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

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

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

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

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

Progress in the field of insomnia since 2017 necessitated this update of the European Insomnia Guideline. Recommendations for the diagnostic procedure for insomnia and its comorbidities are: clinical interview (encompassing sleep and medical history); the use of sleep questionnaires and diaries (and physical examination and additional measures where indicated) (A). Actigraphy is not recommended for the routine evaluation of insomnia (C), but may be useful for differential-diagnostic purposes (A). Polysomnography should be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep-related breathing disorders, etc.), treatment-resistant insomnia (A) and for other indications (B). Cognitive-behavioural therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (including patients with comorbidities), either applied in-person or digitally (A). When cognitive-behavioural therapy for insomnia is not sufficiently effective, a pharmacological intervention can be offered (A). Benzodiazepines (A), benzodiazepine receptor agonists (A), daridorexant (A) and low-dose sedating antidepressants (B) can be used for the short-term treatment of insomnia (≤ 4 weeks). Longer-term treatment with these substances may be initiated in some cases, considering advantages and disadvantages (B). Orexin receptor antagonists can be used for periods of up to 3 months or longer in some cases (A). Prolonged-release melatonin can be used for up to 3 months in patients ≥ 55 years (B). Antihistaminergic drugs, antipsychotics, fast-release melatonin, ramelteon and phytotherapeutics are not recommended for insomnia treatment (A). Light therapy and exercise interventions may be useful as adjunct therapies to cognitive-behavioural therapy for insomnia (B).

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

The brain and its health are essential for our (physical mental, social, and spiritual) wellbeing, for being able to realize our potential as individuals, and also for a fair, well-functioning, and productive society. However, today the world is facing a healthcare crisis related to the very high (and increasing) burden of brain disorders. As a response to this crisis, the “Swiss Brain Health Plan” (SBHP) was conceptualized in the context of other initiatives launched to value, promote, and protect brain health over the entire life course. In the first section of this position paper, the following fundamental considerations of the SBHP are discussed: (1) the high (and increasing) burden of brain disorders in terms of prevalence (>50% of the population suffers from a brain disorder), disability, mortality, and costs; (2) the prevention of brain disorders; (3) the operational definition of brain health; (4) determinants of brain health; (5) international initiatives to promote brain (including mental) health including the World Health Organization (WHO) intersectorial global action plan on epilepsy and other neurological disorders (NDs) (IGAP) and the WHO comprehensive mental health action plan. In the second section of the paper, the five strategic objectives of the SBHP, which has the vision of promoting brain health for all across the entire life course, are presented: (1) to raise awareness; (2) strengthen cross-disciplinary and interprofessional training/educational programs for healthcare professionals; (3) foster research on brain health determinants and individualized prevention of brain disorders; (4) prioritize a holistic (non-disease-specific), integrated, person-centered public health approach to promote brain health and prevent brain disorders through collaborations across scientific, health care, commercial, societal and governmental stakeholders and insurance providers; (5) support, empower, and engage patients, caregivers, and patient organizations, an

Purpose: This study aims to enhance the clinical use of automated sleep-scoring algorithms by incorporating an uncertainty estimation approach to efficiently assist clinicians in the manual review of predicted hypnograms, a necessity due to the notable inter-scorer variability inherent in polysomnography (PSG) databases. Our efforts target the extent of review required to achieve predefined agreement levels, examining both in-domain and out-of-domain data, and considering subjects diagnoses. Patients and methods: Total of 19578 PSGs from 13 open-access databases were used to train U-Sleep, a state-of-the-art sleep-scoring algorithm. We leveraged a comprehensive clinical database of additional 8832 PSGs, covering a full spectrum of ages and sleep-disorders, to refine the U-Sleep, and to evaluate different uncertainty-quantification approaches, including our novel confidence network. The ID data consisted of PSGs scored by over 50 physicians, and the two OOD sets comprised recordings each scored by a unique senior physician. Results: U-Sleep demonstrated robust performance, with Cohen's kappa (K) at 76.2% on ID and 73.8-78.8% on OOD data. The confidence network excelled at identifying uncertain predictions, achieving AUROC scores of 85.7% on ID and 82.5-85.6% on OOD data. Independently of sleep-disorder status, statistical evaluations revealed significant differences in confidence scores between aligning vs discording predictions, and significant correlations of confidence scores with classification performance metrics. To achieve K of at least 90% with physician intervention, examining less than 29.0% of uncertain epochs was required, substantially reducing physicians workload, and facilitating near-perfect agreement.

