Classification of narcolepsy type 1 using machine learning on Stanford Cataplexy Questionnaire responses and HLA-DQB1∗06:02.

Narcolepsy type 1 (NT1) is a chronic disease characterized by excessive daytime sleepiness and cataplexy. NT1 often strikes at a young age, severely impairing quality of life, and is frequently underdiagnosed or misdiagnosed. NT1 is tightly linked to deficiency in the wake-promoting and state-stabilizing hypocretin (HCRT) neuropeptides, which are produced by a small group of hypothalamic neurons. Given its strong association with the HLA-DQB1*06:02 allele, NT1 is widely assumed to result from autoimmune destruction of HCRT neurons. However, whether autoreactive immune responses represent a cause or a consequence of the disease remains an open question, and immune-mediated pathogenic mechanisms distinct from autoimmune cell killing are being explored. The observation that genes highly expressed in the hypothalamus, including HCRT, are epigenetically altered in post-mortem brain tissue from patients with NT1 has led to an alternative model whereby immune-triggered HCRT gene silencing, rather than HCRT neuron degeneration, causes HCRT deficiency. In this Perspective, we critically appraise the autoimmune and epigenetic models and their therapeutic implications and consider whether they can be reconciled.

A clinical diagnosis of narcolepsy type 1 can be challenging, particularly in relation to cataplexy. Despite its specificity, cerebrospinal fluid (CSF) orexin testing is under-utilised in Australasia. We describe the use of CSF orexin testing in 15 clinically indicated patients from two sleep centres, highlighting its utility in the Australasian context.

Test-retest repeatability of the multiple sleep latency test in non-cataleptic hypersomnolence disorders.

Redefining hypersomnia disorders in the context of psychiatry.

Central disorders of hypersomnolence (CDH) are, except for Narcolepsy Type 1 (NT1), difficult to diagnose and manage because of overlapping features and the lack of reliable biomarkers. Machine learning (ML) has the potential to improve diagnosis by detecting subtle physiological patterns and distinguishing between CDH subtypes. This review systematically explores current ML applications in CDH, assesses their limitations, and suggests future directions. Following PRISMA guidelines, MEDLINE, Embase, PsycINFO, IEEE Xplore, CINAHL, Web of Science, and Google Scholar (up to June 2025) were searched for studies using ML to classify or characterize CDH in adults. ML methods, data types, and diagnostic outcomes were extracted and analyzed. Out of 3274 studies, 41 met the inclusion criteria (37 peer-reviewed articles and 4 preprints). Data sources included neuroimaging (fMRI, PET), sleep assessments (MSLT, polysomnography), demographics, and standardized questionnaires. Supervised ML reliably identified known features, including early REM onset, hypocretin deficiency, and spectral EEG changes, showing strong performance for NT1 but limited generalizability across other CDH subtypes. Although many studies reported high accuracy, clinical relevance was often limited by rigid diagnostic labels that may not reflect the true complexity of CDH. Unsupervised learning uncovered heterogeneous phenotypes and exposed limitations in existing diagnostic labels. ML has the potential to improve CDH diagnosis. Deep learning models are promising for feature extraction; however, their black-box nature and high data requirements hinder clinical application. Future advancements depend on large, diverse datasets, multimodal and longitudinal data, and close collaboration between clinicians and data scientists.

Narcolepsy and metabolic disease: A meta-analytic synthesis.

Narcolepsy type 1: an autoimmune disease.

Narcolepsy and epilepsy are chronic neurological disorders that occasionally coexist. Overlapping symptoms, such as sudden loss of muscle tone and uncertainty regarding preservation of awareness, frequently complicate accurate diagnosis and ambiguity remains regarding optimal therapeutic strategies. To characterise the clinical features and treatment outcomes in individuals with comorbid narcolepsy and epilepsy, we described a 17-year-old girl with concomitant epilepsy and narcolepsy presented in our clinic. The overlapping symptomatology of narcolepsy and epilepsy can lead to significant diagnostic pitfalls, particularly when excessive daytime sleepiness is overlooked or attributed to external factors such as mental disorder or the side effects of antiseizure medications. Careful evaluation of clinical features, sleep studies and immunological markers through a multidisciplinary team approach is essential for accurate differentiation and optimal treatment. Prompted by this encounter, we additionally conducted a literature review and then synthesised ten reported cases of narcolepsy-epilepsy comorbidity, focusing on demographic profiles, diagnostic findings, treatment approaches and therapeutic outcomes. All ten published cases were diagnosed with narcolepsy type 1, predominantly with childhood or adolescent onset. EEG commonly showed 3–5 Hz generalised spike-and-wave discharges, and most individuals reported carrying the HLA-DQB1*06:02 allele. In more than 80% of cases, narcolepsy preceded or coincided with epilepsy, though diagnostic delays for narcolepsy were frequent. Both conditions generally responded well to combined standard treatments, such as pitolisant, sodium oxybate, lamotrigine and valproate, though antiseizure medications occasionally worsened sleepiness. This study underscores the diagnostic pitfalls associated to overlapping symptoms of narcolepsy and epilepsy and emphasises the value of multidisciplinary diagnostic collaboration for the timely recognition and effective management of these coexisting neurological disorders.

