSG, so even though patients were not sedated, sleep could not be quantified. Even in patients without delirium, sleep could only be quantified in one of four patients. Paroxystic activity is frequent in unsedated patients, unresponsive to voice, but the implication is unknown.

Background and purpose: Dementia causes morbidity, disability and mortality, and as the population ages the societal burden will grow. The direct health costs and indirect costs of lost productivity and social welfare of dementia were estimated compared with matched controls in a national register based cohort study. Methods: Using records from the Danish National Patient Registry (1997–2009) all patients with a diagnosis of Alzheimer's disease, vascular dementia or dementia not otherwise specified and their partners were identified and compared with randomly chosen controls matched for age, gender, geographical area and civil status. Direct health costs included primary and secondary sector contacts, medical procedures and medication. Indirect costs included the effect on labor supply. All cost data were extracted from national databases. The entire cohort was followed for the entire period – before and after diagnosis. Results: In all, 78 715 patients were identified and compared with 312 813 matched controls. Patients' partners were also identified and matched with a control group. Patients had lower income and higher mortality and morbidity rates and greater use of medication. Social- and health-related vulnerability was identified years prior to diagnosis. The average annual additional cost of direct healthcare costs and lost productivity in the years before diagnosis was 2082 euros per patient over and above that of matched controls, and 4544 euros per patient after the time of diagnosis. Conclusions: Dementias cause significant morbidity and mortality, consequently generating significant socioeconomic costs.

Objective Light plays an important role in the synchronization of the internal biological clock and the environmental day/night pattern. Thus, absence of vision is often associated with both increases in reported sleep disturbances and incidence of free-running circadian rhythms. In this study we discuss variability in the sleep–wake pattern between blind and normal-sighted individuals. Methods Thirty-day actigraphy recordings were collected from 11 blind individuals without residual light perception and 11 age- and sex-matched normal-sighted controls. From these recordings, we extracted parameters of sleep and wake, including episodes of rest, day-time and night-time sleep periods, and the number of awakenings throughout sleep. A measure of sleep efficiency was derived from these measures for each night-time sleep episode. We also examined complementary measures of sleep quality, using the Pittsburgh Sleep Quality Index, and chronotype, using the Morningness-Eveningness Questionnaire. Results Although no group differences were found when averaging over the entire recording period, we found a greater variability throughout the 30-days in both sleep efficiency and timing of the night-time sleep episode in blind participants as compared to sighted control participants. We also confirm previous reports of reduced sleep quality in blind individuals. Notably, the variability in sleep efficiency and in the timing of sleep correlated with the severity of sleep disturbances. Conclusion The timing and physiology of sleep are strongly dependent on the endogenous circadian phase; therefore, observed findings support the hypothesis of free-running circadian rhythms as a dominant factor for the sleep disturbances experienced in blindness.

BACKGROUND AND PURPOSE: Cluster headache (CH) is a primary headache disorder characterized by severe attacks of unilateral pain following a chronobiological pattern. There is a close connection with sleep as most attacks occur during sleep. Hypothalamic involvement and a particular association with rapid eye movement (REM) sleep have been suggested. Sleep in a large, well-characterized population of CH patients was investigated.METHODS: Polysomnography (PSG) was performed on two nights in 40 CH patients during active bout and one night in 25 age, sex and body mass index matched controls in hospital. Macrostructure and other features of sleep were analyzed and related to phenotype. Clinical headache characterization was obtained by semi-structured interview.RESULTS: Ninety-nine nights of PSG were analyzed. Findings included a reduced percentage of REM sleep (17.3% vs. 23.0%, P = 0.0037), longer REM latency (2.0 vs. 1.2 h, P = 0.0012) and fewer arousals (7.34 vs. 14.1, P = 0.003) in CH patients. There was no difference in prevalence of sleep apnea between patients (38%) and matched controls (32%, P = 0.64) although the apnea index in patients was numerically higher (mean apnea-hypopnea index 10.75 vs. 4.93). No temporal association between nocturnal attacks (n = 45) and particular sleep stages was observed.CONCLUSIONS: To date, this is the largest study of sleep in CH. It is demonstrated that REM sleep is affected which is in line with our current understanding of CH and hypothalamic involvement in the regulation of this sleep stage. Further, fewer arousals were found in CH patients but no association between apnea events or specific sleep stages. The findings support a central role of the hypothalamus and arousal systems in CH.

