The autoimmune hypothesis of narcolepsy and its unexplored clinical features

The mechanisms involved in the autoimmune hypothesis of narcolepsy are investigated in this thesis. The role of HLA, auto- and cross-reactive T cells is explored and immune cell populations of interest are identified by a new technique, called mass cytometry. The second part of the thesis assesses unexplored clinical features of narcolepsy, such as weight gain and sleep state misperception.Bioprojet (kosten drukken proefschrift); SEIN (Stichting Epilepsie Instellingen Nederland); NSWO; SVNLLUMC / Geneeskund

H1N1 hemagglutinin-specific HLA-DQ6-restricted CD4+ T cells can be readily detected in narcolepsy type 1 patients and healthy controls

Following the 2009 H1N1 influenza pandemic, an increased risk of narcolepsy type 1 was observed. Homology between an H1N1 hemagglutinin and two hypocretin sequences has been reported. T cell reactivity to these peptides was assessed in 81 narcolepsy type 1 patients and 19 HLA-DQ6-matched healthy controls. HLA-DQ6-restricted H1N1 hemagglutinin-specific T cell responses were detected in 28.4% of patients and 15.8% of controls. Despite structural homology between HLA-DQ6-hypocretin and -H1N1 peptide complexes, T cell cross-reactivity was not detected. These results indicate that it is unlikely that cross-reactivity between H1N1 hemagglutinin and hypocretin peptides presented by HLA-DQ6 is involved in the development of narcolepsy

The autoimmune hypothesis of narcolepsy and its unexplored clinical features

The mechanisms involved in the autoimmune hypothesis of narcolepsy are investigated in this thesis. The role of HLA, auto- and cross-reactive T cells is explored and immune cell populations of interest are identified by a new technique, called mass cytometry. The second part of the thesis assesses unexplored clinical features of narcolepsy, such as weight gain and sleep state misperception.</table

The development of hypocretin deficiency in narcolepsy type 1 can be swift and closely linked to symptom onset: clues from a singular case

Paroxysmal Cerebral Disorder

Daytime sleep state misperception in a tertiary sleep centre population

Study objectives: Sleep state misperception is common in various sleep disorders, especially in chronic insomnia with a prevalence ranging between 9-50%. Most prior studies used nocturnal polysomnography (PSG) for the identification of sleep state misperception during nighttime. Our objective was to assess sleep state misperception during daytime in people with sleep disorders with excessive daytime sleepiness (EDS).Methods: In this prospective observational study, we assessed the occurrence of, and factors influencing sleep state misperception in consecutive patients undergoing a routine multiple sleep latency test (MSLT) in a tertiary sleep-wake centre included between 2014 and 2017. Mixed models were applied to assess the influence of patients' clinical data on sleep state perception.Results: People with narcolepsy type 1 (NT1, n = 33) and type 2 (NT2, n = 14), idiopathic hypersomnia (IH, n = 56), obstructive sleep apnea (OSA, n = 31) and insufficient sleep syndrome (ISS, n = 31) were included. The prevalence of both classical and reverse sleep state misperception did not differ between the sleep disorders (mean 25%, range 8-37%) after correction for sleep stage, sleep onset latency and age. Longer sleep onset latency and reaching only non-rapid eye movement (REM) sleep stage 1 were significant predictors for classical sleep state misperception.Conclusions: Sleep state misperception is common in people with NT1 and NT2, IH, OSA, and ISS. Classical sleep state misperception is more frequent in patients with longer sleep onset latencies who only reach non-REM sleep stage 1 during a nap. (C) 2020 Elsevier B.V. All rights reserved.Paroxysmal Cerebral Disorder