Narcolepsy type I is a rare neurological sleep disorder characterised by chronic excessive daytime sleepiness, cataplexy, and low orexin (hypocretin) levels. Infection with SARS-CoV-2 has been linked to neurological and neuropsychiatric sequelae, but cases of post-COVID narcolepsy remain extremely uncommon. We report a previously healthy 42-year-old Caucasian female who developed excessive daytime sleepiness, cataplexy, and hypnagogic/hypnopompic hallucinations within 3 months of confirmed SARS-CoV-2 infection. Polysomnography (PSG) showed disturbed nocturnal sleep with a high arousal index and periodic limb movements and mild sleep apnea, while the multiple sleep latency test (MSLT) showed a mean latency of 1 min with sleep-onset rapid eye movement (REM) periods in all naps. Cerebrospinal fluid hypocretin was markedly reduced (< 40 ng/L), confirming narcolepsy type I. Following the diagnosis, medical treatment was initiated-with methylphenidate for hypersomnolence followed by venlafaxine for cataplexy, which led to a substantial symptomatic improvement, enabling a return to daily functioning. The case contributes to the minimal literature on narcolepsy following COVID-19 and supports hypotheses of autoimmune-mediated destruction of hypocretin-producing neurons triggered by viral infection. Clinicians should maintain a high index of suspicion for primary sleep disorders in patients with persistent fatigue and hypersomnolence after COVID-19, as early recognition and targeted treatment markedly improve outcomes.

We evaluated the diagnostic potential of detecting narcolepsy type 1 (NT1) by systematically measuring cerebrospinal fluid hypocretin-1 (CSF-HCRT1) in patients with suspected central disorder of hypersomnolence (CDH), after the multiple sleep latency test (MSLT) was negative for narcolepsy criteria. Consecutive untreated patients with suspected CDH were hospitalized at the Bologna Narcolepsy Center (Italy) from 2013 to 2024. They underwent a standardized protocol of two-day continuous polysomnography (PSG), MSLT, and systematic CSF-HCRT1 measurement. Our focus was the identification of additional NT1 cases through the detection of low CSF-HCRT1 < 110pg/mL among those with negative PSG-MSLT for narcolepsy (i.e., mean sleep latency>8min or sleep onset REM periods-SOREMPs<2). Features of patients with CSF-HCRT1 < 110pg/mL and negative PSG-MSLT were explored. Out of 870 patients with suspected CDH (all with CSF-HCRT1 assay, 52% males, 30.1% pediatric), 342 had PSG-MSLT criteria consistent with narcolepsy with cataplexy (NT1). Sixty-four had PSG-MSLT criteria consistent with narcolepsy but did not have cataplexy (31.3% with CSF-HCRT1 deficiency). In the remaining 464 cases with a PSG-MSLT negative for narcolepsy, CSF-HCRT1 < 110 was detected in 34 (five without cataplexy), increasing NT1 diagnoses by 9.9% and re-classifying 7.3% of MSLT negative cases (p < 0.001 vs. PSG-MSLT+cataplexy). Among the 378 cases with CSF-HCRT1 < 110, the 34 patients with negative PSG-MSLT carried HLA-DQB1*0602 less often (88.2% vs. 96.5%, p = 0.046), had fewer SOREMPs, and higher CSF-HCRT1 values in comparison to the 344 positive at the first PSG-MSLT. In suspected CDH, systematically measuring CSF-HCRT1 in the presence of a negative PSG-MSLT identifies about 10% additional NT1 cases (of which 15% without cataplexy), otherwise possibly misdiagnosed.

