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Narcolepsy and idiopathic hypersomnia cannot be cured; all available treatments are symptomatic. It is of paramount importance for patients, and their relatives, to be informed about the consequences of these chronic diseases and to become ready to accept the consequences of the diagnosis before starting any treatment. This facilitates the implementation of behavioral modifications and the proper use of medication to decrease the disease burden. A supportive social environment (eg, family members, friends, employer, colleagues, and patient support groups) is instrumental. Current treatment options are discussed with a focus on pharmacologic treatment, including future directions.

Idiopathic hypersomnia (IH) is characterized by excessive daytime sleepiness despite normal or prolonged sleep. IH is distinguished from narcolepsy by the female predominance, severe morning inertia, continuous drowsiness (rather than sleep attacks), unrefreshing naps, absence of cataplexy, sleep onset in REM periods, and hypocretin deficiency. In IH, the multiple sleep latency test demonstrates low sensitivity, specificity, and reproducibility, compared with prolonged sleep monitoring. In some IH cases, an endogenous hypnotic peptide stimulating GABA receptors during wakefulness is suspected, which are improved by anti-GABA drugs. The benefits of modafinil, sodium oxybate, mazindol, and pitolisant were found in mostly retrospective studies.

Background: GHB (gamma-hydroxybutyric acid; sodium oxybate) is a general anaesthetic that is clinically used for the treatment of narcolepsy, cataplexy, alcohol withdrawal and alcohol relapse prevention. In addition, GHB is recreationally used. Most clinical and recreational users regard GHB as an innocent drug devoid of adverse effects, despite its high dependence potential and possible neurotoxic effects. At high doses, GHB may lead to a comatose state. This paper systematically reviews possible cognitive impairments due to clinical and recreational GHB use. Methods: PubMed and PsychINFO were searched for literature data about the acute and residual cognitive deficits following GHB use. This review is conducted using the PRISMA protocol. Results: A total of 43 reports covering human and animal data on GHB-induced cognitive impairments were eligible and reviewed. This systematic review found no indication for cognitive impairments after clinical GHB use. However, it supports the view that moderate GHB use may result in acute short-term cognitive impairments, whereas regular high-dose GHB use and/or multiple GHB-induced comas are probably neurotoxic resulting in long-term residual cognitive impairments. Conclusion: These results emphasize the need for awareness among clinicians and recreational users to minimize negative health consequences of recreational GHB use, particularly when high doses are used and GHB-induced comas occur.

Introduction: The core symptoms of narcolepsy such as excessive daytime sleepiness and cataplexy are well known. However, there is mounting evidence for a much broader symptom spectrum, including psychiatric symptoms. Disordered sleep has previously been linked with dissociative symptoms, which may imply that patients with narcolepsy are more prone to develop such symptoms. Objectives: To investigate the frequency of dissociative symptoms in adult patients with narcolepsy type 1 compared to population controls. Methods: In a retrospective case control study, sixty adult patients fulfilling the criteria for narcolepsy type 1 and 120 matched population control subjects received a structured interview using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) to assess dissociative symptoms and disorders. Results: A majority of narcolepsy patients reported dissociative symptoms, and even fulfilled the DSM-IV-TR criteria of a dissociative disorder (62% vs 1% in controls, p < .001). Most frequently reported symptoms were "dissociative amnesia" (37% vs 1%, p < .001) and "dissociative disorder of voluntary movement" (32% vs 1%, p < .001). Conclusion: Dissociative symptoms are strikingly prevalent in adult patients with narcolepsy type 1. Although a formal diagnosis of dissociation disorder should not be made as the symptoms can be explained by narcolepsy as an underlying condition, the findings do illustrate the extent and severity of the dissociative symptoms. As for the pathophysiological mechanism, there may be symptom overlap between narcolepsy and dissociation disorder. However, there may also be a more direct link between disrupted sleep and dissociative symptoms. In either case, the high frequency of occurrence of dissociative symptoms should result in an active inquiry by doctors, to improve therapeutic management and guidance.

The Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) measures daytime sleepiness, but had not previously been validated in children12 years of age.Data from a sodium oxybate (SXB) study in pediatric participants with narcolepsy with cataplexy (ClinicalTrials.gov, NCT02221869) were used in this validation study. SXB-naive participants completed an open-label titration period prior to entering a 2-week stable-dose period; participants taking SXB at study entry entered a 3-week stable-dose period.The analysis population (N = 100) had a mean (SD) age of 11.9 (2.39) years. Internal consistency as assessed by Cronbach's alpha was 0.750 (95% CI, 0.681-0.819). The intraclass correlation coefficient for the test-retest reliability assessment (n = 64 with stable or no stimulant use at study entry) was 0.755 (95% CI, 0.626-0.844). Responsiveness to change, measured as the mean within-person change in 1-week ESS-CHAD score over time in SXB-naive participants (n = 59) from baseline (before taking SXB) to end of the stable-dose period (taking the titrated amount of SXB), was -6.31 (95% CI: -7.61, -5.00; nominal P 0.0001). For convergent construct validity, the mean (SD) scores for female (n = 40) and male (n = 60) participants were 13.98 (4.440) and 14.65 (4.050), respectively (nominal P = 0.4430). For divergent construct validity, the mean (SD) scores were 16.31 (2.978) in the group who were taking neither SXB nor stimulants at study entry (n = 32) and 13.47 (4.400) in the group taking SXB with or without stimulants at study entry (n = 68; nominal P = 0.0003).This evidence supports the validity of the 1-week ESS-CHAD in a pediatric population with narcolepsy.

STUDY OBJECTIVES: In some patients, it is difficult to correctly nosologically classify daytime sleepiness. Clinical manifestations may be nonspecific; on the basis of objective measures it is possible to determine the current severity of sleepiness, but they do not always allow accurate diagnosis. It is especially difficult to distinguish between idiopathic hypersomnia (IH) and hypersomnia associated with a psychiatric disorder (PSY). METHODS: To find significant differences between the IH and PSY groups, we included 67 patients (IH, n = 15; PSY, n = 52) in the study, focusing on differences in self-reported symptoms, evaluating current depressive symptoms using the Beck Depression Inventory-II score and personality traits measured by the Temperament and Character Inventory. All of the patients underwent polysomnography, the Multiple Sleep Latency Test, and ad libitum sleep monitoring. RESULTS: The patients with IH showed greater difficulty than those in the PSY group with waking up in the morning (P < .001) and complained of memory (P = .04) and attention deficit (P = .006). They also showed higher total sleep time (P < .001) and sleep efficiency (P = .007) and a shorter mean sleep latency on the Multiple Sleep Latency Test (P < .001). Nevertheless, the IH and PSY groups did not differ in Beck Depression Inventory scores or personality characteristics. CONCLUSIONS: IH is a syndrome in which depression/external life stressors and personality characteristics also play a role. Patients with IH may benefit from the cooperation of sleep specialists with psychotherapists/psychiatrists. CITATION: Bušková J, Novák T, Miletínová E, et al. Self-reported symptoms and objective measures in idiopathic hypersomnia and hypersomnia associated with psychiatric disorders: a prospective cross-sectional study. J Clin Sleep Med. 2022;18(3):713–720.

STUDY OBJECTIVES: To assess the responsiveness of the Idiopathic Hypersomnia Severity Scale (IHSS) to medications and estimate the minimum clinically important difference, to report clinically relevant score ranges, and to confirm its psychometric properties and whether items need to be weighted in drug-free and treated patients with idiopathic hypersomnia (IH). METHODS: Two-hundred twenty-six (166 drug-free and 60 treated) patients with IH (cross-sectional sample) completed the 14-item IHSS to quantify the severity of the 3 major IH symptoms (excessive daytime sleepiness, prolonged nighttime sleep, and sleep inertia) and consequences; 77 untreated patients were evaluated again after treatment (longitudinal sample). Patients filled in the Epworth Sleepiness Scale, Beck Depression Inventory II, and European Quality of Life questionnaires. RESULTS: The IHSS confirmed adequate psychometric properties with a factor analysis indicating a 3-component solution. IHSS total score was lower in treated than untreated patients, with a mean difference of 4–5 points in the cross-sectional and longitudinal samples. Distribution-based methods were used to estimate that 4 points represented the minimum clinically important difference. Four severity levels were defined with between-group differences related to treatment. The probability of having severe sleepiness, depressive symptoms, and low quality of life increased with the severity level. Our results showed that IHSS item-weighting was not necessary. CONCLUSIONS: The IHSS is a valid and reliable tool to quantify IH symptoms, with 4 severity score levels of clinical importance. The IHSS has adequate psychometric properties and can detect symptom changes after treatment. These findings should stimulate its use in clinical settings and in research studies. CITATION: Rassu AL, Evangelista E, Barateau L, et al. Idiopathic Hypersomnia Severity Scale to better quantify symptoms severity and their consequences in idiopathic hypersomnia. J Clin Sleep Med. 2022;18(2):617–629.

