The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias
The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias
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DOI：
10.1001/archneur.59.10.1553
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发表时间：
2002-10-01
影响因子：
--
通讯作者：
Nishino, S
中科院分区：
文献类型：
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作者：
Mignot, E;Lammers, GJ;Nishino, S
内容：发作性睡病是一种神经系统疾病，发病率为1/2000，与HLA-DQB 1 *0602和脑脊液（CSF）下丘脑泌素（食欲素）水平低有关。目的：描述下丘脑泌素缺乏综合征的谱，并建立CSF下丘脑泌素-1测量作为发作性睡病的诊断工具。设计：诊断，HLA-DQ，临床资料，多次睡眠潜伏期试验（MPEG4），和CSF下丘脑泌素-1在1999年至2002年的一系列睡眠障碍患者的情况下进行了研究。使用信号检测分析来确定对国际睡眠障碍分类（ICSD）定义的发作性睡病最佳预测的CSF下视泌素-1水平（盲法标准）。临床和人口统计学特征进行了比较，在发作性睡病受试者和没有低CSF hypocretin-1 level.Setting：睡眠障碍和神经病学诊所在美国和欧洲，与生物测试进行了斯坦福大学，斯坦福大学，加利福尼亚州。和非典型的嗜睡症病例，如家族性病例、无紧张症或无HLA-DQB 1 *0602的发作性睡病、复发性嗜睡症和症状性病例（例如帕金森病、抑郁症、Prader-Willi综合征、C型尼曼-皮克病）。受试者组还包括296名对照者干预：静脉穿刺进行HLA分型，腰椎穿刺进行CSF分析，使用国际睡眠障碍分类进行初步诊断，斯坦福大学睡眠量表评估发作性睡病，以及睡眠记录研究。主要结果测量：CSF下丘脑泌素-1、HLA-DQB 1 *0602阳性以及临床和多导睡眠图特征的诊断阈值。HLA-DQB 1 *0602频率在发作性睡病伴典型癫痫发作（93% vs对照组17%）、发作性睡病不伴癫痫发作（56%）和原发性嗜睡（52%）中增加。下丘脑泌素-1水平低于110 pg/mL诊断为嗜睡症。高于200 pg/mL的值被认为是正常的。大多数具有低水平的受试者是HLA-DQB 1 *0602阳性的发作性睡病-紧张症患者。这些患者并不总是有异常的二尖瓣。罕见的无cataeprazole，DQB 1 *0602，和/或继发性嗜睡症的受试者有低水平。10例嗜睡症受试者为中等水平，7例发作性睡病（通常为HLA阴性，继发性，和/或非典型性紧张症或无紧张症），1例周期性嗜睡症。健康对照组和其他睡眠障碍的受试者都有正常水平。神经系统受试者的水平通常正常（n=194）。在各种急性神经病理学疾病中观察到中等（n=30）和低（n=3）水平。结论：发作性睡病-突倒伴下丘脑分泌素缺乏是一种真正的疾病实体。测量CSF下丘脑泌素-1是一种明确的诊断测试，前提是在临床背景下进行解释。它可能是最有用的情况下，catabalism和当Mesophageal是难以解释（即，在受试者已接受精神活性药物或其他并发睡眠障碍）。
Context: Narcolepsy, a neurological disorder affecting 1 in 2000 individuals, is associated with HLA-DQB1*0602 and low cerebrospinal fluid (CSF) hypocretin (orexin) levels.Objectives: To delineate the spectrum of the hypocretin deficiency syndrome and to establish CSF hypocretin-1 measurements as a diagnostic tool for narcolepsy.Design: Diagnosis, HLA-DQ, clinical data, the multiple sleep latency test (MSLT), and CSF hypocretin-1 were studied in a case series of patients with sleep disorders from 1999 to 2002. Signal detection analysis was used to determine the CSF hypocretin-1 levels best predictive for International Classification of Sleep Disorders (ICSD)-defined narcolepsy (blinded criterion standard). Clinical and demographic features were compared in narcoleptic subjects with and without low CSF hypocretin-1 levels.Setting: Sleep disorder and neurology clinics in the United States and Europe, with biological testing performed at Stanford University, Stanford, Calif.Participants: There were 274 patients with narcolepsy; hypersomnia; obstructive sleep apnea; restless legs syndrome; insomnia; and atypical hypersomnia cases such as familial cases, narcolepsy without cataplexy or without HLA-DQB1*0602, recurrent hypersomnias, and symptomatic cases (eg, Parkinson disease, depression, Prader-Willi syndrome, Niemann-Pick disease type C). The subject group also included 296 controls (healthy and with neurological disorders).Intervention: Venopuncture for HLA typing, lumbar puncture for CSF analysis, primary diagnosis using the International Classification of Sleep Disorders, Stanford Sleep Inventory for evaluation of narcolepsy, and sleep recording studies.Main Outcome Measures: Diagnostic threshold for CSF hypocretin-1, HLA-DQB1*0602 positivity, and clinical and polysomnographic features.Results: HLA-DQB1*0602 frequency was increased in narcolepsy with typical cataplexy (93% vs 17% in controls), narcolepsy without cataplexy (56%), and in essential hypersomnia (52%). Hypocretin-1 levels below 110 pg/mL were diagnostic for narcolepsy. Values above 200 pg/mL were considered normal. Most subjects with low levels were HLA-DQB1*0602-positive narcolepsy-cataplexy patients. These patients did not always have abnormal MSLT. Rare subjects without cataplexy, DQB1*0602, and/or with secondary narcolepsy had low levels. Ten subjects with hypersomnia had intermediate levels, 7 with narcolepsy (often HLA negative, of secondary nature, and/or with atypical cataplexy or no cataplexy), and 1 with periodic hypersomnia. Healthy controls and subjects with other sleep disorders all had normal levels. Neurological subjects had generally normal levels (n=194). Intermediate (n=30) and low (n=3) levels were observed in various acute neuropathologic conditions.Conclusions: Narcolepsy-cataplexy with hypocretin deficiency is a genuine disease entity. Measuring CSF hypocretin-1 is a definitive diagnostic test, provided that it is interpreted within the clinical context. It may be most useful in cases with cataplexy and when the MSLT is difficult to interpret (ie, in subjects already treated with psychoactive drugs or with other concurrent sleep disorders).