Variability of excessive daytime sleepiness and cataplexy according to seasonality: A study in central disorders of hypersomnolence.

To assess the impact of coronavirus disease 2019 (COVID-19)-related restrictions on narcolepsy type 1 (NT2), narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH). Participants with NT1, NT2, and IH followed in a university hospital completed an online 78-question survey assessing demographic, clinical, and occupational features of the population during the first COVID-19-related lockdown. A total of 219 of 851 (25.7%) respondents of the survey reported a mean increase of 1.2 ± 1.9 hours (P < .001) in night sleep time and a mean decrease of 1.0 ± 3.4 points (P < .001) on the Epworth Sleepiness Scale during lockdown. Bedtime was delayed by 46.1% of participants and wakeup time was delayed by 59.6%, driven primarily by participants with IH. Teleworkers (but not in-person workers) reported a mean increase of 0.9 ± 1.2 hours in night sleep (P < .001) and a mean decrease in sleepiness score of 1.6 ± 3.1 (P < .001). Cataplexy improved in 54.1% of participants with NT1. Sleepiness correlated with psychological wellness (r = .3, P < .001). As many as 42.5% enjoyed the lockdown, thanks to reallocation of time usually spent commuting toward longer sleep time, hobbies, and family time, and appreciated a freer napping schedule. Conversely, 13.2% disliked the lockdown, feeling isolation and psychological distress. Extended sleep time, circadian delay (in patients with IH), and teleworking resulted in decreased symptoms of central hypersomnias. These findings suggest that people with IH, NT1, and NT2 may benefit from a decrease in social and professional constraints on sleep-wake habits, and support advocacy efforts aimed at facilitating workplace and schedule accommodations for this population. Nigam M, Hippolyte A, Dodet P, etal. Sleeping through a pandemic: impact of COVID-19-related restrictions on narcolepsy and idiopathic hypersomnia. J Clin Sleep Med. 2022;18(1):255-263.

Excessive daytime sleepiness (EDS) is a key symptom of obstructive sleep apnea (OSA). The Psychomotor Vigilance Task (PVT) has been suggested as an objective easy-to-use, inexpensive alternative to the Multiple Sleep Latency Test (MSLT) to measure EDS. In patients with OSA, physiological sleepiness, but not subjective EDS (Epworth Sleepiness Scale [ESS]), has been associated with increased levels of the sleep- inducing proinflammatory cytokine interleukin-6 (IL-6). The goal of this study was to assess the association of PVT with objectively measured sleepiness (MSLT) and subjectively measured sleepiness (ESS) and IL-6 levels in patients with OSA. We studied 58 untreated patients with OSA who underwent an 8-hour in-laboratory polysomnography for 4 consecutive nights. MSLT, PVT, and 24-hour serial profiles of IL-6 were assessed on the fourth day. PVT variables included number of lapses, mean reciprocal of the fastest 10% and slowest 10% reaction times, and median of 1/reaction time. ESS was assessed on day 1 of the study. Higher ESS scores were significantly associated with greater number of lapses (β = .34, P = .02) and lower values of 1/RT (β = -.36, P = .01) and slowest 10% RTs (β = -.30, P = .04). No significant association was observed between PVT and MSLT, nor PVT and IL-6 levels. Our findings suggest that PVT is associated with subjectively assessed daytime sleepiness, but not with physiological sleepiness nor IL-6 levels in patients with OSA. It appears that ESS and PVT may be useful in predicting risks associated with impaired performance, such as traffic accidents, in patients with OSA.

This guideline establishes clinical practice recommendations for the treatment of central disorders of hypersomnolence in adults and children. 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. 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. We recommend that clinicians use modafinil for the treatment of narcolepsy in adults. (STRONG). We recommend that clinicians use pitolisant for the treatment of narcolepsy in adults. (STRONG). We recommend that clinicians use sodium oxybate for the treatment of narcolepsy in adults. (STRONG). We recommend that clinicians use solriamfetol for the treatment of narcolepsy in adults. (STRONG). We suggest that clinicians use armodafinil for the treatment of narcolepsy in adults. (CONDITIONAL). We suggest that clinicians use dextroamphetamine for the treatment of narcolepsy in adults. (CONDITIONAL). We suggest that clinicians use methylphenidate for the treatment of narcolepsy in adults. (CONDITIONAL). We recommend that clinicians use modafinil for the treatment of idiopathic hypersomnia in adults. (STRONG). We suggest that clinicians use clarithromycin for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). We suggest that clinicians use methylphenidate for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). We suggest that clinicians use pitolisant for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). We suggest that clinicians use sodium oxybate for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). We suggest that clinicians use lithium for the treatment of Kleine-Levin syndrome in adults. (CONDITIONAL). We suggest that clinicians use armodafinil for the treatment of hypersomnia secondary to dementia with Lewy bodies in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to Parkinson's disease in adults. (CONDITIONAL). We suggest that clinicians use sodium oxybate for the treatment of hypersomnia secondary to Parkinson's disease in adults. (CONDITIONAL). We suggest that clinicians use armodafinil for the treatment of hypersomnia secondary to traumatic brain injury in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to traumatic brain injury in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to myotonic dystrophy in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to multiple sclerosis in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of narcolepsy in pediatric patients. (CONDITIONAL). We suggest that clinicians use sodium oxybate for the treatment of narcolepsy in pediatric patients. (CONDITIONAL). 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.

