Search Results (6)

Narcolepsy type 1 (NT1) is an uncommon, persistent sleep disorder distinguished by significant daytime sleepiness, episodes of cataplexy, and irregularities in rapid eye movement sleep. The etiology of NT1 is linked to the destruction of hypothalamic neurons responsible for the synthesis of the wake-promoting neuropeptide known as hypothalamic orexin. The pathophysiological mechanisms underlying NT1 remain inadequately elucidated; however, a model that incorporates the interplay of genetic predisposition, environmental influences, immune system factors, and a deficiency in hypocretin (HCRT) provides a framework for elucidating the pathogenesis of NT1. The prevalence of NT1 has been observed to rise following influenza A (H1N1) pdm09 and the administration of the Pandemrix influenza vaccine. The strong association between narcolepsy and the HLA-DQB1*06:02 allele strongly indicates an autoimmune etiology for this condition. Increasing evidence suggests that T cells play a critical role in this autoimmune-mediated HCRT neuronal loss. Studies have identified specific T cell subsets, including CD4⁺ and CD8⁺ T cells, that target HCRT neurons, contributing to their destruction. Clarifying the pathogenesis of NT1 driven by autoimmune T cells is crucial for the development of effective therapeutic interventions for this disorder. This review examines the risk factors associated with the pathogenesis of NT1, explores the role of T cells within the immune system in the progression of NT1, and evaluates immune-mediated animal models alongside prospective immunotherapeutic strategies. Full article

Nearly 25 years have passed since the ground-breaking discovery that hypocretin deficiency underlies human narcolepsy with cataplexy. Over time, it has become increasingly evident that hypocretin deficiency goes beyond the conventional core symptoms, or pentad, traditionally associated with narcolepsy. The emergence of hypocretin receptor 2 agonists presents an exciting opportunity, prompting us to explore the role of receptor 2 in the complete spectrum of NT1 symptoms. In this review, several clinical manifestations beyond the core symptoms will be discussed. We will outline what is currently known about the involvement of hypocretin receptors to reflect on what we expect with current knowledge from treatment with specific receptor agonists. Full article

Narcolepsy type 1 (NT1), a central disorder of hypersomnolence, is associated with mood, anxiety or hyperactivity mental disorders. Association with psychotic episode or schizophrenia is rare and could be the source of diagnostic and therapeutic difficulties. Their frequency in the national narcolepsy database has not been systematically studied. The aim of the presented study was to calculate the frequency of NT1 patients diagnosed with psychosis and/or schizophrenia, to identify clinical characteristics of these cases, and to look for narcoleptic and psychotic symptoms during re-evaluation years later. We identified three (4%) cases diagnosed with a psychotic episode in the course of NT1. They were diagnosed with NT1 by age ≤18 years. In the re-evaluation (mean follow-up 9.8 years), we identified one case with a dual diagnosis of NT1 and schizophrenia; two cases were diagnosed with a solitary psychotic episode in the course of NT1. NT1 patients diagnosed in the age ≤18 years are at higher risk of psychotic episode, and this may be related to higher vulnerability during the ongoing neurodevelopmental period. Comorbid schizophrenia with NT1 in the Slovakian Narcolepsy Database was within the prevalence expected in the general population. The solitary psychotic episode in the course of NT1 did not reduce the possibility of subsequent symptomatic treatment afterwards. Full article

