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Background and Objective: Although there are several treatments for narcolepsy type 2 and idiopathic hypersomnia, studies that assess amphetamines, symptoms beyond sleepiness, and comparative effectiveness are needed. We performed a randomized, fully blinded, noninferiority trial of modafinil versus amphetamine-dextroamphetamine in these disorders., Methods: Forty-four adults were randomized to modafinil or amphetamine-dextroamphetamine, individually titrated to a maximum of modafinil 200 mg twice daily or amphetamine-dextroamphetamine 20 mg twice daily, for 12 weeks. Primary outcome was change in Epworth from baseline to week 12, with a noninferiority threshold of 2 points. Secondary outcomes were (1) patient global impression of change measures of disease severity, sleepiness, sleep inertia, and cognition; (2) change from baseline in Hypersomnia Severity Index; and (3) change from baseline in Sleep Inertia Questionnaire. Adverse events were compared between groups., Results: Epworth improved 5.0 [± standard deviation (SD) 2.7] points with modafinil and 4.4 (± SD 4.7) with amphetamine-dextroamphetamine; noninferiority of amphetamine-dextroamphetamine was not demonstrated (P = 0.11). Noninferiority of amphetamine-dextroamphetamine was demonstrated for change scores of severity, sleepiness, sleep inertia, Hypersomnia Severity Index, and Sleep Inertia Questionnaire. Dropouts due to adverse events were 31.8% for modafinil (including two severe events) and 9.1% for amphetamine-dextroamphetamine, P = 0.13. Anxiety was more common with modafinil and appetite suppression with amphetamine-dextroamphetamine., Conclusion: Noninferiority of amphetamine-dextroamphetamine to modafinil was not demonstrated for the primary outcome. However, amphetamine-dextroamphetamine was noninferior on multiple secondary measures of disease severity and symptomatology. These data may inform shared decision-making regarding treatment for idiopathic hypersomnia and narcolepsy type 2., Registration: Clinicaltrials.gov Registration (NCT03772314) 12/10/18. ., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Optimal measurement tools for problematic sleep inertia, common in some central disorders of hypersomnolence (CDH), have not yet been determined. We evaluated the performance of the Sleep Inertia Questionnaire (SIQ) in CDH, and how well it distinguished hypersomnolent groups from controls, and IH (idiopathic hypersomnia) from narcolepsy type 1 (NT1)., Methods: This prospective, bi-centric study included 63 control, 84 IH, 16 NT1, 18 narcolepsy type 2 (NT2), and 88 subjective excessive daytime sleepiness (sEDS) participants, using ICSD-3 criteria. 126 (47.2 %) participants were on any medication at the time of SIQ completion. We assessed construct validity of SIQ scores, and sleep inertia duration (SID), and compared them across diagnoses, controlling for age and center. We derived cutpoints to distinguish hypersomnolent patients from controls and IH from NT1. Sensitivity analyses for depression, chronotype, and medication were performed., Results: The SIQ sum and composite score were significantly lower in controls than in other groups (p < 0.0001), demonstrating outstanding ability to distinguish patients from controls (AUCs 0.92), without differences among hypersomnolent groups. SID (AUC 0.76) was significantly shorter in controls than in all hypersomnolent groups except NT1, and was shorter in NT1 than in IH or sEDS. Optimal SIQ sum cutpoint was 42 (J = 0.71) for patients versus controls. Optimal SID cutpoint in distinguishing IH from NT1 was 25 min (J = 0.39)., Conclusion: The SIQ has excellent ability to distinguish hypersomnolent patients from healthy controls, after controlling for depression, eveningness, and medication. SID is best at distinguishing IH from NT1., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Lynn Marie Trotti reports financial support was provided by National Institutes of Health. David T. Plante reports financial support was provided by American Academy of Sleep Medicine Foundation. Dr. Lynn Marie Trotti reports a relationship with American Academy of Sleep Medicine Foundation that includes: board membership and funding grants. Lynn Marie Trotti reports a relationship with American Academy of Sleep Medicine that includes: board membership, speaking and lecture fees, and travel reimbursement. Lynn Marie Trotti reports a relationship with American Board of Sleep Medicine that includes: board membership. Lynn Marie Trotti reports