bluuebunny/crossref_metadata_2025_split huggingface dataset:
0649 Samelisant Improves the Symptoms of Excessive Daytime Sleepiness in Narcolepsy: Results from a Phase-2 Study
Authors: Nirogi Ramakrishna , Ravula Jyothsna , Jayarajan Pradeep , Goyal Vinod Kumar , Benade Vijay , Jetta Satish , Shinde Anil , Dogiparti Dhanunjay , Subramanian Ramkumar , Kalaikadhiban Ilayaraja , Jasti Venkat 
Published: April 2024

Abstract

Introduction
Narcolepsy is a lifelong sleep disorder characterized by a classic tetrad of excessive daytime sleepiness (EDS) with irresistible sleep attacks, cataplexy, hypnagogic hallucination, and sleep paralysis. The currently available treatments suffer from major limitations like side effects, modest efficacy or they must be prescribed in combination. Samelisant (SUVN-G3031) is a potent and selective histamine 3 receptor inverse agonist. In orexin knockout mice, samelisant produced wake-promoting and anticataplectic effects suggesting its potential therapeutic utility in the treatment of narcolepsy. Safety and tolerability studies in animals and healthy human volunteers suggest a favorable risk/benefit profile for samelisant.

Methods
Samelisant had been evaluated as monotherapy in a Phase-2 proof of concept study in the USA and Canada for the treatment of EDS in patients with narcolepsy (ClinicalTrials.gov Identifier: NCT04072380). Patients diagnosed with narcolepsy as per ICSD-3 criteria, aged between 18 to 65 years with an Epworth Sleepiness Scale (ESS) score of ≥12 and mean Maintenance of Wakefulness Test (MWT) time of &lt; 12 min were recruited in the study. A total of 190 patients were randomized into 3 treatment arms (placebo, samelisant 2 mg and samelisant 4 mg) in 1:1:1 ratio and received either placebo or samelisant, once daily for 2 weeks. The primary efficacy endpoint was change in ESS score from baseline to Day 14. Secondary endpoints were changes from baseline to week 2 in Clinical Global Impression - Severity (CGI-S) and MWT scores. The medical monitor and the data safety monitoring committee monitored safety throughout the study.

Results
The baseline characteristics and demographics were consistent with the general narcolepsy population and equally distributed between treatment groups. The study met the pre-specified primary efficacy endpoint. In comparison against placebo, samelisant as monotherapy demonstrated statistically significant (p&lt; 0.024) and clinically meaningful reduction (-2.1 point) in EDS measured by ESS. Samelisant was generally safe and well tolerated.

Conclusion
Samelisant holds promise as a monotherapy treatment of EDS in narcolepsy.

Support (if any)
0651 Pharmacokinetics of Morning and Nighttime Doses of KP1077, an Investigational Treatment for Idiopathic Hypersomnia
Authors: Braeckman Rene , Smith Adam , Lubert Adam , Vrishabhendra Leela 
Published: April 2024

Abstract

Introduction
KP1077 is under development as an oral medication for the treatment of rare sleep disorders with Excessive Daytime Sleepiness (EDS), including idiopathic hypersomnia (IH). The active ingredient in KP1077 is serdexmethylphenidate (SDX), a prodrug of d-methylphenidate (d-MPH). SDX is converted to d-MPH in the lower intestinal tract, with a delay and kinetics leading to a unique pharmacokinetic (PK) profile and an extended duration product. The objectives of the study were to assess the PK and safety after single morning and nighttime doses in healthy volunteers.

Methods
Heathy adult subjects received single oral doses of 240 mg SDX, either in the morning or at night, just before bedtime, in a randomized fashion with a washout of 6 days between treatments. Multiple blood PK samples and safety parameters were collected after each administration.

Results
A total of 15 subjects (9 males/6 females) were randomized with 14 completing both treatments. Both treatments were well-tolerated with adverse events typical for d-MPH. After the morning dose, d-MPH exposure was characterized by little or no d-MPH exposure for the first 4 hours followed by a gradual rise up to ~7 hour post-dose (Tmax), followed by a gradual decline. The rise in d-MPH concentrations after the nighttime dose was even more gradual than after the morning dose, with substantial levels reached around 10 hours postdose and a statistically significantly longer Tmax of 15 hours. Mean d-MPH peak concentrations were lower after the evening dose (22.0 ng/mL) compared to the morning dose (26.8 ng/mL) while total exposures (AUCinf) were similar (594 and 557 h*ng/mL, respectively).

