Lipford, Melissa C.

Abstract Introduction Sleep apnea impacts 50-70% of patients following stroke. Treatment of obstructive sleep apnea (OSA) in patients with stroke using continuous positive airway pressure (CPAP) has been recommended in recent American Heart Association/American Stroke Association guidelines. However, stroke patients poorly tolerate CPAP and often remain untreated. There is a paucity of data regarding alternative treatments such as oral appliance therapy (OAT) in stroke patients. We hypothesized that oral appliance therapy would be an efficacious option in the treatment of OSA in stroke patients, defined as a ≥50% reduction in apnea-hypopnea index (AHI) or oxygen desaturation index (ODI) or reduction in total AHI or ODI to < 10/h. Methods We performed a retrospective review of patients with OSA treated with OAT at our institution and had a history of stroke prior to receiving the oral appliance. Chart abstraction included demographic data, stroke type, sleep apnea diagnostic data, and efficacy data. Efficacy data included repeat sleep studies, overnight oximetry, patient reported outcomes, and subjective benefit, as available. Results 23 patients (52% female, mean age 63) were identified with a history of stroke prior to use of OAT for OSA. Baseline parameters (mean, SD) included BMI (30.8, 4.2), AHI (15.0, 10.6), and Epworth Sleepiness Scale (ESS) (9.3, 5.4). Post-treatment parameters included (mean, SD) BMI (30.1, 4.2), AHI (12.4, 12.0), and ESS (6.5, 4.0). 12 patients had both baseline and follow-up sleep studies performed which met criteria for AHI efficacy of OAT in 7 of 12 (58%). Wilcoxon signed rank exact test demonstrated improvement in median AHI of 9.3 (0.40-17.6, p< 0.05) among these 12 patients. 2 of 3 (67%) patients with overnight oximetry follow-up met criteria for ODI efficacy of OAT. Of 8 patients with only subjective follow-up, 6 (75%) reported subjective improvement and 2 (25%) did not tolerate the device. Conclusion This study demonstrated that oral appliance therapy is efficacious in reducing the AHI by at least 50% or to a value below 10 in a majority of patients. Oral appliance therapy may be a viable alternative to CPAP in selected OSA patients with a history of stroke. Support (if any) No support

Abstract Study Objectives Narcolepsy has a complex phenotype owing to differences in symptomatology, disease severity, and comorbidities. This is the first study to use aggregate electronic health record (EHR) data and natural language processing (NLP) algorithms to characterize the demographics and comorbidities of a large cohort of patients with narcolepsy. Methods First-time Mayo Clinic patients (2000–2020) who had ≥1 narcolepsy-specific ICD-9/10 code and ≥1 disease-supportive statement in the clinical notes (identified using an NLP algorithm) were identified. A control cohort was propensity matched for birth year, age at first institutional encounter, sex, race, ethnicity, number of diagnosis codes, and mortality. Common comorbidities were compared and ranked between cohorts. Results In the EHR database (N = 6 389 186 patients), 2057 patients with narcolepsy were identified (median age, 32 years; 59.6% female; 92.6% white; and 89.2% non-Hispanic) and propensity matched with a control cohort. Among the top 20 comorbidities occurring more frequently in the narcolepsy cohort compared with the control cohort (odds ratio [OR], 1.67–3.94; p < .001]) were sleep disorders (restless legs syndrome, obstructive sleep apnea, and insomnia), mood disorders (depression, dysthymia, and anxiety), and pain disorders (chronic pain syndrome, migraine, fibromyalgia, carpal tunnel syndrome, and myalgia). Other comorbidities significantly associated with narcolepsy (OR, 1.33–1.95) were irritable bowel syndrome (p < .001), asthma (p < .001), cervical spondylosis (p < .01), syncope (p < .01), and hypothyroidism (p < .05). Conclusions This propensity-matched cohort study demonstrates increased psychiatric, sleep, and pain disorders in patients living with narcolepsy and challenges beyond narcolepsy-specific symptoms in this population. Understanding common narcolepsy-associated comorbidities may assist in tailoring treatment modalities.