BACKGROUND AND OBJECTIVES: Recent studies fueled doubts as to whether all currently defined central disorders of hypersomnolence are stable entities, especially narcolepsy type 2 and idiopathic hypersomnia. New reliable biomarkers are needed and the question arises whether current diagnostic criteria of hypersomnolence disorders should be reassessed. The main aim of this data-driven observational study was to see if data-driven algorithms would segregate narcolepsy type 1 and identify more reliable subgrouping of individuals without cataplexy with new clinical biomarkers.METHODS: We used agglomerative hierarchical clustering, an unsupervised machine learning algorithm, to identify distinct hypersomnolence clusters in the large-scale European Narcolepsy Network database. We included 97 variables, covering all aspects of central hypersomnolence disorders such as symptoms, demographics, objective and subjective sleep measures, and laboratory biomarkers. We specifically focused on subgrouping of patients without cataplexy. The number of clusters was chosen to be the minimal number for which patients without cataplexy were put in distinct groups.RESULTS: We included 1078 unmedicated adolescents and adults. Seven clusters were identified, of which four clusters included predominantly individuals with cataplexy. The two most distinct clusters consisted of 158 and 157 patients respectively, were dominated by those without cataplexy and, amongst other variables, significantly differed in presence of sleep drunkenness, subjective difficulty awakening and weekend-week sleep length difference. Patients formally diagnosed as narcolepsy type 2 and idiopathic hypersomnia were evenly mixed in these two clusters.DISCUSSION: Using a data-driven approach in the largest study on central disorders of hypersomnolence to date, our study identified distinct patient subgroups within the central disorders of hypersomnolence population. Our results contest inclusion of

Background and purpose Health risks associated with SARS-CoV-2 infection are undisputed. Moreover, the capability of vaccination to prevent symptomatic, severe, and fatal COVID-19 is recognized. There is also early evidence that vaccination can reduce the chance for long COVID-19. Nonetheless, the willingness to get vaccinated and receive booster shots remains subpar among people with neurologic disorders. Vaccine scepticism not only jeopardizes collective efforts to end the COVID-19 pandemic but puts individual lives at risk, as some chronic neurologic diseases are associated with a higher risk for an unfavorable COVID-19 course. Methods In this position paper, the NeuroCOVID-19 Task Force of the European Academy of Neurology (EAN) summarizes the current knowledge on the prognosis of COVID-19 among patients with neurologic disease, elucidates potential barriers to vaccination coverage, and formulates strategies to overcome vaccination hesitancy. A survey among the Task Force members on the phenomenon of vaccination hesitancy among people with neurologic disease supports the lines of argumentation. Results The study revealed that people with multiple sclerosis and other nervous system autoimmune disorders are most skeptical of SARS-CoV-2 vaccination. The prevailing concerns included the chance of worsening the pre-existing neurological condition, vaccination-related adverse events, and drug interaction. Conclusions The EAN NeuroCOVID-19 Task Force reinforces the key role of neurologists as advocates of COVID-19 vaccination. Neurologists need to argue in the interest of their patients about the overwhelming individual and global benefits of COVID-19 vaccination. Moreover, they need to keep on eye on this vulnerable patient group, its concerns, and the emergence of potential safety signals.

AASM guidelines are the result of decades of efforts aiming at standardizing sleep scoring procedure, with the final goal of sharing a worldwide common methodology. The guidelines cover several aspects from the technical/digital specifications,e.g., recommended EEG derivations, to detailed sleep scoring rules accordingly to age. Automated sleep scoring systems have always largely exploited the standards as fundamental guidelines. In this context, deep learning has demonstrated better performance compared to classical machine learning. Our present work shows that a deep learning based sleep scoring algorithm may not need to fully exploit the clinical knowledge or to strictly adhere to the AASM guidelines. Specifically, we demonstrate that U-Sleep, a state-of-the-art sleep scoring algorithm, can be strong enough to solve the scoring task even using clinically non-recommended or non-conventional derivations, and with no need to exploit information about the chronological age of the subjects. We finally strengthen a well-known finding that using data from multiple data centers always results in a better performing model compared with training on a single cohort. Indeed, we show that this latter statement is still valid even by increasing the size and the heterogeneity of the single data cohort. In all our experiments we used 28528 polysomnography studies from 13 different clinical studies.

BACKGROUND AND OBJECTIVES: Recent studies fueled doubts as to whether all currently defined central disorders of hypersomnolence are stable entities, especially narcolepsy type 2 and idiopathic hypersomnia. New reliable biomarkers are needed and the question arises whether current diagnostic criteria of hypersomnolence disorders should be reassessed. The main aim of this data-driven observational study was to see if data-driven algorithms would segregate narcolepsy type 1 and identify more reliable subgrouping of individuals without cataplexy with new clinical biomarkers.METHODS: We used agglomerative hierarchical clustering, an unsupervised machine learning algorithm, to identify distinct hypersomnolence clusters in the large-scale European Narcolepsy Network database. We included 97 variables, covering all aspects of central hypersomnolence disorders such as symptoms, demographics, objective and subjective sleep measures, and laboratory biomarkers. We specifically focused on subgrouping of patients without cataplexy. The number of clusters was chosen to be the minimal number for which patients without cataplexy were put in distinct groups.RESULTS: We included 1078 unmedicated adolescents and adults. Seven clusters were identified, of which four clusters included predominantly individuals with cataplexy. The two most distinct clusters consisted of 158 and 157 patients respectively, were dominated by those without cataplexy and, amongst other variables, significantly differed in presence of sleep drunkenness, subjective difficulty awakening and weekend-week sleep length difference. Patients formally diagnosed as narcolepsy type 2 and idiopathic hypersomnia were evenly mixed in these two clusters.DISCUSSION: Using a data-driven approach in the largest study on central disorders of hypersomnolence to date, our study identified distinct patient subgroups within the central disorders of hypersomnolence population. Our results contest inclusion of