Conclusion
Peak exposure of SDX-derived d-MPH and the bulk of the total d-MPH exposure after a nighttime dose of SDX occurs during the next morning compared to a morning dose where most exposure occurs the same day. This difference is likely due to a longer intestinal transit time and lower intestinal activity during the nighttime sleeping hours. This delay supports nighttime dosing of SDX in patients with IH who suffer from EDS and Sleep Inertia (difficulty waking up in the morning).

Support (if any)
Zevra Therapeutics
0652 Abnormal Sleep Slow Wave Morphology in Idiopathic Hypersomnia
Authors: Deshaies-Rugama Anne-Sophie , Mombelli Samantha , Blais Hélène , Sekerovic Zoran , Massicotte Miaclaude , Thompson Cynthia , Nigam Milan , Carrier Julie , Desautels Alex , Moderie Christophe , Montplaisir Jacques , Gosselin Nadia 
Published: April 2024

Abstract

Introduction
Abnormal cortical synchronization during sleep could affect the restorative function of sleep and consequently, increase daytime sleepiness. Slow wave (SW) density and characteristics provide a unique window of how cortical neurons synchronize during non-rapid eye movement (NREM) sleep. Here, we aimed at verifying whether NREM sleep SW density and characteristics differed between patients with idiopathic hypersomnia (IH) and healthy controls.

Methods
56 participants (38.18 ± 11.21 years old; 53% women) with diagnosed IH (full night of in-laboratory polysomnography followed by a multiple sleep latency test; MSLT) were compared to 128 healthy controls (38.16 ± 14.02 years old; 59% women) studied at our center and matched for age and sex. Exclusion criteria were apnea-hypopnea index ≥15, psychiatric conditions, neurological disorders, other sleep disorders, shift work, and use of psychoactive medications before the PSG. SW were automatically detected on C3 and C4 electrodes in N2 and N3 sleep stages. Group X Sleep cycle ANOVAs were used for SW density and characteristics (e.g., duration, amplitude, and slope, averaged for C3 and C4). Age was added as a control variable in all analyses. Statistical significance was set at p &lt; 0.05.

Results
Several group effects were found where, compared to healthy controls, IH patients had significantly smaller slow wave negative amplitudes, peak-to-peak amplitudes, and smoother slopes (p &lt; 0.05). The only significant interaction was for slow wave negative amplitudes, where the sleep cycle effect observed in healthy controls was not found in IH patients (p &lt; 0.05).

Conclusion
Compared to healthy controls, IH patients have slow wave characteristics that suggest a lower cortical synchrony during NREM sleep and could explain the non-restorative effect of sleep often reported by these patients.

Support (if any)
This project was made possible by an award from the American Academy of Sleep Medicine Foundation, a foundation of the American Academy of Sleep Medicine. Nadia Gosselin hold the Canada Research Chair in sleep disorders and brain health.
0654 Longitudinal Symptoms of Idiopathic Hypersomnia in the Hypersomnia Foundation Registry
Authors: Chattaraj Audrika , Saini Prabhjyot , Bliwise Donald , Freeman Amanda , Murray Catherine Friederich , King Rebecca , Nichols Kendall , Ong Jason , Plante David , Trotti Lynn Marie 
Published: April 2024

Abstract

Introduction
Idiopathic hypersomnia (IH) is a chronic neurologic disorder characterized by excessive daytime sleepiness; difficulty awakening, long sleep durations, and cognitive symptoms are variably present. Although spontaneous remission has been reported, little is known about IH’s natural history. We characterized longitudinal changes in a large registry of people with IH.

Methods
Data were collected via the Hypersomnia Foundation's registry at CoRDS from 6/2016 through 8/2023. Participants were considered to have IH if they selected IH from a dropdown diagnosis menu, had a current diagnosis of IH or were told by a doctor that IH explained their symptoms, and reported at least 7 hours sleep/night. Participants who met these criteria and completed the questionnaire at least twice over at least 6 months were included in analyses. Responses from each participant’s earliest and latest entries were compared, via paired t-test for continuous variables and McNemar test for categorical.

