Citations

Abstract Introduction Inflammatory Bowel Disease (IBD) is a chronic, immune-mediated condition, encompassing Crohn's disease (CD) and ulcerative colitis (UC). Up to 80% of individuals with IBD report poor sleep quality. However, there is limited information on factors that predict sleep characteristics in this population. This study aims to explore the associations between demographic, clinical, and psychological factors with sleep characteristics in adults with IBD. Methods We conducted a retrospective analysis of two IBD sleep studies. Participants aged 18-64 years old with a diagnosis of IBD were recruited from two academic medical centers and completed Patient-Reported Outcomes Measure Information System (PROMIS) depression and anxiety questionnaires and wore a wrist actigraph for 10 days continuously. We employed Independent T-Tests and Pearson’s correlation to assess the association of biologic treatment, IBD type, sex, depression, and anxiety on sleep efficiency (SE), total sleep time (TST), and sleep onset latency (SOL). Results We included 58 participants with a mean age of 35.6 years (SD=12.1). 60.3% were female, and 60.3% were diagnosed with CD. The mean depression score was 51.3 (SD = 10.2) and the anxiety score was 52.2 (SD = 15.5). The mean SOL was 19.3 minutes (SD = 15.5), TST was 413.3 minutes (SD = 53.2), and SE was 83.5% (SD = 5.7). TST was significantly longer in females compared to males (427.4 vs. 391.9 minutes , p< 0.05). SE was significantly higher among females compared to males (85.1% vs. 81.0%, p< 0.001) and among individuals with Crohn's disease compared to Ulcerative colitis ((85.1% vs. 81.0%, p< 0.01). SOL was longer among individuals with Ulcerative colitis compared to Crohn's disease (15.6 vs.25.0minutes , p< 0.05). Depression and anxiety scores were not significantly correlated with any sleep characteristic. Conclusion Sleep continuity was poor in people with IBD. Given that we found sex and IBD type impacted sleep continuity, these factors should be considered in future precision sleep health interventions for this population. Support (if any) This study was funded by the University of Washington School of Nursing, NINR (K23 NR020044) (Kendra Kamp, and the American Nurses Foundation (Samantha Conley).

Abstract Introduction Quantitative rapid eye movement (REM) sleep without atonia (RSWA) recorded during polysomnography (PSG) represents loss of normal REM sleep atonia. RSWA is the neurophysiologic signature of REM sleep behavior disorder (RBD). Visually scored RSWA is a candidate biomarker for synucleinopathies. However, visual RSWA scoring requires expert scoring, limiting widespread application. We comparatively analyzed RSWA in DLB and iRBD using the automated Ferri REM Atonia Index (RAI). Methods We quantitatively analyzed the RAI in 17 DLB and 20 iRBD patients, compared to 20 controls using Hypnolab Software for Sleep Analysis (SWS Soft, Colognola ai Colli, Italy). PSG data were converted to European Data Format (.EDF), and the submentalis surface electromyogram (EMG) signal was notch-filtered at 60 Hertz and rectified. Automatically calculated RAI scores were comparatively analyzed across groups (DLB, iRBD, controls) using Kruskal Wallis H tests for group comparisons, and regression analyses determined relationships between diagnosis, age, and sex. Logistic regression ROC determined optimal RAI for distinguishing iRBD from DLB. When interpreting RAI, lower values represent greater amounts of RSWA, and higher values represent more normal REM atonia. Results Median age was no different between DLB (72.6 years), iRBD (69.4 years), and controls (68.0 years). The DLB group consisted of 16 men and one woman, the iRBD group had 18 men and 2 women, and controls were comprised of 16 men and 4 women. Median RAI was lowest in DLB (0.32), intermediate in iRBD (0.84) and highest in controls (0.96), indicating a gradient in RSWA amounts from DLB patients (highest) to controls (lowest). Regression demonstrated diagnosis independently predicted RAI, controlling for age and sex (adjusted R2=0.64, p=0.0001). The RAI that optimally distinguished iRBD from DLB was 0.48 (specificity 85%, sensitivity 76%, AUC=0.88). Conclusion The RAI demonstrated a clear gradient throughout the Lewy body spectrum; highest (indicating lowest RSWA amounts) in controls, intermediate in iRBD, and lowest (indicating greatest RSWA) in DLB. The RAI is a promising, time efficient and broadly applicable candidate biomarker for DLB and iRBD. Automated quantitative RSWA could be a valuable tool for deep phenotyping throughout the Lewy body disease spectrum. Support (if any) This study was supported by: U01NS100620, R34AG056639, U19AG071754, and P30AG62677.