a relationship with Sleep Research Society that includes: speaking and lecture fees. Lynn Marie Trotti reports a relationship with CHEST that includes: speaking and lecture fees and travel reimbursement. Lynn Marie Trotti reports a relationship with Haymarket Medical Education that includes: speaking and lecture fees and travel reimbursement. Lynn Marie Trotti reports a relationship with Per CME that includes: speaking and lecture fees and travel reimbursement. Lynn Marie Trotti reports a relationship with Efficient CME that includes: speaking and lecture fees. Lynn Marie Trotti reports a relationship with Clinical Care Options LLC that includes: speaking and lecture fees and travel reimbursement. David T. Plante reports a relationship with National Institutes of Health that includes: funding grants. David T. Plante reports a relationship with Wisconsin Alumni Research Foundation Inc that includes: funding grants. David T. Plante reports a relationship with Harmony Biosciences that includes: consulting or advisory and funding grants. David T. Plante reports a relationship with Alzheimer's Association that includes: funding grants. David T. Plante reports a relationship with Jazz Pharmaceuticals Inc that includes: consulting or advisory. David T. Plante reports a relationship with Aditium Biosci that includes: consulting or advisory. David T. Plante reports a relationship with Alkermes that includes: consulting or advisory. David T. Plante reports a relationship with Teva Pharmaceutical Australia that includes: consulting or advisory. David T. Plante reports a relationship with American Academy of Sleep Medicine that includes: speaking and lecture fees. David Rye reports a relationship with National Institutes of Health that includes: funding grants. David T. Plante reports a relationship with NextSense that includes: funding grants. David Rye reports a relationship with Jazz Pharmaceuticals Inc that includes: consulting or advisory. David Rye reports a relationship with Takeda that includes: consulting or advisory. Ana Maria Vascan reports a relationship with National Institutes of Health that includes: funding grants. Ana Maria Vascan reports a relationship with Wisconsin Alumni Research Foundation Inc that includes: funding grants. Ana Maria Vascan reports a relationship with NASA that includes: funding grants. Prabhjyot Saini reports a relationship with NextSense that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. Royalty from Cambridge University Press to David T. Plante. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Study Objectives: The central disorders of hypersomnolence (CDH) manifest with daytime sleepiness, often accompanied by cognitive symptoms. Objective tests characterizing cognitive dysfunction may have diagnostic utility. Further, because some people with CDH report worsening cognition upon awakening, cognitive testing before and after napping may provide additional diagnostic information., Methods: Patients with CDH with idiopathic hypersomnia (n = 76), narcolepsy type 1 (n = 19), narcolepsy type 2 (n = 22), and self-reported excessive daytime sleepiness not meeting current diagnostic criteria (n = 76) and nonsleepy controls (n = 33) underwent testing with the Psychomotor Vigilance Test (PVT), a 10-minute reaction-time test. A subset of participants underwent repeat testing during a Multiple Sleep Latency Test, before and immediately after naps 2 and 4., Results: Most PVT metrics were significantly better in controls than in patients with CDH. Minimal group differences in PVT performance were observed by CDH diagnosis. PVT performance was weakly correlated to Epworth Sleepiness Scale and Multiple Sleep Latency Test mean sleep latency in the CDH group. Before and after naps, PVT metrics were minimally different for controls, while PVT performance generally worsened following naps in the CDH group, with significant worsening compared with controls for nap 2 mean, median, lapses, and fastest 10% of responses and nap 4 lapses and slowest 10% of responses. Change in performance did not differ based on CDH diagnostic group for any metric on either nap., Conclusions: The PVT, at baseline and following a short nap, may provide adjunctive diagnostic utility in separating individuals with CDH from controls., Citation: Trotti LM, Saini P, Bremer E, et al. The Psychomotor Vigilance Test as a measure of alertness and sleep inertia in people with central disorders of hypersomnolence. J Clin Sleep Med . 2022;18(5):1395-1403., (© 2022 American Academy of Sleep Medicine.)

