发作性睡病的药物治疗进展

发作性睡病是致残性白天睡眠增多的最常见原因之一，其治疗旨在减少白天睡眠增多和猝倒，改善夜间睡眠紊乱、睡眠瘫痪及与睡眠有关的幻觉。2019年，组胺H3受体拮抗剂替洛利生（Pitolisant）和多巴胺及去甲肾上腺素再摄取抑制剂索利氨酯（Solriamfetol）分别在欧盟和美国上市，前者具有促醒和抗猝倒作用，后者也有促醒作用，且戒断症状和滥用的发生率更低。目前，控释型羟丁酸钠（FT218）、低钠型羟丁酸盐（JZP-258）、选择性去甲肾上腺素再摄取抑制剂（瑞波西汀，又称AXS-12）以及莫达非尼联合氟卡尼制剂（THN102）等药物仍在开发和测试中，均可作为治疗发作性睡病相关白天睡眠增多和猝倒的潜在药物。本文重点介绍这些最近研发的发作性睡病治疗药物。     

儿童发作性睡病的临床与视频脑电图特征

目的 探讨小儿发作性睡病的临床与视频脑电图特征。方法 对15例发作性睡病患儿进行睡眠脑电图监测，结合临床特点予以诊断，采用利他林治疗。结果 15例患儿均有过度或发作性的白日睡眠，7例伴猝倒，3例出现睡眠瘫痪，4例出现睡眠幻觉，3例伴有自动样行为。睡眠脑电图监测显示12例平均睡眠潜伏期〈5min，有2次或2次以上直接进入快速眼动相睡眠。经过治疗，有10例白天过度睡眠改善。结论 视频脑电图有助于发作性睡病的诊断。利他林治疗有确切疗效。     

Attention deficit hyperactivity disorder symptom severity and sleep problems in adult participants of the Netherlands sleep registry

BackgroundWe examined whether current overall attention deficit hyperactivity disorder (ADHD), inattention, or hyperactivity symptom severities are associated with the current presence and persistent history of sleep problems.MethodsN = 942 participants of the Netherlands Sleep Registry filled out online several validated questionnaires. Regression analyses were performed to assess the association between (1) current overall ADHD symptom severity and the current presence of sleep problems, (2) current ADHD symptom-severity groups and the persistent history of sleep problems, and (3) current inattention or hyperactivity symptom severities and the current presence of sleep problems.Results(1) Current overall ADHD symptom severity was associated with the odds of suffering from probable obstructive sleep apnea syndrome (OSAS), restless legs syndrome (RLS), periodic limb movement disorder (PLMD), insomnia disorder (ID) with predominant difficulties initiating sleep (DIS) and maintaining sleep (DMS), but not with the odds of suffering from narcolepsy or ID with predominant early-morning awakening (EMA). Current overall ADHD symptom severity was also associated with an extreme evening chronotype but not with short sleep. (2) The group with the most severe current ADHD symptoms was more likely to have a history of persistent OSAS, RLS, and ID. (3) The severity of symptoms of hyperactivity, but not of inattention, was specifically associated with probable RLS, PLMD, ID with DIS or DMS, and short sleep. Inattention symptom severity was only related to the probability of being an extreme evening chronotype.ConclusionADHD severity, especially the severity of hyperactivity, is associated with the current presence and persistent history of sleep problems.     