A 76-year-old incarcerated man presented with word-finding difficulties and underwent a routine EEG. Shortly after reaching stage N2 sleep, EEG showed brisk lateral eye movements with concurrent sawtooth waves (figure), indicating sleep-onset REM period (SOREMP). Normal REM sleep is reached 90–120 minutes after sleep onset. SOREMP is an abnormal EEG finding thought to be suggestive of narcolepsy. However, it may also be present in 3.9% of the general population1 and is normal in infants. It is also associated with severe sleep deprivation, obstructive sleep apnea, and alcohol or medication (selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors) withdrawal. In the inpatient setting, it is usually caused by sleep deprivation.2

Background and ObjectivesNarcolepsy type 1 (NT1) is an orphan brain disorder caused by the irreversible destruction of orexin neurons. Metabolic disturbances are common in patients with NT1 who have a body mass index (BMI) 10% to 20% higher than the general population, with one-third being obese (BMI >30 kg/m2). Besides the destruction of orexin neurons in NT1, the metabolic alterations in obese and nonobese patients with NT1 remain unknown. The aim of this study was to identify possible differences in plasma metabolic profiles between patients with NT1 and controls as a function of their BMI status.MethodsWe used a targeted liquid chromatography–mass spectrometry metabolomics approach to measure 141 circulating, low-molecular-weight metabolites in drug-free fasted plasma samples from 117 patients with NT1 (including 41 obese individuals) compared with 116 BMI-matched controls (including 57 obese individuals).ResultsCommon metabolites driving the difference between patients with NT1 and controls, regardless of BMI, were identified, namely sarcosine, glutamate, nonaylcarnitine (C9), 5 long-chain lysophosphatidylcholine acyls, 1 sphingolipid, 12 phosphatidylcholine diacyls, and 11 phosphatidylcholine acyl-akyls, all showing increased concentrations in NT1. Metabolite concentrations significantly affected by NT1 (n = 42) and BMI category (n = 40) showed little overlap (n = 5). Quantitative enrichment analysis revealed common metabolic pathways that were implicated in the NT1/control differences in both normal BMI and obese comparisons, namely glycine and serine, arachidonic acid, and tryptophan metabolism. The metabolites driving these differences were glutamate, sarcosine, and ornithine (glycine and serine metabolism); glutamate and PC aa C34:4 (arachidonic acid metabolism); and glutamate, serotonin, and tryptophan (tryptophan metabolism). Linear metabolite-endophenotype regression analyses highlight that as part of the NT1 metabolic phenotype, most of the relationships between the sleep parameters (i.e., slow-wave sleep duration, sleep latency, and periodic leg movement) and metabolite concentrations seen in the controls were lost.DiscussionThese results represent the most comprehensive metabolic profiling of patients with NT1 as a function of BMI and propose some metabolic diagnostic biomarkers for NT1, namely glutamate, sarcosine, serotonin, tryptophan, nonaylcarnitine, and some phosphatidylcholines. The metabolic pathways identified offer, if confirmed, possible targets for treatment of obesity in NT1.Classification of EvidenceThis study provides Class II evidence that a distinct metabolic profile can differentiate patients with NT1 from patients without the disorder.

Narcolepsy is a chronic disorder and its phenotype is dichotomized into narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2). The clinical course and pathophysiological mechanisms of these two clinical entities and their differences are not adequately defined. This study aimed to explore the differential longitudinal patterns of polysomnography (PSG) and multiple sleep latency test (MSLT) in NT1 and NT2. In this retrospective study demographic characteristics, PSG, and MSLT parameters at baseline and follow-up were compared between NT1 and NT2 patients. Patients with both follow-up MSLT and PSG were selected for sub-group analysis. Baseline and follow-up MSLT and PSG parameters were compared. Of 55 patients with narcolepsy, mean follow-up periods were 7.4 ± 3.5 years for NT1 and 5.5 ± 2.9 for NT2. Demographic data showed increased body mass index and prevalence of sleep paralysis in NT1. Baseline PSG characteristics between NT1 and NT2 showed decreased sleep latency (p = 0.016) and REM latency (p = 0.046) in NT1 group when compared with NT2. Nocturnal SOREMP on PSG was more prevalent in NT1 (p = 0.017), and half of NT2 patients with nocturnal SOREMP on PSG changed their diagnoses to NT1. On follow-up PSG, NT1 displayed reductions in sleep stage N2 (p = 0.006) and N3 (p = 0.048), while wake after sleep onset (WASO) (p = 0.023) and apnea–hypopnea index (AHI) (p = 0.007) were significantly increased. Differential MSLT and PSG characteristics of NT1 and NT2 in at baseline and follow-up indicate that NT1 and NT2 are distinct disease phenotypes, and that they present with a contrasting course of disease.

Background Pitolisant is approved in the USA and Europe for the treatment of excessive daytime sleepiness or cataplexy in adults with narcolepsy. Objective Analyses evaluated the time to onset of clinical response during treatment with pitolisant. Methods Data were obtained from two randomized, double-blind, 7-week or 8-week, placebo-controlled studies (HARMONY 1, HARMONY CTP). Study medication was individually titrated to a maximum dose of pitolisant 35.6 mg/day and then remained stable. Efficacy assessments included the Epworth Sleepiness Scale and weekly rate of cataplexy (calculated from patient diaries). Onset of clinical response was defined as the first timepoint at which there was statistical separation between pitolisant and placebo. Results The analysis included 61 patients in HARMONY 1 (pitolisant, n = 31; placebo, n = 30) and 105 patients in HARMONY CTP (pitolisant, n = 54; placebo, n = 51). Onset of clinical response began at week 2 (HARMONY 1) or week 3 (HARMONY CTP) for the mean change in Epworth Sleepiness Scale score, and week 2 (HARMONY CTP) or week 5 (HARMONY 1) for the mean change in weekly rate of cataplexy, with further improvements observed in pitolisant-treated patients through the end of treatment. The percentage of treatment responders was significantly greater with pitolisant vs placebo beginning at week 3 for excessive daytime sleepiness (defined as an Epworth Sleepiness Scale score reduction ≥ 3) and week 2 for cataplexy (defined as a ≥ 50% reduction in weekly rate of cataplexy [HARMONY CTP]). Conclusions Onset of clinical response for excessive daytime sleepiness and/or cataplexy was generally observed within the first 2-3 weeks of pitolisant treatment in patients with narcolepsy. CLINICALTRIALS. Gov identifier NCT01067222 (February 2010), NCT01800045 (February 2013).

Idiopathic hypersomnia (IH) is a rare sleep disorder characterized by excessive daytime sleepiness, great difficulty upon awakening, and prolonged sleep time. In contrast to narcolepsy type 1, which is a well-recognized hypersomnia, the etiology of IH remains poorly understood. No susceptibility loci for IH have been identified, although familial aggregations have been observed among patients with IH. Narcolepsy type 1 is strongly associated with human leukocyte antigen (HLA)-DQB1*06:02; however, no significant associations between IH and HLA alleles have been reported. To identify genetic variants that affect susceptibility to IH, we performed a genome-wide association study (GWAS) and two replication studies involving a total of 414 Japanese patients with IH and 6587 healthy Japanese individuals. A meta-analysis of the three studies found no single-nucleotide polymorphisms (SNPs) that reached the genome-wide significance level. However, we identified several candidate SNPs for IH. For instance, a common genetic variant (rs2250870) within an intron of PDE9A was suggestively associated with IH. rs2250870 was significantly associated with expression levels of PDE9A in not only whole blood but also brain tissues. The leading SNP in the PDE9A region was the same in associations with both IH and PDE9A expression. PDE9A is a potential target in the treatment of several brain diseases, such as depression, schizophrenia, and Alzheimer’s disease. It will be necessary to examine whether PDE9A inhibitors that have demonstrated effects on neurophysiologic and cognitive function can contribute to the development of new treatments for IH, as higher expression levels of PDE9A were observed with regard to the risk allele of rs2250870. The present study constitutes the first GWAS of genetic variants associated with IH. A larger replication study will be required to confirm these associations.