Role of Brown Adipose Tissue in Adiposity Associated With Narcolepsy Type 1

Narcolepsy type 1 is a neurological sleep-wake disorder caused by the destruction of orexin (hypocretin)-producing neurons. These neurons are particularly located in the lateral hypothalamus and have widespread projections throughout the brain, where they are involved, e.g., in the regulation of the sleep-wake cycle and appetite. Interestingly, a higher prevalence of obesity has been reported in patients with narcolepsy type 1 compared to healthy controls, despite a normal to decreased food intake and comparable physical activity. This suggests the involvement of tissues implicated in total energy expenditure, including skeletal muscle, liver, white adipose tissue (WAT), and brown adipose tissue (BAT). Recent evidence from pre-clinical studies with orexin knock-out mice demonstrates a crucial role for the orexin system in the functionality of brown adipose tissue (BAT), probably through multiple pathways. Since BAT is a highly metabolically active organ that combusts fatty acids and glucose toward heat, thereby contributing to energy metabolism, this raises the question of whether BAT plays a role in the development of obesity and related metabolic diseases in narcolepsy type 1. BAT is densely innervated by the sympathetic nervous system that activates BAT, for instance, following cold exposure. The sympathetic outflow toward BAT is mainly mediated by the dorsomedial, ventromedial, arcuate, and paraventricular nuclei in the hypothalamus. This review focuses on the current knowledge on the role of the orexin system in the control of energy balance, with specific focus on BAT metabolism and adiposity in both preclinical and clinical studies.Paroxysmal Cerebral Disorder

Warm ears, a red flag for sleepiness?

Core body and skin temperatures are intimately linked to sleep and alertness. The distal-to-proximal skin temperature gradient has been described as a good physiological predictor for sleep onset. Increased ear skin temperature is often caused by increased blood flow reflected in redness, which is commonly noticed in people who are sleepy, especially anecdotally in children. Nonetheless, no prior study investigated the possible relation between sleepiness and ear skin temperature as a separate measurement. We assessed the relation between ear skin temperature and sleepiness in patients undergoing regular electroencephalographic examinations, because of suspicion of epilepsy, both without and after sleep deprivation. Subjective sleepiness was measured using the Stanford Sleepiness Scale, and objective sleepiness by determining sleep onset with electroencephalography. Distal, proximal and ear skin temperature were measured repeatedly using wireless measurement devices (iButtons). Forty-four adult patients were included. Ear skin temperature correlates weakly with distal skin temperature (r = 0.174, p < 0.001) and distal-to-proximal gradient (r = 0.160, p < 0.001), but not with proximal skin temperature (r = -0.001, p = 0.975). Ear skin temperature increased significantly in a subgroup of 13 patients, between 5 and 1 min before sleep onset (p = 0.002; eta(2) = 0.059), even though this increase was also associated with supine posture. iButtons is a valid method to measure ear skin temperature, which appears to function partly like a distal and partly like a proximal skin temperature measurement. Change in ear skin temperature is associated with sleep onset and supine posture.Paroxysmal Cerebral Disorder

Standard radiotherapy but not chemotherapy impairs systemic immunity in non-small cell lung cancer

Pathogenesis and treatment of chronic pulmonary disease

Endosonography for lung cancer staging: predictors for false-negative outcomes

Development and application of statistical models for medical scientific researc

Good night and good luck: sleep n the ICU

Sleep in the ICU is poor and improving sleep proves to be challenging. However, clinical trials on the use of pharmacological and non-pharmacological interventions to improve sleep in the ICU are scarce. The few clinical trials that have been performed are hampered by difficulty in obtaining reliable objective sleep measurements in the ICU environment. Therefore, firm evidence on the effect of all commonly used interventions is limited. Strategies to decrease noise and light exposure seem promising, since pilot studies and small clinical trials suggest that implementation is feasible and most interventions are low-cost. Standardisation of sleep-promoting protocols might lead to a possibility of performing multicentre trials that can provide much needed evidence on the efficacy of non-pharmacological interventions to improve sleep in the ICU. Although many different medications are used to improve sleep in the ICU, there is insufficient evidence in the literature to support the use of any of them to effectively improve sleep. The use of benzodiazepines is not recommended based on the lack of evidence for their efficacy and the association with increased risk of delirium. Emphasis on non-pharmacological sleep-promoting measures before prescribing medication is warranted, as it is currently not clear to what extent prescribing sleep-promoting medications is actually beneficial to ICU patients. Clinical trials on existing pharmacological options and expanding treatment options by considering sodium oxybate or suvorexant are logical future directions to improve the treatment of sleep problems in the ICU.Paroxysmal Cerebral Disorder