Morbidity of childhood onset narcolepsy: a controlled national study

Narcolepsy is associated with significant morbidities. We evaluated the morbidities and mortality in a national group of child and adolescent patients after a first diagnosis of narcolepsy.MethodsIdentified from the Danish National Patient Registry (NPR), 243 patients (128 boys) aged 0–19 years diagnosed with narcolepsy between 1998 and 2012 with follow-up until 2014 were compared with 970 controls who were randomly chosen from the Danish Civil Registration System Statistics and matched by age, gender and geography. Comorbidities were calculated three years before and after diagnoses.ResultsIn addition to the more frequent health contacts due to neurological diseases, patients showed elevated odds ratios before and after diagnosis of endocrine and metabolic conditions (4.4 (95% CI, 1.9–10.4); 3.8 (1.7–8.4)), nervous disorders (16.6 (8.0–34.4); 198 (49.0–804)), psychiatric illnesses (4.5 (2.3–9.1)/5.8 (2.8–12.1)), pulmonary diseases, and other diseases (3.1 (2.0–4.9); 3.1 (2.0–4.9)). Congenital abnormalities (2.5 (1.1–5.5)), respiratory (2.9 (1.5-5-5)) and eye (5.7 (2.2–15.0)) diseases were more common before diagnosis. Injuries were also more common after diagnosis (1.5 (1.0–2.1)). Narcoleptic children presented significantly more diagnoses of multiple comorbidities than controls before and after diagnosis.ConclusionBefore and after a diagnosis of narcolepsy in children, morbidity is more frequent in several domains, including metabolic, psychiatric, neurological and other diseases.     

Underutilization of the MSLT in sleepy patients with a short onset REM period (SOREMP) in the sleep clinic

Objective/BackgroundA nocturnal sleep onset REM period (defined as REM onset latency ≤ 15 min; SOREMP) occurs rarely and research has shown that the phenomenon is specific for type 1 and 2 narcolepsy. However, little is known about the meaningfulness of the phenotype in general sleep clinic patients because those that exhibit the phenomenon often present with few traditional narcolepsy symptoms. As such, this study aimed to (1) evaluate the rate of eventual MSLT testing for those with a SOREMP on routine PSG when the phenomenon occurred in the absence of potential explanatory factors and (2) quantify the stability of the SOREMP phenotype.Patients/MethodsThis was a retrospective analysis of a large repository of de-identified PSG and MSLT test results from 2008 to 2015. Patient records were retrieved from a repository of studies completed at a variety of sleep laboratories across the USA. A total of 118,046 baseline polysomnograms were evaluated for a PSG SOREMP (occurred in 0.7% of the sample). Patients were excluded if they indicated working either shift or night work at the time of the SOREMP or if their self-reported habitual weekday time in bed was less than 7 h. A final sample of 391 cases with a SOREMP were sequestered and previous or consecutive studies were searched for each individual.ResultsThe vast majority of patients (n = 347/391; 89%) with a PSG SOREMP never received MSLT testing. Patients that were evaluated by MSLT (n = 44; 11%) were typically very sleepy and 82% ended up with a diagnosis of narcolepsy or had MSLTs consistent with current narcolepsy criteria (ie, including the nocturnal SOREMP). Only seven of the 140 patients (n = 5%) that with OSA that first underwent one or more PAP titrations were subsequently seen for an MSLT. Compared to those that eventually received an MSLT, patients that did not receive MSLT testing were older (52 vs. 41 years, p < 0.001), more likely to have moderate to severe OSA (AHI ≥ 15; 39% vs. 16%, p < 0.001), and were generally less likely to report severe sleepiness (ESS ≥ 16; 25% vs. 55%, p < 0.001) and vehicle or workplace accidents or injuries. However, 12% of those that never received an MSLT reported such extreme sleepiness that they endorsed a near-miss car accident due to sleepiness, almost twice as prevalent than that found in a random sample of matched moderate-to-severe OSA patients (p < 0.01). Overall, the reliability of the SOREMP phenotype was low at 9.8%, but was much higher for those diagnosed with type 2 narcolepsy (31%) compared to those without narcolepsy (IH or normal MSLTs; 0%; p < 0.01) or where narcolepsy status was unknown because an MSLT was not conducted (7%; p < 0.01).ConclusionsThe MSLT has been historically underutilized for those exhibiting a SOREMP on diagnostic PSG, a potential marker of narcolepsy. This is presumably because patients with a PSG SOREMP reported variable levels of sleepiness (although some severe) and many had some degree of OSA, which may either be a partial factor in symptomology or even obscure true narcolepsy. Some patients with a PSG SOREMP were very sleepy and most, when an MSLT was conducted, received a diagnosis of type 2 narcolepsy despite few presenting with some of the associated features of narcolepsy. Well-controlled longitudinal studies with high quality data on cataplexy and hypocretin status are needed to understand where the PSG SOREMP phenomenon falls on the hypersomnolence spectrum and to establish which comorbidities share variance with and/or potentially mask narcolepsy. However because untreated narcolepsy can have high social, functional, and financial burden, until such studies are done, physicians should consider a narcolepsy workup when a SOREMP is observed (especially if multiple are seen) as well as close follow-up for symptom resolution when, for example, a patient is treated for sleep apnea.     