Objectives To describe the pharmacological treatments (2005-2017) and the healthcare utilization (1997-2016) for patients with narcolepsy in Sweden in order to create a framework for future organizational and economic analyses. Material & Methods Patients of all ages with a diagnosis of narcolepsy registered in the National Patient Registry in specialist care in Sweden were included and information on treatments for narcolepsy was retrieved from The Swedish Prescribed Drug Register. Results We collected 2508 patients with narcolepsy, 43,3% men and 56,7% women and 47,9% were prescribed modafenil, 33,8% metylphenidate and 26,2% amphetamine. In total, 3817 treatments were initiated. Patients treated with amphetamine had a higher mean age. More women than men used modafinil, methylphenidate, amphetamine and antidepressants. The narcolepsy population had more outpatient than inpatient healthcare. Patients treated with sodium oxybate had more outpatient visits than other narcolepsy patients, before and during treatment (p = .00). Conclusions This study gives valuable information on pharmaceutical treatments and healthcare utilization for patients with narcolepsy and can be used to estimate the healthcare cost in the future. Patients with sodium oxybate treatment had more outpatient visits than other patients before and during treatment which may be due to the need to monitor potentially severe side-effects or may indicate that patients with sodium oxybate treatment have a severe disease. The number of included patients was less than expected; however, this may depend on patients escaping our collection of data, which does not contain information from primary care. Funding Agencies|UCBUCB Pharma SA

Chenyang Li,1 Liang Xie,2 Shaomei Shang,1 Xiaosong Dong,3 Xiaoling Wang,4 Long Zhao,3 Chi Zhang,3 Fang Han3 1Peking University School of Nursing, Beijing, People’s Republic of China; 2Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, People’s Republic of China; 3Sleep Medicine Center, Department of Respiratory and Critical Care Medicine, Peking University People’s Hospital, Beijing, People’s Republic of China; 4PKU-UPenn Sleep Center, Peking University International Hospital, Beijing, People’s Republic of ChinaCorrespondence: Fang HanSleep Medicine Center, Department of Respiratory and Critical Care Medicine, Peking University People’s Hospital, Beijing, 100044, People’s Republic of ChinaEmail hanfang1@hotmail.comObjective: This study aimed to translate and validate the narcolepsy quality-of-life instrument with 21 questions (NARQoL-21) in Chinese pediatrics with narcolepsy.Methods: NARQoL-21 was translated following the 10 steps of scale translation. The translated version was tested by exploratory factor analysis (EFA), confirmatory factor analysis (CFA), known-group validity, criterion validity, Cronbach’s α and test-rest reliability.Results: The Chinese version of NARQoL-21 consisted of two factors: (psychosocial factors and future outlook factor), including 20 items. EFA yielded 3 domains for psychosocial factors and 1 domain for future outlook factor. The Chinese version had a negative correlation with the overall Modified Epworth Sleepiness Scale (r = − 0.518, p< 0.001) and meaningful difference in score between drug naïve and treated group (p< 0.05). The Cronbach’s α coefficient was higher than 0.7 and intraclass correlation coefficient (ICC) ranged from 0.75 to 0.905, indicating that it had good reliability.Conclusion: The Chinese version of the NARQoL-21 is available and can be used to evaluate the health-related quality of life (HRQoL) of pediatric narcoleptics, despite that there is a shift in factors compared to the English version due to cultural differences. Future studies are recommended to further validate the scale in Chinese pediatrics with narcolepsy.Keywords: narcolepsy, pediatrics, quality of life, validation study

STUDY OBJECTIVES: Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, is approved in the United States and European Union for excessive daytime sleepiness in adults with narcolepsy (75–150 mg/day) or obstructive sleep apnea (OSA; 37.5–150 mg/day). In 12-week studies, solriamfetol was associated with improvements in quality of life in participants with narcolepsy or OSA. These analyses evaluated the long-term effects of solriamfetol on quality of life. METHODS: Participants with narcolepsy or OSA who completed previous solriamfetol studies were eligible. A 2-week titration was followed by a maintenance phase ≤ 50 weeks (stable doses: 75, 150, or 300 mg/day). Quality of life assessments included Functional Outcomes of Sleep Questionnaire short version, Work Productivity and Activity Impairment Questionnaire: Specific Health Problem, and 36-Item Short Form Health Survey version 2. Mean (standard deviation) changes from baseline to end of study were evaluated. Data were summarized descriptively. Adverse events were assessed. RESULTS: Safety population comprised 643 participants (417 OSA, 226 narcolepsy). Solriamfetol improved Functional Outcomes of Sleep Questionnaire short version Total scores (mean change [standard deviation], 3.7 [3.0]) and 36-Item Short Form Health Survey version 2 Physical and Mental Component Summary scores (3.1 [6.9] and 4.3 [8.4], respectively); improvements were sustained throughout treatment. On Work Productivity and Activity Impairment Questionnaire: Specific Health Problem, solriamfetol reduced (improved) % presenteeism, % overall work impairment, and % activity impairment by a minimum of 25%. Common adverse events (≥ 5%): headache, nausea, nasopharyngitis, insomnia, dry mouth, anxiety, decreased appetite, and upper respiratory tract infection. CONCLUSIONS: Long-term solriamfetol treatment was associated with clinically meaningful, sustained improvements in functional status, work productivity, and quality of life for up to 52 weeks. Adverse events were similar between narcolepsy and OSA. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: A Long-Term Safety Study of JZP-110 in the Treatment of Excessive Sleepiness in Subjects with Narcolepsy or OSA; Identifier: NCT02348632; URL: https://clinicaltrials.gov/ct2/show/NCT02348632 CITATION: Weaver TE, Pepin J-L, Schwab R, et al. Long-term effects of solriamfetol on quality of life and work productivity in participants with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea. J Clin Sleep Med. 2021;17(10):1995–2007.

Multiple sleep-onset rapid eye movement periods (SOREMPs) are involved in the pathophysiology of narcolepsy, but it is not clear whether the lack of multiple SOREMPs is associated with the pathophysiology of idiopathic hypersomnia or not. We examined the significance of multiple SOREMPs in patients with pathological sleep prolongation. Participants were consecutive patients complaining of unexplained sleepiness and agreed to a 3-day-sleep studies; 24 h polysomnography (PSG) followed by standard PSG and multiple sleep latency test (MSLT). Forty-one (26 females, 21.9 ± 8.1 years old, BMI 20.4 ± 2.3 kg/m2) of 54 eligible patients without other sleep pathologies showed pathological sleep prolongation. We subdivided them into those with and without multiple SOREMPs on MSLT and compared clinical and PSG variables between groups. Six of 41 (14.6%) patients showed multiple SOREMPs on MSLT. There were almost no differences in sleep variables between those with and without multiple SOREMPs. We only found shorter mean sleep latency on MSLT and more REM cycles on 24 h PSG in those with multiple SOREMPs (adjusted p = 0.016 and 0.031). The frequencies of REM-related phenomena and clinical symptoms related to idiopathic hypersomnia were not different between groups. Our results indicated that patients with pathological sleep prolongation had the same clinical profiles regardless of the status of SOREMPs, suggesting the absence of multiple SOREMPs, prerequisite for the diagnosis of idiopathic hypersomnia, is not a specific feature of pathological sleep prolongation. Confirmation of sleep prolongation alone could be a diagnostic tool for idiopathic hypersomnia.

To determine whether narcolepsy Human Leukocyte Antigen (HLA) risk allele DQB1*0602 is associated with excessive daytime sleepiness (EDS) and inappropriate sleep in patients with Parkinson disease (PD). EDS is a common and disabling non-motor manifestation of PD, affecting quality of life and driving performance. DQB1*0602 is an HLA risk allele for narcolepsy. It is present in 12–30% of the general population. We hypothesize that DQB1*0602 is associated with an increased risk of EDS and inappropriate sleep in PD patients. This was a cross-sectional observational study of 150 PD individuals on dopaminergic agents. Main outcome measures were DQB1*0602 status and the modified Epworth Sleepiness Scale. Individuals with dementia, loss of independence, narcolepsy and untreated sleep apnea were excluded. Confounding variables for EDS were assessed using Parkinson Disease Sleep Scale, Mayo Sleep Questionnaire, Unified PD Rating Scale, Hoehn and Yahr scale. DQB1*06:02 positive PD patients were approximately three times more likely to experience EDS and fall asleep inappropriately during activities that required sustained alertness (e.g. driving, eating, attending work etc.). Exploratory post hoc analysis showed a dopaminergic drug dose- and type- dependent effect on daytime sleepiness in DQB1*06:02 positive individuals. No significant differences were found in confounding variables. PD individuals are more likely to experience EDS and fall asleep inappropriately during activities if DQB1*0602 positive. Genetic vulnerability may explain EDS risk in PD.

Diencephalic region of the brain harbors sites with a considerable amount of aquaporin-4 expression. Neuromyelitis optica spectrum disorder (NMOSD) primarily involves autoimmune processes against this molecule. However, little is known about the frequency of symptoms of diencephalic involvement in NMOSD patients. To investigate the frequency of symptoms of diencephalic involvement in NMOSD patients and describe the associated characteristics in patients presenting such symptoms. This retrospective cohort included 145 NMOSD patients (39 males and 106 females) who visited Isfahan Multiple Sclerosis Center from January 2013 to February 2020 for approximately 61 months. Demographic and clinical information of patients and findings from radiological and serological investigations were retrieved. The frequency of diencephalic involvement in NMOSD patients was 3.4% (five cases). Diencephalic syndrome-associated symptoms observed in this cohort consisted of narcolepsy (n = 2; 40%), hypotension (n = 1; 20%), amenorrhea (n = 1; 20%), and syndrome of inappropriate antidiuretic hormone secretion (n = 1; 20%). These manifestations responded well to NMOSD-associated treatments, i.e., rituximab and azathioprine. Although rarely manifested through symptoms suggestive of diencephalic involvement, NMOSD should be considered when encountering patients with the diencephalic syndrome to identify the primary cause of these manifestations.

