Association between idiopathic hypersomnia and a genetic variant in the PER3 gene.

We aim to identify genetic markers associated with idiopathic hypersomnia, a disabling orphan central nervous system disorder of hypersomnolence that is still poorly understood. In our study, DNA was extracted from 79 unrelated patients diagnosed with idiopathic hypersomnia with long sleep time at the National Reference Center for Narcolepsy-France according to very stringent diagnostic criteria. Whole exome sequencing on the first 30 patients with idiopathic hypersomnia (25 females and 5 males) allowed the single nucleotide variants to be compared with a control population of 574 healthy subjects from the French Exome project database. We focused on the identification of genetic variants among 182 genes related to the regulation of sleep and circadian rhythm. Candidate variants obtained by exome sequencing analysis were then validated in a second sample of 49 patients with idiopathic hypersomnia (37 females and 12 males). Our study characterised seven variants from six genes significantly associated with idiopathic hypersomnia compared with controls. A targeted sequencing analysis of these seven variants on 49 other patients with idiopathic hypersomnia confirmed the relative over-representation of the A➔C variant of rs2859390, located in a potential splicing-site of PER3 gene. Our findings support a genetic predisposition and identify pathways involved in the pathogeny of idiopathic hypersomnia. A variant of the PER3 gene may predispose to idiopathic hypersomnia with long sleep time.

Home nocturnal infrared video to record non-rapid eye movement sleep parasomnias.

To assess the feasibility, the acceptability and the usefulness of home nocturnal infrared video in recording the frequency and the complexity of non-rapid eye movement sleep parasomnias in adults, and in monitoring the treatment response. Twenty adult patients (10 males, median age 27.5 years) with a diagnosis of non-rapid eye movement parasomnia were consecutively enrolled. They had a face-to-face interview, completed self-reported questionnaires to assess clinical characteristics and performed a video-polysomnography in the Sleep Unit. Patients were then monitored at home during at least five consecutive nights using infrared-triggered cameras. They completed a sleep diary and questionnaires to evaluate the number of parasomniac episodes at home and the acceptability of the home nocturnal infrared video recording. Behavioural analyses were performed on home nocturnal infrared video and video-polysomnography recordings. Eight patients treated by clonazepam underwent a second home nocturnal infrared video recording during five consecutive days. All patients had at least one parasomniac episode during the home nocturnal infrared video monitoring, compared with 75% during the video-polysomnography. A minimum of three consecutive nights with home nocturnal infrared video was required to record at least one parasomniac episode. Most patients underestimated the frequency of episodes on the sleep diary compared with home nocturnal infrared video. Episodes recorded at home were often more complex than those recorded during the video-polysomnography. The user-perceived acceptability of the home nocturnal infrared video assessment was excellent. The frequency and the complexity of the parasomniac episodes decreased with clonazepam. Home nocturnal infrared video has good feasibility and acceptability, and may improve the evaluation of the phenotype and severity of the non-rapid eye movement parasomnias and of the treatment response in an ecological setting.

Changes in Sleep Pattern During the COVID-19 Lockdown in Patients With Narcolepsy, Idiopathic Hypersomnia, and Restless Legs Syndrome.

BACKGROUND AND OBJECTIVES: To explore the first coronavirus disease 2019 (COVID-19) lockdown effect on sleep symptoms in patients with narcolepsy, idiopathic hypersomnia (IH), and restless legs syndrome (RLS). METHODS: Between March and May 2020, a sample of adult patients regularly followed up in a Reference Hospital Sleep Unit (299 with narcolepsy, 260 with IH, and 254 with RLS) was offered an online survey assessing their sleep-wake habits, daily activities, medication intake, and validated scales: International RLS Study Group questionnaire, Narcolepsy Severity Scale (NSS), IH Severity Scale (IHSS), Epworth Sleepiness Scale (ESS), Insomnia Severity Index, Beck Depression Inventory-II, and European Quality of Life (QoL) scale. The survey was proposed once, and the questions were answered for the prelockdown (recall of the month before the confinement) and the lockdown (time of study) periods. RESULTS: Overall, 331 patients completed the survey (response rate 40.7%): 102 with narcolepsy, 81 with IH, and 148 with RLS. All patients reported later bedtimes, with reduced differences for time in bed (TIB) and total sleep time (TST) over 24 hours between weekdays and weekends. Patients with narcolepsy spent more TIB and increased TST overnight, with more daytime napping. They had more awakenings, higher ESS scores, lower QoL, and no NSS changes. Patients with IH also increased their TIB, TST overnight and 24 hours on weekdays. Nocturnal sleep latency and the number of awakenings increased but with no change in ESS, QoL, and IHSS scores. Patients with RLS reported longer nocturnal sleep latency, more awakenings, more naps, decreased TIB, and TST overnight. RLS severity increased while QoL decreased. A significant portion of patients reported disease worsening during the lockdown (narcolepsy: 39.4%, IH: 43.6%, and RLS: 32.8%), and some patients stopped or lowered their medication (narcolepsy: 22.5%, IH: 28%, and RLS: 9.5%). DISCUSSION: During the lockdown, all patients reported later bedtimes; those with narcolepsy and IH extended their sleep duration unlike patients with RLS. These changes were often associated with negative consequences on QoL. In the current context of recurrent COVID-19 waves, the recent development of teleconsultations should enable physicians to monitor patients with chronic sleep disorders more closely and to recommend optimized sleep schedules and duration, in order to prevent psychological problems and improve their QoL.