发作性睡病与异态睡眠的诊治

本文目的是探讨发作性睡病与异态睡眠的诊断与治疗。发作性睡病被漏诊和误诊的几率较高,危害较大,共患异态睡眠比例高。文章从发作性睡病临床特征、REM睡眠的作用、发作性睡病与异态睡眠(睡眠瘫痪、睡眠幻觉、快眼动睡眠期行为障碍)共病特征及治疗这四个方面进行了讨论。     

The clinical characteristics of cataplectic attack in narcolepsy type 1

ObjectiveCataplexy is a pathognomonic symptom of narcolepsy type 1. This study was conducted to clarify the clinical characteristics of cataplexy by staging, and to further analyse the correlations of clinical features and cataplectic stages in patients with narcolepsy type 1 (NT1).MethodsWe experimentally triggered patients with NT1 into cataplexy while under video-polysomnography (v-PSG) monitoring in the sleep lab. The most serious cataplectic attack from each patient was analysed. Each cataplectic episode was segmented into four stages according to the v-PSG. Correlations were analysed between cataplectic stages in pairs, and between cataplectic stages and other clinical features.ResultsWe observed 81 cataplectic episodes in 21 patients with diverse triggers, including humorous or exciting videos, tickling, recalling horrible memories and exercising. Nine patients (43%) went through complete cataplectic attacks while the others experienced partial attacks. Four cataplectic stages (ie, triggering, resisting, atonic, and recovering) were identified according to clinical and electromyograms characteristics. Resisting stage is predominant (56.4%) in cataplexy, while atonic stage is most related with the total duration of cataplexy. The Epworth Sleepiness Scale score (ESS) has a positive correlation with the total duration of cataplexy. Both duration of cataplexy and ESS score are negatively correlated with disease course. However, medication history seems have no influence on either cataplexy duration or ESS score.ConclusionFour-stage segmentation shows the dynamic process of the cataplectic attack, which is different from the traditional classification of complete or partial cataplexy. Resisting stage is necessary for every cataplexy and might reflect the compensation mechanism, while atonic stage may be omitted in some patients. The severity of narcolepsy reduces with the extension of natural course regardless of medication history.     

