第二十四届国际诱发反应测听协作组学术年会(2015韩国釜山)会议纪要

李林珂1　耿佳2　申恬1　钟鸣骏2　熊文羽2　赵海燕2　卢宇2,3　袁慧军3　刘世喜1　孙艺4LI Lin-ke, GENG Jia, SHEN Tian, ZHONG Ming-jun, XIONG Wen-yu, ZHAO Hai-yan, LU Yu, YUAN Hui-jun, LIU Shi-xi, SUN Yi导致HDR综合征的2例GAT A3基因变异的致病性分析作者单位：1 四川大学华西医院耳鼻咽喉头颈外科 成都 610041 2 四川大学华西医院罕见病研究院 成都 6100413 陆军军医大学第一附属医院医学遗传中心 重庆 4000384 中部战区总医院耳鼻咽喉头颈外科 武汉 430070作者简介：李林珂 博士 住院医师; 研究方向：耳聋遗传学 通讯作者：孙艺，E-mail:*******************耳聋是临床上常见的影响人类身心健康的疾病之一。

据世界卫生组织统计，接近5亿的人口患有不同程度的听力损失。

我国现有听力残疾患者2780万人，仅次于肢体残疾[1]。

耳聋病因复杂，遗传因素是最主要的致病因素，约占60%[2]。

遗传性耳聋可分为非综合征型耳聋和综合征型耳聋。

截至2021年，遗传性耳聋网站（）已收录遗传性非综合征型耳聋基因123个。

综合征型耳聋种类繁杂，目前已报道400余种。

综合征型耳聋除耳聋的临床表现，还存在其他器官或系统异常。

临床常见的综合征型耳聋包括Usher综合征、Waardenburg综合征、Alport综合征等。

本文通过对两个因感音神经性耳聋就诊的先证者进行临床表现分析，对这两个家系的样本进行已知耳聋基因二代测序，结合生物信息学分析结果，确定两个家系的致病基因突变位点分别为GATA3的c.186dup和c.835_836dup杂合变异，从而诊断为甲状旁腺功能减退-感音神经性耳聋-肾发育不良综合征（hypoparathyroidism-sensorineural deafness-renal dysplasia,HDR）。

㊀㊀卢㊀宇，四川大学华西医院罕见病研究院临床遗传学部负责人㊂中华医学会医学遗传分会遗传咨询学组委员，中国生物物理学会听觉㊁语言和交流分会委员，ＣｌｉｎＧｅｎ耳聋基因突变解读专家组成员，美国耳鼻喉科学研究协会（ＡｓｓｏｃｉａｔｉｏｎｆｏｒＲｅｓｅａｒｃｈｉｎＯｔｏｌａｒｙｎｇｏｌｏｇｙ，ＡＲＯ）会员，担任ＨｕｍａｎＧｅｎｅｔｉｃｓ㊁ＦｒｏｎｔｉｅｒｓｉｎＧｅｎｅｔｉｃｓ等杂志审稿人㊂从事耳鼻咽喉头颈外科临床和研究工作近２０年，主要工作和研究专长包括耳科学㊁临床遗传咨询等㊂２０１３ ２０２０年全程参与设计和执行中国耳聋基因研究战略联盟（ＣｈｉｎｅｓｅＤｅａｆｎｅｓｓＧｅｎｅｔｉｃｓＣｏｎｓｏｒｔｉｕｍ，ＣＤＧＣ）大型耳聋队列项目研究，带领数据分析解读团队为１万余例耳聋患者明确了致病基因㊂已参与发表中文核心期刊和ＳＣＩ论文６０余篇，曾获全国第十一次医学遗传学年会 青年优秀论文奖 ㊂㊀㊀［摘要］㊀目的㊀鉴定１例重度感音神经性耳聋患者的遗传病因，明确检出突变的致病性，以及患者人工耳蜗康复效果，为该家庭再生育提供遗传指导㊂方法㊀采集广西壮族自治区一个耳聋小家系样本３例，包括１例重度感音神经性耳聋患儿和其正常听力父母㊂对该家系成员进行病史调查㊁体格及听力学检查，采集外周静脉血㊂进行全基因组测序和生物信息学分析鉴定致病基因，评估人工耳蜗术后听觉与言语康复效果㊂结果ＥＳＰＮ基因ｃ．１９１６⁃１Ｇ＞Ａ纯合突变是该家系的致聋原因，人工耳蜗术后听觉与言语康复效果良好㊂结论㊀研究发现了ＥＳＰＮ基因一个新的突变，是该耳聋家系的致病原因㊂回访发现人工耳蜗术后患儿言语康复效果好㊂该研究丰富了遗传性聋的突变谱，并对人工耳蜗植入的术前评估具有指导意义㊂㊀㊀［关键词］㊀ＥＳＰＮ基因；㊀遗传性耳聋；㊀人工耳蜗㊀㊀［中图分类号］㊀Ｒ７６４㊀［文献标识码］㊀Ａ㊀［文章编号］㊀１６７４－３８０６（２０２３）０５－０４３２－０５㊀㊀ｄｏｉ：１０．３９６９／ｊ．ｉｓｓｎ．１６７４－３８０６．２０２３．０５．０３ＧｅｎｅｔｉｃｄｉａｇｎｏｓｉｓｏｆａｕｔｏｓｏｍａｌｒｅｃｅｓｓｉｖｅｄｅａｆｎｅｓｓｃａｕｓｅｄｂｙｒａｒｅｈｏｍｏｚｙｇｏｕｓｍｕｔａｔｉｏｎｏｆＥＳＰＮｇｅｎｅａｎｄｅｖａｌｕａｔｉｏｎｏｆｃｏｃｈｌｅａｒｉｍｐｌａｎｔｒｅｈａｂｉｌｉｔａｔｉｏｎｏｕｔｃｏｍｅｓ㊀ＬＩＵＹａｎ，ＺＨＯＮＧＭｉｎｇ⁃ｊｕｎ，ＸＩＯＮＧＷｅｎ⁃ｙｕ，ｅｔａｌ．ＤｅｐａｒｔｍｅｎｔｏｆＯｔｏｌａｒｙｎｇｏｌｏｇｙＨｅａｄａｎｄＮｅｃｋＳｕｒｇｅｒｙ，ＷｅｓｔＣｈｉｎａＨｏｓｐｉｔａｌ，ＳｉｃｈｕａｎＵｎｉｖｅｒｓｉｔｙ，Ｃｈｅｎｇｄｕ６１００４１，Ｃｈｉｎａ；ＩｎｓｔｉｔｕｔｅｏｆＲａｒｅＤｉｓｅａｓｅｓ，ＷｅｓｔＣｈｉｎａＨｏｓｐｉｔａｌ，ＳｉｃｈｕａｎＵｎｉｖｅｒｓｉｔｙ，Ｃｈｅｎｇｄｕ６１００４１，Ｃｈｉｎａ㊀㊀［Ａｂｓｔｒａｃｔ］㊀Ｏｂｊｅｃｔｉｖｅ㊀Ｔｏｉｄｅｎｔｉｆｙｔｈｅｇｅｎｅｔｉｃｅｔｉｏｌｏｇｙｏｆａｐａｔｉｅｎｔｗｉｔｈｓｅｖｅｒｅｓｅｎｓｏｒｉｎｅｕｒａｌｈｅａｒｉｎｇｌｏｓｓ，ｔｏｃｌａｒｉｆｙｔｈｅｐａｔｈｏｇｅｎｉｃｉｔｙｏｆｔｈｅｄｅｔｅｃｔｅｄｍｕｔａｔｉｏｎａｎｄｔｈｅｒｅｈａｂｉｌｉｔａｔｉｏｎｏｕｔｃｏｍｅｓｏｆｔｈｅｐａｔｉｅｎｔᶄｓｃｏｃｈｌｅａｒｉｍｐｌａｎｔ，ａｎｄｔｏｐｒｏｖｉｄｅｇｅｎｅｔｉｃｇｕｉｄａｎｃｅｆｏｒｔｈｅｆａｍｉｌｙᶄｓｒｅｐｒｏｄｕｃｔｉｏｎ．