Hypersomnia Disorders Research Articles

Probabilistic Sleep Staging in MSLTs across Hypersomnia Disorders.

This study aimed to identify novel markers of narcolepsy type 1 (NT1) using between-nap opportunity periods ('Lights On') and in-nap opportunity periods ('Lights Off') features of Multiple Sleep Latency Test (MSLT) recordings. We hypothesized that NT1 could be identified both from sleep-wake instability and patterns of sleepiness during wakefulness. Further, we explored if MSLTs from NT1 and narcolepsy type 2 (NT2) patients could be distinguished despite having the same diagnostic thresholds. We analyzed 'Lights On' and 'Lights Off' periods of the MSLT, extracting 163 features describing sleepiness, microsleep, and sleep stage mixing using data from 177 patients with NT1, NT2, Idiopathic Hypersomnia (IH), and Subjective Hypersomnia (sH) from three sleep centers. These features were based on automated probabilistic sleep staging, also denoted as hypnodensities, using U-Sleep. Hypersomnias were differentiated using either or both features from 'Lights On' and 'Lights Off'. Patients with NT1 could be distinguished from NT2, IH, and sH using features solely from 'Lights On' periods with a sensitivity of 0.76 and specificity of 0.71. When using features from all periods of the MSLT, NT1 was distinguished from NT2 alone with a sensitivity of 0.77 and a specificity of 0.84. The findings of this study demonstrate microsleeps and sleep stage mixing as potential markers of the sleep attacks and unstable sleep-wake states common in NT1. Further, NT1 and NT2 could be frequently distinguished using 'Lights Off' features.

TAK-861, a potent, orally available orexin receptor 2-selective agonist, produces wakefulness in monkeys and improves narcolepsy-like phenotypes in mouse models

Narcolepsy type 1 (NT1) is associated with severe loss of orexin neurons and characterized by symptoms including excessive daytime sleepiness and cataplexy. Current medications indicated for NT1 often show limited efficacy, not addressing the full spectrum of symptoms, demonstrating a need for novel drugs. We discovered a parenteral orexin receptor 2 (OX2R) agonist, danavorexton, and an orally available OX2R agonist, TAK-994; both improving NT1 phenotypes in mouse models and individuals with NT1. However, danavorexton has limited oral availability and TAK-994 has a risk of off-target liver toxicity. To avoid off-target-based adverse events, a highly potent molecule with low effective dose is preferred. Here, we show that a novel OX2R-selective agonist, TAK-861 [N-{(2S,3R)-4,4-Difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3′,5′-trifluoro[1,1′-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide], activates OX2R with a half-maximal effective concentration of 2.5 nM and promotes wakefulness at 1 mg/kg in mice and monkeys, suggesting ~ tenfold higher potency and lower effective dosage than TAK-994. Similar to TAK-994, TAK-861 substantially ameliorates wakefulness fragmentation and cataplexy-like episodes in orexin/ataxin-3 and orexin-tTA;TetO DTA mice (NT1 mouse models). Compared with modafinil, TAK-861 induces highly correlated brain-wide neuronal activation in orexin-tTA;TetO DTA mice, suggesting efficient wake-promoting effects. Thus, TAK-861 has potential as an effective treatment for individuals with hypersomnia disorders including narcolepsy, potentially with a favorable safety profile.

Discovery of a highly potent and orally available orexin 2 receptor-selective agonist, TAK-861, as a novel therapeutic agent for narcolepsy and other hypersomnia disorders

Discovery of a highly potent and orally available orexin 2 receptor-selective agonist, TAK-861, as a novel therapeutic agent for narcolepsy and other hypersomnia disorders

The application of machine learning on brain imaging features of different narcolepsy subtypes.