Parkinson's disease (PD) is a neurodegenerative disease affecting about 2% of the population. A neuropeptide, orexin, is linked with sleep abnormalities in the parkinsonian patient. This study aimed to review the changes in the orexinergic system in parkinsonian subjects and the effects of orexin. A number of search techniques were used and presumed during the search, including cloud databank searches of PubMed and Medline using title words, keywords, and MeSH terms. PD is characterised by motor dysfunctions (postural instability, rigidity, tremor) and cognitive disorders, sleep-wake abnormalities grouped under non-motor disorders. The Orexinergic system found in the hypothalamus is linked with autonomic function, neuroprotection, learning and memory, and the sleep-wake cycle. Prepro-orexin, a precursor peptide (130 amino acids), gives rise to orexins (Orx-A and Orx-B). Serum orexin level measurement is vital for evaluating several neurological disorders (Alzheimer's disease, Huntington's disease, and PD). Orexinergic neurons are activated by hypoglycemia and ghrelin, while they are restrained by food consumption and leptin. Orexinergic system dysfunctioning was found to be linked with non-motor symptoms (sleep abnormalities) in PD. Orexinergic neuron's behaviour may be either inhibitory or excitatory depending on the environment in which they are present. As well, orexin antagonists are found to improve the abnormal sleep pattern. Since the orexinergic system plays a role in several psychological and neurological disorders, therefore, these disorders can be managed by targeting this system.

Tien-Yu Chen,1– 3,&ast; Vincent Yi-Fong Su,4,5,&ast; Chung-Hsin Lee,6 Chi-Hsiang Chung,7– 9 Chia-Kuang Tsai,3,10 Chung-Kan Peng,3,11 Hsiao-Ching Lai,1 Wu-Chien Chien,7– 9,12 Nian-Sheng Tzeng1,13 1Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan; 2Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan; 3Sleep Medicine Center, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan; 4Department of Internal Medicine, Taipei City Hospital, Taipei, Taiwan; 5Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan; 6Department of Neurosurgery, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan; 7Department of Medical Research, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 8School of Public Health, National Defense Medical Center, Taipei, Taiwan; 9Taiwanese Injury Prevention and Safety Promotion Association, Taipei, Taiwan; 10Department of Neurology, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan; 11Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan; 12Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan; 13Student Counseling Center, National Defense Medical Center, Taipei, Taiwan&ast;These authors contributed equally to this workCorrespondence: Wu-Chien ChienDepartment of Medical Research, Tri-Service General Hospital, National Defense Medical Center, 7115R, No. 325, Section 2, Cheng-Kung Road, Neihu District, Taipei, 11490, TaiwanTel +886 2-87923311, Ext. 19189Fax +886 2-87927235Email chienwu@mail.ndmctsgh.edu.twNian-Sheng TzengDepartment of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, 325, Section 2, Cheng-Kung Road, Neihu District, Taipei City, 11490, TaiwanTel +886 2-87927299Fax +886 2-87927221Email pierrens@mail.ndmctsgh.edu.twPurpose: Asthma, which is caused by inflammation of the airways, affects the sensitivity of nerve endings. Narcolepsy is a chronic sleep disorder that may be caused by autoimmunity. Recent studies have reported a positive association between narcolepsy and asthma. We aimed to examine the association between asthma and narcolepsy and determine the effects of therapeutic corticosteroid or bronchodilator use.Materials and Methods: We conducted a nationwide population-based, nested case-control study using Taiwan’s National Health Insurance Research Database (NHIRD) between 2000 and 2013. Subjects with narcolepsy (ICD-9-CM code 347) were enrolled, with 1:3 estimated propensity score-matched controls based on sex, age, and index year. The association between narcolepsy and asthma was assessed using multiple logistic regression analyses. The covariates included sex, age, monthly insurance premiums, geographical area of residence, urbanization level of residence, level of care, and presence of diseases related to immune response and central nervous system. The effects of corticosteroid and bronchodilator use were also analyzed.Results: Overall, 2008 subjects were identified from the NHIRD (502 patients with narcolepsy and 1506 controls). The participants with narcolepsy had almost three times the level of previous asthma diagnosis than controls. Compared to those without asthma, patients with asthma had an adjusted odds ratio (OR) of 3.181 for narcolepsy comorbidity (95% confidence interval [CI]: 2.048– 4.941, p< 0.001). The use of inhaled corticosteroids was associated with a lower risk of narcolepsy comorbidity, with an adjusted OR of 0.465 (95% CI, 0.250– 0.634; p< 0.001), in patients with asthma when compared to those without treatment.Conclusion: This study demonstrated a significantly higher level of previous asthma diagnosis in patients with narcolepsy. The use of inhaled corticosteroids was associated with a lower risk of narcolepsy comorbidity in asthma patients, compared to those without treatment.Keywords: asthma, narcolepsy, corticosteroid, bronchodilators

This review article covers the vaccination related issues in autoimmune disorders of central nervous system (CNS) including narcolepsy, anti-NMDAR encephalitis, Rasmussen encephalitis and febrile infection related epilepsy syndrome (FIRES). Beyond these conditions the immune mediated epilepsies related with autoimmune CNS disorders are discussed and indications and contraindications of vaccinations in these cases are also considered.

INTRODUCTION: This systematic review provides supporting evidence for the accompanying clinical practice guideline on the treatment of central disorders of hypersomnolence in adults and children. The review focuses on prescription medications with U.S. Food & Drug Administration approval and nonpharmacologic interventions studied for the treatment of symptoms caused by central disorders of hypersomnolence. METHODS: The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine to perform a systematic review. Randomized controlled trials and observational studies addressing pharmacological and nonpharmacological interventions for central disorders of hypersomnolence were identified. Statistical analyses were performed to determine the clinical significance of all outcomes. Finally, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) process was used to assess the evidence for the purpose of making specific treatment recommendations. RESULTS: The literature search identified 678 studies; 144 met the inclusion criteria and 108 provided data suitable for statistical analyses. Evidence for the following interventions is presented: armodafinil, clarithromycin, clomipramine, dextroamphetamine, flumazenil, intravenous immune globulin (IVIG), light therapy, lithium, l-carnitine, liraglutide, methylphenidate, methylprednisolone, modafinil, naps, pitolisant, selegiline, sodium oxybate, solriamfetol, and triazolam. The task force provided a detailed summary of the evidence along with the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations. CITATION: Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2021;17(9):1895–1945.

We describe the case of a male patient who was diagnosed with narcolepsy type 1 on the basis of sleep and wake symptoms, and the results of investigations including video-polysomnography, multiple sleep latency test, human leukocyte antigen status and orexin level in cerebrospinal fluid. During the first years after disease onset, the patient did not show any significant improvement despite treatment with a variety of stimulant and anti-cataplectic drugs. However, spontaneous remission of disease occurred after 15 years.

Objective Differentiating between the central hypersomnias presents a challenge to the diagnosis of patients with hypersomnolence. Actitigraphy may support efforts to distinguish them. We aimed to evaluate: 1) the ability of actigraphy to quantify sleep continuity measures in comparison with polysomnography in patients with hypersomnolence; 2) whether actigraphy can distinguish patients with hypersomnolence with normal hypocretin-1 in cerebrospinal fluid from patients with narcolepsy type 1 and from sleep-healthy controls; and 3) the distinct activity profiles and circadian rhythms of patients with narcolepsy type 1, patients with hypersomnolence with normal hypocretin-1 in cerebrospinal fluid, and sleep-healthy controls. Method Polysomnography, multiple sleep latency tests and actigraphy were conducted in 14 patients with narcolepsy type 1, 29 patients with hypersomnolence with normal hypocretin-1 in cerebrospinal fluid and 15 sleep-healthy controls. Results Actigraphy quantified several sleep continuity measures consistently with polysomnography in all the patients. Actigraphy distinguished patients with hypersomnolence with normal hypocretin-1 in cerebrospinal fluid from patients with narcolepsy type 1 and sleep-healthy controls. Patients with narcolepsy type 1 had poor sleep quality and altered circadian rest-activity rhythm compared with controls. Conclusion Actigraphy is an adequate tool for establishing the amount of night sleep and supports the differential diagnosis of patients with hypersomnolence.