Introduction Central Disorders of Hypersomnolence (CDH) are classified primarily by polysomnography-multiple sleep latency test (PSG-MSLT). Lack of biomarkers and variable MSLT results in disorders other than narcolepsy type 1 (NT1) contribute to under- and mis-diagnosis. Limited studies explore PSG characteristics that may differentiate CDH subtypes using large datasets. Methods This retrospective cohort included 1,330 patients who underwent PSG-MSLT for hypersomnolence (January 2003-August 2024) at Cleveland Clinic. Cases were classified as NT1, narcolepsy type 2 (NT2), idiopathic hypersomnia (IH) and undifferentiated hypersomnia (UH; not meeting CDH criteria) based on physician clinical diagnosis. 557 patients with disorders associated with hypersomnia (i.e. OSA) were excluded. Demographic and PSG characteristics were compared with ANOVA, Kruskal-Wallis, and Pearson chi-square tests. Results Of 773 patients (33.7±14.0 yr, 79.4% female), 72(9.3%) had NT1,121(15.7%) NT2, 296(38.3%) IH, and 284(36.7%) UH. While groups did not differ in age or gender, more Caucasians had IH and UH than NT1(78.6, 80.8 vs. 62.5%, p=0.001). Epworth Sleepiness Scale scores were lower in UH than CDH groups (12.6±5.0 vs NT1-15.9±5.6,NT2-16.1±5.1,IH-14.2±5.2, p&amp;lt; 0.001). Self-reported sleep time was longer for UH than NT2 without other group differences (UH-9.1±2.1,NT2-8.4±1.7,NT1-8.6±2.1,IH-8.8±1.9 hours, p=0.003). PSG sleep onset REM periods (SOREMPs) were more common in NT1 and NT2 than IH and UH (NT1-27.8%,NT2-9.1%,IH-1.01%,UH-1.06%, p&amp;lt; 0.001). NT1 and NT2 had shorter REM latency than IH and UH(NT1-73.5[7.0,123.0],NT2-74.0[53.0,112.0],IH-103.0[71.0,161.5],UH-105.0[74.5,183.0] min, p&amp;lt; 0.001). NT1 and UH showed more wakefulness after sleep onset than NT2 and IH (NT1-43.5[26.0,97.0],UH-47.5[25.5, 85.0],NT2-32.5[17.3,61.5],IH-30.5[17.5, 62.5] min, p&amp;lt; 0.001). Sleep latency was shorter in CDH than UH (NT1-10.8[4.5,26.0],NT2-14.0[6.0,24.5],IH-17.5[7.8,30.5],UH-24.5[12.5,39.0] min, p&amp;lt; 0.001), and sleep efficiency higher in NT2 and IH than UH (NT2-87.4±7.3,IH-86.3±8.8,UH-82.0±10.0, p&amp;lt; 0.001). NT1 had greater, though non-significant, arousal index, stage shifts, and N1 percentage, along with lower sleep efficiency than NT2 and IH. No significant differences were observed between NT2 and IH in sleep latency, sleep efficiency, arousal index, WASO, stage shifts, or stage percentages. Conclusion We found significant differences in PSG variables between CDH that confirm and extend prior observations. Minimal differences between NT2 and IH support a common pathophysiology. Recognizing the larger group of UH with distinct PSG features from CDH is important in clinical practice. Support (if any)