Linking clinical complaints and objective measures of disrupted nighttime sleep in narcolepsy type 1.

STUDY OBJECTIVES: Despite its high frequency in narcolepsy type 1(NT1), disrupted nocturnal sleep (DNS) remains understudied, and its determinants have been poorly assessed. We aimed to determine the clinical, polysomnographic (PSG), and biological variables associated with DNS in a large sample of patients with NT1, and to evaluate the effect of medication on DNS and its severity. METHODS: Two hundred and forty-eight consecutive adult patients with NT1 (145 untreated, 103 treated) were included at the National Reference Center for Narcolepsy-France; 51 drug-free patients were reevaluated during treatment. DNS, assessed with the Narcolepsy Severity Scale (NSS), was categorized in four levels (absent, mild, moderate, severe). Clinical characteristics, validated questionnaires, PSG parameters (sleep fragmentation markers: sleep (SB) and wake bouts (WB), transitions), objective sleepiness, and orexin-A levels were assessed. RESULTS: In drug-free patients, DNS severity was associated with higher scores on NSS, higher sleepiness, anxiety/depressive symptoms, autonomic dysfunction, worse quality of life (QoL). Patients with moderate/severe DNS (59%) had increased sleep onset REM periods, lower sleep efficiency, longer wake after sleep onset, more N1, SB, WB, sleep instability, transitions. In treated patients, DNS was associated with the same clinical data, and antidepressant use; but only with longer REM sleep latency on PSG. During treatment, sleepiness, NSS scores, depressive symptoms decreased, as well as total sleep time, WB, SB, transitions. DNS improved in 55% of patients, without predictors except more baseline anxiety. CONCLUSION: DNS complaint is frequent in NT1, associated with disease severity based on NSS, several PSG parameters, and objective sleepiness in untreated and treated conditions. DNS improves with treatment. We advocate the systematic assessment of this symptom and its inclusion in NT1 management strategy.

Idiopathic Hypersomnia Severity Scale to better quantify symptoms severity and their consequences in idiopathic hypersomnia.

STUDY OBJECTIVES: To assess the responsiveness of the Idiopathic Hypersomnia Severity Scale (IHSS) to medications and estimate the minimum clinically important difference, to report clinically relevant score ranges, and to confirm its psychometric properties and whether items need to be weighted in drug-free and treated patients with idiopathic hypersomnia (IH). METHODS: Two-hundred twenty-six (166 drug-free and 60 treated) patients with IH (cross-sectional sample) completed the 14-item IHSS to quantify the severity of the 3 major IH symptoms (excessive daytime sleepiness, prolonged nighttime sleep, and sleep inertia) and consequences; 77 untreated patients were evaluated again after treatment (longitudinal sample). Patients filled in the Epworth Sleepiness Scale, Beck Depression Inventory II, and European Quality of Life questionnaires. RESULTS: The IHSS confirmed adequate psychometric properties with a factor analysis indicating a 3-component solution. IHSS total score was lower in treated than untreated patients, with a mean difference of 4-5 points in the cross-sectional and longitudinal samples. Distribution-based methods were used to estimate that 4 points represented the minimum clinically important difference. Four severity levels were defined with between-group differences related to treatment. The probability of having severe sleepiness, depressive symptoms, and low quality of life increased with the severity level. Our results showed that IHSS item-weighting was not necessary. CONCLUSIONS: The IHSS is a valid and reliable tool to quantify IH symptoms, with 4 severity score levels of clinical importance. The IHSS has adequate psychometric properties and can detect symptom changes after treatment. These findings should stimulate its use in clinical settings and in research studies. CITATION: Rassu AL, Evangelista E, Barateau L, et al. Idiopathic Hypersomnia Severity Scale to better quantify symptoms severity and their consequences in idiopathic hypersomnia. J Clin Sleep Med. 2022;18(2):617-629.

