Tippmann‐Peikert, Maja

Abstract Introduction Isolated REM sleep behavior disorder (iRBD) is characterized by loss of normal REM sleep atonia and dream enactment behavior. iRBD is strongly associated with α-synucleinopathies and risk for developing Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), yet phenoconversion risk for long-term outcomes of younger women and men remains undefined. We aimed to ascertain longitudinal outcomes and phenoconversion risk in the Mayo Clinic iRBD cohort. Methods Eighty-nine of 165 registry participants with at least one-year follow-up were included. Retrospective chart review attained baseline demographics, age at presentation, baseline Timed Up and Go (TUG) and Montreal Cognitive Assessment (MoCA) scores, and phenoconversion status (iRBD, PD, DLB, mild cognitive impairment [MCI], MSA, or other). Kaplan–Meier survival analysis and Cox proportional hazards modeling were analyzed with alpha at p < 0.05. Results 68 men and 21 women had a mean age of 63 years at polysomnographic diagnosis. At follow-up, 64 (71.9%) remained iRBD; 7 (7.9%) developed PD, 11 (12.4%) developed DLB, 3 (3.4%) developed MCI, 1 (1.1%) developed MSA, and 3 (3.4%) developed another dementia. Abnormal TUG (>12 seconds) occurred in 5.9% and abnormal MoCA (< 24) in 23.3%. Phenoconversion rates were similar in women and men (p = 0.44). Older age at PSG predicted phenoconversion, corresponding to a two-fold increase in risk with each 10-year increase (HR 2.00, 95% CI 1.15–3.52). Neither abnormal TUG nor MoCA predicted conversion. Cumulative phenoconversion was approximately 1% at 1 year, 7% at 3 years, 10% at 5 years, 30% at 10 years, 34% at 12 years, and 49% at 15 years. Mean and median time to phenoconversion was 7 years (range, 1-18 years). Conclusion We found that iRBD phenoconversion rates were lower than historically reported. Only age at presentation predicted phenoconversion, with risk doubling per decade. At 12 years, cumulative phenoconversion rate was approximately 34%. Support (if any)

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 Background Restless legs syndrome (RLS) is a prevalent sensorimotor disorder that can dramatically impair sleep quality, daytime function, and quality of life. Although many patients benefit from standard pharmacological therapy, some patients suffer from insufficient treatment response or medication intolerance. Novel treatment approaches are therefore necessary. Objective Given the overlap between RLS and pain syndromes in both pathophysiological mechanisms and certain treatment options, we aimed to perform a scoping review of the available evidence on spinal cord stimulation (SCS) for RLS and discuss potential mechanistic implications. Methods We identified a total of 16 cases of patients with RLS who underwent SCS, all from case reports or case series. Discussion The published evidence is insufficient to assess SCS efficacy in patients with RLS, but SCS remains a promising investigational therapy in RLS on the basis of its potential mitigatory effects in the central hyperexcitability of the sensorimotor cortex through neuromodulation of spinal, subcortical, and cortical areas. A call for further research in this field is presented, with suggestions for future directions and trial designs.

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 Restless legs syndrome (RLS) can dramatically impair sleep quality and quality of life. Some patients have insufficient treatment response or intolerance to available pharmacological options. Exploration of novel therapeutic approaches is needed. Methods We report a case of spinal cord stimulation (SCS) providing benefit in RLS. We also performed a scoping review of SCS in RLS with comprehensive literature search of MEDLINE, EMBASE, Cochrane, and Scopus. Results A 77-year-old woman with DM2, OSA (on ASV), depression, familial RLS and iron deficiency with typical RLS symptoms for all of her adult life presented for management in 2000. In 2011 she developed intractable painful peripheral neuropathy and chronic back pain. Levodopa, pramipexole, oral/intravenous iron, gabapentin, pregabalin, tramadol, oxycodone, and methadone were ineffective or poorly tolerated. A 7-day percutaneous SCS trial resulted in RLS symptoms improvement initially by 50%. A Medtronic stimulator with lead placement at T8-T9 was implanted. 6 months later, the patient toggled between a tonic program (2.1-4.6 mA, 200 us, 50 Hz) and a sub-perception, differential target multiplexed program duty-cycled to 1:2 on:off (3.7 mA, 170 us, 300 Hz). She reported 75% improvement in RLS symptoms. Pain improved by 50%. Total daily dose of Oral Morphine Equivalents was reduced from 48.75mg/day to 37.5mg/day, with a stable once daily dose of 400 mg gabapentin at night. Uninterrupted sleep went from 2-5 hours to 6 hours. RLS worsened when the device was off. Our case corroborates the current evidence of benefit of SCS for RLS from the literature. We identified other 16 unique patients from case reports and series who had undergone SCS for RLS. Leads were most often implanted in mid or low thoracic levels. Stimulation waveforms were high frequency in 4 patients, tonic in 3 patients, burst stimulation in 1 patient, and undescribed in the others. All patients had RLS symptom reduction. Comorbid pain was reported in 14 patients, which also improved with SCS. Complication with lead erosion was reported in one case. Conclusion SCS remains a promising therapeutic approach for refractory RLS that deserves further investigation. SCS may reduce hyperexcitability seen in RLS by modulating dysfunctional spinal, subcortical, and cortical networks. Support (if any)

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