Coronavirus disease 2019 (COVID-19), a multi-organ disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to challenge health and care systems around the globe. The pandemic has disrupted acute neurology services and routine patient care and has impacted the clinical course in patients with chronic neurological disease. COVID-19 appears to have exposed inequalities of societies and healthcare systems and had a disproportionate impact on already vulnerable communities. The next challenge will be to set up initiatives to stop disparities in all aspects related to COVID-19. From the medical perspective, there is a need to consider inequalities in prevention, treatment and long-term consequences. Some of the issues of direct relevance to neurologists are summarised. With this appraisal, the European Academy of Neurology NeuroCOVID-19 Task Force intends to raise awareness of the potential impact of COVID-19 on inequalities in healthcare and calls for action to prevent disparity at individual, national and supranational levels.

Background and purpose: The COVID-19 (SARS-CoV-2) outbreak has disrupted residency programmes due to university and hospitals' priorities to face this emergency at all cost. Most research projects and clinical trials were temporarily stopped or postponed. The Resident and Research Fellow Section (RRFS) of the European Academy of Neurology (EAN) has decided to assess the impact of the COVID-19 pandemic on neurology training. Methods: All EAN RRFS members were invited to fill out an online questionnaire of 40 items concerning their clinical involvement during the COVID-19 emergency, and the impact of the pandemic on their training (Appendix S1). Results: Of the 227 RRFS members who completed the questionnaire, 222 were from Europe, and of those 111 were from Portugal, Italy or France. Responders highlighted that severe restrictions have been imposed to face this pandemic, including reduction of inpatient beds, prohibition of in-person visits and limitation to hospital access for patients' relatives. This was accompanied by an increase in email correspondence and phone calls with 50% of countries allowing telemedicine to reach outpatients. Seventy-nine per cent of the respondents felt that the pandemic will probably have a serious impact on their training and career. Conclusion: The pandemic led to a disruption of neurology activities, including medical training and research. The long-run impact of these changes remains unknown, but it will probably change the way neurology practice and training will be organized for future generations.

Pareidolias, the illusory perception of patterns like faces or animals in backgrounds or textures (e.g., clouds), may be a potentially interesting paradigm to assess creativity. The present study investigates the relationship between production of pareidolias, divergent thinking, and associative thinking. To analyze creative aspects of pareidolias a tablet-based task was devised, the Divergent Pareidolias Task (DPT), where participants were presented with photographs of natural landscapes and they were asked to produce pareidolias. Pareidolic outputs were analyzed in terms of fluency, flexibility, and originality. Creativityrelated cognitive tasks (i.e., tasks assessing alertness, cognitive inhibition, and verbal intelligence) and a short interview assessing creative interests in everyday life were additionally administered. Regression analyses revealed that divergent thinking, in terms of fluency of the Alternative Uses Task significantly predicted fluency and originality of pareidolias produced in the DPT. Moreover, fluent and rarer associations in an Associative Fluency Task were predictive of fluent and original aspects of pareidolias in the DPT, respectively. Taken together, the results of this pilot study indicate the involvement of creative processes in the production of pareidolias and suggest that the DPT could represent a possible future way to investigate divergent aspects of creative cognition.

Coronavirus disease 2019 (COVID-19), a multi-organ disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to challenge health and care systems around the globe. The pandemic has disrupted acute neurology services and routine patient care and has impacted the clinical course in patients with chronic neurological disease. COVID-19 appears to have exposed inequalities of societies and healthcare systems and had a disproportionate impact on already vulnerable communities. The next challenge will be to set up initiatives to stop disparities in all aspects related to COVID-19. From the medical perspective, there is a need to consider inequalities in prevention, treatment and long-term consequences. Some of the issues of direct relevance to neurologists are summarised. With this appraisal, the European Academy of Neurology NeuroCOVID-19 Task Force intends to raise awareness of the potential impact of COVID-19 on inequalities in healthcare and calls for action to prevent disparity at individual, national and supranational levels.

