Stridor combined with other sleep breathing disorders in multiple system atrophy: a tailored treatment?

Objectives: To determine the frequency of sleep breathing disorders in multiple systemic atrophy (MSA, combining Parkinsonism, cerebellar syndrome, and dysautonomia) and evaluate the benefit/ tolerance of various modes of ventilation. Methods: Weretrospectivelyanalyzed45patientswithMSAhavingundergoneavideopolysomnography. Their sleep characteristics were compared to those of 45 patients with Parkinson's disease and 45 healthy controls, matched for age and sex. Patients with MSA received fixed continuous positive airway pressure (CPAP) when stridor was isolated, auto-adjusting CPAP when it was combined with obstructive sleep apnea, and adaptive servo-ventilation (ASV) when combined with central sleep apnea. Results: Higher periodic leg movements index and more frequent REM sleep behavior disorder were observed in MSA patients, compared to patients with Parkinson's disease and healthy controls. In MSA, 28/45 (62.2%) patients had sleep breathing disorders, including (overlapping samples) stridor (n 1⁄4 17, 38%), obstructive sleep apnea (n 1⁄4 14, 31%), central sleep apnea (n 1⁄4 4, 9%), and ataxic breathing (n 1⁄4 1). Except for three initial refusals and two yet untreated patients, fixed CPAP (n 1⁄4 9), auto-adjusting CPAP (n 1⁄4 8) and ASV (n 1⁄4 2) were well-tolerated (limited leaks and good compliance) and successfully controlled stridor plus sleep apnea. Treated patients had survival times similar to those of patients without any sleep breathing disorder. Conclusion: In this small group, tailored management of stridor in MSA as an independent issue or combined with obstructive and central sleep apnea, yields a survival similar to survival in patients without sleep breathing disorders

Smoking, Alcohol, Drug Use, Abuse and Dependence in Narcolepsy and Idiopathic Hypersomnia: A Case-Control Study.

STUDY OBJECTIVES: Basic experiments support the impact of hypocretin on hyperarousal and motivated state required for increasing drug craving. Our aim was to assess the frequencies of smoking, alcohol and drug use, abuse and dependence in narcolepsy type 1 (NT1, hypocretin-deficient), narcolepsy type 2 (NT2), idiopathic hypersomnia (IH) (non-hypocretin-deficient conditions), in comparison to controls. We hypothesized that NT1 patients would be less vulnerable to drug abuse and addiction compared to other hypersomniac patients and controls from general population. METHODS: We performed a cross-sectional study in French reference centres for rare hypersomnia diseases and included 450 adult patients (median age 35 years; 41.3% men) with NT1 (n = 243), NT2 (n = 116), IH (n = 91), and 710 adult controls. All participants were evaluated for alcohol consumption, smoking habits, and substance (alcohol and illicit drug) abuse and dependence diagnosis during the past year using the Mini International Neuropsychiatric Interview. RESULTS: An increased proportion of both tobacco and heavy tobacco smokers was found in NT1 compared to controls and other hypersomniacs, despite adjustments for potential confounders. We reported an increased regular and frequent alcohol drinking habit in NT1 versus controls but not compared to other hypersomniacs in adjusted models. In contrast, heavy drinkers were significantly reduced in NT1 versus controls but not compared to other hypersomniacs. The proportion of patients with excessive drug use (codeine, cocaine, and cannabis), substance dependence, or abuse was low in all subgroups, without significant differences between either hypersomnia disorder categories or compared with controls. CONCLUSIONS: We first described a low frequency of illicit drug use, dependence, or abuse in patients with central hypersomnia, whether Hcrt-deficient or not, and whether drug-free or medicated, in the same range as in controls. Conversely, heavy drinkers were rare in NT1 compared to controls but not to other hypersomniacs, without any change in alcohol dependence or abuse frequency. Although disruption of hypocretin signaling in rodents reduces drug-seeking behaviors, our results do not support that hypocretin deficiency constitutes a protective factor against the development of drug addiction in humans

Prevalence and Phenotype of Sleep Disorders in 60 Adults With Prader-Willi Syndrome

Study Objectives: Excessive sleepiness is a common symptom in Prader–Willi syndrome (PWS), and it negatively impacts the quality of life. Obstructive sleep apnea and narcolepsy phenotypes have been reported in PWS. We characterized sleep disorders in a large cohort of adults with PWS. Methods: All consecutive patients with genetically confirmed PWS unselected for sleep-related symptoms, underwent a clinical interview, polysomnography, and multiple sleep latency tests (MSLT, n = 60), followed by long-term (24 hours) polysomnography (n = 22/60). Results: Among 60 adults evaluated (57% female, aged 25 ± 10 years, body mass index: 39 ± 12 kg/m2), 67% reported excessive sleepiness. According to the sleep study results, 43% had a previously unrecognized hypersomnia disorder, 15% had an isolated sleep breathing disorder, 12% had combined hypersomnia disorder and untreated breathing sleep disorder, and only 30% had normal sleep. Isolated hypersomnia disorder included narcolepsy in 35% (type 1, n = 1, and type 2, n = 8), hypersomnia in 12% (total sleep time >11 hours, n = 2, and MSLT <8 minutes, n = 1), and borderline phenotype in 53% (≥2 sleep onset in REM periods and MSLT >8 minutes, n = 10, and 8 minutes < MSLT < 10 minutes, n = 4). Sleep breathing disorders, isolated and combined, included obstructive sleep apnea (n = 14, already treated in seven), sleep hypoxemia (n = 1) and previously undiagnosed hypoventilation (n = 5). Modafinil was taken by 16 patients (well tolerated in 10), resulting in improved sleepiness over a mean 5-year follow-up period. Conclusion: Sleepiness affects more than half of adult patients with PWS, with a variety of hypersomnia disorder (narcolepsy, hypersomnia, and borderline phenotypes) and breathing sleep disorders. Earlier diagnosis and management of sleep disorders may improve sleepiness, cognition, and behavior in these patients

IV steroids during long episodes of Kleine-Levin syndrome.