Abstract Introduction Restless leg syndrome (RLS/WED) is a neurological sleep condition which is characterized by an uncontrollable urge to move an individual’s legs and sometimes arms when at rest. Symptoms typically arise in the evening and nighttime hours and can be associated with severe insomnia and negative impact on quality of life. Here we present a case of severe RLS/WED exacerbations temporally associated with androgen receptor inhibitor therapy. Report of case(s) A 58 year old male was referred to the sleep medicine clinic for refractory RLS/WED. He was previously treated with high dose ropinirole, which was associated with severe augmentation. Trials of gabapentin, pregabalin, tramadol, and hydrocodone were associated with persistence of severe symptoms. He was eventually treated with methadone at a dose of 10 mg in addition to Rotigotine patch at a dose of 2 mg, with adequate symptom relief. He was later diagnosed with prostate cancer, and initiated on enzalutamide, an androgen receptor inhibitor. Within two weeks of starting this medication, he had a severe exacerbation of his RLS symptoms and associated insomnia. The medication was discontinued, with subsequent abatement of RLS symptoms. He was then switched to apalutamide by his urologist (another androgen receptor inhibitor), but again developed severe RLS exacerbation. Dosing of the Rotigotine patch and methadone were increased to 4 mg and 12.5 mg daily respectively. In addition, he was started on pramipexole 0.25 mg, which was later increased to 0.5 mg, but he continued to have severe residual symptomatology. After discussing with his oncologist, he went on a trial of 3-4 weeks where apalutamide was discontinued. During this time, his RLS symptoms resolved, and he was sleeping well. He then restarted apalutamide and again experienced a similar a severe RLS flare. Conclusion Our case demonstrates an association between androgen receptor inhibitor therapy and RLS exacerbations. Further work is needed to understand the possible relationships between RLS and these common treatments for prostate cancer. Support (if any)

Abstract Introduction Growing evidence suggests that there are sleep health disparities in the United States that disadvantage communities of color, and other socioeconomically marginalized groups in medical and mental health settings. Research in public policy indicates several points of intervention for increasing engagement with treatment services in communities of color at the primary care level, including individual beliefs about mental health/health issues, and perceptions of various points of treatment engagement, as well as community factors (e.g., neighbors and church; Davey & Watson, 2007). Accordingly, the current study implemented a community-level virtual intervention that targeted beliefs about sleep and perceptions of behavioral sleep treatment with the aim to increase willingness to engage with treatment at the primary care level. Methods We conducted 12 semi-structured qualitative focus groups with 35 individuals from communities of color about their awareness, perception of, and access to behavioral sleep treatment in healthcare settings. Transcripts were coded using the Rapid and Rigorous Qualitative Data Analysis method for themes relevant to the guiding question, 'What are people/persons of color experiences and perspectives of sleep, and specific areas of improvement to increase people/persons of color groups' utilization of behavioral sleep services?'. Results After a brief period of education (range = 15-20 minutes) about cognitive-behavioral therapy for insomnia (CBTi), participants perceived behavioral sleep treatment as a favorable option both over and in conjunction with pharmacological options. Medical mistrust was mentioned as the most significant barrier in each focus group, with participants highlighting that increased attention to collaborative care and comprehensive education about treatment options at the primary care level would be helpful for reducing mistrust. Pre- and post-group survey analysis indicated a significant increase in participants’ willingness to use primary care as an entry point to access/utilization of behavioral sleep treatment (pre-group willingness = 54.84%, post-group willingness = 91.42%, p<.001). Conclusion Findings suggest that intervention at the community level can be powerful for increasing the willingness of communities of color to engage in treatment at the primary care level. It is paramount that future research continues to examine ways to increase engagement with behavioral sleep treatment to help reduce sleep health disparities. Support (if any)

