在现代社会生活中,保持清醒的能力是维持健康生活和社会功能所必需的。日间过度思睡(excessivedaytimesleepiness,EDS)是指个体在白天无法保持应有的清醒和警觉,出现过度的睡眠需求甚至不自主地入睡。EDS影响个体多方面的表现,造成学习能力下降、家庭和职业角色表现不佳,并因潜在的交通事故风险而威胁生命。流行病学研究发现,超过20%的人群受到EDS的困扰[1-2],但其定义、评估方法和处理存在差异,从而延误诊断和治疗。
【1】
专家共识的制定方法
【2】
定义
根据ICSD-3的定义,EDS几乎每天发生并连续至少3个月时,具有特殊临床意义,是诊断多种中枢起源的睡眠增多症的必要条件[5]。但某些特殊原因所致的EDS,如睡眠剥夺,或者药物(如镇静催眠药物、某些降压药物、抗帕金森病药物等)所致的日间思睡可以短期内突然发生。
3.睡眠发作(sleepattack):多数情况下EDS发生于安静、久坐、单调枯燥的场景下,患者在入睡前能意识到自己的困倦。但有些EDS患者在没有任何预警的情况下会突然睡着,称为睡眠发作,常见于发作性睡病,也可见于使用非麦角类多巴胺受体激动剂的帕金森病患者[5,7]。
4.疲劳(fatigue):指主观感觉体力和精力的缺乏,难以启动活动,或维持日常需求的活动困难。临床疲劳症状由三种成分按照不同比例构成:(1)启动活动困难:即个体主观感觉全身乏力,而客观检查无肌无力的体征,但开始活动发生困难;(2)维持活动困难:在活动中容易产生疲劳而更早需要休息;(3)精神疲劳:集中注意力困难,记忆力和情绪稳定性下降[8-9]。
在病史采集中,患者可能使用疲劳、无力、精力不足、犯困、容易睡着等词汇来描述EDS症状。正确区分上述概念对于疾病诊断的导向有重要意义。另一方面,睡眠障碍或多种躯体疾病患者也存在上述症状的重叠,诊疗时应加以鉴别。治疗方法得当,上述症状可相应得到缓解。
【3】
流行病学
EDS的患病率因调查对象和判断标准的不同而有很大差异。Young等[10]综述欧美为主的普通人群的大样本流调资料,发现EDS的患病率为2.5%~52.4%,两性患病率差异无统计学意义。在年龄方面,青少年EDS的患病率最高,其次是老年人群和中青年人群。我国高质量流调资料相对缺乏,香港地区流调资料显示,6~18岁儿童青少年人群EDS发生率为29.2%。EDS患病率伴随着青春期的到来快速增长,由青春前期的19.8%,快速增长到青春期后期的47.2%[1]。美国一项调查显示,33%的成人报告EDS[2],通过访谈收集到青少年诉日间困倦者的比例高达41.5%,其中达到睡眠增多症诊断标准者为11.7%[11]。
多数研究以调查对象的主观判断作为评价依据。如果以“是否存在睡眠增多”提问,获得的EDS患病率最低,在0.3%~4.0%之间;以“日间频繁入睡或者出现睡眠发作”作为评价标准,中青年人群的患病率为5%~10%,老年人群的患病率为20%~30%;如果以“感觉到困倦”为标准,则EDS的患病率为10%~15%[10];EDS合并功能损害的患病率为15.6%[12]。
【4】
临床表现
此外,EDS的患者可能不会抱怨EDS本身,而是会抱怨其后果,如疲劳、精疲力竭、昏昏沉沉、缺乏主动性、记忆力减退、注意力不集中、在学习和工作中容易出错等,这也是EDS常伴随的表现[23]。然而,应注意思睡与疲劳的区别。疲劳可能伴随着EDS和睡眠增多,但它在本质上是一种与思睡不同的主诉[20]。疲劳指的是主观上缺乏体力或精力,启动或维持活动的能力降低,可伴随注意力、记忆力和情绪稳定性下降[9,13]。思睡多在静坐不动的情况下出现,而疲劳通常会妨碍参加主动的、需要努力的活动,或在此类活动后出现,在休息后往往是可逆的[19]。
【5】
诊断思路
图1日间过度思睡诊断思路
2.临床评估:体质指数(bodymassindex,BMI)、颅面结构(如小下颌、扁桃体肿大、鼻中隔偏曲等),根据病史做相应内科查体、神经系统查体、精神检查及必要的辅助检查,排查内科、神经精神疾病、药物或物质滥用所致EDS。
4.实验室检查:脑脊液下丘脑分泌素-1检测可帮助鉴别1型和2型发作性睡病以及特发性嗜睡症[24]。
5.共病鉴别及诊断:EDS也可能是两个及以上疾病共患所致,如发作性睡病可共患睡眠呼吸障碍、失眠症、精神障碍(如抑郁症)、周期性肢体运动障碍、REM睡眠行为障碍等,需结合临床病史、睡眠评估及检测结果综合判断。
