Introduction Narcolepsy is a serious neurological condition causing sleep-wake dysregulation and is characterized by excessive daytime sleepiness (EDS) and cataplexy. Cataplexy is seen in ...approximately 70% of patients and is a sudden reduction or loss of muscle tone while a patient is awake. Narcolepsy interferes with cognitive, psychological, and social functioning, increases the risk of accidents, and is associated with greater mortality. Depression is reported in up to 57% of patients. Currently-approved treatments are few for this under-diagnosed orphan condition, and are limited by variability in efficacy, tolerability issues and the need for scheduling. AXS-12 (reboxetine) is a highly selective and potent inhibitor of norepinephrine reuptake. The scientific rationale for developing AXS-12 for the treatment of narcolepsy is based on in vivo nonclinical physiological and pharmacological studies suggesting a strong role for adrenergic neurotransmission in cataplexy, anti-cataplectic effects of reboxetine in orexin-deficient mice, and positive preliminary clinical evidence from an open-label pilot study of reboxetine in patients with narcolepsy. Methods Reboxetine has been investigated in animal models of narcolepsy as well as in an open-label study in patients with narcolepsy. AXS-12 is being evaluated in a randomized, double-blind, crossover, placebo-controlled Phase 2 trial in narcoleptic subjects with cataplexy and EDS. Subjects are randomized equally to placebo for three weeks followed by AXS-12 for three weeks, or to AXS-12 for three weeks followed by placebo for three weeks. Outcomes measured include the change in the number of cataplexy attacks, maintenance of wakefulness, and reduction in sleepiness. Results In orexin-deficient mice, reboxetine treatment markedly reduced episodes of cataplexy and sleep attacks. In an open-label pilot trial in patients with narcolepsy, reboxetine significantly improved EDS and cataplexy versus baseline. Results from the double-blind, placebo-controlled Phase 2 study of AXS-12 in narcolepsy may be presented. Conclusion There is strong scientific rationale for the clinical development of AXS-12 for narcolepsy. If nonclinical and preliminary clinical findings are confirmed in late-stage studies, AXS-12 would represent a significant advance in the identification of safer, more effective treatments for narcolepsy without abuse potential. Support (If Any) Axsome Therapeutics Inc.
Introduction There is limited real-world data on dosing-related practices and perceptions among patients with narcolepsy treated with sodium oxybate (SXB). This study characterized dosing patterns ...among narcolepsy patients taking SXB. Methods An IRB-approved, cross-sectional, web-based survey targeting 100 patients ≥18 years, with narcolepsy taking SXB for ≥12 months, was conducted. Participants were recruited through community collaborations and patient panels. Participants were asked about their usual SXB dosing regimen and the frequency, reasons, methods and perceptions of varying their SXB dosing regimen to accommodate a change in routine. A subset (N=25) was asked telephonically about how the inability to adjust their SXB regimen would impact their lives. Descriptive statistics summarized survey responses. Voice responses were analyzed thematically. Results The cohort (N=110) was 80% female with a mean (±SD) age of 36.9 (±8.9) years. The majority took twice-nightly doses (95%) that were equally divided (80%) with 2.5-4 hours between doses (79%). Of 82 participants that reported varying their SXB dosing at least once in the past 6 months, 29% reported varying at least once-weekly and 35% reported varying several times per month. Staying up late (76%) and waking up early (67%) to be able to attend social events (49%), work events (46%), and eat meals within 2 hours of bedtime (46%) were the most common reasons for varying dosing. Changing timing of the first dose (84%), second dose (69%) and skipping the second dose (44%) were the preferred methods of adjusting. Seventy-nine percent of participants perceived their ability to vary dosing schedules as important. Of 25 participants who provided voice responses, 68% expressed that losing the ability to vary SXB dosing would have a highly negative impact on their lives. Conclusion Participants frequently vary their usual SXB dosing regimen to accommodate changes in their routine. Participants perceive the ability to vary as important and predict facing significant limitations in day-to-day activities if unable to vary. Further investigation to identify real-world SXB dosing, association with goal attainment, and impact on sleep and other outcomes is warranted. Support (If Any) Jazz Pharmaceuticals.