Autonomic dysfunction in childhood hypersomnia disorders

ObjectiveOrthostatic intolerance (OI) is a common manifestation of autonomic dysfunction. It is characterized by light-headedness and palpitations in the upright position, with relief when supine. It can affect the quality of life. Other symptoms that may accompany OI include headache, fatigue, nausea, palpitations and abdominal pain. The prevalence and characteristics of autonomic symptoms in childhood hypersomnia disorders of childhood has not been examined, and hence were studied.MethodsThe medical records of children and adolescents with hypersomnia disorders were reviewed. Subjects had been diagnosed with narcolepsy types 1 or 2 (NT1 or NT2), idiopathic hypersomnia (IH) or the KLS, or hypersomnia related to medical conditions, were under 18 years of age at sleep diagnosis, and had been evaluated at our sleep center between 2000 and 2018. Those with comorbidities such as obstructive sleep apnea and major depression were excluded. The medical records were reviewed for symptoms at initial presentation suggestive of autonomic dysfunction, such as orthostatic intolerance, headache, fatigue, nausea, palpitations and abdominal pain. If these symptoms had been recorded, the chart was examined further to determine if an autonomic reflex screen (ARS) battery had been conducted. The ARS battery examines both sympathetic and parasympathetic function. It is composed of a tilt table test, heart rate and blood pressure responses to the Valsalva maneuver and deep breathing, a quantitative sudomotor axon reflex test and beat-to-beat blood pressure measurements during the Valsalva maneuver. Results of the ARS battery were interpreted by an autonomic neurology specialist (WS), who was not otherwise involved in the care of the patients. Medications taken at the time of autonomic testing were recorded.ResultsThere were 89 patients with hypersomnia disorders. Forty six patients had NT1, 17 had NT2, 18 had IH, 1 with KLS, and 7 had hypersomnia associated with medical disorders. Thirty three of 89 subjects (37%) had the symptom of OI at initial presentation, hence had undergone autonomic reflex screen testing. The median age at diagnosis of hypersomnia in the 33 subjects with the OI symptom was 14.5 years (interquartile range 12–16) and similar (14.5 years, interquartile range 11.5–16) in the 56 subjects without OI. In the group with OI, 25/33 had not received medications for treating hypersomnia at the time of autonomic testing. OI was not related to the degree of sleepiness– the mean sleep latency in the subjects with OI was 5.3 ± 2.9 min while in those without OI it was 4.5 ± 3.8 min. The symptom of OI was not more likely to occur in any specific type of hypersomnia.OI however tended to occur predominantly in females – the female: male ratio in the OI subgroup was 2:1 (n = 33) while in the subgroup without OI, it was 1: 2.1 (n = 56; p = 0.0015). Additional symptoms recorded in the OI subgroup included lightheadedness in 25/33, palpitations in 6/33, nausea and vomiting in 4/33, fatigue in 25/33, headache in 15/33 and constipation in 3/33. The symptoms of OI were reproduced during the tilt table test in 17/33 subjects; 5 of these patients had a rise in heart rate consistent with postural orthostatic tachycardia syndrome (POTS).ConclusionIn this retrospective sample, one third of children with hypersomnia disorders exhibited the symptom of OI at initial presentation, with female predominance. A smaller subgroup met criteria for POTS. Screening for autonomic symptoms in children with hypersomnia is important because the former seems to be a treatable co-morbidity that impacts the sense of well-being.     

Xingshentongqiao Decoction Mediates Proliferation,Apoptosis, Orexin-A Receptor and Orexin-B Receptor Messenger Ribonucleic Acid Expression and Represses Mitogen-activated Protein Kinase Signaling

Background:Hypocretin (HCRT) signaling plays an important role in the pathogenesis of narcolepsy and can be significantly influenced by Chinese herbal therapy.Our previous study showed that xingshenton...     

Speaker Abstracts

Narcolepsy is a rare disorder characterised by sleep disturbances, cataplexy, sleep paralysis and hypnagogic, hypnopompic hallucinations. Although several treatment modalities, such as tricyclic antidepressants or selective serotonin reuptake inhibitors, have been used to treat different symptoms, there is no definite treatment for narcolepsy. Modafinil or amphetamine-like stimulants, such as dexamphetamine or methylphenidate, are used to treat sleepiness. Our case was a 58-year-old woman who was diagnosed as narcolepsy cataplexy syndrome. Her Epworth Sleepiness Scale (ESS) score was 14 and Beck Depression Inventory (BDI) score was 29 in the first evaluation. Imipramine and modafinil were begun for the treatment, but there was no improvement in her symptoms. Subsequently, bupropion was started at 150 mg/day and then dosage was increased to 300 mg/day. She was asymptomatic at the end of 3 months. To our knowledge, this is the second depressive narcoleptic patient who has responded to 300 mg/day of bupropion.