Many patients with severe obstructive sleep apnea (OSA) do not complain of excessive daytime sleepiness (EDS), possibly due to increased sympathetic nervous activity (SNA) and accompanying heightened alertness. We hypothesized that in patients with OSA, those without subjective EDS (Epworth Sleepiness Scale, ESS score < 11) would have higher very low frequency (VLF) heart rate variability (HRV) during sleep, reflecting greater sympathetic heart rate modulation than patients with an ESS score ≥ 11. Patients with severe OSA (AHI ≥ 30: 26 with and 65 without heart failure) were divided into those with and without EDS. Heart rate (HR) signals were acquired in stage 2 sleep during periods of recurrent apneas and hypopneas and submitted to coarse graining spectral analysis, which extracts harmonic, neurally mediated contributions to HRV from total spectral power. Because the apnea-hyperpnea cycle entrains muscle SNA at VLF (0 to 0.04 Hz), VLF power was our principal between-group comparison. Subjects without EDS had higher harmonic VLF power (944 ± 839 vs 447 ± 461 msec(2), p = 0.003) than those with EDS, irrespective of the presence or absence of heart failure (1218 ± 944 vs 426 ± 299 msec(2), p = 0.043, and 1029 ± 873 vs 503 ± 533 msec(2), p = 0.003, respectively). ESS scores correlated inversely with VLF power in all (r = -0.294, p = 0.005) and in heart failure subjects (r = -0.468, p = 0.016). Patients with severe OSA but without EDS have higher VLF-HRV than those with EDS. This finding suggests that patients with severe OSA but without EDS have greater sympathetic modulation of HRV than those with EDS that may reflect elevated adrenergically mediated alertness. Taranto Montemurro L; Floras JS; Picton P; Kasai T; Alshaer H; Gabriel JM; Bradley TD. Relationship of heart rate variability to sleepiness in patients with obstructive sleep apnea with and without heart failure.

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. 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. 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. Maski K, Trotti LM, Kotagal S, etal. 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.

Subjective-objective sleepiness discrepancy in adult-onset myotonic dystrophy type 1.

PurposeMyotonic dystrophy type 1 (DM1) is often characterized by excessive daytime sleepiness (EDS) and sleep-onset rapid eye movement periods caused by muscleblind-like protein 2. The EDS tends to persist even after treatment of sleep apnea. We measured the cerebrospinal fluid (CSF) orexin levels in DM1 patients with EDS and compared the clinical characteristics with narcolepsy type 1 and idiopathic hypersomnia (IHS) patients.Patients and methodsWe measured the CSF orexin levels in 17 DM1 patients with EDS and evaluated subjective sleepiness using the Epworth Sleepiness Scale (ESS), objective sleepiness using mean sleep latency (MSL), and sleep apnea using apnea-hypopnea index (AHI). We compared the ESS scores and MSL between decreased (≤200 pg/mL) and normal (>200 pg/mL) CSF orexin group in DM1 patients. Furthermore, we compared the CSF orexin levels, ESS scores, MSL, and AHI among patients with DM1, narcolepsy type 1 (n=46), and IHS (n=30).ResultsSeven DM1 patients showed decreased CSF orexin levels. There were significant differences in the ESS scores and MSL between decreased and normal CSF orexin groups in DM1 patients. The ESS scores showed no significant difference among patients with DM1, narcolepsy type 1, and IHS. The MSL in DM1 and IHS patients were significantly higher than narcolepsy type 1 patients (p=0.01, p<0.001). The AHI in DM1 patients was significantly higher than narcolepsy type 1 patients (p=0.042) and was insignificantly different from IHS patients. The CSF orexin levels in DM1 patients were significantly lower than IHS patients and higher than narcolepsy type 1 patients (p<0.001, p<0.001).ConclusionThe CSF orexin levels of DM1 patients moderately decreased compared to those of IHS patients as the control group. However, the EDS of DM1 patients may not be explained by only orexin deficiency.