Abstract
This White Paper presents the results from a workshop cosponsored by the Sleep Research Society (SRS) and the Society for Research on Biological Rhythms (SRBR) whose goals were to bring ...together sleep clinicians and sleep and circadian rhythm researchers to identify existing gaps in diagnosis and treatment and areas of high-priority research in circadian rhythm sleep–wake disorders (CRSWD). CRSWD are a distinct class of sleep disorders caused by alterations of the circadian time-keeping system, its entrainment mechanisms, or a misalignment of the endogenous circadian rhythm and the external environment. In these disorders, the timing of the primary sleep episode is either earlier or later than desired, irregular from day-to-day, and/or sleep occurs at the wrong circadian time. While there are incomplete and insufficient prevalence data, CRSWD likely affect at least 800,000 and perhaps as many as 3 million individuals in the United States, and if Shift Work Disorder and Jet Lag are included, then many millions more are impacted. The SRS Advocacy Taskforce has identified CRSWD as a class of sleep disorders for which additional high-quality research could have a significant impact to improve patient care. Participants were selected for their expertise and were assigned to one of three working groups: Phase Disorders, Entrainment Disorders, and Other. Each working group presented a summary of the current state of the science for their specific CRSWD area, followed by discussion from all participants. The outcome of those presentations and discussions are presented here.
Many processes in the human body - including brain function - are regulated over the 24-hour cycle, and there are strong associations between disrupted circadian rhythms (for example, sleep-wake ...cycles) and disorders of the CNS. Brain disorders such as autism, depression and Parkinson disease typically develop at certain stages of life, and circadian rhythms are important during each stage of life for the regulation of processes that may influence the development of these disorders. Here, we describe circadian disruptions observed in various brain disorders throughout the human lifespan and highlight emerging evidence suggesting these disruptions affect the brain. Currently, much of the evidence linking brain disorders and circadian dysfunction is correlational, and so whether and what kind of causal relationships might exist are unclear. We therefore identify remaining questions that may direct future research towards a better understanding of the links between circadian disruption and CNS disorders.
Abstract
Introduction
Recent studies reported the diagnostic value of sequential occurrence of sleep stages (stage transition) in addition to the conventional sleep macrostructure (sleep onset REM ...period) for diagnosis of narcolepsy type 1. However these analyses did not utilize the information of bout duration which may potentially serve as a marker for sleep stage continuity. We focused on the variation of bout (episode) duration in the nocturnal PSG records from hypersomnia patients to investigate the clinical relevance and found the specific changes in subjects with narcolepsy type1.
Methods
Data were obtained from nocturnal PSG data of 460 consecutive subjects who underwent diagnostic PSG during Oct 2014 to Nov 2017 for the differential diagnosis of hypersomnia. After exclusion of cases with medication and comorbid sleep disorders, total 207 subjects (M/F=123/84, age 26.5(9.1) mean(SD)) with written informed consent were included in this study (29 narcolepsy type1, 30 narcolepsy type2, 63/49 idiopathic hypersomnia with/without long sleep time, 36 non hypersomnia control. To further evaluate the continuity / stability of nocturnal sleep PSG, we analyzed bout counts of each sleep stage, mean bout duration (min), and median values of all NREM and REM sleep episodes. We additionally calculated the correlation of these variables with subjective and objective sleep quality indexes.
Results
Narcolepsy type 1 showed significant increase in N1 mean bout duration (1.54(0.54) vs 1.13(0.35) min) and significant decrease in REM mean bout duration (9.10(2.73) vs 13.43(4.57) min) compared to other conditions. N1 and REM sleep median values showed the similar significant changes (long N1: 2.40(1.20) vs 1.55(0.78) min and short REM: 13.20(4.9) vs 19.20(6.21) min) in narcolepsy type1. We confirmed that both markers were correlated with perceived number of nocturnal awakenings and also showed good correlation with sleep transition index in each sleep stage.
Conclusion
Our new analyses revealed the diagnostic value of sleep bout duration, which could reflect the REM sleep instability and compensatory increase in N1 sleep in narcolepsy type1. Further clinical relevance of these bout length markers are required.
Support (If Any)
None.
Abstract
Introduction
REM sleep without atonia (RSWA) occurs in up to 90% of narcolepsy patients. REM behavior disorder (RBD), however, is reported to occur in only 12% to 36% of patients with ...narcolepsy. Use of RSWA has been proposed as an additional marker for narcolepsy diagnosis and as a tool to differentiate between narcolepsy and idiopathic hypersomnia. We describe a case of narcolepsy without cataplexy (N-C) with RSWA on polysomnogram (PSG), but no RBD on PSG or by history.