Results
Three hundred twenty-three participants with IH (mean age 35.0 +/-SD 12.2; 86.5% women) had an average time between first and last response of 2.4 (+/-1.4) years. Most participants (79.5%) were on IH medications at both timepoints; 5.6% started and 6.5% stopped IH treatment between timepoints. The most used medications at both timepoints were modafinil (21.7%), amphetamine-dextroamphetamine (19.8%), methylphenidate (17.7%), and armodafinil (13.6%). The only medication for which there was a significant usage change over time was modafinil, decreasing from 33.0% to 25.1%, p = 0.0005. Between the two time points, there was no change in proportion endorsing daily excessive sleepiness, long sleep durations, intentional or unintentional naps, requiring multiple alarms, or brain fog, but there was slight improvement in difficulty awakening (78.7% to 73.0%, p=0.01) and slight worsening of automatic behaviors (9.9% to 12.8%, p = 0.05). The most endorsed daily symptoms at final assessment were difficulty awakening (73.0%), excessive sleepiness (61.8%), requiring multiple alarms (55.3%), brain fog (48.4%), and poor memory (43.4%).

Conclusion
Over 2½ years, symptoms of IH remained largely stable. While this may suggest a lack of progression over time, the high proportion of residual symptoms also suggests a failure of current treatments to achieve comprehensive symptom control.

Support (if any)
NS111280
0658 Validity and Reliability of the Pediatric Narcolepsy Patient-Reported Outcomes Scale (PN-PROS)
Authors: Maski Kiran , Mignot Emmanuel , Narang Indra , Marie Morse Anne , Meltzer Lisa 
Published: April 2024

Abstract

Introduction
There are currently no validated, patient-reported outcome measures for pediatric narcolepsy that assess disease burden, determine treatment efficacy, and guide future drug development. To ensure optimal clinical management of pediatric narcolepsy, we developed the Pediatric Narcolepsy Patient-Reported Outcomes Scale (PN-PROS) through literature review, content expert interviews, patient focus groups, and cognitive testing with patients (ages 9-17 years) and their parents. The aim of this study is to provide interim data from our multi-site validation and reliability study of the PN-PROS.

Methods
We performed field testing for validity and reliability of the PN-PROs in pediatric narcolepsy patients (9-17 years) with a comparator group of pediatric obstructive sleep apnea patients. We recruited participants from Boston Children’s Hospital, Stanford Medical Center, Toronto Hospital for Sick Children (SickKids), and Geisinger Medical Center, as well as from narcolepsy patient advocacy meetings and websites. Participants completed the PN-PROS, Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD), Peds QL, and PROMIS Life Satisfaction using the REDCap data capture platform. Participants completed the PN-PROS item bank 1 week later for test-retest reliability.

Results
83 pediatric patients with narcolepsy (mean age=15(2) years, 52.3% female, 26% non-Caucasian) and 60 pediatric patients with OSA (mean age=13.2(2.6), 46.3% female, 22% non-Caucasian) have completed all study measures. Discriminant Validity: Participants with narcolepsy reported a higher PN-PROS mean total score than participants with OSA [narcolepsy=126.9 (28.6), OSA=95 (31.2), p&lt; 0.001]; results retain significance controlling for age, race and gender [group main effect: F=36.6, p&lt; 0.001]. Content Validity: For participants with narcolepsy, the PN-PROS total score was significantly correlated with the ESS-CHAD (r=0.64, p&lt; 0.001), Peds QL (r=-0.84, p&lt; 0.001), and PROMIS Life Satisfaction (r=-0.55, p&lt; 0.001). Reliability: Internal consistent was strong for both participants with narcolepsy (Cronbach alpha=0.94) and OSA (Cronbach alpha=0.93). Test-retest reliability was high for both participants with narcolepsy (interclass coefficient=0.94) and OSA (interclass coefficient=0.93).

Conclusion
Interim results suggest the PN-PROS is a valid and reliable measure for the evaluation of symptom frequency and burden for pediatric patients with narcolepsy. Data collection is ongoing, utilizing additional sites in other regions of the United States to ensure generalizability of our findings.

Support (if any)
American Academy of Sleep Medicine
0659 Establishment of a Hypersomnia Board: A Multidisciplinary Approach to Complex Hypersomnia Cases
Authors: Mallampalli Antara , Sharafkhaneh Amir , Singh Supriya , Dang LeQuan , Moghtader Shahram , Crew Earl , Thomas Tara , Agrawal Ritwick 
Published: April 2024

Abstract

Introduction
Narcolepsy and other central disorders of hypersomnolence are conditions that often present challenging diagnostic and management dilemmas for clinicians. Inspired by the example of the Oncology Tumor Board system, we established a multidisciplinary board to aid in managing these complex sleep disorders with the specific goals of enhancing patient care while also offering additional educational opportunities for trainees. Here we present our initial experience with this Hypersomnia Board.