The aim of the current study was to evaluate an attention test as a discriminative tool to measure neurocognitive impairment in patients with disorders of hypersomnolence. Chronic excessive daytime sleepiness is the main symptom in central disorders of hypersomnolence. For diagnostic purposes and treatment evaluation, reliable assessment of excessive daytime sleepiness is required. Thirty-six patients with central disorders of hypersomnolence were compared with 20 healthy controls. All participants performed the 'Perception and Attention Functions' (WAF) of the Vienna Test System. Patients underwent polysomnography, Multiple Sleep Latency Test and Maintenance of Wakefulness Test. Patients were divided into two groups: (i) patients who met the criteria of disorder of hypersomnolence (objective excessive daytime sleepiness); and (ii) patients with subjective excessive daytime sleepiness, i.e. with normal Multiple Sleep Latency Test results. Group 1 consisted of 23 patients with objective excessive daytime sleepiness (11 with idiopathic hypersomnia, nine with narcolepsy type 1, three with narcolepsy type 2); group 2 included 13 patients with subjective excessive daytime sleepiness. The results showed cognitive impairment in patients with objective excessive daytime sleepiness and even in patients with subjective excessive daytime sleepiness. WAF tests identified distinct attention profiles in patients with narcolepsy type 1, idiopathic hypersomnia/narcolepsy type 2, and patients with subjective excessive daytime sleepiness. WAF test measures correlated with Maintenance of Wakefulness Test and the Epworth Sleepiness Scale, but not with Multiple Sleep Latency Test and the Fatigue Severity Scale. In conclusion, the multidimensional WAF test battery detects cognitive impairment even in patients that complain of excessive daytime sleepiness but have normal Multiple Sleep Latency Test results. WAF tests offer valuable information that adds to the existing polysomnographic measures in discriminating patients with different types of chronic excessive daytime sleepiness. The results provide new insights into cognitive dysfunction underlying different types of chronic excessive daytime sleepiness.

To assess the efficacy and safety of pitolisant, a selective histamine H₃ receptor antagonist/inverse agonist, for excessive daytime sleepiness (EDS) in narcolepsy or obstructive sleep apnea (OSA). PubMed, Cochrane, Embase, Scopus, and Web of Science were searched through August 2025 for randomized placebo-controlled trials (RCTs). Eligible RCTs reported Epworth Sleepiness Scale (ESS) or Pediatric Daytime Sleepiness Scale (PDSS), mean sleep latency, EQ-5D, or global impression outcomes. Two reviewers independently screened studies, extracted data, and assessed bias using Cochrane RoB 2.0. Publication bias was evaluated using funnel plots and Egger's test; certainty of evidence was rated with GRADE. Six RCTs (n = 1149) met the inclusion criteria. Compared with placebo, pitolisant significantly reduced Sleepiness Scale scores (SSS) (mean difference [MD] = -2.97; 95% confidence interval [CI] -3.62 to -2.33), increased mean sleep latency (MD = 3.06; 95% CI 2.12-3.99), and improved EQ-5D scores (MD = 2.68; P = 0.009). Patient global opinion (risk ratio [RR] = 1.40) and clinical global impression of change (CGI-C) (RR = 1.41) also favored pitolisant. Rates of treatment-emergent adverse events, serious adverse events, and withdrawals were comparable with placebo, and common adverse effects, such as headache, insomnia, nausea, and anxiety, were infrequent and not significantly increased. Pitolisant provides an effective, nonstimulant option for EDS in narcolepsy and OSA, including residual symptoms despite continuous positive airway pressure (CPAP). Its distinct mechanism and tolerability profile make it a valuable alternative or adjunct to existing therapies, supporting personalized care and enhanced daily functioning. Pitolisant significantly improves subjective and objective wakefulness and quality of life in EDS due to narcolepsy or OSA, with robust evidence for ESS benefit and a favorable safety profile.

Introduction Narcolepsy and idiopathic hypersomnia (IH) are characterized by excessive daytime sleepiness. They can be caused by deficiency of orexin/hypocretin, a neuropeptide that regulates sleep and wakefulness. It is estimated that 1 in 2000 people in the United States of America have been diagnosed with some form of narcolepsy or idiopathic hypersomnia. Around the world, about 3 million people are narcoleptic. Little data are available regarding the lifestyle factors in these patients. In this study, we sought to find whether lifestyle factors, including diet and physical activity are associated with the severity of sleepiness in narcolepsy and idiopathic hypersomnia. Methods We collaborated with “Hypersomnia Foundation” and “Wake Up Narcolepsy” who distributed our survey to their subscribers. The survey consisted of a series of four short subsurveys asking about the substance use, diet (MiniEAT screen), exercise (IPAQ questionnaire), and daytime sleepiness (Epworth Sleepiness Scale). The survey was anonymous and included baseline characteristics, diagnosis (Narcolepsy type 1 (NT1), Narcolepsy type 2 (NT2), or Idiopathic Hypersomnia (IH)). We considered hypersomnolence and moderate to severe hypersomnolence to be present if ESS &amp;gt;10 and ≥15, respectively. Results We received total of 377 individual responses. Of those, 191 responders had IH, 97 had NT1 and 89 had NT2. Median age was 31 (25, 42) and 323 identified as females, 44 males and 10 others. Median ESS was 15 (12, 18), where 285 responders had ESS &amp;gt;10 (76%) and 194 (51%) had ESS &amp;gt;/=15. The ressponders with NT1 had significantly higher median ESS: 17 (12,19), than NT2: 15 (10, 17), or IH: 15(12, 17) responders (p&amp;lt; 0.01). In multiple univariate analyses, none of the baseline characteristics, habits (smoking, alcohol or caffeine), dietary consumption (fruit, vegetable, legumes/nuts/seeds, whole or refined grains, dairy and fish/seafood) or exercise (vigourous, moderate or walking) had significant association with the degree of responders’ subjective sleepiness. Conclusion Most survey responders continue to be excessively sleepy, particularly those with NT1. There were no apparent univariate associations of underlying hypersomnolence with the baseline characteristics, habits, diet and exercise levels. Disorders of central hypersomnolence are of complex nature without easily identifiable modifiers. Support (if any) Mayo Clinic CRISP