Cerebrospinal fluid (CSF) orexin-A is the gold-standard biomarker for narcolepsy type 1 (NT1), however, conventional radioimmunoassays (RIA) often suffer from cross-reactivity and overestimation, fueling long-standing conundrum regarding orexin detection in peripheral blood. In this study, we developed an ultrasensitive LC-MS/MS method (LLOQ = 0.1 pg/mL) incorporating a streamlined one-step protein precipitation protocol coupled with acid-shielding and cocktail-protection strategies to mitigate severe nonspecific adsorption and enzymatic degradation. Verification in paired CSF and blood samples from narcolepsy patients and controls revealed that orexin-B and peripheral orexins remain consistently below the detection limit (<0.1 pg/mL), proving that previously reported ng/mL levels in blood are analytical artifacts. Our LC-MS/MS approach resolved a 50-fold quantitative overestimation by RIA and significantly improved diagnostic resolution for narcolepsy type 2 (AUC = 0.73, P < 0.05) where RIA failed to achieve statistical significance (P = 0.297). This study establishes a high-specificity analytical framework as a practical reference standard for refined sleep disorder diagnostics and confirms that CSF orexin-A remains the currently the most reliable clinical biomarker.

Narcolepsy type 1: an environment-influenced disease.

Loss of cerebrospinal fluid hypocretin-1/orexin-A (Hcrt-1) immunoreactivity is a biomarker for narcolepsy type 1 (NT1). The current radioimmunoassay (RIA) does not allow precise quantification, limiting the assessment of disease severity and evolution. This study aimed to reproduce previously proposed workflows to quantify Hcrt-1 and Hcrt-2 by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), identify RIA antibody targets, and to compare two purification methods in their ability to identify patients with NT1. Solid phase extraction (SPE) and LC-MS/MS measurements of Hcrt-1 and -2 levels from 10 NT1 patients and 21 controls were implemented based on existing literature. Immunoprecipitation (IP) with magnetic beads coupled to the RIA antibody (Phoenix) was performed and peptides identified by MS. Finally, Hcrt-1 (full-length) and Hcrt-1 fragment1-16 levels were analyzed in 4 patients and 4 controls prepared from both workflows by nano-LC coupled to high-resolution mass spectrometry (nLC-HRMS). Despite linear calibration curves for Hcrt-1 and Hcrt-2 (R2> 0.99) could be assessed with LC-MS/MS, full-length Hcrt-1 concentrations were at the low end of the calibration curve with slightly lower levels in NT1 (p= 0.04). Hcrt-2 was undetectable. The discovery experiment with IP most reliably identified Hcrt-1 fragment1-16. SPE revealed much higher concentrations than IP. Hcrt-11-16-levels allowed distinguishing patients and controls after SPE and IP, whereas full-length Hcrt-1-levels after IP did not. Hcrt-11-16 appears stable and abundant in CSF of controls, allows identification of patients with NT1 and is a promising surrogate marker. SPE seems more suitable for further method validation in clinical routine.

Most patient-reported outcome measures for narcolepsy focus on excessive daytime sleepiness or do not focus on specific disease impacts (eg, cataplexy, cognitive difficulties, fatigue, daily function). The Functional Impacts of Narcolepsy Instrument (FINI) was developed to measure key functional impacts in people with narcolepsy type 1 and 2 (NT1/NT2). The instrument was developed separately in NT1/NT2 populations with input from patients, clinical experts experienced in narcolepsy management, and clinical outcome scientists. Development included: patient experience interview studies informing item development; item development including de novo items, and modified/original items from the Patient-Reported Outcomes Measurement Information System (PROMIS) library; two waves of patient-debriefing interviews testing initial/modified item drafts; determination of factor structure using exploratory factor and Rasch analyses, and confirmatory factor analyses for NT2; consensus meetings between clinical sleep experts/clinical outcome experts to finalize the FINI draft items and structure with a 7-day recall period. The final FINI for NT1 had 28 items within 6 independent domains: Tiredness, Cognitive Functioning, Cataplexy, Social Activities, Everyday Activities, and Everyday Responsibilities. The final NT2 version (FINI-NT2) included the same items excluding the Cataplexy domain (23 items). Final FINI and FINI-NT2 items demonstrated good content validity and covered the main impacts of NT1 and NT2, respectively, as confirmed by patient interviews, exploratory/confirmatory factor analyses, and Rasch analysis. The novel FINI assesses key functional impacts of narcolepsy in people with NT1/NT2 for use across clinical settings, and adds to the number of existing clinical outcome assessments for central disorders of hypersomnolence.