Sleep inertia measurement with the psychomotor vigilance task in idiopathic hypersomnia.

STUDY OBJECTIVES: Sleep inertia is a frequent and disabling symptom in idiopathic hypersomnia (IH), but poorly defined and without objective measures. The study objective was to determine whether the psychomotor vigilance task (PVT) can reliably measure sleep inertia in patients with IH or other sleep disorders (non-IH). METHODS: A total of 62 (51 women, mean age: 27.7 ± 9.2) patients with IH and 140 (71 women, age: 33.3 ± 12.1) with non-IH (narcolepsy = 29, non-specified hypersomnolence [NSH] = 47, obstructive sleep apnea = 39, insomnia = 25) were included. Sleep inertia and sleep drunkenness in the last month (M-sleep inertia) and on PVT day (D-sleep inertia) were assessed with three items of the Idiopathic Hypersomnia Severity Scale (IHSS), in drug-free conditions. The PVT was performed four times (07:00 pm, 07:00 am, 07:30 am, and 11:00 am) and three metrics were used: lapses, mean 1/reaction time (RT), and slowest 10% 1/RT. RESULTS: Sleep inertia was more frequent in patients with IH than non-IH (56.5% and 43.6% with severe sleep inertia in the past month, including 24% and 12% with sleep drunkenness). Lapse number increase and slowest 10% 1/RT decrease, particularly at 07:00 am and 07:30 am, were proportional with M-sleep inertia severity, but regardless of sleep drunkenness and sleep disorders. Similar results were obtained when PVT results were compared in patients with/without D-sleep inertia, with the largest increase of the lapse number at 07:00 am and 07:30 am associated with severe sleep inertia and sleep drunkenness. CONCLUSIONS: PVT is a reliable and objective measure of sleep inertia that might be useful for its characterization, management, and follow-up in patients with IH.

Narcolepsy with intermediate cerebrospinal level of hypocretin-1.

STUDY OBJECTIVES: To describe the phenotype of narcolepsy with intermediate cerebrospinal fluid hypocretin-1 levels (CSF hcrt-1). METHODS: From 1600 consecutive patients with narcolepsy from Bologna and Montpellier sleep centers, we selected patients with intermediate CSF hcrt-1 levels (110-200 pg/mL). Clinical, neurophysiological, and biological data were contrasted for the presence of cataplexy, human leukocyte haplotype (HLA)-DQB1*06:02, and median CSF hcrt-1 levels (149.34 pg/mL). RESULTS: Forty-five (55% males, aged 35 ± 17 years) patients (2.8% of all cases) were included. Thirty-three (73%) were HLA-DQB1*06:02, 29 (64%) reported cataplexy (21, 72.4% with typical features), and 5 (11%) had presumed secondary etiology. Cataplexy was associated with other core narcolepsy symptoms, increased sleep onset rapid eye movement periods, and nocturnal sleep disruption. Cataplexy and irrepressible daytime sleep were more frequent in HLA-DQB1*06:02 positive patients. Lower CSF hcrt-1 levels were associated with hallucinations. CONCLUSIONS: Narcolepsy with intermediate CSF hcrt-1 level is a rare condition with heterogeneous phenotype. HLA-DQB1*06:02 and lower CSF hcrt-1 were associated with typical narcolepsy features, calling for future research to distinguish incomplete from secondary narcolepsy forms.

Measurement of Narcolepsy Symptoms in School-Aged Children and Adolescents: The Pediatric Narcolepsy Severity Scale.