To retrospectively compare the benefits (episode cessation) and risks of IV methylprednisolone (IV-MP) vs abstention during prolonged Kleine-Levin syndrome (KLS) episodes. A total of 26 patients with KLS received 1 g/d IV-MP for 3 days during 1 to 6 episodes each (totaling 43 IV-MP sessions). The change of episode duration with IV-MP (vs previous episode duration) was compared with the change duration between 2 consecutive episodes in 48 untreated patients matched for age, sex, age at KLS onset, number of episodes, and disease duration (more treated than untreated patients had long episodes). Eleven patients (42.3%) had an episode that was at least 1 week shorter than the preceding one when they received IV-MP therapy, whereas shorter episodes were significantly less frequent (10.4%) in the untreated group. This benefit was more marked (65.5% responders, 12 fewer days in an episode vs 0 days in the untreated patients) when IV-MP was infused before the 10th day of the episode. Mild, transient adverse effects (insomnia, muscle pain, nervousness/restlessness, but no manic switching) were reported by 61.3% of patients. No specific responder profile was identified. In this open-labeled, naturalistic study, early IV-MP (following the protocol for multiple sclerosis relapses) had a good benefit/risk ratio during KLS episodes in patients with long episodes (with half of the patients having an early cessation of episodes). This study provides Class IV evidence that for patients with long episodes of KLS, IV steroids decrease the duration of KLS episodes

Car Crashes and Central Disorders of Hypersomnolence: A French Study

Drowsiness compromises driving ability by reducing alertness and attentiveness, and delayed reaction times. Sleep-related car crashes account for a considerable proportion of accident at the wheel. Narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH) are rare central disorders of hypersomnolence, the most severe causes of sleepiness thus being potential dangerous conditions for both personal and public safety with increasing scientific, social, and political attention. Our main objective was to assess the frequency of recent car crashes in a large cohort of patients affected with well-defined central disorders of hypersomnolence versus subjects from the general population.We performed a cross-sectional study in French reference centres for rare hypersomnia diseases and included 527 patients and 781 healthy subjects. All participants included needed to have a driving license, information available on potential accident events during the last 5 years, and on potential confounders; thus analyses were performed on 282 cases (71 IH, 82 NT2, 129 NT1) and 470 healthy subjects.Patients reported more frequently than healthy subjects the occurrence of recent car crashes (in the previous five years), a risk that was confirmed in both treated and untreated subjects at study inclusion (Untreated, OR = 2.21 95\%CI = [1.30-3.76], Treated OR = 2.04 95\%CI = [1.26-3.30]), as well as in all disease categories, and was modulated by subjective sleepiness level (Epworth scale and naps). Conversely, the risk of car accidents of patients treated for at least 5 years was not different to healthy subjects (OR = 1.23 95\%CI = [0.56-2.69]). Main risk factors were analogous in patients and healthy subjects.Patients affected with central disorders of hypersomnolence had increased risk of recent car crashes compared to subjects from the general population, a finding potentially reversed by long-term treatment

Proteomic biomarkers of Kleine-Levin syndrome

STUDY OBJECTIVES: Kleine-Levin syndrome (KLS) is characterized by relapsing-remitting episodes of hypersomnia, cognitive impairment, and behavioral disturbances. We quantified cerebrospinal fluid (CSF) and serum proteins in KLS cases and controls. METHODS: SomaScan was used to profile 1133 CSF proteins in 30 KLS cases and 134 controls, while 1109 serum proteins were profiled in serum from 26 cases and 65 controls. CSF and serum proteins were both measured in seven cases. Univariate and multivariate analyses were used to find differentially expressed proteins (DEPs). Pathway and tissue enrichment analyses (TEAs) were performed on DEPs. RESULTS: Univariate analyses found 28 and 141 proteins differentially expressed in CSF and serum, respectively (false discovery rate <0.1%). Upregulated CSF proteins included IL-34, IL-27, TGF-b, IGF-1, and osteonectin, while DKK4 and vWF were downregulated. Pathway analyses revealed microglial alterations and disrupted blood-brain barrier permeability. Serum profiles show upregulation of Src-family kinases (SFKs), proteins implicated in cellular growth, motility, and activation. TEA analysis of up- and downregulated proteins revealed changes in brain proteins (p < 6 × 10-5), notably from the pons, medulla, and midbrain. A multivariate machine-learning classifier performed robustly, achieving a receiver operating curve area under the curve of 0.90 (95% confidence interval [CI] = 0.78-1.0, p = 0.0006) in CSF and 1.0 (95% CI = 1.0-1.0, p = 0.0002) in serum in validation cohorts, with some commonality across tissues, as the model trained on serum sample also discriminated CSF samples of controls versus KLS cases. CONCLUSIONS: Our study identifies proteomic KLS biomarkers with diagnostic potential and provides insight into biological mechanisms that will guide future research in KLS