Report of Case
A 26 year old female with history of depression, anxiety, and migraine headaches presented with excessive daytime sleepiness requiring daytime naps since childhood. She endorsed sleep paralysis but not hypnagogic hallucinations, dream enactment or cataplexy. Sleep disordered breathing or other abnormalities were absent on overnight PSG. RSWA was seen, however, video recording did not reveal dream enactment behavior. The subsequent multiple sleep latency test showed a mean sleep latency of 3 minutes over 5 naps and 2 sleep onset REM periods.
Conclusion
REM related motor findings occur at a higher frequency in patients with narcolepsy than in the general population. Hypocretin deficiency is believed to be the major determinant of REM sleep motor dysregulation observed in narcolepsy. Patients with narcolepsy with cataplexy (N+C) are more frequently involved than patients with N-C.
RBD associated with narcolepsy differs from idiopathic RBD in that it has equal gender predominance, earlier age at onset, and is associated with less violent and less complex behaviors. Interestingly, RSWA may be absent in RBD with narcolepsy. In addition, RSWA in narcolepsy is frequent even in the absence of RBD. This highlights the need to develop diagnostic criteria for RBD specific to the context of narcolepsy.
RSWA is seen in high frequency in narcolepsy and should be strongly considered as a secondary diagnostic criteria.
Abstract
Introduction
The objective was to estimate the prevalence of narcolepsy and idiopathic hypersomnia (IH) and the use of diagnostic sleep tests in a large US healthcare claims database. There ...are no recent data in a large US population.
Methods
Nationwide medical/prescription claims (Symphony Health) were utilized to assess the prevalence of diagnosed narcolepsy and IH per 100,000 persons for each calendar year (2013–2016). Approximately 66 million persons annually were available for review. Cases were identified as having ≥2 claims with a narcolepsy (or IH) diagnosis within 6 months, or for narcolepsy, a diagnosis following multiple sleep latency testing (MSLT) or maintenance of wakefulness testing (MWT). Direct standardization was applied to narcolepsy prevalence to control for possible changes in the age-sex distribution of the database. Use of diagnostic sleep tests (polysomnography PSG, MSLT/MWT, and home sleep apnea testing HSAT) was also reported as a rate per 100,000 persons tested.
Results
Standardized narcolepsy prevalence increased from 37.0 per 100,000 persons (95% confidence interval CI 36.7–37.3) in 2013 to 42.1 (95% CI 41.9–42.4) in 2016. This was a 13.8% increase over the 4 years, with annual increases of 8.4%, 2.5%, and 2.4% in 2014, 2015, and 2016, respectively. Prevalence of IH increased by 33.8% from 2013 to 2016 (7.7 to 10.3 per 100,000 persons) with 13.0%, 2.3%, and 15.7% annual increases, respectively. During 2013 to 2016, use of PSG declined 13.9% (677.6 to 583.6 per 100,000 persons) and use of MSLT/MWT also declined 22.1% (17.2 to 13.4), while use of HSAT increased 118.2% (96.8 to 211.2).
Conclusion
The prevalence of both narcolepsy and IH increased over the study period (2013–2016), with a larger percentage change in IH than narcolepsy. The increasing prevalence of narcolepsy slowed in the latter part of the study period, while IH increased. Further research is needed to understand the changing utilization patterns for sleep testing and the etiology of changes in the prevalence of narcolepsy and IH.
Support (If Any)
Jazz Pharmaceuticals.
Abstract
Introduction
The HARMONY III study is assessing long-term (up to 5 years) safety and efficacy of pitolisant, the first potent and highly selective histamine H3-receptor antagonist/inverse ...agonist, in the treatment of patients with narcolepsy.
Methods
This ongoing, pragmatic, open-label, multicenter study evaluated the effect of pitolisant (18 or 36 mg once daily) in adult patients with narcolepsy (with or without cataplexy) according to ICSD-2 criteria with excessive daytime sleepiness (EDS; Epworth Sleepiness Scale ESS score ≥12). Concomitant use of stimulants and anticataplectic agents was permitted. The 1-year results are presented here.
Results
Of 102 patients who received study drug, 73 were not previously treated (de novo) with pitolisant; 29 were previously treated (compassionate use program n=16, another pitolisant trial n=13). Mean age was 36 years; 44.1% were male. At baseline, mean ESS was 17.1 ± 3.1; 73.5% of patients had cataplexy. Sixty-eight patients completed ≥12 months of treatment. Mean pitolisant exposure was 260 and 548 days for de novo and previously treated patients, respectively; 72% of patients received pitolisant 36 mg/d. During this 12-month period, 56.9% of patients reported adverse events: headaches (11.8%), insomnia (8.8%), weight gain (7.8%), anxiety (6.9%), depression (4.9%), and nausea (9%). Mean ESS reduction was 4.3 points overall; 4.9 (P<0.01) in de novo patients and 4.2 in previously treated patients. Overall, 63.2% (43/68) of patients were responders (ESS final ≤10 and/or ESS baseline - ESS final ≥3) and 36.8% (25/68) were normalized (ESS final ≤10); mean ESS decreased from 15.3 to 6.6 in normalized patients. Partial and total cataplexy attacks were reduced (-64% and -75%, respectively), as were hypnagogic hallucinations (-54%) and sleep paralysis (-63%).