Background and purpose: The COVID-19 (SARS-CoV-2) outbreak has disrupted residency programmes due to university and hospitals' priorities to face this emergency at all cost. Most research projects and clinical trials were temporarily stopped or postponed. The Resident and Research Fellow Section (RRFS) of the European Academy of Neurology (EAN) has decided to assess the impact of the COVID-19 pandemic on neurology training. Methods: All EAN RRFS members were invited to fill out an online questionnaire of 40 items concerning their clinical involvement during the COVID-19 emergency, and the impact of the pandemic on their training (Appendix S1). Results: Of the 227 RRFS members who completed the questionnaire, 222 were from Europe, and of those 111 were from Portugal, Italy or France. Responders highlighted that severe restrictions have been imposed to face this pandemic, including reduction of inpatient beds, prohibition of in-person visits and limitation to hospital access for patients' relatives. This was accompanied by an increase in email correspondence and phone calls with 50% of countries allowing telemedicine to reach outpatients. Seventy-nine per cent of the respondents felt that the pandemic will probably have a serious impact on their training and career. Conclusion: The pandemic led to a disruption of neurology activities, including medical training and research. The long-run impact of these changes remains unknown, but it will probably change the way neurology practice and training will be organized for future generations.

Background and purpose Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based guidelines for the management of narcolepsy in both adults and children. Methods The European Academy of Neurology (EAN), European Sleep Research Society (ESRS), and European Narcolepsy Network (EU-NN) nominated a task force of 18 narcolepsy specialists. According to the EAN recommendations, 10 relevant clinical questions were formulated in PICO format. Following a systematic review of the literature (performed in Fall 2018 and updated in July 2020) recommendations were developed according to the GRADE approach. Results A total of 10,247 references were evaluated, 308 studies were assessed and 155 finally included. The main recommendations can be summarized as follows: (i) excessive daytime sleepiness (EDS) in adults-scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong); methylphenidate, amphetamine derivatives (both weak); (ii) cataplexy in adults-SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) EDS in children-scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivatives (all weak); (iv) cataplexy in children-SXB (strong), antidepressants (weak). Treatment choices should be tailored to each patient's symptoms, comorbidities, tolerance and risk of potential drug interactions. Conclusion The management of narcolepsy involves non-pharmacological and pharmacological approaches with an increasing number of symptomatic treatment options for adults and children that have been studied in some detail.

Background and purpose Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based guidelines for the management of narcolepsy in both adults and children. Methods The European Academy of Neurology (EAN), European Sleep Research Society (ESRS), and European Narcolepsy Network (EU-NN) nominated a task force of 18 narcolepsy specialists. According to the EAN recommendations, 10 relevant clinical questions were formulated in PICO format. Following a systematic review of the literature (performed in Fall 2018 and updated in July 2020) recommendations were developed according to the GRADE approach. Results A total of 10,247 references were evaluated, 308 studies were assessed and 155 finally included. The main recommendations can be summarized as follows: (i) excessive daytime sleepiness (EDS) in adults-scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong); methylphenidate, amphetamine derivatives (both weak); (ii) cataplexy in adults-SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) EDS in children-scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivatives (all weak); (iv) cataplexy in children-SXB (strong), antidepressants (weak). Treatment choices should be tailored to each patient's symptoms, comorbidities, tolerance and risk of potential drug interactions. Conclusion The management of narcolepsy involves non-pharmacological and pharmacological approaches with an increasing number of symptomatic treatment options for adults and children that have been studied in some detail.

Study Objectives: Narcolepsy with cataplexy is tightly associated with the HLA class II allele DQB1*06:02. Evidence indicates a complex contribution of HLA class II genes to narcolepsy susceptibility with a recent independent association with HLA-DPB1. The cause of narcolepsy is supposed be an autoimmune attack against hypocretin-producing neurons. Despite the strong association with HLA class II, there is no evidence for CD4+ T-cell-mediated mechanism in narcolepsy. Since neurons express class I and not class II molecules, the final effector immune cells involved might include class I-restricted CD8+ T-cells. Methods: HLA class I (A, B, and C) and II (DQB1) genotypes were analyzed in 944 European narcolepsy with cataplexy patients and in 4,043 control subjects matched by country of origin. All patients and controls were DQB1*06:02 positive and class I associations were conditioned on DQB1 alleles. Results: HLA-A*11:01 (OR = 1.49 [1.18-1.87] P = 7.0*10−4), C*04:01 (OR = 1.34 [1.10-1.63] P = 3.23*10−3), and B*35:01 (OR = 1.46 [1.13-1.89] P = 3.64*10−3) were associated with susceptibility to narcolepsy. Analysis of polymorphic class I amino-acids revealed even stronger associations with key antigen-binding residues HLA-A-Tyr9 (OR = 1.32 [1.15-1.52] P = 6.95*10−5) and HLA-C-Ser11 (OR = 1.34 [1.15-1.57] P = 2.43*10−4). Conclusions: Our findings provide a genetic basis for increased susceptibility to infectious factors or an immune cytotoxic mechanism in narcolepsy, potentially targeting hypocretin neurons. Significance Although evidence strongly indicates that immune-related mechanisms are involved in the pathogenesis of narcolepsy with hypocretin deficiency, functional data are missing. The strong association with HLA class II genes is not corroborated by any CD4+ T Cell implication and inflammation. Additionally, these genes are not normally expressed in the brain. Here, we show that several HLA class I variants are associated with narcolepsy. Since these mol