Narcolepsy is a central hypersomnia disorder, and differential diagnoses between its subtypes can be difficult. Hence, we applied machine learning to analyze the positron emission tomography (PET) data of patients with type 1 or type 2 narcolepsy, and patients with type 1 narcolepsy and comorbid schizophrenia, to construct predictive models to facilitate the diagnosis. This is a retrospective and prospective case-control study of adolescent and young adult patients with type 1 or type 2 narcolepsy, and type 1 narcolepsy and comorbid schizophrenia. All participants received 18-F-fluorodeoxy glucose PET, sleep studies, neurocognitive tests, sleep questionnaires, and human leukocyte antigen typing. The collected PET data were analyzed by feature selections and classification methods in machine learning to construct predictive models. A total of 314 participants with narcolepsy were enrolled; 204 had type 1 narcolepsy, 90 had type 2 narcolepsy, and 20 had type 1 narcolepsy and comorbid schizophrenia. We used three filter methods for feature selection followed by a comparative analysis of classification methods. To apply a small number of regions of interest (ROI) and high classification accuracy, the Naïve Bayes classifier with the Term Variance as feature selection achieved the goal with only three ROIs (left basal ganglia, left Heschl, and left striatum) and produced an accuracy of higher than 99%. The accuracy of our predictive model of PET data are promising and can aid clinicians in the diagnosis of narcolepsy subtypes. Future research with a larger sample size could further refine the predictive model of narcolepsy.

0645 Prevalence of sleep disorders and their association with posttraumatic stress and anxiety symptoms among college students

Abstract Introduction Incidence of diagnosed psychiatric disorders tend to peak during early adulthood. Furthermore, sleep complaints are highly prevalent among college students, and often exacerbate psychiatric disorders. This study aimed to explore the prevalence of sleep disorders, and their association with posttraumatic stress disorder (PTSD) and generalized anxiety disorder (GAD) symptoms among college students. Methods College students completed self-report measures as part of a larger study (n=56; mean age 20.23 (SD=1.5); 83.9% females). The SLEEP-50 questionnaire estimated the prevalence of sleep disorders. Each sleep disorder required a cutoff score and at least one sleep complaint, with a minimum score of three or four used to classify a sleep complaint. The GAD-7 scale assessed for generalized anxiety disorder symptoms, and the PCL-5 determined PTSD symptomatology. Linear regression models identified the association between each sleep disorder on posttraumatic stress and generalized anxiety symptoms. Results Approximately 19.6% of students were at risk for at least one sleep disorder. The most frequent sleep disorder was hypersomnia (69.5%), followed by narcolepsy (53.6%), insomnia (48.2%), affective disorder (28.6%), and restless leg syndrome (21.4%). In contrast, circadian rhythm disorder (16.1%) and sleep apnea (7.1%) were infrequently reported. Linear regression models indicated that affective disorder (t=2.83, p<.007; t=3.13, p<.003) and hypersomnia disorder (t=2.31, p=.025; t=2.39, p=.020) significantly predicted PTSD and GAD symptoms respectively. Additionally, insomnia (t=3.97, p<.001) and restless leg syndrome (t=2.34, p=.023) were significant predictors for GAD only, and circadian rhythm disorder (t=2.760, p=.008) was a significant predictor for PTSD only. Conclusion Results suggest that risk of sleep disorders was significantly associated with PTSD and GAD symptoms in college students. Given these findings, health promotion programs are needed to promote good sleep hygiene and early interventions for mental health during college years. Support (if any) This study was funded by a Center Grant from the National Institutes of General Medical Sciences (Grant # P20GM103653).

0898 Title: Test - Retest Reliability of the Multiple Sleep Latency Test in Non-cataplectic Central Hypersomnia Disorders