Methods
Beginning in early 2022, clinical practitioners from various disciplines relevant to the care of hypersomnia patients were recruited for board participation. Participants represent sleep medicine, psychiatry, neurology, clinical psychology, and pharmacy. Board meetings are held virtually once a month. Cases are selected for presentation from the participants’ respective clinics and are presented by the treating physicians. Outcomes of the discussion including any recommended changes to the management plan are documented in the patient’s medical record.

Results
To date, 14 hypersomnia cases have been presented to the board for discussion. Clinical dilemmas prompting board discussion have included refractory daytime sleepiness despite standard therapies, uncertainty related to a previous narcolepsy diagnosis, confounding mental health issues, or medication side effects. Etiology of hypersomnia was thought to be narcolepsy type 1 in 6/14 patients, NT2 in 4/14, idiopathic hypersomnia in 2/14, and obstructive sleep apnea (primary or co-morbid) in 6/14. Comorbid mental illness was common in the cases discussed (PTSD in 5/14, depression in 7/14, both in 2/14), as was concomitant OSA. Board discussion led to recommendations for medication changes in 4/14 and to other interventions (such as earlier referral to mental health specialists) or additional diagnostic testing in the remainder of patients. Clinicians involved including trainees have reported satisfaction with the opportunity to better collaborate on management of these complex cases and the added exposure to challenging hypersomnia cases.

Conclusion
The management of complex and relatively rare sleep disorders such as narcolepsy and other central disorders of hypersomnolence often requires multidisciplinary input, which our Hypersomnia Board has been able to facilitate. Further research is needed to assess the impact on patient-centered outcomes and on improving access to coordinated care for these disorders.

Support (if any)
None
0661 Slow Wave Alterations During Nocturnal Sleep in Hypersomnolence Disorder
Authors: Cook Jesse , Riedner Brady , Tran Michelle , Rumble Meredith , Vascan Ana Maria , Plante David 
Published: April 2024

Abstract

Introduction
Hypersomnolence disorder (HD) is characterized by excessive daytime sleepiness of undetermined etiology. HD is poorly understood with no established biomarkers. Slow waves during non-rapid eye movement (NREM) sleep are associated with the restorative aspects of sleep. Since nonrestorative sleep is a core feature of HD, it is hypothesized that alterations in sleep slow waves may be an HD feature. Thus, this investigation was designed to evaluate slow wave activity (SWA) and characteristics (SWC) in HD, relative to healthy sleeper controls (HSC).

Methods
60 unmedicated clinical patients meeting criteria for HD were compared against 29 HSC. All participants underwent polysomnography (PSG) and multiple sleep latency testing (MSLT) at Wisconsin Sleep, with other subjective and objective measures also collected. All-night, six-channel electroencephalography (EEG) data from ad libitum, nocturnal PSG were processed using a validated automatic protocol followed by manual inspection. For each channel of artifact-free EEG from NREM staged epochs, normalized SWA (1-4.5hz) and SWC (incidence, pre-slope, post-slope, and peak amplitude) were calculated in accordance with previously utilized methodology. Post-hoc analyses evaluated slow wave characteristic differences between low- and high-amplitude (≥40μV) slow waves. Linear regression compared groups across normalized SWA and SWC, with adjusted models accounting for relevant, available covariates.

Results
HD participants were young- to middle-aged (mean age = 28.6 ± 8.6) and predominantly female (percentage female = 78.3%), and HSC were comparable. HD participants displayed significantly reduced SWA across all channels, with effects most pronounced frontally and centrally, and greater in the left relative to right hemispheres. HD participants displayed significant alterations across all SWC, with generally consistent patterns of reductions in incidence, amplitude, and slope across frontal and central EEG derivations. SWC alterations varied significantly by both brain region and low- versus high-amplitude waves.

Conclusion
This study demonstrates and expands on a growing evidence base that alterations in slow waves may be a core feature of HD. Targeted studies that manipulate NREM slow waves in disorders of unexplained hypersomnolence, including modification of incidence and morphology varied by brain region and hemisphere, are required to clarify whether alterations in slow waves are causal to symptoms of hypersomnolence.