Conclusion
This 1-year analysis of a long-term, open-label study supported the safety and efficacy of pitolisant for the treatment of EDS in narcolepsy and cataplexy in narcolepsy.
Support (If Any)
Study funded by Bioprojet, France.
Abstract
Introduction
Objectively measured total sleep time (TST) greater than 11 hours is a diagnostic criterion for idiopathic hypersomnia (IH). Guidelines for quantifying TST using extended ...duration polysomnography (PSG) are well established, however, optimal actigraphic parameters to quantify excessive sleep time in IH are not clear. Since device settings such as activity threshold and immobility time can sizably impact actigraphically-derived sleep and wake values, this investigation was conducted to determine the optimal actigraphy settings to quantify TST relative to polysomnography (PSG) in IH.
Methods
Thirteen individuals with IH underwent nocturnal, ad-libitum PSG while concurrently wearing the Actiwatch-2 (AW2) on their nondominant wrist. PSG lights-off and lights-on time-stamps were used to create AW2 rest intervals. Epochs were 30 seconds for both PSG and AW2. For each recording, sleep-wake threshold was modified using low (20), medium (40), and high (80) activity counts; and sleep-immobility onset/offset was adjusted using 5, 10, 15, 20, 25, and 30 epochs. Sleep variables for all AW2 setting combinations were subsequently compared against PSG using Bland-Altman analysis. Epoch-by-epoch comparisons were also performed to assess sensitivity, specificity, and accuracy of AW2 setting combinations relative to PSG.
Results
Standard AW2 settings (medium activity threshold; 20 epoch immobility time) significantly overestimated TST by 28.5 minutes (p = .026). Device performance was consistently better using the low activity threshold, with all permutations demonstrating non-significant differences from PSG. Of combinations tested, low activity threshold and 30 epoch immobility time was most congruent with PSG, underestimating TST by only 4.5 minutes. All sleep-wake thresholds exhibited strong sensitivity and accuracy, with poor specificity.
Conclusion
Our results demonstrate actigraphic settings significantly impact the quantification of TST in IH. Device settings should be adjusted accordingly when actigraphy is used to objectively quantify sleep duration in the disorder.
Support (If Any)
This research was supported by a grant from the American Sleep Medicine Foundation.
Abstract
Introduction
A previously healthy 17-year-old male presented with 3 months of severe hypersomnolence, and frequent episodes of diffuse, symmetrical leg weakness preceded with laughter. He ...was witnessed by his family to experience amnestic nocturnal spells characterized by confusion, and inappropriate behavior.
Report of Case
Significant symptoms include also sleep paralysis, snoring, increased appetite and weight gain of 20 pounds in previous 2 months.
An overnight polysomnogram (PSG) demonstrated a total sleep time of 7.18 hours with sleep efficiency of 88%. Sleep onset latency was 9 minutes and REM sleep latency of 3 minutes. There was no evidence of sleep disordered breathing. Patient demonstrated REM sleep without atonia in several epochs, recorded along with dream enactment behavior. Spells characterized by abrupt arousal and confused semiology out of N3 sleep were also captured, along with frequent periodic leg movements during NREM sleep and non-ictal EEG.
Multiple Sleep Latency Test revealed a mean sleep onset latency of <1 minute, sleep onset REM periods in 5 out of 5 naps, along with a sixth SOREM on patient’s PSG the night prior.
Patient met narcolepsy type 1 diagnostic criteria of ICSD-3 with his symptoms, electrographic findings, and unequivocal videographic evidence of cataplexy. The case illustrates concomitant presence of NREM and REM parasomnias representing the first report of parasomnia overlap in NT1.
Conclusion
We report the first case of a patient with an overlap diagnosis of Narcolepsy Type I and concomitant REM and NREM parasomnias using video polysomnographic confirmation. This case provides support that the loss of hypocretin signaling in NT1 confers to instability of sleep-wake states, contributing to parasomnia overlap disorder.
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