Abstract Introduction Central sleep apnea (CSA) is associated with several medical conditions (e.g., heart failure, atrial fibrillation) and medications (e.g., opioids, ticagrelor, sodium oxybate and valproic acid). We report a case of a 31-year-old female with bipolar disorder treated with valproic acid diagnosed with central sleep apnea on polysomnography, which revealed an apnea-hypopnea index of 150/hour, central apnea index of 112/hour, nadir oxygen saturation of 78%, and 38.6 minutes with oxygen saturation ≤ 88%. Echocardiogram, electrocardiogram, brain magnetic resonance imaging, serum acylcarnitine and serum ammonia levels were unremarkable. Total and free serum valproic acid level was 33 and < 3 mcg/mL, respectively. Two cases of central sleep apnea associated with valproic acid use, both of which improved upon discontinuation of valproic acid, have been reported in the literature. We started the patient on positive airway pressure and suggested she taper off valproic acid and then repeat polysomnography. Given the possible association between central sleep apnea and valproic acid use, we retrospectively analyzed patients receiving valproic acid at time of polysomnography. Methods We retrospectively identified patients between 2005-2017 who were prescribed valproic acid (n=6,169), and of these 72 received valproic acid within 90 days of polysomnography. After chart review, we were able to confirm that 29 received valproic acid at time of polysomnography via blood levels or clear chart documentation. Results Four patients (13.8 %) demonstrated a central apnea index ≥ 5 per hour (mean apnea-hypopnea index 39.2/hour +/- 32.2/ hour including a central apnea index 11.7 +/- 6.6/hour) during polysomnography. Although one patient (3.4 %), a 2-year-old child with Dravet syndrome and refractory/drug resistant generalized epilepsy, was diagnosed clinically with central sleep apnea, the other three patients were diagnosed with obstructive sleep apnea and had other potential reason(s) for the elevated central apnea index (e.g., opioid use as needed for migraines). Conclusion Our case describes a third report of central sleep apnea possibly associated with valproic acid, and our retrospective study indicates that this association is rare. Prospective sleep studies on patients before and after receiving valproic acid are warranted to determine if valproic acid causes central sleep apnea. Support (if any)

Abstract Introduction Patients with excessive daytime sleepiness (EDS) associated with narcolepsy or obstructive sleep apnea (OSA) struggle to maintain wakefulness. Solriamfetol (Sunosi®) is a dopamine/norepinephrine reuptake inhibitor with agonistic properties at TAAR1 and serotonin 1A receptors; it is approved to treat EDS associated with narcolepsy (75–150 mg/day) or OSA (37.5–150 mg/day). This post-hoc analysis characterized the effects of solriamfetol on the propensity of participants with EDS associated with narcolepsy or OSA to maintain wakefulness. Methods The safety and efficacy of solriamfetol has been evaluated in participants with EDS and narcolepsy or OSA in the phase 3 trials, TONES 2 and TONES 3. Participants were randomized to placebo or solriamfetol (37.5 mg [OSA only], 75 mg, 150 mg, or 300 mg) once daily for 12 weeks. This post-hoc analysis evaluated the proportion of participants who achieved improvement from baseline on various 40-minute Maintenance of Wakefulness Test (MWT) thresholds (≥5, ≥10, ≥15, and ≥20 minutes) and mean sleep latencies ≥30 and ≥40 minutes at weeks 1, 4, and 12. Comparisons between solriamfetol and placebo were evaluated using Fisher’s exact test. Results A greater proportion of participants with narcolepsy achieved improvement from baseline of ≥15 and ≥20 minutes on the MWT with solriamfetol 150 mg (36% and 18%, respectively) and 300 mg (38% and 28%) compared with placebo (4% and 4%) at week 12 (P≤0.028); findings were similar at week 12 in participants with OSA with solriamfetol 75 mg (28% and 13%), 150 mg (37% and 25%), and 300 mg (44% and 28%) compared with placebo (8% and 3%; P≤0.034). A greater proportion of participants with narcolepsy achieved MWT sleep latency ≥30 minutes at week 12 with solriamfetol 150 mg (24%) and 300 mg (30%) compared with placebo (2%; P≤0.002); results were similar in participants with OSA for MWT sleep latency ≥30 minutes at week 12 with solriamfetol 75 mg (28%), 150 mg (34%), and 300 mg (44%) compared with placebo (11%; P≤0.012). Conclusion These findings suggest solriamfetol leads to substantial improvements on objective propensity to stay awake in a large proportion of patients with narcolepsy or OSA when compared with placebo. Support (if any) Axsome Therapeutics, Jazz Pharmaceuticals