Abstract Introduction Narcolepsy Type 1 (NT1) is often under-recognized, partly due to symptom overlap with other sleep and psychiatric disorders. With emerging therapies targeting orexin deficiency, timely and accurate diagnosis is critical. This program aimed to characterize current challenges faced by clinicians in NT1 recognition, diagnosis, and management, and to identify potential strategies to support practice improvement. Methods This ongoing, multi-phase initiative involved five in-clinic educational sessions across U.S. sleep centers and a national symposium held at SLEEP 2025. Clinicians completed pre- (n=99) and post-session (n=57) or pre- (n=175) and post-symposium (n=165) surveys assessing perceived challenges around NT1 diagnosis and care. A longitudinal follow-up survey will evaluate how site-specific strategies developed during the sessions were sustained in clinical practice. Results Across in-clinic sessions, clinicians identified key barriers to timely NT1 recognition and diagnosis, including overlapping symptoms with other sleep or psychiatric disorders (50%), lack of familiarity with diagnostic criteria (32%), and limited reporting of cataplexy (35%). System-level challenges included inconsistent knowledge of diagnostic criteria across multidisciplinary teams (27%), and difficulty coordinating referrals across health systems (40%). To address identified gaps, clinicians proposed strategies including integrating the Epworth Sleepiness Scale into assessment and referral workflows and enhancing clinician education on pathophysiology and symptom recognition. Teams committed to increase NT1 symptom screening during visits and regularly discuss emerging therapies and clinical data. Insights from the national symposium aligned with these findings, with the top challenge identified as differentiating NT1 from other disorders. Following the sessions, knowledge of pathophysiology including the role of orexin deficiency increased from 44% to 89%, confidence in differentiating NT1 from other disorders improved from 47% to 86%, and familiarity with emerging treatment mechanisms and clinical trial data rose from 42% to 82% (all Likert 3/4/5), suggesting that targeted educational programs can help address current challenges in NT1 care. Conclusion This initiative highlighted national barriers to NT1 recognition and diagnosis and identified actionable strategies, including enhanced symptom screening, team education, care coordination, and review of emerging therapies, to support timely, accurate, and multidisciplinary NT1 management. Support (if any) This program was supported by an educational grant from Takeda Pharmaceuticals U.S.A., Inc.

Abstract 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

Abstract Introduction As targeted treatments for narcolepsy type 1 (NT1) emerge, timely diagnosis and care planning are essential to optimize outcomes. This ongoing initiative aims to identify and address barriers to NT1 recognition and treatment to support practice improvements and patient-centered care. Methods Patient surveys (N=38) were collected in August 2025 through collaboration with the Hypersomnia Foundation to inform an ongoing initiative at five US sleep centers. Results from patient surveys are reviewed at expert-led clinic-based sessions to identify patient needs in care, and case-based discussions challenge participants to apply the latest evidence into practice scenarios. Pre- and post-session surveys are designed to measure the impact on knowledge, confidence, and self-reported performance. Additionally, clinicians will develop strategies for care improvement. Results The top patient-reported barriers to NT1 diagnosis were finding a provider familiar with sleep disorders (42%) and limited appointments/referrals (26%). Ninety-five percent waited over 1 year for formal diagnosis (1-5 years, 71%; 5-10 years, 19%; &amp;gt;10 years, 5%). Narcolepsy symptoms had a significant impact on daily living (82%; 4 or 5 on a 5-point Likert scale), with many patients reporting fatigue (63%), excessive daytime sleepiness (58%), disrupted nighttime sleep (53%), sleep paralysis (50%), and cataplexy (37%) despite treatment. Patients’ top treatment goals were finding a treatment that is effective for their symptoms/type of narcolepsy (61%) and that improves daily functioning/quality of life (55%). However, 19% (1, 2, or 3 on a 5-point Likert scale) reported their care team had not discussed treatment options and 37% (1, 2, or 3 on a 5-point Likert scale) were not routinely asked about treatment goals. Patients were interested in discussing the cause of narcolepsy (63%) and their preferences for treatment (61%). Preliminary findings from the clinic-based sessions have generated practical strategies to address identified gaps in NT1 care. Conclusion Patient surveys uncovered persistent challenges in NT1 diagnosis, communication, and treatment planning. Incorporating these perspectives and case-based scenarios into clinic-based sessions have the potential to improve focused approaches to care and can provide a foundation for integrating evidence into practice as the NT1 landscape evolves. Support (if any) This program was supported by an educational grant from Takeda Pharmaceuticals U.S.A., Inc.