OBJECTIVE Slow waves are thought to mediate an overall reduction in synaptic strength during sleep. The specific contribution of the thalamus to this so-called synaptic renormalization is unknown. Thalamic stroke is associated with daytime sleepiness, along with changes to sleep electroencephalography and cognition making it a unique "experiment of nature" to assess the relationship between sleep rhythms, synaptic renormalization, and daytime functions. METHODS Sleep was studied by polysomnography and high-density electroencephalography over 17 nights in patients with thalamic (n = 12) and 15 nights in patients with extra-thalamic (n = 11) stroke. Sleep electroencephalography overnight slow wave slope changes, and their relationship with subjective daytime sleepiness, cognition, and other functional tests were assessed. RESULTS Thalamic and extra-thalamic patients did not differ in terms of age, sleep duration or apnea-hypopnea index. Conversely, overnight slope changes were reduced in a large cluster of electrodes in thalamic compared to extra-thalamic stroke patients. This reduction was related to increased daytime sleepiness. No significant differences were found in other functional tests between the two groups. INTERPRETATION In patients with thalamic stroke a reduction in overnight slow wave slope change and increased daytime sleepiness was found. Sleep- and wake-centered mechanisms for this relationship are discussed. Overall, this study suggests a central role of the thalamus in synaptic renormalization. This article is protected by copyright. All rights reserved.

Narcolepsy type 1 (NT1) is a disorder with well-established markers and a suspected autoimmune aetiology. Conversely, the narcoleptic borderland (NBL) disorders, including narcolepsy type 2, idiopathic hypersomnia, insufficient sleep syndrome and hypersomnia associated with a psychiatric disorder, lack well-defined markers and remain controversial in terms of aetiology, diagnosis and management. The Swiss Primary Hypersomnolence and Narcolepsy Cohort Study (SPHYNCS) is a comprehensive multicentre cohort study, which will investigate the clinical picture, pathophysiology and long-term course of NT1 and the NBL. The primary aim is to validate new and reappraise well-known markers for the characterization of the NBL, facilitating the diagnostic process. Seven Swiss sleep centres, belonging to the Swiss Narcolepsy Network (SNaNe), joined the study and will prospectively enrol over 500 patients with recent onset of excessive daytime sleepiness (EDS), hypersomnia or a suspected central disorder of hypersomnolence (CDH) during a 3-year recruitment phase. Healthy controls and patients with EDS due to severe sleep-disordered breathing, improving after therapy, will represent two control groups of over 50 patients each. Clinical and electrophysiological (polysomnography, multiple sleep latency test, maintenance of wakefulness test) information, and information on psychomotor vigilance and a sustained attention to response task, actigraphy and wearable devices (long-term monitoring), and responses to questionnaires will be collected at baseline and after 6, 12, 24 and 36 months. Potential disease markers will be searched for in blood, cerebrospinal fluid and stool. Analyses will include quantitative hypocretin measurements, proteomics/peptidomics, and immunological, genetic and microbiota studies. SPHYNCS will increase our understanding of CDH and the relationship between NT1 and the NBL. The identification of new disease markers is expected to lead to better and earlier diagn

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. 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. 13 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 included. Statements were generated regarding current evidence and clinical practice. 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, while CPAP may improve stroke outcome. It is not clear if insomnia increases stroke risk, while 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, while treatment data are scarce. 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.

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. 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. 13 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 included. Statements were generated regarding current evidence and clinical practice. 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, while CPAP may improve stroke outcome. It is not clear if insomnia increases stroke risk, while 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, while treatment data are scarce. 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.

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.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. 13 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 included. Statements were generated regarding current evidence and clinical practice.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, while CPAP may improve stroke outcome. It is not clear if insomnia increases stroke risk, while 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, while treatment data are scarce.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.

Obstructive sleep apnoea (OSA) is a major challenge for physicians and healthcare systems throughout the world. The high prevalence and the impact on daily life of OSA oblige clinicians to offer effective and acceptable treatment options. However, recent evidence has raised questions about the benefits of positive airway pressure therapy in ameliorating comorbidities. An international expert group considered the current state of knowledge based on the most relevant publications in the previous 5 years, discussed the current challenges in the field, and proposed topics for future research on epidemiology, phenotyping, underlying mechanisms, prognostic implications and optimal treatment of patients with OSA. The group concluded that a revision to the diagnostic criteria for OSA is required to include factors that reflect different clinical and pathophysiological phenotypes and relevant comorbidities (e.g. nondipping nocturnal blood pressure). Furthermore, current severity thresholds require revision to reflect factors such as the disparity in the apnoea-hypopnoea index (AHI) between polysomnography and sleep studies that do not include sleep stage measurements, in addition to the poor correlation between AHI and daytime symptoms such as sleepiness. Management decisions should be linked to the underlying phenotype and consider outcomes beyond AHI.