Ｍｅｔｈｏｄｓ㊀ＴｈｒｅｅｓａｍｐｌｅｓｗｅｒｅｃｏｌｌｅｃｔｅｄｆｒｏｍａｓｍａｌｌｄｅａｆｐｅｄｉｇｒｅｅｉｎＧｕａｎｇｘｉＺｈｕａｎｇＡｕｔｏｎｏｍｏｕｓＲｅｇｉｏｎ，ｉｎｃｌｕｄｉｎｇｏｎｅｐａｔｉｅｎｔｗｉｔｈｓｅｖｅｒｅｓｅｎｓｏｒｉｎｅｕｒａｌｈｅａｒｉｎｇｌｏｓｓａｎｄｈｉｓｐａｒｅｎｔｓｗｉｔｈｎｏｒｍａｌｈｅａｒｉｎｇ．Ｔｈｅｆａｍｉｌｙｍｅｍｂｅｒｓｆｒｏｍｔｈｅｄｅａｆｐｅｄｉｇｒｅｅｗｅｒｅｉｎｖｅｓｔｉｇａｔｅｄｆｏｒｍｅｄｉｃａｌｈｉｓｔｏｒｙ，ａｎｄｗｅｒｅｇｉｖｅｎｐｈｙｓｉｃａｌａｎｄａｕｄｉｏｌｏｇｉｃａｌｅｘａｍｉｎａｔｉｏｎｓ，ａｎｄｔｈｅｉｒｐｅｒｉｐｈｅｒａｌｖｅｎｏｕｓｂｌｏｏｄｗａｓｃｏｌｌｅｃｔｅｄ．Ｗｈｏｌｅｇｅｎｏｍｅｓｅｑｕｅｎ⁃ｃｉｎｇａｎｄｂｉｏｉｎｆｏｒｍａｔｉｃｓａｎａｌｙｓｉｓｗｅｒｅｃｏｎｄｕｃｔｅｄｔｏｉｄｅｎｔｉｆｙｔｈｅｐａｔｈｏｇｅｎｉｃｇｅｎｅｓａｎｄｅｖａｌｕａｔｅｔｈｅｏｕｔｃｏｍｅｓｏｆｈｅａｒｉｎｇａｎｄｓｐｅｅｃｈｒｅｈａｂｉｌｉｔａｔｉｏｎａｆｔｅｒｃｏｃｈｌｅａｒｉｍｐｌａｎｔａｔｉｏｎ．Ｒｅｓｕｌｔｓ㊀ＡｈｏｍｏｚｙｇｏｕｓｎｅｗｍｕｔａｔｉｏｎｏｆＥＳＰＮｇｅｎｅｗａｓｔｈｅｃａｕｓｅｏｆｄｅａｆｎｅｓｓｉｎｔｈｅｄｅａｆｐｅｄｉｇｒｅｅ，ａｎｄｔｈｅｈｅａｒｉｎｇａｎｄｓｐｅｅｃｈｒｅｈａｂｉｌｉｔａｔｉｏｎｏｕｔｃｏｍｅｓａｆｔｅｒｃｏｃｈｌｅａｒｉｍｐｌａｎｔａｔｉｏｎｗｅｒｅｇｏｏｄ．Ｃｏｎｃｌｕｓｉｏｎ㊀ＴｈｅｓｔｕｄｙｉｄｅｎｔｉｆｉｅｓａｎｅｗｍｕｔａｔｉｏｎｏｆＥＳＰＮｇｅｎｅ，ｗｈｉｃｈｉｓｔｈｅｐａｔｈｏｇｅｎｉｃｃａｕｓｅｏｆｄｅａｆｎｅｓｓｉｎｔｈｅｄｅａｆｐｅｄｉｇｒｅｅ．Ｔｈｅｆｏｌｌｏｗ⁃ｕｐｓｔｕｄｙｆｉｎｄｓｔｈａｔｔｈｅｓｐｅｅｃｈｒｅｈａｂｉｌｉｔａｔｉｏｎａｆｔｅｒｃｏｃｈｌｅａｒｉｍｐｌａｎｔａｔｉｏｎｉｓｅｆｆｅｃｔｉｖｅｉｎｔｈｅｐａｔｉｅｎｔ．Ｔｈｉｓｓｔｕｄｙｅｎｒｉｃｈｅｓｔｈｅｍｕｔａｎｔｓｐｅｃｔｒｕｍｏｆｈｅｒｅｄｉｔａｒｙｄｅａｆｎｅｓｓａｎｄｈａｓｇｕｉｄｉｎｇｓｉｇｎｉｆｉｃａｎｃｅｆｏｒｔｈｅｐｒｅｏｐ⁃ｅｒａｔｉｖｅｅｖａｌｕａｔｉｏｎｏｆｃｏｃｈｌｅａｒｉｍｐｌａｎｔａｔｉｏｎ．