Abstract Introduction Differentiation of narcolepsy type II (NT2) and idiopathic hypersomnia (IH) is challenging in clinical practice. Diagnostic criteria rely on the multiple sleep latency test (MSLT), previously shown to have poor reproducibility in these disorders. We leveraged a large polysomnographic database to study test-retest reliability in non-cataplectic central hypersomnia disorders. Methods Patients evaluated at Cleveland Clinic Sleep Disorders Center from 2008-2021 with suspected central hypersomnia disorders excluding narcolepsy type I with >1 PSG/MSLT were included. Studies not meeting validity criteria (< 7hr sleep time on PSG, < 5 MSLT trials, use of REM suppressants/alerting medications within 14 days) were excluded. Diagnostic groupings included NT2, IH and Normal/Indeterminate based on ICSD-3. Reliability and correlation between tests was performed using intra-class and Spearman’s correlations, respectively. Data is presented as mean+SD or median [25th,75th percentiles] for continuous variables and N(%) for categorical variables. Results A total of 58 patients (62.1% female, age 31.9 yr [18.5, 48.6]) were included. Interval between MSLTs was 3.6 + 3.18 yr (same diagnosis on both tests: 3.24 + 3.15; changed diagnosis: 3.98 + 3.22). Diagnosis based on MSLT 1 was NT2 8(13.8%), IH 20(34.5%) and Normal/Indeterminate 30(51.7%). Overall, 33(56.9%) patients remained in the same diagnostic category including 3(5.2%) NT2, 12(20.7%) IH and 18(31.0 %) Normal/Indeterminate. Of 25(43.1%) cases changing diagnosis, 3(5.2%) changed from NT2 to IH and 2(3.4%) to Normal/Indeterminate; 4(6.9%) changed from IH to NT2 and 4(6.9%) to Normal/Indeterminate; 5(8.6%) changed from Normal/Indeterminate to NT2 and 7(12.1%) to IH. Median MSL on tests 1 and 2 were 10.8 [4.6,12.9] and 9.0 [4.5,13.1], respectively. Correlation was moderate MSL [0.59 (0.39, 0.73), p< 0.001] and fair for SOREMPs [0.32 (0.07, 0.53), p=0.015]. Intra-class correlation showed moderate reliability in test-retest for MSL [0.56 (0.36, 0.72)] and SOREMPs [0.54 (0.33, 0.70)]. Conclusion MSLT test-retest reproducibility in non-cataplectic central hypersomnias was moderate in a tertiary care clinic population. While more favorable than prior studies, these findings underscore diagnostic challenges that may contribute to misdiagnosis of patients with hypersomnia. Support (if any)

TAK-994, a Novel Orally Available Brain-Penetrant Orexin 2 Receptor-Selective Agonist, Suppresses Fragmentation of Wakefulness and Cataplexy-Like Episodes in Mouse Models of Narcolepsy.

Loss of orexin neurons is associated with narcolepsy type 1 (NT1), which is characterized by multiple symptoms including excessive daytime sleepiness and cataplexy. Orexin 2 receptor (OX2R) knockout (KO) mice, but not orexin 1 receptor (OX1R) KO mice, show narcolepsy-like phenotypes, thus OX2R agonists are potentially promising for treating NT1. In fact, in early proof-of-concept studies, intravenous infusion of danavorexton, an OX2R-selective agonist, significantly increased wakefulness in individuals with NT1. However, danavorexton has limited oral availability. Here, we report pharmacological characteristics of a novel OX2R agonist, TAK-994 [N-{(2S,3S)-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluorobiphenyl-3-yl)methyl]pyrrolidin-3-yl}methanesulfonamide sesquihydrate]. TAK-994 activated recombinant human OX2R (EC50 value of 19 nM) with > 700-fold selectivity against OX1R and activated OX2R-downstream signaling similar to those by orexin peptides in vitro. Oral administration of TAK-994 promoted wakefulness in normal mice but not in OX2R KO mice. TAK-994 also ameliorated narcolepsy-like symptoms in two mouse models of narcolepsy: orexin/ataxin-3 mice and orexin-tTA;TetO diphtheria toxin A mice. The wake-promoting effects of TAK-994 in orexin/ataxin-3 mice were maintained after chronic dosing for 14 days. These data suggest that overall in vitro and in vivo properties, except oral availability, are very similar between TAK-994 and danavorexton. Preclinical characteristics of TAK-994 shown here, together with upcoming clinical study results, can improve our understanding for orally available OX2R agonists as new therapeutic drugs for NT1 and other hypersomnia disorders. SIGNIFICANCE STATEMENT: Narcolepsy type 1 (NT1) is caused by a loss of orexin neurons, and thus an orexin 2 receptor (OX2R) agonist is considered to address the underlying pathophysiology of NT1. Oral administration of TAK-994, a novel OX2R agonist, promoted wakefulness in normal mice, but not in OX2R knockout mice, and ameliorated fragmentation of wakefulness and cataplexy-like episodes in mouse models of narcolepsy. These findings indicate that TAK-994 is an orally available brain-penetrant OX2R-selective agonist with potential to improve narcolepsy-like symptoms.

Novel Objective Measures of Hypersomnolence.