(一)中枢性嗜睡(centraldisordersofhypersomnolence)
中枢性嗜睡是指中枢源性的思睡疾病,其EDS并不是由于夜间睡眠障碍或昼夜节律紊乱所致,包括发作性睡病、特发性嗜睡症和复发性嗜睡症。
发作性睡病因临床表现多样,患者可以不同症状为主诉就诊,导致误诊、漏诊、诊断延迟。目前发作性睡病的诊断是根据ICSD-3的诊断标准[5],其鉴别诊断也非常重要:(1)严重的EDS和睡眠发作也可发生在慢性睡眠剥夺或睡眠不足、睡眠呼吸障碍、倒班、心境障碍和特发性嗜睡症中;(2)猝倒发作易误诊为癫痫、晕厥或短暂性缺血发作等;(3)其他症状,如睡瘫或睡眠幻觉,需与癫痫、精神病性症状中的幻觉等进行鉴别。此外,也应注意排除继发因素导致的发作性睡病,如下丘脑肿瘤、自身免疫性脑炎等[5]。
3.复发性嗜睡症(recurrenthypersomnia):复发性嗜睡症又名克莱恩-莱文综合征(Kleine-Levinsyndrome,KLS),以反复发作的思睡伴认知、精神和行为异常为基本特征。复发性嗜睡症患病率约为(1~5)/1000000[44-46],男性较女性多见[47-48],中位发病年龄为16岁[47]。目前病因尚不明确,遗传、感染和免疫介导均有报道[47,49]。
根据ICSD-3,对存在两次以上反复发作的思睡,伴有认知功能、情绪及行为改变,且发作间期恢复正常的患者,需考虑复发性嗜睡症[5]。第三脑室肿瘤、脑炎、多发性硬化等神经系统疾病以及抑郁症、双相情感障碍等精神障碍也可出现类似的思睡症状,但其思睡很少突然出现或消失,发作间期也会存在部分症状;其他睡眠障碍如发作性睡病、阻塞性睡眠呼吸暂停(obstructivesleepapnea,OSA)导致的思睡通常无反复性和周期性特点。
(二)其他睡眠障碍所致EDS
除中枢性嗜睡以外,凡是可改变睡眠连续性、质量、节律以及时长的睡眠问题均可引起EDS。其他常见的睡眠障碍列举如下。
2.失眠症:EDS在失眠患者中并不少见。然而,与其他EDS患者相反,失眠症患者很少或很难在无意中自发入睡。此外,患者常伴有疲劳的主诉,应注意与思睡相区分。疲劳主要表现为缺乏能量和精力做事,以致活动量减少。这种症状很容易与主观思睡以及无意识的睡眠发作相区别。
PSG不是失眠的常规检查手段。因此,如果怀疑EDS是由失眠症引起,不会首先考虑进行PSG。EDS在失眠症缓解后可得到改善。如果患者存在失眠合并EDS,尤其怀疑发作性睡病时,需要进行PSG和MSLT[5]。
(三)精神障碍所致EDS
此类患者除EDS外,通常表现出夜间睡眠过多,因此很难与精神障碍合并特发性嗜睡症鉴别。然而,患者常常感到睡眠质量差,睡眠后无精力恢复感。
(四)躯体疾病所致EDS
很多内科疾病或神经系统疾病等躯体疾病可引起EDS,如果该躯体疾病是导致EDS的直接原因,可确定为EDS的唯一诊断。常见的导致EDS的躯体疾病包括:全身性疾病,如肥胖、慢性感染、风湿病、癌症、中毒[5,59-66];代谢性脑病,如肝性脑病、肾性脑病[67-68];内分泌疾病,如甲状腺功能减退、垂体瘤[69,70];神经系统疾病,如脑炎(如病毒性脑炎、自身免疫性脑炎)、脑外伤、卒中、脑肿瘤(如下丘脑肿瘤、副肿瘤综合征)、神经变性疾病(帕金森病、痴呆)[5,66,71-82];遗传性疾病等[83-91]。
(五)药物或物质所致EDS
药物、物质滥用或戒断可引起EDS,其中药物包括镇静药物如苯二氮类、巴比妥类药物,以及抗精神病药物、抗组胺药、多巴胺受体激动剂、抗癫痫药、某些抗生素等[5,66,92-94];物质滥用,如酒精、阿片类或大麻滥用可出现EDS[5,66];兴奋性物质,如可卡因、苯丙胺、咖啡因等撤除或戒断可出现严重思睡[95-96]。
【6】
评估
通常会综合临床病史、体格检查、量表问卷评估以及实验室检查等多个维度来评估EDS的严重程度,详见本文诊断思路部分。以下是评估思睡常用的主观评估工具、客观评估工具以及生化-基因检测等。
主观评估工具
3.KSS:是用于测量当前个体主观感知的思睡和警觉性问卷,属于评估主观思睡和警觉程度的指标,其优点在于操作简单,并可反复多次进行。该量表需要被试对包含10个选项的题目作答,被试根据自己当前的清醒和思睡状态选择相应的选项,得到1~10之间的评分,分数越高代表清醒程度越低、思睡程度越重[99]。