Abstract Introduction n this cross-validation study, the distributions of sleep biomarker-based neurodegenerative disorder (NDD) risk were evaluated across a spectrum of NDD patients and presumed controls which were independent of the model development dataset. Methods Variables that included age, time-REM, non-REM hypertonia, autonomic-activation index, spindle-duration, atypical-N3, time-supine, sleep-efficiency, relative-theta, and theta/alpha obtained with Sleep Profiler were used to train a 4-class machine learning algorithm that generated probabilities of NDD risk for the groups: Alzheimer’s dementia (AD), Lewy body disorder (LBD), prodromal synucleinopathy (pSYN based on REM sleep behavior disorder patients), and controls (CG). Records with CG output probabilities >70% were labeled Probably-normal, and from 45-70% Likely-normal with indications of a NDD added when the LBD, AD or pSYN risks exceeded approximately 25%. Similar thresholds were used to assign Likely- or Probable- LBD, AD, pSYN or Mixed based on the group probabilities. This cross-validation study was designed to use datasets that were independent of those used to train the classification algorithm. Thus, NDD risk distributions were evaluated in patients with mild cognitive impairment (MCI=71), Parkinson’s disease (PD=16), progressive supranuclear palsy (PSP=21) and control subjects (NC=41) with Mini-Mental State Exam scores>28 and/or normal for MCI by Petersen criteria. Results In the MCI group, NDD risk assignments were Probable-AD=26%, -Mixed=10%, -LBD=1%, Likely-AD= 7%, -Mixed=6%, -LBD=3%, -pSYN=1%, Likely-Normal indications-AD=9%, -pSYN=7%, -Mixed=4%, and Probably-Normal=26% In the PSP group, Probable-LBD=43%, -Mixed=29% and -pSYN=4%, Likely-Mixed=10%, Likely-Normal indications AD=10%, and Probably-Normal=4%. In the PD group, Probable-LBD=13%, -pSYN=13%, -AD=6%, Likely-Mixed=19%, -pSYN=6%, Likely-Normal Indications-pSYN=19%, -AD=12%, Likely-Normal=6% and Probably-Normal=6% In the NC group, 83% were assigned minimal NDD risk with Probably-Normal=70%, Likely-Normal plus indications=13%, but with Likely NDD=13% and Probable NDD=4%. Conclusion NDD risks were disbursed in a manner consistent with the range of severities expected In MCI and PD groups, with 25% exhibiting relatively normal sleep patterns. Over 70% of the PSP patients exhibited probable NDD risk, with patterns similar to those with LBD. The NC NDD risk distributions were consistent with those assigned to the CG used for model development. Support (if any) NIH grants R44AG050326, R44AG054256, RO1AG060477, R33AG064271, ULRR024150, R34AG056639.

Abstract Introduction In this pilot study, the diagnostic agreement for sleep biomarker-based neurodegenerative disorder (NDD) risk probabilities was evaluated in patients with Alzheimer’s disease dementia (AD), Lewy Body disease (LBD), and isolated REM sleep behavior disorder (iRBD) and controls with a Mini-Mental State Exam scores>28. Methods Sleep biomarkers recorded with the Sleep Profiler (Advanced Brain Monitoring, Inc) were used as inputs to a 4-class machine learning algorithm trained to assign NDD risk probabilities to AD=27, LBD=19, iRBD=15 and controls (CG=58). Input variables included age, time-REM, non-REM hypertonia, autonomic-activation index, spindle-duration, atypical-N3, time-supine, sleep-efficiency, relative-theta, and theta/alpha. Records with CG output probabilities >70% were labeled Probably-normal, and from 45-70% Likely-normal with indications of a NDD added when the LBD, AD or prodromal synucleinopathy (pSYN) risks exceeded approximately 25%. Similar thresholds were used to assign Likely- or Probable- LBD, AD, or pSYN based each of the group probabilities. Classification accuracies were evaluated in AD=37, LBD=19, iRBD=19 and CG=61 records. Longitudinal test-retest reliabilities were assessed for CG (n=45, range 8-56 months), and after six-months for LBD (n=10) and AD (n=9). Results In the AD group, NDD risk assignments were consistent with diagnoses=85%, with Probable-NDD=59%, Likely-NDD=11%, Normal plus AD/Mixed indications=15%, but with 5%=Probably-normal. In the LBD group, assigned risks were consistent with the diagnosis=79%, with Probable-NDD=74%, Normal with pSYN indications=5%, but with 11%=Probably-normal. In the iRBD group, Probable-NDD=42%, Normal plus pSYN indications=26% and Probably-normal=32%. In the CG group, 89% were assigned minimal NDD risks with Probably-normal=67%, Normal plus indications=22%, but with Likely NDD=8% and Probable NDD=3%. The AD test-retest reliability showed the same NDD classifications=78%, with slightly increasing=11% and decreased=11%. In the LBD group, the same NDD classifications were achieved=80%, with trending equivalence=10%, and decreasing severity=20%. The CG test-retest reliability showed the same NDD classifications=76%, with trending equivalence=22%, and increased severity=2%. Conclusion Consistencies between the diagnoses and assigned NDD risks and test-retest classification agreements were approximately 80% in the AD, LBD, and CG groups. In the iRBD group, the NDD risks were disbursed consistent with the range of expected severities. These results needed to be cross-validated in independent NDD datasets. Support (if any) NIH grants R44AG050326, R44AG054256, RO1AG060477, R33AG064271, ULRR024150, R34AG056639.