To provide a brief overview of current objective measures of hypersomnolence, discuss proposed measure modifications, and review emerging measures. There is potential to optimize current tools using novel metrics. High-density and quantitative EEG-based measures may provide discriminative informative. Cognitive testing may quantify cognitive dysfunction common to hypersomnia disorders, particularly in attention, and objectively measure pathologic sleep inertia. Structural and functional neuroimaging studies in narcolepsy type 1 have shown considerable variability but so far implicate both hypothalamic and extra-hypothalamic regions; fewer studies of other CDH have been performed. There is recent renewed interest in pupillometry as a measure of alertness in the evaluation of hypersomnolence. No single test captures the full spectrum of disorders and use of multiple measures will likely improve diagnostic precision. Research is needed to identify novel measures and disease-specific biomarkers, and to define combinations of measures optimal for CDH diagnosis.

Objective Diagnosis of Circadian Rhythm Disorders.

Circadian sleep-wake disorders are common. Because they represent conflict between the timing of the patient's endogenous rhythms and desired timing of sleep, the presenting complaints may include both difficulty of sleep initiation or maintenance and undesired or unplanned daytime or early evening sleepiness. Therefore, circadian disorders may be misdiagnosed as either a primary insomnia or a hypersomnia disorder, depending on which complaint is more troublesome for the patient. Objective information about sleep and wake patterns over long periods is crucial for accurate diagnosis. Actigraphy provides long-term information about the rest/activity pattern about an individual. However, caution should be applied in interpretation of the results because the information provided only includes information of movements, and activity is only an indirect circadian phase marker. Timing of light and melatonin therapy is critical for successful treatment of circadian rhythm disorders. Therefore, results of actigraphy are useful and should be used in conjunction with additional measurements, including 24 hours sleep-wake history, sleep log, and melatonin measurements.

Update on Central Hypersomnia Disorders in Children

Update on Central Hypersomnia Disorders in Children

Danavorexton, a selective orexin 2 receptor agonist, provides a symptomatic improvement in a narcolepsy mouse model

Narcolepsy type 1 (NT1), caused by loss of orexin neurons, is a neurological disorder characterized by excessive daytime sleepiness, cataplexy, disrupted nighttime sleep, hypnagogic/hypnopompic hallucinations and sleep paralysis, as well as a high risk of obesity. Danavorexton (TAK-925) is a novel brain-penetrant orexin 2 receptor (OX2R)-selective agonist currently being evaluated in clinical trials for the treatment of hypersomnia disorders including NT1. Thus, detailed characterization of danavorexton is critical for validating therapeutic potential of OX2R-selective agonists. Here, we report preclinical characteristics of danavorexton as a therapeutic drug for NT1. Danavorexton showed rapid association/dissociation kinetics to OX2R. The activation mode of endogenous OX2R by danavorexton and orexin peptide was very similar in an electrophysiological analysis. In orexin/ataxin-3 mice, a mouse model of NT1, danavorexton promoted wakefulness, and ameliorated fragmentation of wakefulness during the active phase after both acute and repeated administration, suggesting a low risk of receptor desensitization. Electroencephalogram (EEG) power spectral analysis revealed that danavorexton, but not modafinil, normalized dysregulated EEG power spectrum in orexin/ataxin-3 mice during the active phase. Finally, repeated administration of danavorexton significantly suppressed the body weight gain in orexin/ataxin-3 mice. Danavorexton may have the potential to treat multiple symptoms of NT1. These preclinical findings, together with upcoming clinical observations of danavorexton, could improve our understanding of the pathophysiology of NT1 and therapeutic potential of OX2R agonists.

Discovery of a novel orally available selective orexin 2 receptor agonist, E2086, as a therapeutic drug for narcolepsy and other hypersomnia disorders

Discovery of a novel orally available selective orexin 2 receptor agonist, E2086, as a therapeutic drug for narcolepsy and other hypersomnia disorders

Prevalence of Sleep Disorders, Risk Factors and Sleep Treatment Needs of Adolescents and Young Adult Childhood Cancer Patients in Follow-Up after Treatment.