4.PDSS:为11~15岁人群设计,用于评估青少年儿童日常学习生活中思睡的主观感受[100]。问卷共包括8个条目,选项为0(从不)~4(总是)五级评分。分数越高,提示日间思睡越明显。在使用18/19分作为界值时,筛查发作性睡病的灵敏度和特异度较高。
客观评估工具
4.体动仪:通常指置入加速计的类似手表的可穿戴设备,可有效地客观测量数日至数周内的睡眠参数和平均运动时长,用于评估睡眠-觉醒周期[104]。在思睡患者的评估中,体动仪可用于证实EDS的严重程度以及排除睡眠不足,尤其是在MSLT检查前。此外,由于可在患者的家庭环境中进行测量,与单夜PSG相比,体动仪的结果具有较高的外部睡眠环境真实性等优势。但是,当需要脑电图来记录睡眠结构、睡眠分期或睡眠期间的异常运动时,或怀疑存在睡眠呼吸障碍时,体动仪不能替代PSG。
5.其他客观评估工具:牛津睡眠抵抗测验(Oxfordsleepresistancetest,OSLERtest)是MWT的简化版,也是间接量化EDS的客观评估工具[105];精神行为警觉测验(psychomotorvigilancetask,PVT)是基于对视觉刺激的反应来测量警觉性[106];另外,驾车试验也常用于警觉性评估[107]。
生化-基因检测
1.下丘脑分泌素-1(hypocretin-1):对于具有EDS主诉、临床高度怀疑发作性睡病的患者,脑脊液下丘脑分泌素-1(也称食欲素-A)的检测有助于明确诊断,尤其是当MSLT检查1次或多次结果为阴性、MSLT结果阴性却伴有典型猝倒发作、由于个人原因或研究条件限制无法完成MSLT、因服用药物或共患疾病可能干扰MSLT结果时[108-109]。脑脊液中下丘脑分泌素-1浓度≤110pg/ml或小于以同一标准检验正常者平均值的1/3可替代MSLT作为1型发作性睡病的诊断标准。
【7】
治疗
非药物治疗
3.光照疗法(ⅢB):晨起规律的光疗(约1000lux,每日持续≥30min)可使昼夜节律提前,可作为昼夜节律延迟患者的一种尝试手段[120]。此外,昼夜节律延迟患者应避免夜间光照[121-122]。傍晚和夜间早期光疗(如2500~10000lux,持续1~3h)是针对昼夜节律前移患者的主要光照治疗方法[123-124]。倒班者为了维持夜间的清醒状态,可适当提高夜间工作的光照强度[125-126]。
4.OSA所致EDS的治疗:无创正压通气是睡眠呼吸障碍患者治疗的首选[127-128](ⅠA),根据患者的特点,选择合适的模式,并评估患者对无创正压通气的依从性。对于拒绝或不依从无创正压通气的患者,可进行口腔矫治器治疗[129-130](ⅠA)。拒绝口腔矫治器或口腔矫治器疗效差的患者,可进行上气道手术[131-132](ⅠA)。不耐受无创正压通气且无气道塌陷的患者可进行舌下神经刺激术[133](ⅡA)。
5.失眠所致EDS的治疗:针对失眠症的治疗,如认知行为疗法(ⅠA)、经颅电刺激(ⅡA)、经颅磁刺激(ⅡA)可改善睡眠质量,缓解失眠引起的EDS[134]。
药物治疗
3.镇静催眠药物:此类药物主要用于昼夜节律紊乱导致EDS患者的助眠。对于已形成良好睡眠卫生习惯但白天仍难以按时入睡的倒班人员,可适量使用短效苯二氮类、非苯二氮类或食欲素受体拮抗剂[125],但这并不能缓解思睡,使夜班工作时保持警觉。镇静催眠类药物有助于缓解时差所致的失眠症状,但不推荐长期使用。
4.其他药物:针对不宁腿综合征或周期性肢体运动障碍的治疗药物主要目的在于缓解症状,改善夜间睡眠,解决EDS。目前常用的治疗不宁腿综合征的药物包括多巴胺受体激动剂、α-2-δ钙通道配体(加巴喷丁、普瑞巴林)、阿片类等[139]。周期性肢体运动障碍患者可试用多巴胺受体激动剂治疗,如存在禁忌证,可尝试α-2-δ钙通道配体[139]。
本共识编写委员会专家名单
执笔人(以姓氏拼音排序):范滕滕(北京大学第六医院睡眠医学中心);刘帅[南方医科大学南方医院精神心理科(睡眠医学中心)];刘亚平(香港中文大学医学院精神科学系);肖伏龙(北京大学人民医院全科医学科);于欢(复旦大学附属华山医院神经内科);周俊英(四川大学华西医院睡眠医学中心);张斌[南方医科大学南方医院精神心理科(睡眠医学中心)]
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