Narcolepsy is a rare life-long disease that exists in two forms, narcolepsy type-1 (NT1) or type-2 (NT2), but only NT1 is accepted as clearly defined entity. Both types of narcolepsies belong to the group of central hypersomnias (CH), a spectrum of poorly defined diseases with excessive daytime sleepiness as a core feature. Due to the considerable overlap of symptoms and the rarity of the diseases, it is difficult to identify distinct phenotypes of CH. Machine learning (ML) can help to identify phenotypes as it learns to recognize clinical features invisible for humans. Here we apply ML to data from the huge European Narcolepsy Network (EU-NN) that contains hundreds of mixed features of narcolepsy making it difficult to analyze with classical statistics. Stochastic gradient boosting, a supervised learning model with built-in feature selection, results in high performances in testing set. While cataplexy features are recognized as the most influential predictors, machine find additional features, e.g. mean rapid-eye-movement sleep latency of multiple sleep latency test contributes to classify NT1 and NT2 as confirmed by classical statistical analysis. Our results suggest ML can identify features of CH on machine scale from complex databases, thus providing 'ideas' and promising candidates for future diagnostic classifications.

Narcolepsy is a rare life-long disease that exists in two forms, narcolepsy type-1 (NT1) or type-2 (NT2), but only NT1 is accepted as clearly defined entity. Both types of narcolepsies belong to the group of central hypersomnias (CH), a spectrum of poorly defined diseases with excessive daytime sleepiness as a core feature. Due to the considerable overlap of symptoms and the rarity of the diseases, it is difficult to identify distinct phenotypes of CH. Machine learning (ML) can help to identify phenotypes as it learns to recognize clinical features invisible for humans. Here we apply ML to data from the huge European Narcolepsy Network (EU-NN) that contains hundreds of mixed features of narcolepsy making it difficult to analyze with classical statistics. Stochastic gradient boosting, a supervised learning model with built-in feature selection, results in high performances in testing set. While cataplexy features are recognized as the most influential predictors, machine find additional features, e.g. mean rapid-eye-movement sleep latency of multiple sleep latency test contributes to classify NT1 and NT2 as confirmed by classical statistical analysis. Our results suggest ML can identify features of CH on machine scale from complex databases, thus providing 'ideas' and promising candidates for future diagnostic classifications.

Obstructive sleep apnoea (OSA) is a major challenge for physicians and healthcare systems throughout the world. The high prevalence and the impact on daily life of OSA oblige clinicians to offer effective and acceptable treatment options. However, recent evidence has raised questions about the benefits of positive airway pressure therapy in ameliorating comorbidities. An international expert group considered the current state of knowledge based on the most relevant publications in the previous 5 years, discussed the current challenges in the field, and proposed topics for future research on epidemiology, phenotyping, underlying mechanisms, prognostic implications and optimal treatment of patients with OSA. The group concluded that a revision to the diagnostic criteria for OSA is required to include factors that reflect different clinical and pathophysiological phenotypes and relevant comorbidities (e.g. nondipping nocturnal blood pressure). Furthermore, current severity thresholds require revision to reflect factors such as the disparity in the apnoea-hypopnoea index (AHI) between polysomnography and sleep studies that do not include sleep stage measurements, in addition to the poor correlation between AHI and daytime symptoms such as sleepiness. Management decisions should be linked to the underlying phenotype and consider outcomes beyond AHI.

Narcolepsy is a rare life-long disease that exists in two forms, narcolepsy type-1 (NT1) or type-2 (NT2), but only NT1 is accepted as clearly defined entity. Both types of narcolepsies belong to the group of central hypersomnias (CH), a spectrum of poorly defined diseases with excessive daytime sleepiness as a core feature. Due to the considerable overlap of symptoms and the rarity of the diseases, it is difficult to identify distinct phenotypes of CH. Machine learning (ML) can help to identify phenotypes as it learns to recognize clinical features invisible for humans. Here we apply ML to data from the huge European Narcolepsy Network (EU-NN) that contains hundreds of mixed features of narcolepsy making it difficult to analyze with classical statistics. Stochastic gradient boosting, a supervised learning model with built-in feature selection, results in high performances in testing set. While cataplexy features are recognized as the most influential predictors, machine find additional features, e.g. mean rapid-eye-movement sleep latency of multiple sleep latency test contributes to classify NT1 and NT2 as confirmed by classical statistical analysis. Our results suggest ML can identify features of CH on machine scale from complex databases, thus providing 'ideas' and promising candidates for future diagnostic classifications.