Simple SummarySleep disorders negatively impact adolescent and young adult childhood cancer patients’ physical and psychosocial health. Early recognition might improve timely treatment. This national cohort study describes subjective sleep disorders (using a validated self-report questionnaire according to international diagnostic criteria) in childhood cancer patients after treatment, including all types of diagnoses. Sleep disorder prevalence rates ranged from 1.8–9.6%. Insomnia and circadian rhythm sleep disorders were most commonly reported and more prevalent than in the general population. Female sex, young adulthood (18–26 years old) and co-morbid health conditions were risk factors for having a sleep disorder, but cancer-related factors were not. The most commonly used sleep medication was melatonin, which exceeded use described in the general population. Patients with a sleep disorder expressed an unmet need for sleep treatment. Screening for sleep disorders after cancer might improve access to treatment and support childhood cancer patients to maintain optimal health and quality of life.Background: Sleep disorders negatively impact adolescent and young adult childhood cancer patients’ physical and psychosocial health. Early recognition improves timely treatment. We therefore studied the prevalence of subjective sleep disorders, risk factors and sleep treatment needs after completion of childhood cancer treatment. Methods: Childhood cancer patients (12–26 years old), ≥6 months after treatment, were invited to fill out the Holland Sleep Disorders Questionnaire, which distinguishes six sleep disorders in substantial agreement with the International Classification of Sleep Disorders, second edition (ICSD-2). They additionally indicated sleep treatment needs. Prevalence rates and needs were displayed in percentages. Logistic regression models were used for risk factors. Results: 576 patients participated (response rate 55.8%)—49.5% females, mean age 17.0 years, 44.4% hemato-oncology, 31.9% solid tumors, 23.6% neuro-oncology. Prevalence rates were: insomnia (9.6%), circadian rhythm sleep disorder (CRSD; 8.1%), restless legs syndrome (7.6%), parasomnia (3.5%), hypersomnia (3.5%) and sleep-related breathing disorders (1.8%). Female sex, comorbid health conditions and young adulthood seem to be risk factors for sleep disorders, but cancer-related factors were not. Differing per sleep disorder, 42–72% wanted help, but only 0–5.6% received sleep treatment. Conclusions: Insomnia and CRSD were most prevalent. An unmet need for sleep treatment was reported by childhood cancer patients during follow-up. Screening for sleep disorders after cancer might improve access to treatment and patient wellbeing.

502 Idiopathic hypersomnia and co-occurring psychopathology among veterans

Abstract Introduction Idiopathic hypersomnia (IH) is relatively rare and characterized by excessive daytime sleepiness despite prolonged and undisturbed sleep as well as the absence of cataplexy and other causes of hypersomnolence. The etiology of IH is largely unknown. The present study capitalized on electronic medical record (EMR) data from the Veterans Health Administration (VHA) to create a cohort of veterans diagnosed with IH in order to: 1) estimate the prevalence of IH diagnosis in the VHA, and 2) identify co-occurring physical and behavioral health conditions to characterize IH in the sample. Methods Using 2009–19 VHA EMR data, we created two cohorts: those with an IH diagnosis (N = 3,674) or a hypersomnia diagnosis (e.g., primary hypersomnia) other than IH (N = 110,530). Diagnostic data (i.e., ICD 9 and 10 codes) were extracted for the 6-months prior to index diagnosis to examine group differences in the prevalence of physical and behavioral health conditions. Results Veterans diagnosed with IH, as compared to veterans with another hypersomnia disorder, were more likely to be female (30.1% vs 12.3%) and less likely to be obese (16% vs 28.3%; chi-squared = 79.27, p <.001), or carry diagnoses of diabetes (type 1 or 2; 9.7% vs 24.4%; chi-squared = 123.02, p <.001), or anxiety disorders (5.8% vs 9.5%; chi-squared = 16.83, p <.001). Individuals with IH were more likely to carry diagnoses of chronic fatigue syndrome (4.2% vs 1.6%; chi-squared = 45.91, p <.001), depression (31.3% vs 23.4%; chi-squared = 36.04, p <.001), and posttraumatic stress disorder (29.5% vs 26.5%; chi-squared = 5.79, p = .02). Conclusion Data suggest that veterans diagnosed with idiopathic hypersomnia may present with different diagnostic profiles than veterans with other hypersomnia disorders. Far more basic and clinical research is needed in IH. Support (if any) This work was supported by the Hypersomnia Foundation and in part by the VA Center of Excellence for Suicide Prevention in the Finger Lakes Healthcare System.

Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation

Narcolepsy type 1 (NT1) is a chronic neurological disorder that impairs the brain’s ability to control sleep-wake cycles. Current therapies are limited to the management of symptoms with modest effectiveness and substantial adverse effects. Agonists of the orexin receptor 2 (OX2R) have shown promise as novel therapeutics that directly target the pathophysiology of the disease. However, identification of drug-like OX2R agonists has proven difficult. Here we report cryo-electron microscopy structures of active-state OX2R bound to an endogenous peptide agonist and a small-molecule agonist. The extended carboxy-terminal segment of the peptide reaches into the core of OX2R to stabilize an active conformation, while the small-molecule agonist binds deep inside the orthosteric pocket, making similar key interactions. Comparison with antagonist-bound OX2R suggests a molecular mechanism that rationalizes both receptor activation and inhibition. Our results enable structure-based discovery of therapeutic orexin agonists for the treatment of NT1 and other hypersomnia disorders.

Sleep Neurology's Toolkit at the Crossroads: Challenges and Opportunities in Neurotherapeutics Lost and Found in Translation.

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

Autonomic dysfunction in childhood hypersomnia disorders

ObjectiveOrthostatic intolerance (OI) is a common manifestation of autonomic dysfunction. It is characterized by light-headedness and palpitations in the upright position, with relief when supine. It can affect the quality of life. Other symptoms that may accompany OI include headache, fatigue, nausea, palpitations and abdominal pain. The prevalence and characteristics of autonomic symptoms in childhood hypersomnia disorders of childhood has not been examined, and hence were studied. MethodsThe medical records of children and adolescents with hypersomnia disorders were reviewed. Subjects had been diagnosed with narcolepsy types 1 or 2 (NT1 or NT2), idiopathic hypersomnia (IH) or the KLS, or hypersomnia related to medical conditions, were under 18 years of age at sleep diagnosis, and had been evaluated at our sleep center between 2000 and 2018. Those with comorbidities such as obstructive sleep apnea and major depression were excluded. The medical records were reviewed for symptoms at initial presentation suggestive of autonomic dysfunction, such as orthostatic intolerance, headache, fatigue, nausea, palpitations and abdominal pain. If these symptoms had been recorded, the chart was examined further to determine if an autonomic reflex screen (ARS) battery had been conducted. The ARS battery examines both sympathetic and parasympathetic function. It is composed of a tilt table test, heart rate and blood pressure responses to the Valsalva maneuver and deep breathing, a quantitative sudomotor axon reflex test and beat-to-beat blood pressure measurements during the Valsalva maneuver. Results of the ARS battery were interpreted by an autonomic neurology specialist (WS), who was not otherwise involved in the care of the patients. Medications taken at the time of autonomic testing were recorded. ResultsThere were 89 patients with hypersomnia disorders. Forty six patients had NT1, 17 had NT2, 18 had IH, 1 with KLS, and 7 had hypersomnia associated with medical disorders. Thirty three of 89 subjects (37%) had the symptom of OI at initial presentation, hence had undergone autonomic reflex screen testing. The median age at diagnosis of hypersomnia in the 33 subjects with the OI symptom was 14.5 years (interquartile range 12–16) and similar (14.5 years, interquartile range 11.5–16) in the 56 subjects without OI. In the group with OI, 25/33 had not received medications for treating hypersomnia at the time of autonomic testing. OI was not related to the degree of sleepiness– the mean sleep latency in the subjects with OI was 5.3 ± 2.9 min while in those without OI it was 4.5 ± 3.8 min. The symptom of OI was not more likely to occur in any specific type of hypersomnia.OI however tended to occur predominantly in females – the female: male ratio in the OI subgroup was 2:1 (n = 33) while in the subgroup without OI, it was 1: 2.1 (n = 56; p = 0.0015). Additional symptoms recorded in the OI subgroup included lightheadedness in 25/33, palpitations in 6/33, nausea and vomiting in 4/33, fatigue in 25/33, headache in 15/33 and constipation in 3/33. The symptoms of OI were reproduced during the tilt table test in 17/33 subjects; 5 of these patients had a rise in heart rate consistent with postural orthostatic tachycardia syndrome (POTS). ConclusionIn this retrospective sample, one third of children with hypersomnia disorders exhibited the symptom of OI at initial presentation, with female predominance. A smaller subgroup met criteria for POTS. Screening for autonomic symptoms in children with hypersomnia is important because the former seems to be a treatable co-morbidity that impacts the sense of well-being.