INTRODUCTION: This guideline establishes clinical practice recommendations for the treatment of central disorders of hypersomnolence in adults and children. METHODS: The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine to develop recommendations and assign strengths to each recommendation, based on a systematic review of the literature and an assessment of the evidence using the GRADE process. The task force provided a summary of the relevant literature and the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations that support the recommendations. The AASM Board of Directors approved the final recommendations. RECOMMENDATIONS: The following recommendations are intended to guide clinicians in choosing a specific treatment for central disorders of hypersomnolence in adults and children. Each recommendation statement is assigned a strength (“strong” or “conditional”). A “strong” recommendation (ie, “We recommend…”) is one that clinicians should follow under most circumstances. A “conditional” recommendation (ie, “We suggest…”) is one that requires that the clinician use clinical knowledge and experience and strongly consider the individual patient’s values and preferences to determine the best course of action. Under each disorder, strong recommendations are listed in alphabetical order followed by the conditional recommendations in alphabetical order. The section on adult patients with hypersomnia because of medical conditions is categorized based on the clinical and pathological subtypes identified in ICSD-3. The interventions in all the recommendation statements were compared to no treatment. ADULT PATIENTS WITH NARCOLEPSY: 1. We recommend that clinicians use modafinil for the treatment of narcolepsy in adults. (STRONG); 2. We recommend that clinicians use pitolisant for the treatment of narcolepsy in adults. (STRONG); 3. We recommend that clinicians use sodium oxybate for the treatment of narcolepsy in adults. (STRONG); 4. We recommend that clinicians use solriamfetol for the treatment of narcolepsy in adults. (STRONG); 5. We suggest that clinicians use armodafinil for the treatment of narcolepsy in adults. (CONDITIONAL); 6. We suggest that clinicians use dextroamphetamine for the treatment of narcolepsy in adults. (CONDITIONAL); 7. We suggest that clinicians use methylphenidate for the treatment of narcolepsy in adults. (CONDITIONAL). ADULT PATIENTS WITH IDIOPATHIC HYPERSOMNIA: 8. We recommend that clinicians use modafinil for the treatment of idiopathic hypersomnia in adults. (STRONG); 9. We suggest that clinicians use clarithromycin for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL); 10. We suggest that clinicians use methylphenidate for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL); 11. We suggest that clinicians use pitolisant for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL); 12. We suggest that clinicians use sodium oxybate for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). ADULT PATIENTS WITH KLEINE-LEVIN SYNDROME: 13. We suggest that clinicians use lithium for the treatment of Kleine-Levin syndrome in adults. (CONDITIONAL). ADULT PATIENTS WITH HYPERSOMNIA DUE TO MEDICAL CONDITIONS: HYPERSOMNIA SECONDARY TO ALPHA-SYNUCLEINOPATHIES: 14. We suggest that clinicians use armodafinil for the treatment of hypersomnia secondary to dementia with Lewy bodies in adults. (CONDITIONAL); 15. We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to Parkinson’s disease in adults. (CONDITIONAL); 16. We suggest that clinicians use sodium oxybate for the treatment of hypersomnia secondary to Parkinson’s disease in adults. (CONDITIONAL). POSTTRAUMATIC HYPERSOMNIA: 17. We suggest that clinicians use armodafinil for the treatment of hypersomnia secondary to traumatic brain injury in adults. (CONDITIONAL); 18. We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to traumatic brain injury in adults. (CONDITIONAL). ADULT PATIENTS WITH GENETIC DISORDERS ASSOCIATED WITH PRIMARY CENTRAL NERVOUS SYSTEM SOMNOLENCE: 19. We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to myotonic dystrophy in adults. (CONDITIONAL). ADULT PATIENTS WITH HYPERSOMNIA SECONDARY TO BRAIN TUMORS, INFECTIONS, OR OTHER CENTRAL NERVOUS SYSTEM LESIONS: 20. We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to multiple sclerosis in adults. (CONDITIONAL). PEDIATRIC PATIENTS WITH NARCOLEPSY: 21. We suggest that clinicians use modafinil for the treatment of narcolepsy in pediatric patients. (CONDITIONAL); 22. We suggest that clinicians use sodium oxybate for the treatment of narcolepsy in pediatric patients. (CONDITIONAL). CITATION: Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2021;17(9):1881–1893.

Objectives: This study aimed to investigate the prevalence, incidence, and real-world diagnostic and treatment patterns, healthcare resource utilization (HCRU), and associated costs of narcolepsy in Germany. Methods: This study was based on German claims data (2013–2018). Any patient with at least two outpatient specialist diagnoses and/or one inpatient diagnosis of narcolepsy was eligible for inclusion. Three cohorts were specified: 1) narcolepsy-prevalent patients alive on July 1, 2017; 2) narcolepsy-incident patients; and 3) newly treated patients. Descriptive analyses of the outcome measures were conducted. Results: We identified 133 prevalent narcolepsy patients (mean age: 46.2 years, 36.3% female), 71 incident patients, and 41 treatment starters. The prevalence of narcolepsy was 3.1–9.1 per 100,000 persons within the German population; the cumulative incidence between July 1, 2017, and June 30, 2018, was 0.83/100,000 persons. Among the incident patients, 62.0% underwent at least one predefined diagnostic procedure. Modafinil was the most prescribed medication for the treatment starters (46.3%) and prevalent patients (24.1%), but 59.4% of the prevalent patients did not receive any narcolepsy-specific pharmacological treatment. Prevalent patients with narcolepsy consulted physicians significantly more often than a healthy matched control group and experienced more all-cause hospitalizations. The mean total direct healthcare costs were higher for narcolepsy patients by €2,429 per patient-year. Conclusions: Not all narcolepsy patients undergo appropriate diagnostic procedures or narcolepsy-specific medications, as indicated by the treatment guidelines. More emphasis on the optimization of the management of this disease is needed, given its high prevalence and associated economic burden.

Driving is a complicated process that demands coordination between a range of neurocognitive functions, including attention, visuo-perception, and appropriate judgment, as well as sensory and motor responses. Therefore, several factors may reduce the driving performance of an individual, such as sleepiness, distraction, overspeeding, alcohol consumption, and sedative drugs, all of which increase the hazard of motor vehicle accidents. Among them, drowsy driving is a major cause of traffic accidents, leading to more serious injuries as compared to other causes of major traffic accidents. Although sleep disorders have been highly associated among drowsy drivers, they are often untreated and unrecognized as a disease. In particular, obstructive sleep apnea and narcolepsy are some sleep disorders that are highly related to traffic accidents. Insomnia, which can cause inadequate sleep duration and promote sedative effects from sleeping pills, may also cause traffic accidents. These conditions are especially applicable to commercial bus or truck drivers, nocturnal workers, and shift workers, who are highly vulnerable to drowsy driving. Therefore, assertive screening and management of sleep disorders are necessary in general private drivers and relevant occupational drivers.

Introduction Narcolepsy type 1 (NT1) and type 2 (NT2) are chronic sleep disorders primarily characterised by excessive daytime sleepiness (EDS), disturbed sleep-wake regulation, and reduced quality of life. The precise disease mechanism is unclear, but it is certain that in NT1 the hypocretin/orexin (Hcrt) system is affected. Current treatment options are symptomatic - they improve EDS and/or reduce cataplexy. Complete symptom control is relatively rare - particularly problematic is residual daytime sleepiness. Areas covered This review discusses various emerging treatment targets for narcolepsy. The focus is on the Hcrt receptors, but included are also wake-promoting pathways, and sleep-stabilization through GABAergic mechanisms. Additionally, we discuss the potential of targeting the likely autoimmune basis of narcolepsy. PubMed and ClinicalTrials.gov was searched through June 2021 for relevant information. Expert opinion Targeting Hcrt receptors has the potential to alleviate narcolepsy symptoms. Results from ongoing drug development programs are promising, but care needs to be taken when evaluating potential side effects. It is still largely unknown what roles Hcrt receptors play in the periphery and how these might be affected by treatment. Immunotherapies could potentially target the core pathophysiology of narcolepsy, but more work is needed to identify the best therapeutic target for this approach.