BACKGROUND AND AIM: Cluster headache (CH) is the headache disorder with the strongest chronobiological traits. The severe attacks of pain occur with diurnal and annual rhythmicity but the precise rhythm and involvement of potential zeitgebers is unknown. Patients complain of poor sleep quality yet this has never been studied. We investigated triggers, rhythms, sleep quality and chronotypes in CH.METHODS: Patients and controls completed questionnaires and structured interviews composed of new and previously validated parts including the Pittsburgh Sleep Quality Index (PSQI) and Morningness-Eveningness Questionnaire (MEQ). Patients were characterized by a CH index, a unified measure of headache burden.RESULTS: A total of 275 CH patients and 145 matched controls were included. The most common trigger was sleep (80%) and a relationship between clusters and daylight was identified. Of the patients, 82.2% reported diurnal and 56% annual rhythmicity. Patients reported impaired sleep quality (PSQI) (p < 0.0001) and an inverse relationship between time passed since last attack and sleep quality was identified (p < 0.0001). The CH index was positively related to the PSQI (p < 0.0001).CONCLUSION: Diurnally, CH exhibits a relationship with night-time and annually with daylight hours. Patients' sleep quality is reduced compared with controls. Results suggest a complex relationship as sleep quality improves between clusters, but remains pathological.

OBJECTIVE: To describe the experience of physical activity maintenance in patients with rheumatoid arthritis.DESIGN: A qualitative salutogenic-oriented interview study.SETTING: A rheumatology outpatient clinic.SUBJECTS: A purposive sample of 16 physically active patients (mean age 50, range 37-67) diagnosed with rheumatoid arthritis on average 21 years previously (range 4-46 years).METHODS: In-depth interviews were conducted using a semi-structured interview guide to illuminate how the phenomenon 'physical activity maintenance' was experienced by patients with rheumatoid arthritis. The interviews were analysed using systematic text condensation, inspired by Giorgi's descriptive phenomenological methodology.RESULTS: The analysis revealed three categories: (1) knowing and enjoying the body; (2) responsibility and challenges; (3) autonomy and social belonging. On the basis of these categories, the essential meaning of the phenomenon of physical activity maintenance for patients with rheumatoid arthritis was summarized into 'striving for a transparent body and participation', pointing to experiences of sensations of wellbeing, liberation from restrictions and social participation on equal terms with non-arthritis populations.CONCLUSION: This study demonstrates that physical activity in patients with rheumatoid arthritis may be understood as a resource to resist disability and to feel and stay healthy while creating and sustaining meaningfulness in life.

OBJECTIVE: To describe the experience of physical activity maintenance in patients with rheumatoid arthritis.DESIGN: A qualitative salutogenic-oriented interview study.SETTING: A rheumatology outpatient clinic.SUBJECTS: A purposive sample of 16 physically active patients (mean age 50, range 37-67) diagnosed with rheumatoid arthritis on average 21 years previously (range 4-46 years).METHODS: In-depth interviews were conducted using a semi-structured interview guide to illuminate how the phenomenon 'physical activity maintenance' was experienced by patients with rheumatoid arthritis. The interviews were analysed using systematic text condensation, inspired by Giorgi's descriptive phenomenological methodology.RESULTS: The analysis revealed three categories: (1) knowing and enjoying the body; (2) responsibility and challenges; (3) autonomy and social belonging. On the basis of these categories, the essential meaning of the phenomenon of physical activity maintenance for patients with rheumatoid arthritis was summarized into 'striving for a transparent body and participation', pointing to experiences of sensations of wellbeing, liberation from restrictions and social participation on equal terms with non-arthritis populations.CONCLUSION: This study demonstrates that physical activity in patients with rheumatoid arthritis may be understood as a resource to resist disability and to feel and stay healthy while creating and sustaining meaningfulness in life.

Contains fulltext : 117810.pdf (publisher's version ) (Closed access), BACKGROUND: In August 2010 reports of a possible association between exposure to AS03 adjuvanted pandemic A(H1N1)pdm09 vaccine and occurrence of narcolepsy in children and adolescents emerged in Sweden and Finland. In response to this signal, the background rates of narcolepsy in Europe were assessed to rapidly provide information for signal verification. METHODS: We used a dynamic retrospective cohort study to assess the narcolepsy diagnosis rates during the period 2000-2010 using large linked automated health care databases in six countries: Denmark, Finland, Italy, the Netherlands, Sweden and the United Kingdom. RESULTS: Overall, 2608 narcolepsy cases were identified in almost 280 million person years (PY) of follow up. The pooled incidence rate was 0.93 (95% CI: 0. 90-0.97) per 100,000 PY. There were peaks between 15 and 30 year of age (women>men) and around 60 years of age. In the age group 5-19 years olds rates were increased after the start of pandemic vaccination compared to the period before the start of campaigns, with rate ratios (RR) of 1.9 (95% CI: 1.1-3.1) in Denmark, 6.4 (95% CI: 4.2-9.7) in Finland and 7.5 (95% CI: 5.2-10.7) in Sweden. Cases verification in the Netherlands had a significant effect on the pattern of incidence over time. CONCLUSIONS: The results of this incidence study provided useful information for signal verification on a population level. The safety signal of increased narcolepsy diagnoses following the start of the pandemic vaccination campaign as observed in Sweden and Finland could be observed with this approach. An increase in narcolepsy diagnoses was not observed in other countries, where vaccination coverage was low in the affected age group, or did not follow influenza A(H1N1)pdm09 vaccination. Patient level analyses in these countries are being conducted to verify the signal in more detail.