Risk of Sudden Cardiac Death: Ventricular Arrhythmias and Obstructive Sleep Apnea Syndrome

Obstructive sleep apnea (OSA) was shown to significantly increase the risk of cardiac death. However, polysomnography and cardiorespiratory monitoring as methods to verify breathing disorders during sleep are not included in the pilot medical certification standard. Daytime hypersomnia, snoring, fatigue, mood swings, and cognitive disorders combined with overweight may suggest a sleep respiration disorder. OSA cannot be ruled out even when most of the above symptoms are absent, warranting instrumental diagnosis.

Therapeutic Strategies for Mitigating Driving Risk in Patients with Narcolepsy.

Narcolepsy is a central nervous system hypersomnia disorder characterized by uncontrollable episodes of daytime sleep, sleep state instability, and cataplexy (sudden loss of muscle tone precipitated by emotion). Individuals with narcolepsy report more frequent sleep-related crashes, near crashes, and drowsy driving than drivers with other sleep disorders. As such, evaluating risk of sleep-related crashes is of great importance for this patient population. There are no established guidelines for ensuring driving safety in patients with narcolepsy; however, many providers currently use a combination of subjective report, report of prior crashes or near-misses, report of previously falling asleep while driving, sleepiness screening tools, and maintenance of wakefulness testing (MWT) to determine risk. Driving simulator tests, though often unavailable to the clinician, provide data to support the use of MWT for evaluation of alertness in drivers with narcolepsy. Treatments such as modafinil may improve driving performance; however, the impact of other treatments such as stimulants and sodium oxybate on driving has not been extensively studied. Behavioral and lifestyle modifications may also reduce risk, including scheduled naps, driving only short distances, and avoiding driving after meals, sedating medications, and alcohol intake. Even with effective treatment, alertness in patients with narcolepsy may never reach that of normal drivers; however, studies have suggested that narcolepsy patients may be able to drive safely with appropriate limitations.

0757 Increasing Number of Cases Who Had Both Hypersomnolence Disorders and Developmental Disorders With Orexin Measurements

Abstract Introduction Recently, attention has been paid to the relationship between developmental disorders such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), and sleep disorders. We meet many developmental disorder patients who complaint hypersomnolence. Among these patients, cases with coexistence of central hypersomnia and developmental disorders, or developmental disorder alone were increased. Therefore, we first investigated patients with the complaint of hypersomnolence, who were also suspected developmental disorders. Furthermore, we have been measuring CSF orexin in 17 cases suspected of both disorders to investigate orexin levels of these patients. Methods 86patients who complained of EDS with suspicion of developmental disorders had been examined. In order to diagnose hypersomnolence disorders, PSG and MSLT were performed. Psychological examinations were performed for diagnosing developmental disorders.We have been measuring for CSF orexin in 17 cases suspected both hypersomnolence and developmental disorders. We examined the onset of hypersomnolence and the clinical history of these ADHD or ASD cases for more details. Results In 86 examined cases, developmental disorders coexisted in 30 cases. Among 30 cases, ADHD were 18, ASD were 6 and both diagnosed were 6 cases. Among them, 20 cases diagnosed as having coexistence of hypersomnia (8: narcolepsy, 12: IHS) and developmental disorders (ADHD:12, ASD:4, ADHD/ASD:4). In 17 cases with orexin measurements, 10 cases coexisted ADHD and 4 cases coexisted ASD. Two cases diagnosed as both ADHD and ASD. In 10 ADHD cases, 3 cases had low orexin levels, and 7 cases had normal orexin levels. Other 7 ASD cases had normal orexin levels. Conclusion ADHD has a higher rate of central hypersomnia (12/18) compared with ASD and the rate of narcolepsy was also high (5/12). While patients in ASD was diagnosed as IHS (3/6), narcolepsy cases were not observed. It became clear that the majority of patients had developmental disorder or had a tendency for developmental disorder before the onset of hypersomnolence.Although it is possible that ADHD/ASD symptoms may be exacerbated by orexin dysfunctions, ADHD/ASD may not newly occur. There were cases with low orexin levels, but it seems that narcolepsy happened to coexist with developmental disorders. Support a