BACKGROUND The aim of this study was to evaluate the impact of different therapy regimens, including sodium oxybate (SXB)-containing regimens, on patient-reported outcomes (PROs) in people with narcolepsy. METHODS Online surveys were used to collect information from persons with narcolepsy in the Nexus Narcolepsy Registry. Surveys contained questionnaires assessing self-reported sleep quality (SQ; via single question), daytime sleepiness and function (Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire), health-related quality of life (HRQoL; 36-Item Short Form Health Survey [SF-36]), work productivity and impairment (Work Productivity and Activity Impairment: Specific Health Problem), and history of injuries or motor vehicle accidents. Treatment with SXB (including monotherapy or combination therapy; SXB group) was compared with non-SXB therapy (No SXB group). The P values presented are nominal, as there are no adjustments for multiplicity. RESULTS From June 2015 through December 2017, 983 participants completed 1760 surveys. SQ and daytime functioning scores were better in the SXB group compared with the No SXB group (all P

STUDY OBJECTIVES: The Maintenance of Wakefulness Test (MWT) is used to objectively evaluate an individual’s ability to remain awake; however, microsleeps are not included in the assessment. We aimed to determine if microsleep data prior to sleep onset assisted in interpretation of ability to maintain wakefulness across a range of typical patient groups. METHODS: Forty-eight patients referred for overnight polysomnography and subsequent MWT were included. Patients were divided into 3 groups (treated obstructive sleep apnea [OSA], untreated OSA, or treated idiopathic hypersomnia or narcolepsy) based on prior medical diagnosis. Demographics, clinical characteristics, polysomnography, and MWT variables, including frequency, distribution, duration, and latency of microsleeps were compared between groups. RESULTS: Microsleeps were observed in MWT trials significantly more frequently in patients with treated idiopathic hypersomnia/narcolepsy over the course of the day (0.34 ± 0.06 vs 0.07 ± 0.02 microsleeps/min; P < .001) and in patients with untreated OSA toward the end of the day (0.31 ± 0.06 vs 0.05 ± 0.02 microsleeps/min; P < .001) compared to the group with treated OSA. Microsleeps were often observed in series and earlier in patients with treated idiopathic hypersomnia/narcolepsy (10.9 ± 1.6 minutes) and those with untreated OSA (16.2 ± 2.7 minutes) compared to the group with treated OSA (24.9 ± 3.0 minutes; P < .05), and, if taken into consideration, would increase the proportion of patients demonstrating inability to maintain wakefulness by 33% and 22%, respectively. CONCLUSIONS: MWT performance varies significantly across patient groups. Microsleep analysis prior to sleep onset may be a more sensitive measure of patient daytime wakefulness than sleep latency alone and should be considered in MWT assessment. CITATION: Anniss AM, Young A, O’Driscoll DM. Microsleep assessment enhances interpretation of the Maintenance of Wakefulness Test. J Clin Sleep Med. 2021;17(8):1571–1578.

Mobile health, or mHealth, solutions offer great potential in the area of self-monitoring of chronic conditions, where most of the day-to-day management of the condition is done at home by the patient or their caregivers. Narcolepsy is a chronic sleep condition caused by an orexin deficiency in the brain resulting in its inability to regulate sleep cycles, causing poor quality sleep during the day and problems with wakefulness during the day. This paper set out to investigate whether Habitual, an app for tracking symptoms, daily habits and medication adherence for people with narcolepsy could increase their sense of empowerment. Ten participants were asked to test the app during a period of 30 days, after which they were asked to answer a survey to investigate whether their perception of their empowerment towards the management of narcolepsy had changed. Although using the app for only 30 days provides a very limited understanding of the impact of Habitual, this study shows positive indication for future mHealth solutions for the management of narcolepsy. Future studies should test the openness to using an app for the management of narcolepsy with a wider cohort.

To study whether the onset of narcolepsy type 1 (NT1) in children and adolescents affects BMI, specific metabolic risk factors, the onset of puberty, longitudinal growth or other endocrine functions.A population-based study, comprising 34 patients, was performed with a clinical evaluation, an assessment of puberty and growth, actigraphy and blood samples at fasting, from patients and controls, to evaluate pituitary function, growth factors, thyroid gland, gonads, insulin sensitivity, appetite regulation and blood lipids.In the post-H1N1 vaccination (PHV) narcolepsy group, the median BMI SDS was higher 6-12 months after the onset of narcolepsy (p 0.01), but it was no different 10 years after the onset of narcolepsy (p = 0.91), compared with 12-24 months before the onset of narcolepsy. There was a correlation between an increase in BMI and a decrease in total energy expenditure (R = -0.74). In the nPHV group, weight and BMI changes were smaller and no significant changes were recorded. Early puberty was more common in patients with puberty onset after narcolepsy onset (n = 16/19) compared with patients with puberty onset before narcolepsy onset (n = 3/11, p = 0.02). There was no significant change in height SDS during the studied period. Although they were within normal ranges, both median HDL and median TSH levels were significantly lower in NT1 patients, compared with controls.We found a high prevalence of large BMI gain in the period immediately after the onset of narcolepsy, which had almost normalized at the long-term follow-up. The onset of narcolepsy led to early puberty in both sexes. Linear growth was not affected. We did not find any strong indicators of metabolic disturbances.

Background: Multiple sclerosis [MS] is an inflammatory demyelinating disease of the central nervous system, which is the second-most common cause of physical handicap in young individuals. Fatigue is the most prevalent [50%–90%] symptom of MS interfering with everyday life with at least one mild symptom of fatigue even in the early stages of the disease [36.5%] when clinical symptoms are still negligible. The Aim of The Work: To evaluate the prevalence and relation of fatigue in MS patients with sleep disorders and other clinical factors in an attempt to understand the underlying mechanisms of this symptom which might be of help in easing its evaluation and optimizing patient care. Patients and Methods: A cross-sectional study was performed on patients recruited from MS unit at Al-Azhar University Hospitals in Cairo. Fifty patients were investigated and submitted to clinical evaluation as well as fatigue severity assessment using fatigue severity scale and sleep scales: Epworth sleepiness scale for assessment of daytime sleepiness, Pittsburgh sleep scale for assessment of sleep quality, and polysomnography. Results: Fatigue was present in 60% of MS patients. Decreased sleep efficiency, pain and progressive types were significantly higher among MS patients with fatigue. Male patients with fatigue were significantly more than those without fatigue. About 84% of patients with MS were complaining from sleep disorder symptoms, 72% had insomnia, pain and nocturia ranged from 54%-60% while leg spasm and narcolepsy were present in 30% and 20% respectively. Conclusion: The present study emphasized the prevalence of fatigue in MS patients and its relation with sleep disorders and disease progression denoting wide variety of pathological mechanisms and the necessity of multimodal management.

Morphological changes in the cortex of narcolepsy patients were investigated by surface-based morphometry analysis in this study. Fifty-one type 1 narcolepsy patients and 60 demographically group-matched healthy controls provided resting-state functional and high-resolution 3T anatomical magnetic resonance imaging scans. Vertex-level cortical thickness (CT), gyrification, and voxel-wise functional connectivity were calculated. Adolescent narcolepsy patients showed decreased CT in bilateral frontal cortex and left precuneus. Adolescent narcolepsy demonstrated increased gyrification in left occipital lobe, left precuneus, and right fusiform but decreased gyrification in left postcentral gyrus, whereas adult narcolepsy exhibited increased gyrification in left temporal lobe and right frontal cortex. Furthermore, sleepiness severity was associated with altered CT and gyrification. Increased gyrification was associated with reduced long-range functional connectivity. In adolescent patients, those with more severe sleepiness showed increased right postcentral gyrification. Decreased frontal and occipital gyrification was found in cases with hallucination. In adult patients, a wide range of regions showed reduced gyrification in those with adolescence-onset compared adult-onset narcolepsy patients. Particularly the frontal lobes showed altered brain morphology, being a thinner cortex and more gyri. The impact of narcolepsy on age-related brain morphological changes may remain from adolescence to young adulthood, and it was especially exacerbated in adolescence.

ZUSAMMENFASSUNGTagesschläfrigkeit stellt ein häufiges und die Leistungsfähigkeit und Lebensqualität einschränkendes Symptom dar. Die Ursachen für Tagesschläfrigkeit (EDS) sind vielfältig und beinhalten zentralnervöse Erkrankungen mit Hypersomnolenz wie die Narkolepsie oder idiopathische Hypersomnie. Eine Differenzierung von Tagesmüdigkeit, EDS und Hypersomnie stellt eine wichtige Grundlage für eine erfolgreiche Diagnosestellung und somit der weiteren Behandlung dar. Die Diagnostik erfolgt im Wesentlichen klinisch-anamnestisch sowie durch schlafmedizinische Untersuchungen. Narkolepsie ist eine seltene (auto-)immunvermittelte neurologische Erkrankung und geht u. a. mit einer schweren Störung von Wachheit und Schlaf einher. Die Behandlung beinhaltet verhaltenstherapeutische Maßnahmen und eine symptomatische medikamentöse Behandlung.

Background and Objective Pedestrian crashes represent a leading cause of pediatric injury. Children have particular risk due to underdeveloped cognitive and executive function skills. Given children with excessive daytime sleepiness (EDS) face deficiencies in executive function and cognitive skill that impact cognitive functions necessary for safe pedestrian engagement, this study examined whether treatment with the stimulant medication modafinil might improve both cognitive functioning and pedestrian safety among children with EDS. Methods Twelve children aged 8–16 years diagnosed with EDS participated in a within-subjects experiment. Children completed two laboratory visits, one while treated with modafinil and one untreated. During each visit, children completed two self-report sleepiness inventories, two cognitive tests [psychomotor vigilance test (PVT) and Conners’ continuous performance task (CPT; version 3.0, Multi-Health Systems, Inc.)], and 20 virtual pedestrian environment street-crossings. Parents completed a sleepiness survey about children. Results Related samples t-tests found consistent patterns of reduced sleepiness, improved cognitive functioning, and safer pedestrian behavior while children were medicated with modafinil compared to unmedicated. Statistically significant differences emerged for parent-reported child sleepiness (p < 0.01); PVT false starts, indicating improved attention, vigilance and alertness (p < 0.10); CPT omissions, signifying failure to respond to stimuli (p < 0.05); and shortest time-to-contact with oncoming virtual traffic (p < 0.05). Chi-square demonstrated children had fewer collisions with oncoming virtual traffic while medicated than unmedicated (p < 0.05). Conclusions Medication with the stimulant modafinil improved multiple aspects of cognitive functioning and pedestrian safety among children with EDS. The greatest benefits emerged on measures of alertness, attention, and response latency. Results suggest modafinil may improve real-world functioning in tasks like crossing streets.