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 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

Abstract Introduction The definition of respiratory events has evolved over decades. The current American Academy of Sleep Medicine scoring manual recommends hypopneas be defined by a ≥ 30% airflow reduction with either ≥ 3% desaturation or an arousal, while the prior “recommended” criteria of a ≥ 30% airflow reduction and associated ≥ 4% oxygen desaturation (with no requirement of arousal) was changed to “optional”. Consequently, events previously characterized as a respiratory effort related arousal (RERA) may now be defined as a 3% hypopnea. We hypothesized that while the 3% apnea-hypopnea index (3%AHI) will be higher than the 4%AHI, the 3%AHI will be similar to the 4% respiratory disturbance index (4%RDI), and that the measurement of RERAs under 3% scoring criteria will be clinically insignificant. Methods We prospectively collected 70 consecutive in-lab polysomnography results in 4 adult age groups. We re-scored the respiratory events utilizing the 3% hypopnea rule, and compared the differences between 3% and 4% scoring criteria. Results Among the 70 studies (mean age 50, males 46%), the 3%AHI was significantly higher than the 4%AHI (+9.247 ± 1.161, p< 0.001). This was mainly due to increased hypopnea events (+10.313 ± 1.617, p< 0.001). The 3%AHI was significantly different from the 4%RDI (+7.096 ± 1.133, p< 0.001). There were no significant differences between the 3% and 4% RERA indices, with both values being minimal. Results were similar in both diagnostic and titration phases of testing. Conclusion As previously shown, utilizing the 3% hypopnea rule results in an increased AHI. Most of this difference is related to hypopneas with negligible influence of RERAs. This may lead to increased diagnosis and severity of sleep-disordered breathing in the adult population, and potentially be associated with payer ramifications. Our findings demonstrated negligible RERA indices on average with either rule, thus calling into question the clinical significance of this index in most patients. Support (if any) NA

Abstract Introduction Narcolepsy is a chronic sleep disorder with multiple comorbid conditions. Sodium oxybate (SXB) is strongly recommended for treatment of narcolepsy. This study used aggregate electronic health record (EHR) data to characterize demographic characteristics and comorbidities of patients with narcolepsy treated with or without SXB. Methods An EHR-based search identified first-time Mayo Clinic patients between 1975–2020. Patients had ≥1 narcolepsy-specific ICD-9/-10 code and ≥1 diagnostic mention of narcolepsy in clinical notes (natural-language-processing algorithm). Patients with narcolepsy treated with SXB were age/sex matched with a cohort without SXB treatment. Common comorbidities were identified using ICD-9/-10 codes and compared between cohorts (odds ratio [OR]). Results Of 4387 patients identified, 8% received SXB treatment (n=351; mean [IQR] age at first diagnosis code observed at Mayo Clinic, 32 [23.2-46.1] y; 65.5% female; 92.3% white); 4036 patients had no SXB treatment (mean [IQR] age at first diagnosis code observed at Mayo Clinic, 44.8 [29.8-59.0] y; 58.0% female; 88.9% white). The 10 most commonly reported comorbidities (overall population) were insomnia (46.6%), fatigue (46.3%), depression (42.2%), hypertension (36.2%), hyperlipidemia (34.2%), obstructive sleep apnea (32.3%), diabetes mellitus (31.3%), arrhythmia (27.3%), idiopathic hypersomnia (IH; 26.8%), and coronary artery disease (17.6%). A cohort of 351 patients without SXB were age/sex matched to patients with SXB for comparison of comorbidities. In the unadjusted analysis, P values were significant for differences between cohorts (OR [95% CI] SXB vs no SXB) for fatigue (0.72 [0.54-0.97]; P< 0.05; adjusted P>0.9) and IH (0.60 [0.43-0.84]; P< 0.01; adjusted P=0.29). After P value adjustment (Bonferroni correction), there were no significant differences between these cohorts in ORs for any comorbidity. The matched cohorts, which were younger than the overall population, had numerically lower rates of these diagnoses vs the overall population, except fatigue and IH in patients without SXB and depression in patients with SXB. Conclusion Among age-/gender-matched cohorts of patients with/ without SXB, there were no significant differences in comorbidities. Prevalence of comorbid IH/narcolepsy diagnoses highlight the diagnostic challenge in differentiating IH from narcolepsy type 2. SXB is highly effective but used by < 1:10 patients with narcolepsy in the Mayo Clinic health system. Support (if any) Avadel Pharmaceuticals