Study Objectives: Daytime sleepiness is a manifestation of multiple sleep and neurologic disorders. Few studies have assessed patterns of regional brain metabolism across different disorders of excessive daytime sleepiness. One such disorder, idiopathic hypersomnia (IH), is particularly understudied., Methods: People with IH, narcolepsy (NT1), and non-sleepy controls underwent [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) with electroencephalography (EEG). Participants were instructed to resist sleep and were awoken if sleep occurred. Voxel-wise parametric analysis identified clusters that significantly differed between each pair of groups, with a minimum cluster size of 100 voxels at a cluster detection threshold of p < 0.005. Correlations between glucose metabolism and sleep characteristics were evaluated., Results: Participants (77% women) had IH (n = 16), NT1 (n = 14), or were non-sleepy controls (n = 9), whose average age was 33.8 (±10.7) years. Compared to controls, NT1 participants demonstrated hypermetabolism in fusiform gyrus, middle occipital gyrus, superior and middle temporal gyri, insula, cuneus, precuneus, pre- and post-central gyri, and culmen. Compared to controls, IH participants also demonstrated hypermetabolism in precuneus, inferior parietal lobule, superior and middle temporal gyri, and culmen. Additionally, IH participants demonstrated altered metabolism of the posterior cingulate. Most participants fell asleep. Minutes of N1 during uptake was significantly negatively correlated with metabolism of the middle temporal gyrus., Conclusion: NT1 and IH demonstrate somewhat overlapping, but distinct, patterns of regional metabolism., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The hypothalamic peptide hypocretin 1 (orexin A) may be assayed in cerebrospinal fluid to diagnose narcolepsy type 1. This testing is not commercially available, and factors contributing to assay variability have not previously been comprehensively explored. In the present study, cerebrospinal fluid hypocretin concentrations were determined in duplicate in 155 patient samples, across a range of sleep disorders. Intra-assay variability of these measures was analyzed. Inter-assay correlation between samples tested at Emory and at Stanford was high (r = 0.79, p < 0.0001). Intra-assay correlation between samples tested in duplicate in our center was also high (r = 0.88, p < 0.0001); intra-assay variability, expressed as the difference between values as a percentage of the higher value, was low at 9.4% (SD = 7.9%). Although both time the sample spent in the freezer (r = 0.16, p = 0.04) and age of the kit used for assay (t = 3.64, p = 0.0004) were significant predictors of intra-kit variability in univariate analyses, only age of kit was significant in multivariate linear regression (F = 4.93, p = 0.03). Age of radioimmunoassay kit affects intra-kit variability of measured hypocretin values, such that kits closer to expiration exhibit significantly more variability.

Study Objectives: Differentiation of narcolepsy without cataplexy from idiopathic hypersomnia relies entirely upon the multiple sleep latency test (MSLT). However, the test-retest reliability for these central nervous system hypersomnias has never been determined., Methods: Patients with narcolepsy without cataplexy, idiopathic hypersomnia, and physiologic hypersomnia who underwent two diagnostic multiple sleep latency tests were identified retrospectively. Correlations between the mean sleep latencies on the two studies were evaluated, and we probed for demographic and clinical features associated with reproducibility versus change in diagnosis., Results: Thirty-six patients (58% women, mean age 34 years) were included. Inter -test interval was 4.2 ± 3.8 years (range 2.5 months to 16.9 years). Mean sleep latencies on the first and second tests were 5.5 (± 3.7 SD) and 7.3 (± 3.9) minutes, respectively, with no significant correlation (r = 0.17, p = 0.31). A change in diagnosis occurred in 53% of patients, and was accounted for by a difference in the mean sleep latency (N = 15, 42%) or the number of sleep onset REM periods (N = 11, 31%). The only feature predictive of a diagnosis change was a history of hypnagogic or hypnopompic hallucinations., Conclusions: The multiple sleep latency test demonstrates poor test-retest reliability in a clinical population of patients with central nervous system hypersomnia evaluated in a tertiary referral center. Alternative diagnostic tools are needed.

Background: Previous studies have demonstrated both clinical and neurochemical similarities between Parkinson's disease (PD) and narcolepsy. The intrusion of REM sleep into the daytime remains a cardinal feature of narcolepsy, but the importance of these intrusions in PD remains unclear. In this study we examined REM sleep during daytime Maintenance of Wakefulness Testing (MWT) in PD patients., Methods: Patients spent 2 consecutive nights and days in the sleep laboratory. During the daytime, we employed a modified MWT procedure in which each daytime nap opportunity (4 per day) was extended to 40 min, regardless of whether the patient was able to sleep or how much the patient slept. We examined each nap opportunity for the presence of REM sleep and time to fall asleep., Results: Eleven of 63 PD patients studied showed 2 or more REM episodes and 10 showed 1 REM episode on their daytime MWTs. Nocturnal sleep characteristics and sleep disorders were unrelated to the presence of daytime REM sleep, however, patients with daytime REM were significantly sleepier during the daytime than those patients without REM. Demographic and clinical variables, including Unified Parkinson's Disease Rating Scale motor scores and levodopa dose equivalents, were unrelated to the presence of REM sleep., Conclusions: A sizeable proportion of PD patients demonstrated REM sleep and daytime sleep tendency during daytime nap testing. These data confirm similarities in REM intrusions between