To evaluate excessive daytime sleepiness in patients with depressive disorder and to examine its association with the severity of depression and suicidal ideation. Seventy patients were interviewed and assessed by the Epworth Sleepiness Scale (ESS), the Beck Depression Inventory (BDI) and the Beck Scale for Suicidal Ideation (SSI). Descriptive analysis, Pearson correlations and Student's t-test were used for data analyses. Most of the patients (57.1%) obtained high scores on the ESS. Correlation was positive and strongly significant between ESS scores and BDI scores, as well as between ESS scores and SSI scores. Patients with high ESS scores obtained higher mean BDI and SSI scores in comparison to patients with lower ESS scores. Significant differences (p < 0.05) were encountered when the patients with higher (> or = 10) and lower (< 10) ESS scores were compared in terms of total ESS, BDI and SSI scores. Excessive daytime sleepiness was frequent among patients and significantly associated with higher levels of depression and particularly with suicidal ideation. Thus, a careful investigation of daytime sleepiness in depressed patients is required during clinical evaluation.

Introduction Narcolepsy type 1 is caused by destruction of hypocretin-producing neurons, likely via a T-cell mediated autoimmune process, and clinically identified either by CSF hypocretin deficiency or the presence of cataplexy. Individuals with narcolepsy type 1 have an underlying genetic predisposition attributed to the HLA DQB1*0602 gene. This genetic variant has been linked to increased propensity for sleepiness even in healthy adults. Relatives of patients with narcolepsy type 1 appear to be at increased risk for other disorders of hypersomnolence such as idiopathic hypersomnia. Here we describe three siblings, all positive for HLA DQB1*0602, who presented with distinct clinical features diagnostic for narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia. Report of Cases: A 15-year-old female was diagnosed with narcolepsy type 1 based on typical cataplexy, excessive daytime sleepiness, and mean sleep latency of 2 min with 2 SOREMPs on MSLT. Lumbar puncture (LP) performed 5 years after symptom onset showed low CSF hypocretin (9.3 pg/mL). Her older brother presented at age 21 with excessive sleepiness, somewhat atypical cataplexy, hypnagogic hallucinations, and sleep paralysis. MSLT showed mean sleep latency of 6 min with 5 SOREMPs. Despite the presence of cataplexy, LP performed 2 years after symptom onset showed normal CSF hypocretin (296.5 pg/mL) and he was diagnosed with narcolepsy type 2. Their younger sister presented at age 19 with progressive daytime sleepiness. PSG/MSLT showed mild OSA (RDI 9.2) and mean sleep latency of 6.5 min without SOREMPs. She does not have cataplexy, hypnagogic hallucinations, or sleep paralysis. The current findings are most consistent with idiopathic hypersomnia, although an LP to evaluate for hypocretin deficiency is an important next step. Similarly, a repeat LP in the brother might demonstrate change in hypocretin over time. Conclusion These cases may support a familial link between narcolepsy type 1, type 2, and idiopathic hypersomnia. The discordant hypocretin and cataplexy statuses of these siblings implies a mechanism for excessive sleepiness beyond hypocretin deficiency, possibly mediated by HLA DQB1*0602. Identifying the mechanisms of familial aggregation of sleepiness in the central disorders of hypersomnolence may shed light on the pathophysiology of these distinct disorders. Support (If Any)