Abstract Introduction Sodium oxybate (SXB) is strongly recommended for treatment of narcolepsy. Patients treated with available immediate-release oxybates are required to awaken for a second dose 2.5–4 hours after the bedtime dose to cover a full night of sleep. This study characterized SXB treatment patterns and discontinuation in narcolepsy patients. Methods Mayo Clinic patients from 1975–2020 were identified using an electronic health record–based search. Patients with ≥1 narcolepsy-specific ICD-9/-10 code and ≥1 diagnostic mention of narcolepsy in clinical notes (identified using a natural-language-processing [NLP] algorithm) were included. NLP was used to identify SXB non-use events with manual chart reviews performed to characterize reasons for discontinuation, switching, or missing the second dose and effects of missing the second dose. Results Of the patients with narcolepsy prescribed SXB (n=351; mean age at first diagnosis code observed at Mayo Clinic, 32 y [IQR: 23.2–46.1]; 65.5% female; 92.3% white), 113 (32.2%) had clinical notes indicating discontinuation of SXB, with 71 (20.2%) including reasons for discontinuation. The most common reasons for discontinuation (n≥5) included lack of efficacy (n=11), side effects (n=10), gastrointestinal side effects (n=10), neurological side effects (n=9), psychiatric side effects (n=8), lack of access (insurance/cost, n=10), and resolution/absence of cataplexy (n=5). Mentions of switching from SXB to other drugs (n=12 patients) included switching to stimulants (mixed amphetamine salts, n=3; dextroamphetamine, n=2; methylphenidate, n=1), sedative hypnotics (zolpidem, n=2), antidepressants (mirtazapine, n=1), and wake-promoting agents (solriamfetol, n=1). Of the 38 patients (10.8%) with mentions of missing the second nightly SXB dose, reasons were recorded for 24 (63.2%), including inability to wake up (n=14), forgetting the second dose (n=3), and having to wake up early the following day (n=3). Consequences of missing the second dose were recorded for a small subset (increased cataplexy, n=4; lower daytime alertness, n=3; awakens earlier, n=1; tiredness, n=1). Conclusion Limited data are available regarding real-world use of SXB. This novel study used a combination of NLP algorithm and manual chart review to identify difficulties patients have with the second, middle-of-the night immediate-release oxybate dose and patient-experienced consequences of not adhering to the prescribed dosing regimen. Support (if any) Avadel Pharmaceuticals

Abstract Introduction Narcolepsy is a rare, chronic sleep disorder whose symptoms detrimentally impact quality of life. Narcolepsy has a complex phenotype associated with multiple comorbid conditions. This is the first study to use aggregate electronic health record (EHR) data to characterize the demographics and comorbidities of patients with narcolepsy. Methods An EHR-based search identified first-time Mayo Clinic patients between 2000–2020. Included patients had ≥1 narcolepsy-specific ICD-9/10 code and ≥1 disease-supportive statement in the clinical notes (identified using a natural language processing algorithm). A control cohort was propensity-matched for birth year, age at first institutional encounter, sex, race, ethnicity, number of diagnosis codes, and mortality. Common comorbidities were compared and ranked between cohorts by odds ratio (OR); P values were adjusted and calculated based on Bonferroni correction. Results In the EHR database (N=6,389,186 patients), 2057 patients with narcolepsy were identified (median age at first presentation to Mayo clinic, 32 y [range, 17–48]; 59.6% female; 92.6% white; 89.2% non-Hispanic) and propensity-matched with a control cohort of 2057 patients (median age at first presentation to Mayo clinic, 35 y [range, 12–52]; 58.9% female; 94.6% white; 84.5% non-Hispanic). Among the top comorbidities that occurred more frequently in the narcolepsy cohort compared to the control cohort (OR [95% CI]; P< 0.001]) were sleep disorders (restless leg syndrome, 3.94 [3.09–5.02]; obstructive sleep apnea, 3.27 [2.83–3.79]; insomnia, 1.84 [1.57–2.17]); mood disorders (depression, 2.11 [1.86-2.40]; dysthymia, 1.86 [1.54–2.25]; anxiety, 1.67 [1.46–1.89]); and pain disorders (chronic pain syndrome, 2.20 [1.76–2.76]; migraine, 1.96 [1.66–2.31]; fibromyalgia, 1.90 [1.61–2.25]; carpal tunnel syndrome, 1.80 [1.46–2.22]; myalgia, 1.69 [1.45–1.97]). Other comorbidities statistically significantly associated with narcolepsy were (OR range, 1.33–1.95) irritable bowel syndrome (P< 0.001), asthma (P< 0.001), cervical spondylosis (P< 0.01), syncope (P< 0.01), and hypothyroidism (P< 0.05). Conclusion This propensity-matched cohort study affirmed prior studies of increased psychiatric and sleep disorders in patients with narcolepsy. Narcolepsy patients were twice as likely to experience chronic pain syndrome compared to the matched control group. Understanding common narcolepsy comorbidities may help optimize treatment efficacy and increase understanding of the medical/psychiatric challenges of narcolepsy patients. Support (if any) Avadel Pharmaceuticals