㊀㊀［Ｋｅｙｗｏｒｄｓ］㊀ＥＳＰＮｇｅｎｅ；㊀Ｈｅｒｅｄｉｔａｒｙｄｅａｆｎｅｓｓ；㊀Ｃｏｃｈｌｅａｒｉｍｐｌａｎｔ㊀㊀耳聋是临床上最常见的感觉神经系统缺陷之一，据２０２１年‘世界听力报告“统计，目前全世界存在不同程度听力损失的人数超过１５亿，预计到２０５０年可能会增加到２５亿人［１］㊂第二次全国残疾人抽样调查显示，我国听力障碍残疾人口有２７８０万人，占残疾人总数的３３ ５％［２］㊂耳聋在我国是常见的出生缺陷，其中遗传因素占早发性耳聋病因的６０％以上，常染色体隐性遗传是最主要的遗传方式［３］㊂根据是否合并其他系统疾病，耳聋分为非综合征型和综合征型，其中非综合征型约占７０％㊂目前已报道超过１２０个导致非综合征型耳聋的基因，在中国人群中最常见的ＧＪＢ２㊁ＳＬＣ２６Ａ４㊁ＯＴＯＦ㊁ＭＹＯ１５Ａ和ＭＹＯ７Ａ等常染色体隐性遗传耳聋基因已有大量文献报道㊂对早发性重度以上感音神经性听力损失，尽早施行人工耳蜗植入和言语康复训练是最有效的治疗方法［４］㊂人工耳蜗是通过体外设备采集声音信号，经信号处理后无线传输至植入头皮下的信号处理装置，再将电信号传送至植入耳蜗的电极，电极通过放电直接刺激听神经，最终信号传到大脑，从而感知声音㊂人工耳蜗传导的听觉信号绕过耳蜗病变部位，直接刺激患者的螺旋神经节细胞和听神经，帮助患者改善或获得听觉㊂因此，大多数耳聋患者在人工耳蜗植入术后配合规范的听力和言语康复训练可获得不同程度的听力和言语功能的提高㊂但临床上也有部分患者在人工耳蜗植入后康复效果不佳，这不仅与植入年龄㊁言语康复训练等因素有关，还与患者耳聋的病变部位和病理机制有关［５］㊂不同的基因突变导致耳聋的病理机制和病变部位存在差异，因此可能造成人工耳蜗效果的差异㊂通过基因诊断明确患者听觉系统的分子病理学改变，有助于对人工耳蜗植入的预后进行评估，避免无效植入㊂本研究通过二代测序在１例语前极重度非综合征型耳聋患者中发现ＥＳＰＮ基因ｃ．１９１６⁃１Ｇ＞Ａ纯合突变，明确了罕见的剪切位点新突变是该家庭的致聋原因，并对ＥＳＰＮ基因导致耳聋的遗传特点㊁临床表型和人工耳蜗康复效果进行总结分析㊂１㊀对象与方法１ １㊀研究对象㊀本研究家系是来自广西壮族自治区的壮族家系㊂采样小组对先证者及其亲属成员进行了家系调查，收集家系成员临床资料，对先证者进行详细病史资料收集（包括现病史㊁既往史㊁母亲围生期风险和用药史等），进行常规体格检查㊁听力学检查等㊂采集各家庭成员外周静脉血５ｍｌ，提取基因组ＤＮＡ冻存备用㊂本研究获四川大学华西医院伦理委员会批准［批号：２０２１年审（１９０）号］，参与研究的家系成员均签署知情同意书㊂１ ２㊀全基因组检测和数据分析㊀使用华大智造ＤＮＢＳＥＱ⁃Ｔ７测序平台对先证者血液提取到的ＤＮＡ进行全基因组测序，下机原始数据使用ＢＷＡ软件与参考基因组序列（ＧＲＣｈ３８）进行比对，使用基于ＧＡＴＫＨａｐｌｏｔｙｐｅＣａｌｌｅｒ开发的Ｓａｉｌｅｃａｌｌｉｎｇ算法提取突变信息㊂对突变进行质量控制过滤：ｒｅａｄｄｅｐｔｈ＞６，ｇｅｎｏｔｙｐｅｑｕａｌｉｔｉｅｓ＞２０，ａｌｌｅｌｅｆｒｅｑｕｅｎｃｙ＞１０％㊂使用ＶａｒＳｅｑ软件对突变进行人群频率（ｇｎｏｍＡＤ㊁ｄｂＳＮＰ㊁１０００Ｇｅｎｏｍｅｓ人群数据库）注释，过滤次等位基因频率（ｍｉｎｏｒａｌｌｅｌｅｆｒｅｑｕｅｎｃｙ，ＭＡＦ）ȡ０ ００５的突变位点；过滤掉ＣｌｉｎＶａｒ数据库注释为Ｂｅｎｉｇｎ的突变㊂筛选耳聋基因编码区和剪切位点区域的突变，对候选突变进行致病性分析㊂１ ３㊀Ｓａｎｇｅｒ测序验证㊀根据二代测序检出的候选致病基因突变，设计验证引物，对家系相关成员进行双向Ｓａｎｇｅｒ测序验证㊂测序数据通过质控后，应用Ｍｕｔａｔｉｏｎ⁃Ｓｕｒｖｅｙｏｒ软件进行序列比对，判读基因型，分析检出突变是否符合家系内听力表型和基因型共分离㊂１ ４㊀人工耳蜗术后听觉与言语康复效果评价㊀应用有意义听觉整合量表（ＭｅａｎｉｎｇｆｕｌＡｕｄｉｔｏｒｙＩｎｔｅｇｒａｔｉｏｎＳｃａｌｅ，ＭＡＩＳ）和有意义使用言语量表（ＭｅａｎｉｎｇｆｕｌＵｓｅｏｆＳｐｅｅｃｈＳｃａｌｅ，ＭＵＳＳ）对患儿／先证者的实际交流环境下的听觉能力与言语能力进行有效评估［６］㊂ＭＡＩＳ总分为４０分，得分越高提示患者听觉能力发展越好㊂ＭＵＳＳ由患儿家长对开放式问题进行详细回答，可通过举例对患儿日常生活中言语行为进行详细描述，评估者根据患儿家长对言语发生行为出现频率的描述进行评分，每个问题的分值为０ ４分，总分为４０分，分数越高提示患儿的言语能力越强㊂２㊀结果２ １㊀患儿病史及临床表现㊀先证者男性，１岁时父母发现患儿听力下降，４岁就诊于当地医院耳鼻咽喉头颈外科门诊，进行纯音测听㊁声导抗㊁听性脑干反应㊁畸变耳声发射等详细听力学评估，以及颞骨ＣＴ扫描检查，结果提示为双侧对称的重度感音神经性耳聋，无内耳畸形，无前庭功能障碍，无其他系统疾病，无头部外伤史㊁耳毒性药物及噪声暴露史，母亲围生期无特殊疾病和药物接触史㊂父母听力正常，非近亲婚配，无耳聋家族史㊂患儿４岁进行了右耳人工耳蜗植入手术，术后无并发症，开机正常，在当地康复机构进行２年言语康复训练㊂２ ２㊀致病基因鉴定结果㊀对先证者进行全基因组测序，下机数据通过质控㊁去重和过滤后，根据遗传方式㊁表型特征㊁ＶＥＰＩｍｐａｃｔ注释等条件进行筛查后得到１个候选基因突变：ＥＳＰＮ基因纯合突变ｃ．１９１６⁃１Ｇ＞Ａ㊂该突变此前未见报道，在ｇｎｏｍＡＤ数据库中未检出㊂２ ３㊀Ｓａｎｇｅｒ测序验证结果㊀结果表明，患儿基因型为ＥＳＰＮ基因ｃ．１９１６⁃１Ｇ＞Ａ纯合突变㊂患儿父母听力正常，均携带ｃ．１９１６⁃１Ｇ＞Ａ杂合突变㊂先证者的纯合突变分别来自于父母，家系内基因型与表型共分离，初步推断ＥＳＰＮ基因ｃ．１９１６⁃１Ｇ＞Ａ纯合突变为患儿耳聋的致病原因㊂家系图及Ｓａｎｇｅｒ测序图谱见图１㊂２ ４㊀突变致病性分析结果㊀先证者检出的ＥＳＰＮ基因ｃ．