Background There are limited data available on regional differences in the diagnosis and management of narcolepsy. In order to better understand worldwide trends in clinical assessment and management of narcolepsy, a survey of health-care providers was conducted by the World Sleep Society Narcolepsy task force. Methods A total of 146 surveys that included items on the diagnosis and management of narcolepsy were completed by practitioners representing 37 countries. Results Most of the participants were from Europe, North America, Oceania, Asia and Latin America. A consistent approach to applying the diagnostic criteria of Narcolepsy was documented with the exception of measurement of CSF hypocretin-1, which has limited availability. While the majority of practitioners (58%) reported not using the test, 1% indicated always evaluating CSF hypocretin-1 levels. There was much variability in the availability of currently recommended medications such as sodium oxybate and pitolisant; modafinil and antidepressants were the most commonly used medications. Amphetamines were unavailable in some countries. Conclusion The results of the study highlight clinical and therapeutic realities confronted by worldwide physicians in the management of narcolepsy. While the diagnostic criteria of narcolepsy rely in part on the quantification of CSF hypocretin-1, few physicians reported having incorporated this test into their routine assessment of the condition. Regional differences in the management of narcolepsy appeared to be related to geographic availability and expense of the therapeutic agents.

ObjectiveWe validated the Narcolepsy Severity Scale (NSS) in adults with narcolepsy type 1 (NT1) to quantify the severity, frequency, and consequences of the 5 key narcolepsy symptoms over the last month, and we now developed the Pediatric NSS (NSS-P); thus, the aims of this study were to assess NSS-P psychometric properties, validity, and reliability, and to evaluate its responsiveness to treatment in a well-characterized sample of children and adolescents with NT1.MethodsThe NSS was reformulated for children, and the item about driving was removed. The total score of the 14-item NSS-P ranges from 0 to 54, and higher scores reflect more severe disease. Children and adolescents (n = 209, 6–17 years of age) with NT1 diagnosed in 2 Reference Centers for Narcolepsy in France were consecutively asked to fill in the NSS-P. The scale was fully and correctly completed by 160 (10–18 years of age, 68 untreated). Moreover, 65 participants completed it twice (33 before/during treatment, and 32 under the same treatment). The NSS-P psychometric properties, score changes before/during treatment, and convergent validity with other clinical parameters were assessed.ResultsThe NSS-P showed adequate psychometric properties with significant item–total score correlations. Factor analysis indicated a 4-factor solution with good reliability. The NSS-P score was lower in treated than untreated patients with a mean difference of 3.71 ± 1.45, with a minimum clinically important difference between untreated and treated patients in the longitudinal sample estimated at 4 points. Four severity levels were defined (mild, moderate, severe, very severe) with between-group differences related to treatment. The NSS-P total score was associated with self-reported sleepiness, insomnia, and depressive symptoms. Its temporal stability was satisfactory.DiscussionWe validated a brief instrument to assess NT1 symptom frequency, severity, and consequences in ≥10-year-old children and adolescents with 4 clinically relevant severity score ranges. This scale constitutes a relevant tool to improve and provide guidance for NT1 management in pediatric populations. The ease of administration, its good psychometric properties, and its sensitivity to detect symptom changes after treatment ensure future use of the NSS-P in clinical and research settings.

Narcolepsy is a chronic disabling neurological sleep disorder that requires lifelong treatment. We have outlined the clinical features of narcolepsy, the assessment and diagnosis process and have summarised the existing treatment options for children and adolescents with narcolepsy. In the future, the approach to management of paediatric narcolepsy should ideally be in a multidisciplinary setting, involving specialists in sleep medicine, sleep physiology, neurologists and psychologists/psychiatrists. A multidisciplinary approach will help to manage the potential impact of narcolepsy on children and adolescents who are in a stage of their life that is critical to their physical, emotional and social development and their academic attainment.

STUDY OBJECTIVES: We aimed to describe the clinical features of narcolepsy in patients referred to our sleep center between 2009 and 2016, and to compare these features across age groups and between sporadic vs AS03-adjuvanted H1N1 influenza vaccine-related patients. METHODS: This is a retrospective, consecutive study of adult and pediatric narcolepsy patients in the Republic of Ireland. All participants underwent structured assessments, including polysomnography and the Multiple Sleep Latency Test. Brain magnetic resonance imaging, hypocretin levels, and human leukocyte antigen typing were also carried out on the majority of patients. Patients were compared across age groups as well as etiology. RESULTS: The conditions of 40 (74%) patients were vaccine-related. The median age was 13.5 years and time from symptom onset to diagnosis was 112 weeks. Median time from vaccination to symptom onset was 26 weeks. In children, hypnogogic hallucinations and sleep paralysis were less frequent than in adults (17% vs 67%, P = .018 and 0% vs 75%, P < .0005). Sleep latency determined by the Multiple Sleep Latency Test was shorter in children than adults (median 1.75 vs 4 minutes, P = .011). Patients with vaccine-related and sporadic narcolepsies had typical clinical presentations. Vaccine-related patients had longer polysomnography latency (median 10.5 vs 5 minutes, P = .043), longer stage N2 sleep (209.6 ± 44.6 vs 182.3 ± 34.2 minutes, P = .042), and a trend toward longer total sleep times (P = .09). No differences were noted in relation to Multiple Sleep Latency Test, hypocretin, human leukocyte antigen typing, and magnetic resonance imaging. CONCLUSIONS: Results show that vaccine-related patients greatly outnumbered sporadic patients during the study period and suggest that sporadic and vaccine-related narcolepsy are clinically similar entities. CITATION: Ferguson D, Wrigley S, Purcell E, et al. Single center analysis of patients with H1N1 vaccine-related narcolepsy and sporadic narcolepsy presenting over the same time period. J Clin Sleep Med. 2021;17(5):885–895.

This case report evaluates the potential benefit of pitolisant in a 15-year-old female with Prader-Willi syndrome, obsessive-compulsive disorder, autism spectrum disorder, and mild intellectual disability. Due to its action on the H3 receptor, it enhances central activity of histaminergic neurons resulting in increased alertness, irrespective of the loss of orexin neurons seen in narcolepsy. Additionally, it is thought to modulate various other neurotransmitter systems including acetylcholine, norepinephrine, and dopamine. Pitolisant has the potential to improve many symptoms in patients with Prader-Willi syndrome and it appears to be well tolerated with minimal side effects observed. Therefore, the use of pitolisant should be considered in patients with Prader-Willi syndrome who fail a psychostimulant trial.

Excessive daytime sleepiness (EDS) is a highly prevalent condition that is associated with significant morbidity. The causes of EDS are varied, and include inadequate sleep, sleep disordered breathing, circadian rhythm sleep-wake disorders, and central disorders of hypersomnolence (narcolepsy, idiopathic hypersomnia, and Kleine-Levin syndrome). Additionally, EDS could represent a symptom of an underlying medical or psychiatric disorder. Assessment of EDS includes a thorough sleep, medical, and psychiatric history, targeted clinical examination, and appropriate use of actigraphy to measure sleep duration and sleep-wake patterns, polysomnography to assess for associated conditions such as sleep-related breathing disorders or other factors that might disrupt nighttime sleep, multiple sleep latency testing to ascertain objective sleepiness and diagnose central disorders of hypersomnolence, and measurement of cerebrospinal fluid hypocretin-1 concentration. Treatment of EDS secondary to central disorders of hypersomnolence is primarily pharmacologic with wakefulness-promoting agents such as modafinil, stimulants such as methylphenidate and amphetamines, and newer agents specifically designed to improve wakefulness; behavioral interventions can provide a useful adjunct to pharmacologic treatment. When excessive sleepiness is secondary to other conditions, the treatment should focus on targeting the primary disorder. This review discusses current epidemiology, provides guidance on clinical assessments and testing, and discusses the latest treatment options. For this review, we collated the latest evidence using the search terms excessive sleepiness, hypersomnia, hypersomnolence, treatment from PubMed and MEDLINE and the latest practice parameters from the American Academy of Sleep Medicine.

