Narcolepsy type 1 (NT1) is a chronic sleep disorder correlated with loss of hypocretin(orexin). In NT1 post-mortem brains, we observed 88% reduction in corticotropin-releasing hormone (CRH)-positive neurons in the paraventricular nucleus (PVN) and significantly less CRH-positive fibers in the median eminence, while CRH-neurons in the locus coeruleus and thalamus, and other PVN neuronal populations were spared: i.e. vasopressin, oxytocin, tyrosine hydroxylase and thyrotropin releasing hormone-expressing neurons. Other hypothalamic cell groups, i.e. the suprachiasmatic, ventrolateral preoptic, infundibular and supraoptic nuclei and nucleus basalis of Meynert were unaffected. The surprising selective decrease in CRH-neurons provide novel targets for diagnostics and therapeutic interventions.

Excessive daytime sleepiness (EDS) is one of the commonest symptoms in neurological diseases and could impact on the quality of life by increasing the risk of accidents and generally affecting daily life activities. In this review, we will discuss the variety of causes responsible for EDS in neurological diseases: primary sleep disorders including obstructive sleep apnea-hypopnea syndrome,(OSA),circadian rhythms disorders, Restless leg syndrome  (RLS),periodic limb movement disorder (PLMD),CNS pathological abnormalities in arousal/sleep regulation systems, drugs, and comorbid psychiatric disorder. Among neurological diseases, Stroke, Epilepsy, Dementia, Parkinson disease, Multiple sclerosis, and  Encephalitis; represented a model for these interactions between EDS and neurological diseases.An individualized approach to this symptom in neurological patients should be considered with a focus on the location and nature of lesions. When considering EDS in neurological diseases, close attention to lifestyle and sleep hygiene is advisable. Precise diagnosis and treatment of EDS in neurological disease should be always considered.

Diagnosis and Biomarkers of Central disorders of Hypersomnolence

Jiyou Tang

The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong, China

Central disorders of Hypersomnolence are a class of sleep spectrum disorders, which is mainly characterized by excessive daytime sleepiness (EDS). Due to the few clinical biomarkers, the diagnosis of EDS requires a combination of comprehensive and personalized evaluation thread and principles. Hence on the basis of scaling qualitative assessment and electrophysiological quantitative diagnosis as well as disease classification, it is potential to find and use intuitive and specific biomarkers to increase the diagnostic accuracy, such as Orexin, melatonin, HLA and brain function imaging, etc.

Psychostimulants such as caffeine and amphetamine constitute the first generation of wake-promoting compounds. Their use and abuse cause well-known medico-social problems e.g., behavioral overexcitation, addiction and cognitive declines. Sleep medicine had long been looking for an awakening pill with preserved cognitive abilities. In the 1980’s, the discovery of modafinil (2nd generation) and its property of enhancing quiet waking in cats through multiple brain targets allows for the first time a successful therapy of hypersomniac symptoms and excessive sleepiness of diverse origins. Yet, it has a limited effect on cataplexy of narcolepsy with 15-25% of patients unresponsive. Ligands acting on specific brain targets are still in high demand in sleep medicine. The wake-promoting histaminergic neurons control their own release, synthesis and activity through a negative feedback on H3-receptors whose inverse agonists have long been known for their wake enhancement in animals. Yet, a clinically-suitable ligand, Pitolisant (必妥利生), has only recently become available, representing the third generation of wake-promoting compounds. This presentation reviews the three generations of wake-promoting therapies with focus on the discovery, mechanisms of action and clinical use of the histamine H3-receptor inverse agonist Pitolisant (必妥利生) and on the pespectives of sleep disorder therapies.

Neuroimaging studies have provided new information about brain abnormalities in narcolepsy patients to explore the pathologic mechanism of through non-invasive research. The main techniques include structural, functional and neurochemical imaging. Recent studies have found that the structural and functional abnormalities located in Hypothalamic secretin neuron projection system, brainstem reticular ascending activating system, emotion-related limbic system and attentional cognitive cortices, which provided important evidence for the changes of neural structure and pathophysiological mechanism of clinical features in narcolepsy.

Kleine-Levin syndrome (KLS) is a rare disorder characterized by discrete episodes of hypersomnia associated with cognitive and behavioral abnormalities. KLS is more typically seen in adolescence than at other ages, and is more common in males than in females. The etiology, pathophysiology, and optimal management of KLS remain uncertain. The significant body of published literature allows consideration of possible aetiological mechanisms, an understanding of which could guide the development of therapeutic strategies. In the last few years advanced neurophysiological and sophisticated neuroimaging methods enabled to expand our knowledge on possible pathophysiological mechanisms which may be playing a role in KLS and establish a laboratory basis for its complex symptomatology. Functional neuroimaging in KLS have evidenced involvement of frontotemporal, thalamocortical and brain stem networks. Although diencephalic abnormalities are a common finding, no consistent pattern has emerged, and these studies have not revealed the mechanism(s) underlying the development of the abnormalities detected. There are currently neither standard biomarkers nor specific imaging study findings, making the diagnosis of KLS a challenge. Further, multimodal functional imaging and new biomarkers are probably necessary to inquire into the KLS pathology.