１９１６⁃１Ｇ＞Ａ是剪接位点突变，通过影响ｍＲＮＡ剪接导致转录过程中相应外显子缺失，从而生成截短蛋白，造成功能缺陷㊂该突变在ｇｎｏｍＡＤ等人群数据库中均未检出，属于极罕见突变；该突变在家系中符合基因型⁃表型共分离，符合常染色体隐性遗传方式㊂总结ＥＳＰＮ基因在ＣｌｉｎＶａｒ和ＤＶＤ数据库已报道的致病性突变［７⁃１９］，本研究发现的截短突变是ＥＳＰＮ基因常染色体隐性遗传方式最常见的突变类型（见图２），ｃ．１９１６⁃１Ｇ＞Ａ导致截短蛋白缺失了重要的功能域（见图３）㊂ＥＳＰＮ基因ｃ．１９１６⁃１Ｇ＞Ａ为致病性突变㊂ⓐ家系图，父母听力正常；ⓑＳａｎｇｅｒ双向测序结果，父母亲均为ｃ．１９１６⁃１Ｇ＞Ａ杂合突变，先证者为ｃ．１９１６⁃１Ｇ＞Ａ纯合突变图１㊀家系图及Ｓａｎｇｅｒ测序图谱㊀ＣｌｉｎＶａｒ和ＤＶＤ数据库收录的致病性和可能致病性突变，以及本研究发现的突变：错义突变９个，框内突变１个，移码突变７个，无义突变５个，剪切突变２个图２㊀ＥＳＰＮ基因常染色体隐性遗传突变类型比例图㊀图示Ｅｓｐｉｎ蛋白结构及突变所在结构域；绿色字体为本研究发现突变，红色字体为常染色体显性遗传突变，黑色字体为常染色体隐性遗传突变图３㊀Ｅｓｐｉｎ蛋白结构及已报道致病性突变所在位置示意图２ ５㊀人工耳蜗术后听觉与言语康复效果评价㊀患儿术后在当地言语康复机构学习２年，术后５年进行康复效果评估㊂患儿父母认为康复效果良好，能够通过人工耳蜗进行日常言语沟通㊂ＭＡＩＳ评分得分３５分（总分４０分），ＭＵＳＳ评分得分３８分（总分４０分），证明其听觉与言语康复效果良好㊂３㊀讨论３ １㊀本研究报道了１例语前重度感音神经性耳聋患儿，通过全基因组测序检出ＥＳＰＮ基因ｃ．１９１６⁃１Ｇ＞Ａ纯合突变，这是通过改变ｍＲＮＡ剪接导致基因功能缺陷的致病性突变，患儿表型符合ＥＳＰＮ基因导致的常染色体隐性遗传非综合征型耳聋典型特征，因此ＥＳＰＮ基因ｃ．１９１６⁃１Ｇ＞Ａ纯合突变是该患儿的致病原因㊂３ ２㊀ＥＳＰＮ基因由１３个外显子组成，编码８５４个氨基酸的Ｅｓｐｉｎ蛋白，是一种肌动蛋白结合蛋白㊂在Ｅｓｐｉｎ的Ｎ端有８个重复的锚蛋白（ａｎｋｙｒｉｎｒｅｐｅａｔｓ），在２个富含脯氨酸的区域（ＰＲ１和ＰＲ２）中间是１个肌动蛋白结合域ｘＡＢ，接着是ＷＨ２结构域，其包含ＡＴＰ或ＧＴＰ共同结合位点，在Ｃ末端有２个肌动蛋白结合位点构成ＡＢＭ模块［２０］㊂Ｅｓｐｉｎ蛋白在内耳毛细胞纤毛中表达，纤毛是内耳毛细胞顶端表面突出的特殊微绒毛，其核心由平行的肌动蛋白丝束密集排列而成［２１］㊂Ｅｓｐｉｎ可交联肌动蛋白丝使立体纤毛的肌动蛋白丝束规律排列，不同浓度的Ｅｓｐｉｎ可以决定蛋白丝延伸的程度，从而决定平行的肌动蛋白丝束的长度［２２］㊂研究发现小鼠中ＥＳＰＮ基因纯合突变会导致毛细胞缺陷从而引起耳聋和前庭功能障碍［２３］㊂３ ３㊀ＥＳＰＮ基因缺陷导致的常染色体隐性遗传耳聋典型表现为学语前发病的重度或极重度感音神经性耳聋，部分患者可合并前庭功能障碍㊂Ｎａｚ等［７］２００４年报道了２个巴基斯坦的语前极重度耳聋合并前庭功能障碍的近亲婚配家系，通过连锁分析，这２个常染色体隐性遗传家系的致病基因均定位于１ｐ３６ ３，并最终鉴定致病基因均为ＥＳＰＮ基因㊂Ｄｏｎａｕｄｙ等［２４］２００６年报道了ＥＳＰＮ基因杂合突变导致的常染色体显性遗传耳聋，报道的４例患者表型差异较大，发病年龄４ ４２岁，听力损失程度为轻度至重度不等，但其基因型表型关联尚缺乏确定性证据㊂３ ４㊀目前对ＥＳＰＮ突变导致耳聋的病例报告较少，在ＣｌｉｎＶａｒ和ＤＶＤ数据库中收录导致非综合征型耳聋的致病性和可能致病性的突变一共２７个，其中２３个导致常染色体隐性遗传耳聋的突变类型以截短突变（包括移码突变㊁无义突变和剪切突变）为主㊂ＣｌｉｎＶａｒ数据库中有一个剪切突变位点（ｃ．１９１６⁃１Ｇ＞Ｃ）与本研究发现的突变（ｃ．１９１６⁃１Ｇ＞Ａ）位置一致，都会通过影响剪接导致基因功能缺陷，这也进一步验证了本研究报道突变的致病性㊂３ ５㊀ＥＳＰＮ基因已报道的致病性突变中，以常染色体隐性遗传耳聋为主，只有４个非截短突变（错义突变和框内突变）为常染色体显性遗传，提示两种遗传方式可能是不同突变致病机制造成的㊂导致常染色体显性遗传耳聋的突变主要集中在肌动蛋白结合位点ＡＢＭ模块中，该位置的突变可能使Ｅｓｐｉｎ与肌动蛋白丝交联失败，导致纤毛病变而致病㊂３ ６㊀已报道的常染色体隐性遗传耳聋家系中大部分为近亲婚配［７⁃８］，而本研究中发现的广西家庭为非近亲婚配家庭，但患者检出极罕见突变的纯合子㊂基因突变频率及热点突变具有种族特异性和民族特异性，在不同的地区和民族中，耳聋基因突变谱和优势突变不同，本研究中发现的突变位点在各人群数据库中均未检出，其是否为广西当地民族特异性突变有待进一步研究㊂３ ７㊀对于重度和极重度感觉神经性听力损失的患者，人工耳蜗植入是最有效的治疗方法㊂目前全球有６５万人接受了人工耳蜗植入，但是约有７％患者听觉植入后效果差，有多方面的原因［５］㊂其中遗传因素很重要，除ＧＪＢ２㊁ＳＬＣ２６Ａ４基因突变患者人工耳蜗植入效果明确以外，其他基因突变对人工耳蜗植入效果的报道很少㊂ＥＳＰＮ基因缺陷患者的人工耳蜗植入效果此前未见报道，不能形成术前评估的指导性意见㊂本研究中患者人工耳蜗术后经过系统性言语康复训练，言语康复效果良好，证实ＥＳＰＮ基因ｃ．１９１６⁃１Ｇ＞Ａ纯合突变致耳聋可以进行人工耳蜗手术，为人工耳蜗术前评估提供遗传学参考证据㊂对全国不同区域及民族的耳聋人群进行深入研究，明确各地区各民族耳聋基因的诊断率㊁特定耳聋基因突变的人群频率等特点，能够为遗传性耳聋基因筛查和基因诊断提供更加准确的参考依据，对制定精准的遗传咨询服务和人工耳蜗植入评估具有重要意义㊂参考文献［１］ＣｈａｄｈａＳ，ＫａｍｅｎｏｖＫ，ＣｉｅｚａＡ．