OBJECTIVE: We validated the Narcolepsy Severity Scale (NSS) in adults with narcolepsy type 1 (NT1) to quantify the severity, frequency, and consequences of the 5 key narcolepsy symptoms over the last month, and we now developed the Pediatric NSS (NSS-P); thus, the aims of this study were to assess NSS-P psychometric properties, validity, and reliability, and to evaluate its responsiveness to treatment in a well-characterized sample of children and adolescents with NT1. METHODS: The NSS was reformulated for children, and the item about driving was removed. The total score of the 14-item NSS-P ranges from 0 to 54, and higher scores reflect more severe disease. Children and adolescents (n = 209, 6-17 years of age) with NT1 diagnosed in 2 Reference Centers for Narcolepsy in France were consecutively asked to fill in the NSS-P. The scale was fully and correctly completed by 160 (10-18 years of age, 68 untreated). Moreover, 65 participants completed it twice (33 before/during treatment, and 32 under the same treatment). The NSS-P psychometric properties, score changes before/during treatment, and convergent validity with other clinical parameters were assessed. RESULTS: The NSS-P showed adequate psychometric properties with significant item-total score correlations. Factor analysis indicated a 4-factor solution with good reliability. The NSS-P score was lower in treated than untreated patients with a mean difference of 3.71 ± 1.45, with a minimum clinically important difference between untreated and treated patients in the longitudinal sample estimated at 4 points. Four severity levels were defined (mild, moderate, severe, very severe) with between-group differences related to treatment. The NSS-P total score was associated with self-reported sleepiness, insomnia, and depressive symptoms. Its temporal stability was satisfactory. DISCUSSION: We validated a brief instrument to assess NT1 symptom frequency, severity, and consequences in ≥10-year-old children and adolescents with 4 clinically relevant severity score ranges. This scale constitutes a relevant tool to improve and provide guidance for NT1 management in pediatric populations. The ease of administration, its good psychometric properties, and its sensitivity to detect symptom changes after treatment ensure future use of the NSS-P in clinical and research settings.

Speech Biomarkers in Rapid Eye Movement Sleep Behavior Disorder and Parkinson Disease.

OBJECTIVE: This multilanguage study used simple speech recording and high-end pattern analysis to provide sensitive and reliable noninvasive biomarkers of prodromal versus manifest α-synucleinopathy in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD) and early-stage Parkinson disease (PD). METHODS: We performed a multicenter study across the Czech, English, German, French, and Italian languages at 7 centers in Europe and North America. A total of 448 participants (337 males), including 150 with iRBD (mean duration of iRBD across language groups 0.5-3.4 years), 149 with PD (mean duration of disease across language groups 1.7-2.5 years), and 149 healthy controls were recorded; 350 of the participants completed the 12-month follow-up. We developed a fully automated acoustic quantitative assessment approach for the 7 distinctive patterns of hypokinetic dysarthria. RESULTS: No differences in language that impacted clinical parkinsonian phenotypes were found. Compared with the controls, we found significant abnormalities of an overall acoustic speech severity measure via composite dysarthria index for both iRBD (p = 0.002) and PD (p < 0.001). However, only PD (p < 0.001) was perceptually distinct in a blinded subjective analysis. We found significant group differences between PD and controls for monopitch (p < 0.001), prolonged pauses (p < 0.001), and imprecise consonants (p = 0.03); only monopitch was able to differentiate iRBD patients from controls (p = 0.004). At the 12-month follow-up, a slight progression of overall acoustic speech impairment was noted for the iRBD (p = 0.04) and PD (p = 0.03) groups. INTERPRETATION: Automated speech analysis might provide a useful additional biomarker of parkinsonism for the assessment of disease progression and therapeutic interventions. ANN NEUROL 2021;90:62-75.

Systematic assessment of autonomic symptoms in restless legs syndrome.

OBJECTIVES: To compare the clinical features of autonomic dysfunction using the SCOPA-AUT questionnaire in untreated patients with restless legs syndrome (RLS) with controls, to identify factors associated with more severe autonomic symptoms, and to assess the effect of medication in patients. METHODS: The SCOPA-AUT questionnaire that evaluates cardiovascular, gastrointestinal, urinary, thermoregulatory, pupillomotor, and sexual dysfunctions was completed by 409 consecutive untreated patients with RLS (54.1 ± 14.5 y.o; 265 women) and 331 controls (59.0 ± 17.0; 161 women). Clinical and polysomnographic data were assessed in all patients. A subgroup of 57 patients were evaluated a second time after treatment (mostly dopaminergic agonist) after an interval of 0.88 ± 1.42 year. RESULTS: Compared to controls, untreated patients with RLS were younger, more often women, obese, with increased cardiovascular diseases (CVD). The SCOPA-AUT total score was higher in patients than controls in unadjusted and adjusted models. Patients had more autonomic symptoms in all subdomains of the scale (except for sexual dysfunction in men). These results were confirmed in a subgroup of 259 cases and age-sex-matched controls. Female gender, obesity, RLS severity, diabetes mellitus, CVD, sleepiness, insomnia and depressive symptoms but neither periodic legs movements during sleep (PLMS) nor objective sleep parameters were associated with high scores. Despite RLS and PLMS improvement, medication did not change total and subdomain scores. CONCLUSIONS: Patients with RLS have frequent and large spectrum of autonomic symptoms, without effect of PLMS, sleep fragmentation and medication. These results suggest a global autonomic dysfunction in RLS that should be assessed more systematically in severe patients.