Contains fulltext : 118596.pdf (publisher's version ) (Open Access), 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 () and Tumor necrosis factor (ligand) superfamily member 4 (, also called ), 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.

Contains fulltext : 149650.pdf (publisher's version ) (Closed access), 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.

Background: In August 2010 reports of a possible association between exposure to AS03 adjuvanted pandemic A(H1N1)pdm09 vaccine and occurrence of narcolepsy in children and adolescents emerged in Sweden and Finland. In response to this signal, the background rates of narcolepsy in Europe were assessed to rapidly provide information for signal verification. Methods: We used a dynamic retrospective cohort study to assess the narcolepsy diagnosis rates during the period 2000-2010 using large linked automated health care databases in six countries: Denmark, Finland, Italy, the Netherlands, Sweden and the United Kingdom. Results: Overall, 2608 narcolepsy cases were identified in almost 280 million person years (PY) of follow up. The pooled incidence rate was 0.93 (95% CI: 0. 90-0.97) per 100,000 PY. There were peaks between 15 and 30 year of age (women > men) and around 60 years of age. In the age group 5-19 years olds rates were increased after the start of pandemic vaccination compared to the period before the start of campaigns, with rate ratios (RR) of 1.9 (95% CI: 1.1-3.1) in Denmark, 6.4 (95% CI: 4.2-9.7) in Finland and 7.5 (95% CI: 5.2-10.7) in Sweden. Cases verification in the Netherlands had a significant effect on the pattern of incidence over time. Conclusions: The results of this incidence study provided useful information for signal verification on a population level. The safety signal of increased narcolepsy diagnoses following the start of the pandemic vaccination campaign as observed in Sweden and Finland could be observed with this approach. An increase in narcolepsy diagnoses was not observed in other countries, where vaccination coverage was low in the affected age group, or did not follow influenza A(H1N1)pdm09 vaccination. Patient level analyses in these countries are being conducted to verify the signal in more detail.

Contains fulltext : 117810.pdf (publisher's version ) (Closed access), BACKGROUND: In August 2010 reports of a possible association between exposure to AS03 adjuvanted pandemic A(H1N1)pdm09 vaccine and occurrence of narcolepsy in children and adolescents emerged in Sweden and Finland. In response to this signal, the background rates of narcolepsy in Europe were assessed to rapidly provide information for signal verification. METHODS: We used a dynamic retrospective cohort study to assess the narcolepsy diagnosis rates during the period 2000-2010 using large linked automated health care databases in six countries: Denmark, Finland, Italy, the Netherlands, Sweden and the United Kingdom. RESULTS: Overall, 2608 narcolepsy cases were identified in almost 280 million person years (PY) of follow up. The pooled incidence rate was 0.93 (95% CI: 0. 90-0.97) per 100,000 PY. There were peaks between 15 and 30 year of age (women>men) and around 60 years of age. In the age group 5-19 years olds rates were increased after the start of pandemic vaccination compared to the period before the start of campaigns, with rate ratios (RR) of 1.9 (95% CI: 1.1-3.1) in Denmark, 6.4 (95% CI: 4.2-9.7) in Finland and 7.5 (95% CI: 5.2-10.7) in Sweden. Cases verification in the Netherlands had a significant effect on the pattern of incidence over time. CONCLUSIONS: The results of this incidence study provided useful information for signal verification on a population level. The safety signal of increased narcolepsy diagnoses following the start of the pandemic vaccination campaign as observed in Sweden and Finland could be observed with this approach. An increase in narcolepsy diagnoses was not observed in other countries, where vaccination coverage was low in the affected age group, or did not follow influenza A(H1N1)pdm09 vaccination. Patient level analyses in these countries are being conducted to verify the signal in more detail.

Contains fulltext : 118596.pdf (publisher's version ) (Open Access), 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 () and Tumor necrosis factor (ligand) superfamily member 4 (, also called ), 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.

Contains fulltext : 149650.pdf (publisher's version ) (Closed access), 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.