Support (if any)
AASM Foundation (138-SR-16) and NINR (R21NR018288)
0662 Accurate Automated Sleep Staging of Narcoleptic Patients Using a Machine Learning Model
Authors: Cakir Ahmet , Josephs David , Kleinschmidt Dave , Pathmanathan Jay , Donoghue Jacob , Chan Alexander 
Published: April 2024

Abstract

Introduction
Accurate sleep staging of EEG data from polysomnography (PSG) is important in the diagnosis of narcolepsy. Human sleep staging is costly and labor intensive, but automated sleep staging algorithms must be rigorously tested in narcoleptic patients to ensure valid performance. PSGs of narcoleptic patients often tend to be more fragmented and variable than in non-narcoleptic populations, making it challenging for both humans and automated algorithms to accurately stage sleep. Here, we evaluate the performance of a deep learning model validated in a general sleep clinic population for staging nocturnal PSGs in patients with narcolepsy.

Methods
SleepStageML™, a deep-learning model for performing sleep staging on EEG signals, was trained on a large database of polysomnography recordings from a heterogenous population within the Beacon Clinico-PSG Database. The algorithm was evaluated on a held-out set of 28 overnight PSGs from patients with narcolepsy or hypersomnolence and 57 overnight PSGs from individuals without narcolepsy or hypersomnolence. Each PSG was manually scored by a human expert, and the performance of the automated algorithm was compared across the two cohorts.

Results
Automated sleep staging performance was high across both cohorts. The average F1-score for the control cohort and the narcolepsy cohort was 0.758 and 0.744 respectively. The positive percent agreements (PPAs) for the control cohort were 87%, 38%, 84%, 91%, and 93% for stages W, N1, N2, N3, and R respectively. For the narcolepsy cohort, the PPAs across the same stages were 91%, 33%, 81%, 86%, and 88% respectively. The algorithm’s median absolute error in estimating REM latency, REM duration, and REM percentage in the control cohort was 1.25 minutes, 8.5 minutes, and 2% points, respectively. The same metrics for the narcolepsy cohort were 2.75 minutes, 11.75 minutes, and 3% points respectively.

Conclusion
A deep-learning model trained on diverse data automatically and accurately staged PSGs from narcoleptic patients and was comparable to performance of a human expert. The algorithm estimated REM parameters accurately in both cohorts. Automated staging algorithms like the one described here have the potential to accelerate diagnosis and monitor therapeutic efficacy for narcolepsy treatments by more efficiently and consistently staging sleep.

Support (if any)
0663 Assessing the Predictive Accuracy of Quantitative Electroencephalography in the Diagnosis of Narcolepsy
Authors: Nguyen Kim , Amico Francesco , Meskill Gerard , Ruan Cheng , Meskill Sarah 
Published: April 2024

Abstract

Introduction
Narcolepsy is a chronic neurological disorder characterized by excessive daytime sleepiness (EDS), disturbed nocturnal sleep, and features of rapid eye movement (REM) sleep dissociation (i.e., cataplexy, hypnagogic hallucinations, sleep paralysis, and shortened REM-onset latency). the diagnosis is typically made by a multiple sleep latency test (MSLT), with reported sensitivity of 90% and specificity of 95%. However, MSLT can be difficult to schedule and can be influenced by other factors, such as anxiety, fear, and prescription medications (e.g., antidepressants). Building upon previous research demonstrating frequency- and region-specific electroencephalographic (EEG) imbalances in patients with narcolepsy, the present study aimed to assess the ability of quantitative electroencephalography (qEEG) to diagnose narcolepsy as compared to the reference standard MSLT.

Methods
Patients seen at an integrative health center in Houston, TX and identified with symptoms of narcolepsy, including chronic fatigue, underwent qEEG. If qEEG was concerning for narcolepsy, patients were referred to a sleep specialist and were included if they subsequently underwent an MSLT.

Results
Seventy-three patients (64 females, 9 males) were recruited with a mean age of 35±12.5 years. Of these, 35 patients had cataplexy. Sixty-nine (94.5%) of the 73 patients with positive qEEG had positive MSLT for narcolepsy: 31 (88.6%) in the cataplexy group and 38 (100%) in the non-cataplexy group. Of the remaining 4 patients, 2 had idiopathic hypersomnia on MSLT.

Conclusion
The findings suggest that qEEG holds promise as a valuable tool for diagnosing narcolepsy, potentially contributing to improved and timely clinical assessments. While potential variations in accuracy within specific symptoms should be considered, more research in the same population sample should evaluate the role of frequency- and region-specific EEG imbalances.

Support (if any)