BACKGROUND Sleepwalking (SW) is found to affect children predominantly, but it can persist or appear de novo even among adults. In this study, we assessed the demographic, clinical and polysomnographic profile, trigger factors and associated comorbidities of adult-onset (AO-SW) and childhood-onset (CO-SW) adult sleepwalkers. METHODS In adult sleepwalkers, a structured clinical interview, a battery of questionnaires, video-polysomnography (v-PSG) and standard electroencephalography (EEG) were performed. RESULTS Among 63 sleepwalkers, 45% had ≥1 episodes/month, 54% had partial recall of the episodes and 36% reported trigger factors for SW. Almost all subjects reported co-occurring parasomnias. In v-PSG, 4% exhibited episodes of SW, 17% confusional arousals, 21% had an increased apnea-hypopnea-index and 6% exhibited features of an overlap parasomnia disorder. In our cohort, 73% reported CO-SW and 27% AO-SW. In subjects with AO-SW, positive family history for parasomnias was found in 33% (vs. 49% in CO-SW), neurological comorbidities in 44% (vs. 14%), psychiatric comorbidities in 25% (vs. 33%), EEG abnormalities in 50% (vs. 29%). Violence during SW episodes was more frequent in males and in subjects with CO-SW (45% for self-injury and 44% for violent behaviour vs. 33 and 29% respectively in the AO-SW group). CONCLUSIONS Adult SW represents a complex and potentially dangerous condition. The characteristics of AO-SW often differ from those of CO-SW.

BACKGROUND: Subthalamic nucleus (STN) stimulation has been recognized to control resting tremor in Parkinson disease. Similarly, thalamic stimulation (ventral intermediate nucleus; VIM) has shown tremor control in Parkinson disease, essential, and intention tremors. Recently, stimulation of the posterior subthalamic area (PSA) has been associated with excellent tremor control. Thus, the optimal site of stimulation may be located in the surrounding white matter. AIMS: The objective of this work was to investigate the area of stimulation by determining the contact location correlated with the best tremor control in STN/VIM patients. METHODS: The mean stimulation site and related volume of tissue activated (VTA) of 25 tremor patients (STN or VIM) were projected on the Morel atlas and compared to stimulation sites from other tremor studies. RESULTS: All patients showed a VTA that covered ≥50% of the area superior and medial to the STN or inferior to the VIM. Our stimulation areas suggest involvement of the more lateral and superior part of the dentato-rubro-thalamic tract (DRTT), whereas targets described in other studies seem to involve the DRTT in its more medial and inferior part when it crosses the PSA. CONCLUSIONS: According to anatomical and diffusion tensor imaging data, the DRTT might be the common structure stimulated at different portions within the PSA/caudal zona incerta.

Therapeutic angiogenesis with vascular endothelial growth factor (VEGF) is a clinically promising strategy in ischaemic disease. The pathophysiological consequences of enhanced vessel formation, however, are poorly understood. We established mice overexpressing human VEGF165 under a neuron-specific promoter, which exhibited an increased density of brain vessels under physiological conditions and enhanced angiogenesis after brain ischaemia. Following transient intraluminal middle cerebral artery (MCA) occlusions, VEGF overexpression significantly alleviated neurological deficits and infarct volume, and reduced disseminated neuronal injury and caspase-3 activity, confirming earlier observations that VEGF has neuroprotective properties. Brain swelling was not influenced in VEGF-overexpressing animals, while sodium fluorescein extravasation was moderately increased, suggesting that VEGF induces a mild blood-brain barrier leakage. To elucidate whether enhanced angiogenesis improves regional cerebral blood flow in the ischaemic brain, [14C]iodoantipyrine autoradiography was performed. Autoradiographies revealed that VEGF induces haemodynamic steal phenomena with reduced blood flow in ischaemic areas and increased flow values only outside the MCA territory. Our data demonstrate that VEGF protects neurons from ischaemic cell death by a direct action rather than by promoting angiogenesis, and suggest that strategies aiming at increasing vascular density in the whole brain, e.g. by VEGF overexpression, may worsen rather than improve cerebral haemodynamics after stroke

Sleep-wake disturbances (SWD) are common after traumatic brain injury (TBI). In acute TBI, we recently found decreased CSF levels of hypocretin-1, a wake-promoting neurotransmitter. In the present study, we aimed to delineate the frequency and clinical characteristics of post-traumatic SWD, to assess CSF hypocretin-1 levels 6 months after TBI, and to identify risk factors for posttraumatic SWD. A total of 96 consecutive patients were enrolled within the first 4 days after TBI. Six months later, out of 76 TBI patients, who did not die and who did not move to foreign countries, we included 65 patients (86%, 53 males, mean age 39 years) in our study. Patients were examined using interviews, questionnaires, clinical examinations, computed tomography of the brain, laboratory tests (including CSF hypocretin-1 levels, and HLA typing), conventional polysomnography, maintenance of wakefulness and multiple sleep latency tests (MSLT) and actigraphy. Potential causes of post-traumatic SWD were assessed according to international criteria. New-onset sleep-wake disturbances following TBI were found in 47 patients (72%): subjective excessive daytime sleepiness (EDS; defined by the Epworth Sleepiness Scale ≥10) was found in 18 (28%), objective EDS (as defined by mean sleep latency <5 min on MSLT) in 16 (25%), fatigue (daytime tiredness without signs of subjective or objective EDS) in 11 (17%), post-traumatic hypersomnia ‘sensu strictu' (increased sleep need of ≥2 h per 24 h compared to pre-TBI) in 14 (22%) patients and insomnia in 3 patients (5%). In 28 patients (43% of the study population), we could not identify a specific cause of the post-traumatic SWD other than TBI. Low CSF hypocretin-1 levels were found in 4 of 21 patients 6 months after TBI, as compared to 25 of 27 patients in the first days after TBI. Hypocretin levels 6 months after TBI were significantly lower in patients with post-traumatic EDS. There were no associations between post-traumatic SWD and severity or local