narcolepsy and PD, perhaps suggesting parallel neurodegenerative conditions of hypocretin deficiency., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Narcolepsy is a disorder of impaired expression of wakefulness and rapid-eye-movement (REM) sleep. This manifests as excessive daytime sleepiness and expression of individual physiological correlates of REM sleep that include cataplexy and sleep paralysis (REM sleep atonia intruding into wakefulness), impaired maintenance of REM sleep atonia (e.g. REM sleep behaviour disorder [RBD]), and dream imagery intruding into wakefulness (e.g. hypnagogic and hypnopompic hallucinations). Excessive sleepiness typically begins in the second or third decade followed by expression of auxiliary symptoms. Only cataplexy exhibits a high specificity for diagnosis of narcolepsy. While the natural history is poorly defined, narcolepsy appears to be lifelong but not progressive. Mild disease severity, misdiagnoses or long delays in cataplexy expression often cause long intervals between symptom onset, presentation and diagnosis. Only 15-30% of narcoleptic individuals are ever diagnosed or treated, and nearly half first present for diagnosis after the age of 40 years. Attention to periodic leg movements (PLM), sleep apnoea and RBD is particularly important in the management of the older narcoleptic patient, in whom these conditions are more likely to occur. Diagnosis requires nocturnal polysomnography (NPSG) followed by multiple sleep latency testing (MSLT). The NPSG of a narcoleptic patient may be totally normal, or demonstrate the patient has a short nocturnal REM sleep latency, exhibits unexplained arousals or PLM. The MSLT diagnostic criteria for narcolepsy include short sleep latencies (<8 minutes) and at least two naps with sleep-onset REM sleep. Treatment includes counselling as to the chronic nature of narcolepsy, the potential for developing further symptoms reflective of REM sleep dyscontrol, and the hazards associated with driving and operating machinery. Elderly narcoleptic patients, despite age-related decrements in sleep quality, are generally less sleepy and less likely to evidence REM sleep dyscontrol. Nonpharmacological management also includes maintenance of a strict wake-sleep schedule, good sleep hygiene, the benefits of afternoon naps and a programme of regular exercise. Thereafter, treatment is highly individualised, depending on the severity of daytime sleepiness, cataplexy and sleep disruption. Wake-promoting agents include the traditional psychostimulants. More recently, treatment with the 'activating' antidepressants and the novel wake-promoting agent modafinil has been advocated. Cataplexy is especially responsive to antidepressants which enhance synaptic levels of noradrenaline (norepinephrine) and/or serotonin. Obstructive sleep apnoea and PLMs are more common in narcolepsy and should be suspected when previously well controlled older narcolepsy patients exhibit a worsening of symptoms. The discovery that narcolepsy/cataplexy results from the absence of neuroexcitatory properties of the hypothalamic hypocretin-peptidergic system will significantly advance understanding and treatment of the symptom complex in the future.

The macrolide antibiotic clarithromycin can enhance central nervous system excitability, possibly by antagonism of GABA-A receptors. Enhancement of GABA signaling has recently been demonstrated in a significant proportion of patients with central nervous system hypersomnias, so we sought to determine whether clarithromycin might provide symptomatic benefit in these patients. We performed a retrospective review of all patients treated with clarithromycin for hypersomnia, in whom cerebrospinal fluid enhanced GABA-A receptor activity in vitro in excess of controls, excluding those with hypocretin deficiency or definite cataplexy. Subjective reports of benefit and objective measures of psychomotor vigilance were collected to assess clarithromycin’s effects. Clinical and demographic characteristics were compared in responders and non-responders. In total, 53 patients (38 women, mean age 35.2 (SD 12.8 years)) were prescribed clarithromycin. Of these, 34 (64%) reported improvement in daytime sleepiness, while 10 (19%) did not tolerate its side effects, and nine (17%) found it tolerable but without symptomatic benefit. In those who reported subjective benefit, objective corroboration of improved vigilance was evident on the psychomotor vigilance task. Twenty patients (38%) elected to continue clarithromycin therapy. Clarithromycin responders were significantly younger than non-responders. Clarithromycin may be useful in the treatment of hypersomnia associated with enhancement of GABA-A receptor function. Further evaluation of this novel therapy is needed. [ABSTRACT FROM PUBLISHER]

We successfully treated a 46-year-old narcoleptic woman suffering from atypical depression with bupropion hydrochloride. Diagnostic evaluation revealed a Beck Depression Inventory (BDI) score of 24, a short nocturnal REM-sleep latency, subjective and objective sleepiness (mean sleep latency (MSL) = 1.8 minutes), and three sleep onset REM-sleep periods during the five nap multiple sleep latency test. Bupropion (100 mg t.i.d.) Normalized her mood (BDI = 6), sleepiness (MSL = 9.1 minutes), and REM-sleep propensity. Upon discontinuation of bupropion, these parameters reverted to pretreatment levels. This “activating” antidepressant's reversal of the sleepiness and REM-sleep propensity in narcolepsy may be due to blockade of dopamine or norepinephrine reuptake. Clinicians need to be alert to the fact that depression can mask the diagnosis of narcolepsy. Bupropion warrants further investigation as a treatment for narcolepsy in an open-label, double-blind, placebo-controlled paradigm. Depression and Anxiety 7:92–95, 1998. © 1998 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Summary: 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. [ABSTRACT FROM AUTHOR]