Abstract Introduction Sleep inertia (characterized by profound difficulty waking up with grogginess, disorientation, and cognitive impairment immediately after awakening) is a core idiopathic hypersomnia symptom and may also be experienced by individuals with narcolepsy. Sleep inertia in individuals with narcolepsy is not well studied. This post-hoc analysis of the DUET study (NCT05875974) evaluated sleep inertia in narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2) subgroups of the DUET narcolepsy cohort. Methods DUET was a phase 4, prospective, open-label study with baseline (BL), titration/optimization, stable-dose, and end-of-treatment (EOT) periods. Exploratory outcomes included Psychomotor Vigilance Test (PVT; objective performance impairment) and Karolinska Sleepiness Scale (KSS; subjective sleepiness); both administered at BL and EOT, in the morning after overnight polysomnogram. The 10-minute PVT was completed at 10, 40, and 90 minutes after awakening. The KSS, a single-item, 9-point scale, was completed upon awakening and immediately before and after the PVT assessments. Separate nonlinear, mixed-effects regression models were applied to PVT lapses and KSS ratings to estimate objective and subjective sleep inertia magnitudes, respectively, for NT1 and NT2, along with sleep inertia dissipation time constants for the overall cohort. Treatment-emergent adverse events (TEAEs) were assessed. Results Of 55 enrolled participants with narcolepsy, 26 and 29 had NT1 and NT2, respectively. Most (NT1/NT2) were female (73.1%/72.4%) and White (73.1%/86.2%); 16/26 and 18/29 completed the study. Based on PVT lapses, objective sleep inertia ±SE (NT1/NT2) at BL was 33.1±6.2/14.9±3.2, and at EOT was 8.3±1.7/3.2±1.1 (BL-to-EOT changes [95% CI]: −24.8 [−35.5, −14.1] and −11.8 [−17.4, −6.1]). Based on KSS ratings, subjective sleep inertia ±SE (NT1/NT2) at BL was 1.1±0.6/1.1±0.5, and at EOT was 0.8±0.5/1.3±0.5 (BL-to-EOT changes [95% CI]: −0.3 [−1.9, 1.2] and 0.2 [−1.3, 1.6]). Sleep inertia dissipation time constants ±SE were 1.6±0.3h (PVT) and 0.4±0.1h (KSS) for the overall cohort. TEAEs were consistent with the known LXB safety profile. Conclusion Participants with narcolepsy, especially NT1, demonstrated objective sleep inertia at BL. Participants with NT1 or NT2 showed substantial improvements in objective sleep inertia with LXB treatment. Support (if any) Jazz Pharmaceuticals

Abstract Introduction Pitolisant is a histamine 3 receptor antagonist/inverse agonist approved for treatment of excessive daytime sleepiness (EDS) or cataplexy in adult patients with narcolepsy and for EDS in pediatric patients aged ≥6 years with narcolepsy. HBS-301, an optimized pitolisant formulation, with a gastro-resistant coating, at a higher dose (up to 60 mg), has been developed to potentially provide an improved treatment option for patients with narcolepsy or idiopathic hypersomnia (IH). Methods HBS-301-CL-301 and HBS-301-CL-302 are two global phase 3, randomized, double-blind, parallel-group, placebo-controlled studies to examine the efficacy and safety of HBS-301 in patients with narcolepsy and IH, respectively. These studies will consist of a screening/baseline period, an 8-week double-blind treatment period (2-week titration [week 1, 30 mg; week 2, 60 mg], 3-week flexible-dose, and 3-week stable-dose periods), an optional open-label extension period (1 year), and 30 days of safety follow-up. Results In HBS-301-CL-301, ~258 adult participants with narcolepsy (type 1 or 2) will be randomized to receive HBS-301 or placebo (1:1); ~50% of participants will have an average weekly rate of cataplexy ≥3 over 2 consecutive weeks during screening. The primary endpoint will be the change from baseline to Week 8 in EDS as measured by the Epworth Sleepiness Scale (ESS). Key secondary endpoints include MWT sleep onset latency, efficacy in treating cataplexy and fatigue, as well as the onset of efficacy in treating EDS and cataplexy. In HBS-301-CL-302, ~248 adult participants with IH will be randomized to receive HBS-301 or placebo (1:1). The primary endpoint will be the change from baseline to Week 8 in EDS as measured by the ESS. Secondary endpoints include severity of IH symptoms as measured by the IHSS, sleep inertia, and fatigue, as well as the onset of efficacy and IH symptoms. In both studies, safety and pharmacokinetic concentrations of pitolisant will be examined. Conclusion These studies will determine the efficacy and safety of HBS-301, an optimized pitolisant formulation, with a gastro-resistant coating, at a higher dose (up to 60 mg), in patient populations with narcolepsy or IH. Support (if any) Harmony Biosciences