Introduction: Narcolepsy is a chronic neurological sleep disorder, the diagnosis of which is based upon clinical evaluation and additional paraclinical assessments. Awareness of narcolepsy is low and screening tools needed. The Epworth Sleepiness Scale (ESS), the Ullanlinna Narcolepsy Scale (UNS), and more recently the Swiss Narcolepsy Scale (SNS) were used as screening tools for narcolepsy. The aims of the present study are (1) to assess the value of the SNS in a new series of patients with narcolepsy with cataplexy (NC), and (2) to compare its sensitivity and specificity with the ESS and UNS. Patients and Methods: We prospectively assessed by questionnaire patients with NC (n = 80, all with assessment of cerebrospinal fluid (CSF) hypocretin-1 levels) and patients with excessive daytime sleepiness (EDS) of other origin (n = 111) in Zurich and Leiden. Causes of EDS included idiopathic hypersomnia (n = 12), behaviorally induced sleep insufficiency syndrome (n = 32), restless legs syndrome (n = 7), sleep-disordered breathing (n = 22), and hypersomnia due to medical disorders (n = 9). Diagnoses were made according to the International Classification of Sleep Disorders (third edition). Cutoff values of UNS and SNS for diagnosis of narcolepsy were those suggested in the literature. Results: For the diagnosis of narcolepsy, the following sensitivities and specificities were found: SNS (89% and 88%), UNS (100% and 62%), and ESS (91% and 54%). For the diagnosis of narcolepsy with low or non-detectable CSF hypocretin-1, the sensitivities and specificities were: SNS (93% and 88%), UNS (100% and 62%), and ESS (93% and 54%). Discussion: In conclusion, the SNS is accurate and superior to the ESS and the UNS for the screening/diagnosis of NC and allows, in addition, the identification of hypocretin-1 deficient patients. Full article

Narcolepsy type 1 (NT1) and, to a lesser extent, neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies and multiple system atrophy, entail the loss of the hypothalamic neurons that release the hypocretin/orexin (H/O) neuropeptides. NT1 has been associated with autonomic anomalies including alterations in temperature regulation and cardiovascular control, particularly during sleep. A spectrum of autonomic dysfunctions also characterizes neurodegenerative diseases. The central autonomic network (CAN) is an interconnected set of brain structures that are critical for the control of autonomic preganglionic neurons. The H/O neurons include pre-autonomic neurons that directly target preganglionic sympathetic neurons in the intermediolateral column of the spinal cord and parasympathetic neurons in the dorsal motor nucleus of the vagus nerve. The H/O neurons also project to and modulate the activity of other CAN structures that include pre-autonomic neurons, such as the rostral ventromedial medulla and caudal raphe nuclei, the rostral ventrolateral medulla and the hypothalamic paraventricular nucleus. In addition, the H/O neurons project to and modulate the activity of neurons in the nucleus of the solitary tract in the medulla, which receives and relays visceral afferent information, and in higher order structures of the CAN, such as the dorsomedial nucleus of the hypothalamus and the extended amygdala. The H/O neurons should, therefore, be regarded as a key component of the CAN. Functional alterations of the CAN due to H/O neuron deficiency might contribute to autonomic anomalies in patients with neurodegenerative diseases and are likely to underlie autonomic anomalies in patients with NT1. Full article

Orexins/hypocretins are neuropeptides formed by proteolytic cleavage of a precursor peptide, which are produced by neurons found in the lateral hypothalamus. The G protein-coupled receptors (GPCRs) for these ligands, the OX₁ and OX₂ orexin receptors, are more widely expressed throughout the central nervous system. The orexin/hypocretin system has been implicated in many pathways, and its dysregulation is under investigation in a number of diseases. Disorders in which orexinergic mechanisms are being investigated include narcolepsy, idiopathic sleep disorders, cluster headache and migraine. Human narcolepsy has been associated with orexin deficiency; however, it has only rarely been attributed to mutations in the gene encoding the precursor peptide. While gene variations within the canine OX₂ gene hcrtr2 have been directly linked with narcolepsy, the majority of human orexin receptor variants are weakly associated with diseases (the idiopathic sleep disorders, cluster headache and polydipsia-hyponatremia in schizophrenia) or are of potential pharmacogenetic significance. Evidence for functional and/or heterodimerization between wild-type variant orexin receptors and opioid and cannabinoid receptors is discussed in the context of its relevance to depression and epilepsy. Full article