Abstract Introduction Insomnia is a common sleep disorder in pediatric patients with neurodevelopmental disabilities. There are no FDA approved medications for insomnia in the pediatric population, and treatment can be challenging. We present a case of successful treatment of sleep maintenance insomnia in a 15-year-old male with doxepin with supportive actigraphy data. Report of case(s) A 15-year-old male with a past history pertinent for a genetic neurodevelopmental disorder, autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) was evaluated in Pediatric Sleep Medicine Clinic for long standing difficulties with sleep maintenance. He experienced frequent, prolonged nocturnal awakenings and early morning awakenings. Previous polysomnogram was negative for sleep disordered breathing. He previously trialed clonidine, guanfacine, trazodone, melatonin, and mirtazapine without significant benefit. Baseline actigraphy demonstrated frequent and prolonged nocturnal awakenings and early morning awakenings. He was initiated on doxepin 3 mg at bedtime, and it was subsequently increased to 6 mg at bedtime. Parental report and repeat actigraphy 4 months later (on doxepin 6 mg) demonstrated improvement in nocturnal awakenings and early morning awakenings. Conclusion Up to now, there are no FDA approved medications for the treatment of insomnia in the pediatric population. A prior study of patients with ASD and ADHD demonstrated the use of doxepin provided clinical improvement in sleep onset and maintenance insomnia based on subjective evidence with parental report. In this case, doxepin improved subjective report of insomnia and correlated with objective findings on actigraphy. Support (if any) NA

Abstract Introduction Kleine-Levin Syndrome (KLS) is a rare disease with intermittent episodes of hypersomnia with behavioral abnormalities. We present a case of KLS with successful symptomatic treatment with modafinil and eventual remission. Report of case(s) A 19-year-old healthy male with no prior sleep disorders was referred for evaluation of hypersomnia. He developed leg cellulitis requiring antibiotic therapy. Shortly afterwards, he developed abnormal behaviors --quitting school, estrangement from friends, sleeping 20 hours a day, irritability, and suppressed appetite. He also demonstrated hypersexuality and disinhibited behaviors. After 10 days, he abruptly returned to baseline and had limited recall of the prior events. Three months later, he had a second episode with similar behavioral and sleep changes, again followed by spontaneous return to baseline after 10 days. Two months later, a similar spell occurred, prompting arrangement for psychiatric admission and initiation of quetiapine for a proposed diagnosis of rapid-cycling bipolar disorder. His symptoms again resolved spontaneously. Diagnostic tests including liver function tests, thyroid function tests, ammonia level, urine drug screen, Lyme disease, MRI brain, EEG, and CSF analysis were unremarkable. He was eventually referred to the Sleep Medicine clinic for evaluation. There were no symptoms suggesting other comorbid sleep disorders, and he had a normal neurologic and physical exam at time of presentation. A clinical diagnosis of KLS was made. The patient and family deferred prophylactic or abortive treatment (such as lithium, carbamazepine, or steroids) due to potential for side effects. Modafinil provided symptomatic benefits during the three milder episodes he had over the next few years. Episodes subsequently resolved and the patient is currently in remission (over 5 years) without sequalae. Conclusion KLS is a rare disease with typical onset during young adulthood, manifesting with abrupt onset of recurrent episodes of hypersomnia and prolonged sleep duration, lasting from days to several weeks. The diagnosis is clinical and requires at least one additional feature including: cognitive dysfunction, derealization, major apathy, or disinhibited behaviors. Patients revert to baseline between the episodes. Stimulants such as modafinil can promote wakefulness during the episodes. Support (if any) N/A