Video-Polysomnographic Assessment for the Diagnosis of Disorders of Arousal in Children.

OBJECTIVES: To highlight the slow-wave sleep (SWS) fragmentation and validate the video-polysomnographic (vPSG) criteria and cutoffs for the diagnosis of disorders of arousal (DOA) in children, as already reported in adults. METHODS: One hundred children (66 boys, 11.0 ± 3.3 years) with frequent episodes of DOA and 50 nonparasomniac children (32 boys, 10.9 ± 3.9 years) underwent vPSG recording to quantify SWS characteristics (number of N3 sleep interruptions, fragmentation index, slow/mixed and fast arousal ratios, and indexes per hour) and associated behaviors. We compared SWS characteristics in the 2 groups and defined the optimal cutoff values for the diagnosis of DOA using receiver operating characteristic curves. RESULTS: Patients with DOA had higher amounts of N3 and REM sleep, number of N3 interruptions, SWS fragmentation, and slow/mixed arousal indexes than controls. The highest area under the curve (AUC) values were obtained for SWS fragmentation and slow/mixed arousal indexes with satisfactory classification performances (AUC 0.80, 95% confidence interval [CI] 0.73-0.87; AUC 0.82, 95% CI 0.75-0.89). SWS fragmentation index cutoff value of 4.1/h reached a sensitivity of 65.0% and a specificity of 84.0%. Slow/mixed arousal index cutoff of 3.8/h reached a sensitivity of 69.0% and a specificity of 82.0%. At least one parasomniac episode was recorded in 63.0% of patients and none of the controls. Combining behavioral component by vPSG increased sensitivity of both biomarkers to 83% and 89%, respectively. CONCLUSIONS: We confirmed that SWS fragmentation and slow/mixed arousal indexes are 2 relevant biomarkers for the diagnosis of DOA in children, with different cutoffs obtained than those validated in adults. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that SWS fragmentation and slow/mixed arousal indexes on vPSG accurately identify children with DOA.

Sleep-related head jerks: toward a new movement disorder.

STUDY OBJECTIVES: Sleep-related head jerks (SRHJ) are often considered as a physiological motor phenomenon, occurring mainly during rapid eye movement (REM) sleep. Their clinical relevance and links with other sleep parameters are unclear. We characterized the clinical and polysomnographic features of patients with excessive SRHJ and compare them with healthy controls and patients with isolated REM sleep behavior disorder (iRBD). METHODS: A total of 30 patients (19 males, 27.5 y.o., 16.0-51.0) with a REM-HJ index >30/h were identified over a period of 5 years. All had a video-polysomnographic (PSG) recording to characterize the SRHJ, to assess associations with other sleep parameters and to quantify phasic and tonic electromyographic activity during REM sleep, compared with 30 healthy controls and 30 patients with iRBD. RESULTS: Five among the 30 patients had a primary complaint of involuntary nighttime head movements associated with sleepiness or non-restorative sleep. The mean REM-HJ index was 57.22/h ± 24.42, a nonperiodic pattern, stable across the sleep cycles, and with a low between-test variability (for the nine patients with two PSG assessments in untreated condition). REM-HJs were often associated with arousals (65.2%) and leg movements (38.1%) and less with respiratory events (9.6%), without association with increased phasic and tonic electromyographic activities. SRHJ were also found in 36.7% of controls and 56.7% of iRBD patients, but with a lower index in REM sleep (0.79/h ± 1.59 and 2.76/h ± 4.57). CONCLUSIONS: Although SRHJ are frequent in the general population and with uncertain clinical significance, rare severe symptomatic forms should be individualized and eventually be categorized as a new sleep-related movement disorder, distinct from RBD and periodic leg movements.

Characteristics associated with hypersomnia and excessive daytime sleepiness identified by extended polysomnography recording.