To assess the effectiveness of sodium oxybate therapy, modafinil therapy and the combination of the two for excessive daytime sleepiness in narcolepsy patients previously taking modafinil. Double-blind, placebo-controlled, multicenter study. Forty-four sites in the United States, Canada, the Czech Republic, France, Germany, the Netherlands, Switzerland, and the United Kingdom. Two hundred seventy- adult patients with narcolepsy taking 200 to 600 mg of modafinil daily for the treatment of excessive daytime sleepiness. Patients received unchanged doses of modafinil (with sodium-oxybate placebo) during a 2-week baseline phase. Following a baseline polysomnogram and Maintenance of Wakefulness Test, they were randomly assigned to 1 of 4 treatment groups: sodium-oxybate placebo plus modafinil placebo, sodium oxybate plus modafinil placebo, modafinil plus sodium-oxybate placebo, or sodium oxybate plus modafinil. Sodium oxybate was administered as 6 g nightly for 4 weeks and was then increased to 9 g nightly for 4 additional weeks. The primary efficacy measure was the Maintenance of Wakefulness Test; secondary measures included the Epworth Sleepiness Scale, diary recordings, and the Clinical Global Impression-change scale. Following the switch from modafinil to placebo, the mean average daytime sleep latency on the Maintenance of Wakefulness Test decreased from 9.74 minutes at baseline to 6.87 minutes after 8 weeks (p < .001). In the sodium-oxybate group, there was no decrease in sleep latency, suggesting that this drug was as efficacious in treating the excessive daytime sleepiness as the previously administered modafinil. In contrast, the sodium-oxybate/modafinil group demonstrated an increase in daytime sleep latency from 10.43 minutes to 13.15 minutes (p < .001), suggesting that this combination of drugs produced an additive effect. The sodium-oxybate group also demonstrated a decrease in median average Epworth Sleepiness Scale scores, from 15 to 12.0, whereas the sodium-oxybate/modafinil group decreased from 15.0 to 11.0 (for both, p < .001). The Clinical Global Impression-Change scale demonstrated similar results. Sodium oxybate and modafinil are both effective for treating excessive daytime sleepiness in narcolepsy, producing additive effects when used together. Sodium oxybate is beneficial as both monotherapy and as adjunctive therapy for the treatment of excessive daytime sleepiness in narcolepsy.

Differential diagnosis of narcolepsy type 2 (NT2) from type 1 (NT1) and idiopathic hypersomnia (IH) is challenging due to overlapping symptoms. We developed an automated method using nocturnal polysomnography (nPSG) data to differentiate these conditions and clinical controls (CCs), and explored varying sleep phenotypes within NT1, NT2, IH, and CCs. We analyzed nPSG data from drug-free individuals with NT1, NT2, and IH, or CCs. Sleep features were derived at whole-night and per-quarter-night levels, including hypnogram, transition probability, hypnodensity, spindle, and quantitative electroencephalogram (qEEG) features. Random forest machine learning models were used for three classification tasks. Within-diagnosis clustering identified potential diagnosis subgroups. The sample included 350 individuals (52% females; median age 30years; 114 NT1, 90 NT2, 105 IH, and 41 CCs). Our models achieved area under the receiver operating characteristic curve values of 0.87, 0.79, and 0.82 for distinguishing NT2 from CCs, NT2 from IH, and IH from CCs, with corresponding F1 scores of 0.74, 0.71, and 0.69, respectively. qEEG features substantially contributed to model performance, distinguishing NT2 from IH. Cluster analysis revealed two NT1 subgroups (one showing more severe sleep disturbances), two NT2 subgroups (one trended toward NT1, the other toward IH), and two IH subgroups with differences in hypnodensity, qEEG, and spindle characteristics. Our exploratory findings demonstrate strong diagnosis classification performance from nPSG data alone, more easily distinguishing NT2 from CCs than from IH, and IH from CCs. The distinct NT2 subgroups suggest heterogeneity within NT2; further research is warranted to explore these patterns. Statement of Significance Accurate diagnoses of narcolepsy types 2 (NT2) and 1 and idiopathic hypersomnia (IH) remain challenging due to overlapping symptoms. We developed a machine learning model using drug-free nocturnal polysomnography data to automatically differentiate NT2 from clinical controls, NT2 from IH, and IH from clinical controls, with high accuracy. Our model leverages a rich set of sleep features, including spindle and quantitative electroencephalogram (qEEG) metrics. Furthermore, our analysis revealed distinct sleep phenotypes within each diagnosis, suggesting subtypes with varying levels of sleep disturbance and differences at qEEG and spindle levels. These findings provide a novel approach to classifying central disorders of hypersomnolence and suggest disease heterogeneity, which could lead to more accurate and timely diagnoses and personalized treatment strategies.