The vaccination against influenza A-H1N1 applied during the pandemic of 2009 demonstrated a positive association with the appearance of narcolepsy and/or concomitant cataplexy. Narcolepsy is a hypersomnia that affects greatly quality life of people that suffer from it. The present manuscript is an updated literature review regarding scientific evidence in this field. Reviewed scientific literature shows a positive relation between A-H1N1 vaccine and appearance of narcolepsy cases, however, etiopathogenic aspects are still unknown, so more studies are necessary, especially in the current moment, were some authors estipulate that a vaccine against SARS COVID-19 could cause similar effects that is crucial to minimize them.

Background: Acquired narcolepsy has rarely been reported in veterinary medicine. Objective: To describe the presentation, clinicopathological features, diagnostic imaging findings, and management of dogs with suspected-acquired narcolepsy. Animals: Eight dogs with clinical features consistent with acquired narcolepsy. Methods: A call for suspected cases of acquired narcolepsy was made online, followed by a retrospective review of detailed medical records of potential cases. Dogs were included if episodes consistent with cataplexy were present during exami- nation by a board-certified veterinary neurologist and diagnostic work-up included magnetic resonance imaging of the brain and analysis of cerebrospinal fluid. Results: Seven French Bulldogs and 1 Chihuahua (age range, 9-66 months) were included. Meningoencephalitis of unknown origin was diagnosed in 2 dogs, extracra- nial foci of inflammation were identified in 2 dogs (aspiration pneumonia, esophagitis, otitis media), and no abnormalities were found on diagnostic investigations in 4 dogs. Prednisolone was used in the management of all dogs, 6 dogs received imipramine, and 2 received cytosine arabinoside. An initial remission of signs was observed in all dogs, but a subsequent relapse of clinical signs was recorded for 4 dogs, of which 3 responded to adjustment or resumption of treatment. Conclusions and Clinical Importance: The presence of cataplexy episodes should prompt a thorough diagnostic work-up to exclude the presence of intracranial (and extracranial) pathology. The potential for both remission and relapse of signs in suspected acquired cases is important for clinicians and owners to be aware of.

To evaluate the efficacy of pitolisant, a histamine 3 (HData were pooled from two randomized, placebo-controlled, 7- or 8-week studies of pitolisant (titrated to a potential maximum dose of 35.6 mg/day) in adults with narcolepsy. Analyses included three independent patient subgroups: Epworth Sleepiness Scale (ESS) baseline score ≥16, Maintenance of Wakefulness Test (MWT) sleep latency ≤8 min, and ≥15 cataplexy attacks per week.The analysis populations included 118 patients for ESS (pitolisant, n = 60; placebo, n = 58), 105 for MWT (pitolisant, n = 59; placebo, n = 46), and 31 for cataplexy (pitolisant, n = 20; placebo, n = 11). On the ESS, least-squares mean change from baseline was significantly greater for pitolisant (-6.1) compared with placebo (-2.3; P 0.001). Significantly more pitolisant-treated patients were classified as treatment responders: ESS score reduction ≥3, 69.0% in the pitolisant group versus 35.1% in the placebo group (P = 0.001); final ESS score ≤10, 36.2% versus 10.5%, respectively (P = 0.005). On the MWT, mean sleep latency increased from 3.5 min to 10.4 min with pitolisant and from 3.4 min to 6.8 min with placebo (P = 0.017). Least-squares mean change in the weekly rate of cataplexy was significantly greater for pitolisant (-14.5; baseline, 23.9; final, 9.4) compared with placebo (-0.1; baseline, 23.1; final, 23.0; P = 0.004). Headache was the most common adverse event with pitolisant.Pitolisant, at once-daily doses up to 35.6 mg, was efficacious for reducing excessive daytime sleepiness and cataplexy in patients with severe narcolepsy symptom burden.

RATIONALE: Narcolepsy is a chronic sleep disorder, with typical onset in childhood or adolescence. Features of narcolepsy include excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hal...

Narcolepsy is a rare neurological disorder characterized by excessive daytime sleepiness (EDS) with or without cataplexy. A main pathophysiology of narcolepsy is hypocretin deficiency in the central nervous system resulting from a selective loss of hypocretin neurons in the lateral hypothalamus. To date, the pathogenesis of hypocretin neuron loss in narcolepsy is the most commonly accepted autoimmune hypothesis which is supported by genetic risk factors for narcolepsy such as HLA‑DQB1*06:02 allele and T-cell receptor alpha polymorphisms. Other evidence supporting the immune-mediated mechanisms include the presence of anti-Tribbles homolog 2 (TRIB2) and anti-streptococcal antibodies in patients with narcolepsy, seasonal patterns of narcolepsy onset, and increased incidence of narcolepsy after the H1N1 pandemic influenza A infections and vaccinations. Among several types of vaccines, the AS03-adjuvanted vaccine Pandemrix (GlaxoSmithKline) was the only vaccine found to increase the risk of narcolepsy. However, the comprehensive results of several epidemiological studies indicate the adjuvant AS03 alone cannot cause the disease. The genetic predisposition, environmental triggers, molecular mimicry of specific H1N1 antigens, and bystander immune activation caused by the adjuvant AS03 may have combined to contribute to autoimmunity against hypocretin neurons and development of narcolepsy.

We find ourselves at our present crossroads with a well-traveled toolkit, perhaps too well worn but with aspirational hopes and dreams for the field of sleep neurotherapeutics. This volume is organized thematically into six topical domains that parallel the major subspecialty areas of contemporary clinical sleep neurology practice, as well as novel directions and opportunities. The issue begins with an overview of the central disorders of hypersomnolence, including narcolepsy, idiopathic hypersomnia and other hypersomnia disorders, and the related use of the entire broad range of stimulant and wake-promoting pharmacotherapies. Next, the range of behavioral therapies, application of light and light restriction and melatonin therapies, and hypnotic pharmacotherapies useful in insomnia and circadian sleep–wake rhythm disorders are reviewed, followed by an overview of treatment options for sleep-related breathing disorders including positive airway pressure and the novel approach of hypoglossal neurostimulation for obstructive sleep apnea. The parasomnias and sleep-related movement disorders, including NREM disorders of arousal, REM parasomnias (nightmares and isolated sleep paralysis and idiopathic/isolated REM sleep behavior disorder, and restless legs syndrome are then discussed, and the applications of sleep neurotherapeutics in sleep and neurological disease are reviewed, including neurodevelopmental, epileptic, autoimmune encephalopathies, and neurodegenerative diseases. Last, the novel directions and opportunities in sleep neurology offered by cannabinoid therapies and machine learning/artificial intelligence methodology conclude this comprehensive survey of contemporary sleep neurology. We hope that you find this volume to be a useful and inspirational support tool for the work that matters most, your care of all our sleep neurology patients in the clinics. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-021-01032-7.

To evaluate the clinical relevance of solriamfetol in treating excessive daytime sleepiness in participants with narcolepsy or obstructive sleep apnea (OSA).This posthoc analysis includes data from two 12-week, randomized phase 3 studies in participants with narcolepsy or OSA treated with once-daily placebo or solriamfetol 37.5 mg (OSA only), 75 mg, 150 mg, or 300 mg. Excessive daytime sleepiness was assessed with the Epworth Sleepiness Scale (ESS) at baseline and at week 12. Cumulative distribution function plots were generated using a last-observation-carried-forward approach to determine the percentage of participants who achieved ESS scores ≤ 10, within the normal range, and the percentage who achieved a reduction (improvement) in ESS ≥ 25% relative to baseline. Safety was also assessed.In narcolepsy (n = 231), 30.5%-49.2% of participants treated with solriamfetol (across doses) reported ESS scores ≤ 10 and 44.1%-62.7% achieved a ≥ 25% decrease from baseline in ESS scores at week 12, compared with 15.5% and 27.6%, respectively, of placebo recipients. In OSA (n = 459), 51.8%-73.0% of participants treated with solriamfetol (across doses) reported ESS scores ≤ 10 and 50.0%-81.9% achieved a ≥ 25% decrease from baseline in ESS scores at week 12, compared with 37.7% and 36.8%, respectively, of placebo recipients. Results were generally dose-dependent, with more responders at higher solriamfetol doses. Common treatment-emergent adverse events (≥ 5% of solriamfetol recipients in either study) were headache, nausea, decreased appetite, nasopharyngitis, dry mouth, and anxiety.A greater percentage of participants treated with solriamfetol achieved normal ESS scores (≤ 10) or clinically meaningful improvements on the ESS compared with those receiving placebo. The safety profile was similar between participants with narcolepsy and those with OSA.Registry: ClinicalTrials.gov. Names: TONES 2 and TONES 3. URLs: https://www.clinicaltrials.gov/ct2/show/NCT02348593 and https://www.clinicaltrials.gov/ct2/show/NCT02348606. Identifiers: NCT02348593, NCT02348606. Registry: European Union Drug Regulating Authorities Clinical Trials. Names: TONES 2 and TONES 3. URL: https://www.eudract.ema.europa.eu. Identifiers: EudraCT 2014-005487-15, EudraCT 2014-005514-31.