STUDY OBJECTIVES: Hypersomnolence, defined by excessive daytime sleepiness (EDS) or excessive quantity of sleep (EQS), has been associated with increased morbidity. The aim of this study was to determine the clinical and polysomnographic characteristics associated with EQS and EDS assessed objectively during extended polysomnography recording. METHODS: A total of 266 drug-free subjects (201 women; mean age: 26.5 years [16.08; 60.87]) underwent 32-h bed-rest polysomnography recording preceded by polysomnography and modified multiple sleep latency test (mMSLT). Participants were categorized according to their total sleep time (bed-rest TST ≥19 h, hypersomnia), objective EDS (mean sleep latency on MSLT ≤8 min), and self-reported EDS (Epworth sleepiness scale score >10) and EQS (≥9 h/24 h per week). RESULTS: Subjects with hypersomnia were often younger, with normal sleep architecture, high nighttime sleep efficiency, and severe objective EDS. No association with sex, body mass index, Epworth sleepiness scale, EQS, and depressive symptoms was detected. Subjects with objective EDS had less EQS, higher sleep efficiency, and increased hypersomnia. Discrepancies were observed between objective and self-reported measures of sleep duration and EDS. Finally, 71 subjects were identified who had objective hypersomnia and/or EDS, no medical and psychiatric conditions and normal polysomnography parameters, and therefore met the stringent criteria of idiopathic hypersomnia, an orphan disorder. CONCLUSIONS: Sleep duration and EDS should be quantified using self-reported and objective measures in a controlled procedure to differentiate long sleepers, patients with hypersomnia, and patients with idiopathic hypersomnia. This will help to better understand their biology, to identify specific biomarkers, and to assess related health outcomes.

Depression and suicidal thoughts in untreated and treated narcolepsy: Systematic analysis.

OBJECTIVES: To assess the frequency and determinants of depressive symptoms and suicidal thoughts in adults with narcolepsy type 1 (NT1) and controls, as well as the changes after NT1 management and the risk factors of major depressive episode (MDE) and suicide risk (SR) in NT1. METHODS: Two hundred ninety-seven patients with NT1 (age 39 ± 17 years, 172 drug-free) and 346 controls (age 38 ± 16 years) underwent a comprehensive clinical evaluation including the Beck Depression Inventory-II (BDI-II) self-questionnaire, with 1 item on suicidal thoughts. One hundred one drug-free patients with NT1 completed the BDI-II a second time during treatment. In 162 patients with NT1, the face-to-face Mini International Neuropsychiatric Interview was performed to formally diagnose current MDE and SR. RESULTS: BDI-II total scores were higher in patients with NT1 than controls and in untreated than treated patients. Patients with moderate to severe BDI-II scores (24.9%) were less educated, were more frequently obese, and had more severe narcolepsy symptoms, more autonomic dysfunctions, and poorer quality of life. Results were unchanged in models adjusted for NT1 medication intake. Suicidal thoughts were more frequent in untreated patients than controls (22.7% vs 12.4%). Patients with suicidal thoughts were more likely to be men and to have more severe narcolepsy symptoms. After narcolepsy management, BDI-II total score and suicidal thoughts decreased. MDE was diagnosed in 29 (18.1%) and SR in 27 (16.9%) patients. CONCLUSIONS: Depression, depressive symptoms, suicidal thoughts, and SR were frequent in patients with NT1, especially those without treatment, and were associated with NT1 severity. Depressive symptoms and suicidal thoughts improved after NT1 management.

Association of CSF orexin-A levels and nocturnal sleep stability in patients with hypersomnolence.

OBJECTIVE: To evaluate the associations between CSF orexin-A (ORX) levels and markers of nocturnal sleep stability, assessed by polysomnography. METHODS: Nocturnal polysomnography data and ORX levels of 300 drug-free participants (55% men, 29.9±15.5 years, ORX level 155.1±153.7 pg/mL) with hypersomnolence were collected. Several markers of nocturnal sleep stability were analyzed: sleep and wake bouts and sleep/wake transitions. Groups were categorized according to ORX levels, in 2 categories (deficient ≤110; >110), in tertiles (≤26, 26-254, >254), and compared using logistic regression models. Results were adjusted for age, sex, and body mass index. RESULTS: We found higher number of wake bouts (43 vs 25, p < 0.0001), sleep bouts (43 vs 25.5, p < 0.0001), and index of sleep bouts/hour of sleep time, but lower index of wake bouts/hour of wake time (41.4 vs 50.6, p < 0.0001), in patients with ORX deficiency. The percentage of wake bouts <30 seconds was lower (51.3% vs 60.8%, p < 0.001) and of wake bouts ≥1 minutes 30 seconds higher (7.7% vs 6.7%, p = 0.02) when ORX deficient. The percentage of sleep bouts ≤14 minutes was higher (2-5 minutes: 23.7% vs 16.1%, p < 0.0001), and of long sleep bouts lower (>32 minutes 30 seconds: 7.3% vs 18.3%, p < 0.0001), when ORX deficient. These findings were confirmed when groups were categorized according to ORX tertiles, with a dose-response effect of ORX levels in post hoc comparisons, and in adjusted models. INTERPRETATION: This study shows an association between ORX levels and nocturnal sleep stabilization in patients with hypersomnolence. Sleep and wake bouts are reliable markers of nighttime sleep stability that correlate with CSF ORX levels in a dose-dependent manner.