In a controlled, prospective, electrophysiological study, Imbach et al. demonstrate increased sleep need and excessive daytime sleepiness 6 months after traumatic brain injury. Sleep is more consolidated after brain trauma, and an increase in sleep need is associated with intracranial haemorrhage. Trauma patients underestimate their increased sleep need and sleepiness

Human narcolepsy with cataplexy is a neurological disorder, which develops due to a deficiency in hypocretin producing neurons in the hypothalamus. There is a strong association with human leucocyte antigens HLA-DR2 and HLA-DQB1*0602. The disease typically starts in adolescence. Recent developments in narcolepsy research support the hypothesis of narcolepsy being an immune-mediated disease. Narcolepsy is associated with polymorphisms of the genes encoding T cell receptor alpha chain, tumour necrosis factor alpha and tumour necrosis factor receptor II. Moreover the rate of streptococcal infection is increased at onset of narcolepsy. The hallmarks of anti-self reactions in the tissue—namely upregulation of major histocompatibility antigens and lymphocyte infiltrates—are missing in the hypothalamus. These findings are questionable because they were obtained by analyses performed many years after onset of disease. In some patients with narcolepsy autoantibodies to Tribbles homolog 2, which is expressed by hypocretin neurons, have been detected recently. Immune-mediated destruction of hypocretin producing neurons may be mediated by microglia/macrophages that become activated either by autoantigen specific CD4+ T cells or superantigen stimulated CD8+ T cells, or independent of T cells by activation of DQB1*0602 signalling. Activation of microglia and macrophages may lead to the release of neurotoxic molecules such as quinolinic acid, which has been shown to cause selective destruction of hypocretin neurons in the hypothalamus

Although generally considered as mutually exclusive, violence and sleep can coexist. Violence related to the sleep period is probably more frequent than generally assumed and can be observed in various conditions including parasomnias (such as arousal disorders and rapid eye movement sleep behaviour disorder), epilepsy (in particular nocturnal frontal lobe epilepsy) and psychiatric diseases (including delirium and dissociative states). Important advances in the fields of genetics, neuroimaging and behavioural neurology have expanded the understanding of the mechanisms underlying violence and its particular relation to sleep. The present review outlines the different sleep disorders associated with violence and aims at providing information on diagnosis, therapy and forensic issues. It also discusses current pathophysiological models, establishing a link between sleep-related violence and violence observed in other settings

Left-sided spatial neglect is a common neurological syndrome following right-hemispheric stroke. The presence of spatial neglect is a powerful predictor of poor rehabilitation outcome. In one influential account of spatial neglect, interhemispheric inhibition is impaired and leads to a pathological hyperactivity in the contralesional hemisphere, resulting in a biased attentional allocation towards the right hemifield. Inhibitory transcranial magnetic stimulation can reduce the hyperactivity of the contralesional, intact hemisphere and thereby improve spatial neglect symptoms. However, it is not known whether this improvement is also relevant to the activities of daily living during spontaneous behaviour. The primary aim of the present study was to investigate whether the repeated application of continuous theta burst stimulation trains could ameliorate spatial neglect on a quantitative measure of the activities of daily living during spontaneous behaviour. We applied the Catherine Bergego Scale, a standardized observation questionnaire that can validly and reliably detect the presence and severity of spatial neglect during the activities of daily living. Eight trains of continuous theta burst stimulation were applied over two consecutive days on the contralesional, left posterior parietal cortex in patients suffering from subacute left spatial neglect, in a randomized, double-blind, sham-controlled design, which also included a control group of neglect patients without stimulation. The results showed a 37% improvement in the spontaneous everyday behaviour of the neglect patients after the repeated application of continuous theta burst stimulation. Remarkably, the improvement persisted for at least 3 weeks after stimulation. The amelioration of spatial neglect symptoms in the activities of daily living was also generally accompanied by significantly better performance in the neuropsychological tests. No significant amelioration in symptoms was observed after sham sti

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.

Narcolepsy-cataplexy is a sleep-wake disorder and suggested to be immune-mediated, involving genetic and environmental factors. The autoimmune process eventually leads to a loss of hypocretin neurons in the lateral hypothalamus. Epidemiological studies in several countries proved an increased incidence of narcolepsy after H1N1 flu vaccination and infection. This survey in 30 sleep centers in Switzerland led to the identification of 9 H1N1-vaccinated children and adults as newly diagnosed narcolepsy. Clinical features included the abrupt and severe onset of sleepiness, cataplexy and sleep fragmentation.