Symptoms of the central disorders of hypersomnolence extend beyond excessive daytime sleepiness to include non-restorative sleep, fatigue and cognitive dysfunction. They share much in common with myalgic encephalomyelitis/chronic fatigue syndrome, recently renamed systemic exertion intolerance disease, whose additional features include post-exertional malaise and orthostatic intolerance. We sought to determine the frequency and correlates of systemic exertion intolerance disease in a hypersomnolent population. One-hundred and eighty-seven hypersomnolent patients completed questionnaires regarding sleepiness and fatigue; questionnaires and clinical records were used to assess for systemic exertion intolerance disease. Sleep studies, hypocretin and cataplexy were additionally used to assign diagnoses of hypersomnolence disorders or sleep apnea. Included diagnoses were idiopathic hypersomnia (n = 63), narcolepsy type 2 (n = 25), persistent sleepiness after obstructive sleep apnea treatment (n = 25), short habitual sleep duration (n = 41), and sleepiness with normal sleep study (n = 33). Twenty-one percent met systemic exertion intolerance disease criteria, and the frequency of systemic exertion intolerance disease was not different across sleep diagnoses (p = .37). Patients with systemic exertion intolerance disease were no different from those without this diagnosis by gender, age, Epworth Sleepiness Scale, depressive symptoms, or sleep study parameters. The whole cohort reported substantial fatigue on questionnaires, but the systemic exertion intolerance disease group exhibited more profound fatigue and was less likely to respond to traditional wake-promoting agents (88.6% versus 67.7%, p = .01). Systemic exertion intolerance disease appears to be a common co-morbidity in patients with hypersomnolence, which is not specific to hypersomnolence subtype but may portend a poorer prognosis for treatment response.

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Introduction Cytokines are known for their role in inflammation, and more recently in sleepiness and fatigue. There is a paucity of data regarding cytokines in Idiopathic Hypersomnia (IH) and Narcolepsy Type 2 (NT2) as defined by the International Classifications of Sleep Disorders-Third Edition. Additionally the heterogenous cohort of patients with excessive daytime sleepiness (EDS), but do not meet criteria for a sleep disorder, has not been studied separately from IH patients. Methods The study cohort was a convenience sample evaluated at a single tertiary-care sleep center between 2016 and 2019. Diagnoses were IH, NT2, EDS, and controls (based on sleep laboratory testing). The following cytokines were measured using the Mesoscale U-PLEX biomarker assay: G-CSF, IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, MCP-1, and TNF-α. Demographic data and survey data pertaining to sleepiness, depression, and sleep inertia were available for all. Results The study cohort consisted of 22 controls, 26 patients with EDS, 51 patients with IH, and 12 patients with NT2. There were no significant differences between diagnosis and any cytokine. Pearson correlations showed significant negative correlations between G-CSF concentrations with depression (p=0.05) and sleep inertia (p<0.01) in patients but not controls. In controls, hours slept per week positively correlated with G-CSF (p=0.05), but this was not true in patients with EDS, IH, or NT2. IL-8 level was negatively correlated with reported sleep inertia in sleepy patients (p=0.05), but not controls. Conclusion Though differences in cytokines levels between diagnostic groups did not reach significance, several cytokines correlated with severity of reported symptoms in disorders of hypersomnolence. G-CSF and IL-8 may serve as a biomarker for symptoms of depression and sleep inertia in sleepiness disorders, and thus could be a targeted for therapies. Support (if any) Hypersomnia Foundation Grant

The central disorders of hypersomnolence (CDH) are lifelong conditions that cause an irrepressible need for sleep during waking hours. Some of these disorders are due to medications or other conditions, but narcolepsy type 1 (NT1), narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH) occur as primary conditions. In each disorder excessive daytime sleepiness (EDS) may be accompanied by ancillary features such as sleep paralysis, hypnagogic/hypnopompic hallucinations, sleep drunkenness, or, in the case of NT1, cataplexy. Polysomnography and a multiple sleep latency test are used for diagnosis. Diagnostic lumbar puncture may be performed to differentiate NT1 from NT2. Although the mainstay of treatment for CDH is currently pharmacotherapy, management may also involve behavioral approaches such as sleep and nap scheduling, dietary modifications, and cognitive-behavioral therapy. Pharmacologic treatment can include traditional medications such as modafinil, methylphenidate, or sodium oxybate. Novel therapeutic agents such as pitolisant, clarithromycin, flumazenil, and melatonin may be useful in relieving EDS and associated symptoms.