Increased Blood Pressure Dipping in Restless Legs Syndrome With Rotigotine: A Randomized Trial.

OBJECTIVE: The objective of this study was to assess the rotigotine effect on the nocturnal blood pressure (BP) dip by 24-hour ambulatory BP monitoring and on endothelial function in patients with restless legs syndrome (RLS) compared with placebo. METHODS: In this double-blind, placebo-controlled trial, 76 adult patients with moderate to severe RLS and periodic legs movements in sleep index ≥10/hour were randomized to rotigotine at optimal dose of 3 mg per day or placebo for 6 weeks. A total of 6 patients had a major protocol deviation. Polysomnography, ambulatory BP monitoring, and endothelial function were assessed at baseline and end point. The primary outcome was the between-group difference in the percentage of BP nondipper profiles at end point. The main secondary outcomes were the mean BP dip, periodic legs movements in sleep index, and endothelial function. RESULTS: Of the 70 patients (age, 59.4 ± 11.40; 43 women) randomized to rotigotine (n = 34) and placebo (n = 36), 66 (33 rotigotine, 33 placebo) completed the study. The percentage of BP nondippers at end point was higher in the placebo than in the rotigotine group (systolic BP, 72.22% vs 47.06%; diastolic BP, 47.22% vs 20.59%; P < 0.05). Mean BP dip at end point was higher in the rotigotine than in the placebo group (systolic BP, 11.24 ± 6.15 vs 6.12 ± 7.98; diastolic BP, 15.12 ± 7.09 vs 9.36 ± 10.23; P < 0.05). Endothelial function was comparable between the groups. No significant safety concerns were reported with similar incidences of adverse events between groups. CONCLUSION: Rotigotine increased the percentage of BP dipper profiles and the BP dip in patients with RLS. Future studies should assess whether this change is associated with a reduction in the long-term cardiovascular risk in RLS. © 2020 International Parkinson and Movement Disorder Society.

Hepcidin and ferritin levels in restless legs syndrome: a case-control study.

The association between restless legs syndrome (RLS) and iron homeostasis remains unclear. We compared serum hepcidin and ferritin levels in patients with RLS and controls, and assessed their relationships with RLS phenotype, drug intake, and history of augmentation syndrome. 102 drug-free RLS patients (age 58.9 [24.5-77.2], 63 females) and 73 controls (age 56.8 [23.46-76.6], 45 females) underwent a polysomnography recording. Hepcidin levels were quantified by ELISA. 34 RLS patients had a second assessment after starting dopaminergic drugs. Ferritin level was low (< 50 µg/l) in 14.7% of patients and 25% of controls, with no between-group differences in the mean values. Hepcidin levels were higher in patients even after adjustment for confounding factors, and excluding participants with low ferritin levels. Ferritin and hepcidin levels were comparable before and after treatment, and between patients with (n = 17) and without history of augmentation. Ferritin and hepcidin levels correlated with age, body mass index, and periodic leg movements. Higher hepcidin levels were associated with older age, older age at RLS onset, less daytime sleepiness and familial RLS. In conclusion, serum hepcidin levels but not ferritin were higher in RLS patients regardless of treatment and history of augmentation. Serum hepcidin may be a more relevant biomarker of RLS than ferritin.

CSF and serum ferritin levels in narcolepsy type 1 comorbid with restless legs syndrome.

OBJECTIVES: To investigate whether cerebrospinal fluid (CSF) and serum ferritin levels differ between patients with narcolepsy type 1 (NT1) comorbid with restless legs syndrome (RLS) or periodic leg movements during sleep (PLMS), and patients with NT1 or controls without comorbid RLS or PLMS. METHODS: Sixty-six drug-free patients with NT1 (44 males, age 38.5 years [14-81]) were enrolled, including 20 with RLS, 18 with PLMS index ≥15/h (six with both RLS and PLMS). Thirty-eight drug-free patients (12 males, age 22.5 years [12-61]) referred for sleepiness complaint, but without central hypersomnia, RLS, PLMS were included as controls. Clinical, electrophysiological and biological (CSF/serum ferritin, orexin [ORX]) data were quantified. RESULTS: NT1 patients with and without RLS did not differ for age, gender, and body mass index (BMI). No between-group differences were found for CSF ferritin, ORX, and serum ferritin levels. No CSF ferritin, ORX, and serum ferritin level differences were found between NT1 patients with and without PLMS, or with RLS or PLMS versus not. CSF-ferritin levels were not different between NT1 and controls in adjusted analyses. CSF-ferritin levels in the whole population correlated positively with age, serum-ferritin, BMI, negatively with ORX, but not with PLMS index. In NT1, CSF-ferritin levels correlated with age and serum-ferritin but not with PLMS. CONCLUSION: The absence of CSF ferritin deficiency in NT1 with comorbid RLS or PLMS indicates normal brain iron levels in that condition. This result suggests that the frequent association between RLS, PLMS, and NT1 is not based on alterations in brain iron metabolism, a pathophysiological mechanism involved in primary RLS.

Disturbed nighttime sleep in children and adults with rhythmic movement disorder.

STUDY OBJECTIVES: Rhythmic movements (RMs) during sleep are frequent and often considered as benign in children. Disabling forms are diagnosed as RM disorder and may persist in adulthood. Whether RMs severely impact sleep architecture in patients with RM disorder remain unclear. We performed a case-control study to characterize the clinical and polysomnographic patterns of children and adults with a diagnosis of RM disorder in comparison to controls, and to assess the associations between the RMs and the sleep architecture. METHODS: All consecutive patients (n = 50; 27 children, 35 males) with RM disorder from a single sleep clinic (from 2006 to 2019) underwent a comprehensive clinical evaluation and a polysomnographic recording in comparison to 75 controls (42 children and 53 males). RESULTS: About 82% of children and adult patients had a complaint of disturbed nighttime sleep. Comorbid neurodevelopmental, affective or sleep disorders were found in 92% of patients. While RM sequences defined by video polysomnographic criteria were observed in 82% of patients (in wakefulness and in all sleep stages), no similar sequences were observed in controls. Patients had altered sleep continuity, with low sleep efficiency, increased wake time after sleep onset, and frequent periodic leg movements and apnea events. The severity of RMs was associated with disrupted nighttime sleep, even after controlling for comorbid motor and respiratory events. CONCLUSIONS: RM disorder is a rare, highly comorbid and disabling condition both in children and adults with frequent disturbed nighttime sleep that may contribute to the burden of the disease.

Narcolepsy Severity Scale: a reliable tool assessing symptom severity and consequences.

STUDY OBJECTIVES: To define clinically relevant Narcolepsy Severity Scale (NSS) score ranges, confirm its main performances and sensitivity to medications, and determine whether items need to be weighted. METHODS: One hundred and forty-three consecutive untreated and 238 treated adults with narcolepsy type 1 (NT1) completed the NSS, a 15-item self-administered questionnaire (score: 0-57) that assesses the severity and consequences of the five major narcolepsy symptoms such as daytime sleepiness, cataplexy, hallucinations, sleep paralysis, and disturbed nighttime sleep (DNS). They also completed the Epworth Sleepiness scale (ESS; daytime sleepiness), Beck Depression Inventory (BDI; depressive symptoms), and EQ5D (quality of life). RESULTS: The mean symptom number (4.3 vs 3.5), NSS total score (33.3 ± 9.4 vs 24.3 ± 10.2), and number of narcolepsy symptoms (five symptoms: 53.1% vs 24.8%; four symptoms: 26.6% vs 22.7%; three symptoms: 15.4% vs 32.4%; two symptoms: 4.9% vs 20.2%) were significantly different between untreated and treated patients (p < 0.0001). DNS was often the third symptom (95.5 per cent). The symptom number was associated with diagnosis delay, age at onset, and ESS and BDI scores. Comparisons with ESS, BDI and EQ5D showed that NSS item weighting was not necessary to highlight between-group differences. Four NSS severity levels were defined (mild, moderate, severe, and very severe) with between-group differences related to treatment. The probability of having ESS ≥ 16, BDI ≥ 20, and EQ-5D < 60 increased with the severity level. CONCLUSION: NSS is valid, reliable, and responsive to treatment in patients with NT1, with four clinically relevant severity score ranges provided. NSS has adequate clinimetric properties for broadening its use for both clinic and research.