Ｔｈｅｗｏｒｌｄｒｅｐｏｒｔｏｎｈｅａｒｉｎｇ，２０２１［Ｊ］．ＢｕｌｌＷｏｒｌｄＨｅａｌｔｈＯｒｇａｎ，２０２１，９９（４）：２４２－２４２Ａ．［２］第二次全国残疾人抽样调查领导小组．２００６年全国第二次残疾人抽样调查主要数据公报［Ｍ］．北京：华夏出版社，２００７：２－３８．［３］ＭｅｅｎａＲ，ＡｙｕｂＭ．Ｇｅｎｅｔｉｃｓｏｆｈｕｍａｎｈｅｒｅｄｉｔａｒｙｈｅａｒｉｎｇｉｍｐａｉｒｍｅｎｔ［Ｊ］．ＪＡｙｕｂＭｅｄＣｏｌｌＡｂｂｏｔｔａｂａｄ，２０１７，２９（４）：６７１－６７６．［４］ＷｉｌｓｏｎＢＳ，ＤｏｒｍａｎＭＦ．Ｃｏｃｈｌｅａｒｉｍｐｌａｎｔｓ：ｃｕｒｒｅｎｔｄｅｓｉｇｎｓａｎｄｆｕｔｕｒｅｐｏｓｓｉｂｉｌｉｔｉｅｓ［Ｊ］．ＪＲｅｈａｂｉｌＲｅｓＤｅｖ，２００８，４５（５）：６９５－７３０．［５］周㊀凯，胥㊀亮，黄兰诚，等．人工耳蜗植入术７４例临床分析［Ｊ］．中国临床新医学，２０１９，１２（９）：９５０－９５５．［６］ＺｈｏｎｇＹ，ＸｕＴ，ＤｏｎｇＲ，ｅｔａｌ．ＴｈｅａｎａｌｙｓｉｓｏｆｒｅｌｉａｂｉｌｉｔｙａｎｄｖａｌｉｄｉｔｙｏｆｔｈｅＩＴ⁃ＭＡＩＳ，ＭＡＩＳａｎｄＭＵＳＳ［Ｊ］．ＩｎｔＪＰｅｄｉａｔｒＯｔｏｒｈｉｎｏｌａｒｙｎｇｏｌ，２０１７，９６：１０６－１１０．［７］ＮａｚＳ，ＧｒｉｆｆｉｔｈＡＪ，ＲｉａｚｕｄｄｉｎＳ，ｅｔａｌ．ＭｕｔａｔｉｏｎｓｏｆＥＳＰＮｃａｕｓｅａｕｔｏ⁃ｓｏｍａｌｒｅｃｅｓｓｉｖｅｄｅａｆｎｅｓｓａｎｄｖｅｓｔｉｂｕｌａｒｄｙｓｆｕｎｃｔｉｏｎ［Ｊ］．ＪＭｅｄＧｅｎｅｔ，２００４，４１（８）：５９１－５９５．［８］ＢｏｕｌｏｕｉｚＲ，ＬｉＹ，ＳｏｕａｌｈｉｎｅＨ，ｅｔａｌ．ＡｎｏｖｅｌｍｕｔａｔｉｏｎｉｎｔｈｅＥｓｐｉｎｇｅｎｅｃａｕｓｅｓａｕｔｏｓｏｍａｌｒｅｃｅｓｓｉｖｅｎｏｎｓｙｎｄｒｏｍｉｃｈｅａｒｉｎｇｌｏｓｓｂｕｔｎｏａｐｐａｒｅｎｔｖｅｓｔｉｂｕｌａｒｄｙｓｆｕｎｃｔｉｏｎｉｎａＭｏｒｏｃｃａｎｆａｍｉｌｙ［Ｊ］．ＡｍＪＭｅｄＧｅｎｅｔＡ，２００８，１４６Ａ（２３）：３０８６－３０８９．［９］ＰｌｅｖｏｖａＰ，ＴｖｒｄａＰ，ＰａｐｒｓｋａｒｏｖａＭ，ｅｔａｌ．Ｇｅｎｅｔｉｃａｅｔｉｏｌｏｇｙｏｆｎｏｎ⁃ｓｙｎｄｒｏｍｉｃｈｅａｒｉｎｇｌｏｓｓｉｎＭｏｒａｖｉａ⁃Ｓｉｌｅｓｉａ［Ｊ］．Ｍｅｄｉｃｉｎａ（Ｋａｕｎａｓ），２０１８，５４（２）：２８．［１０］ＩｚｕｍｉＹ，ＨａｍａｇｕｃｈｉＡ，ＭｉｕｒａＲ，ｅｔａｌ．ＡｕｔｏｓｏｍａｌｄｏｍｉｎａｎｔＡｌｐｏｒｔｓｙｎｄｒｏｍｅｄｕｅｔｏａＣＯＬ４Ａ４ｍｕｔａｔｉｏｎｗｉｔｈａｎａｄｄｉｔｉｏｎａｌＥＳＰＮｖａｒｉａｎｔｄｅｔｅｃｔｅｄｂｙｗｈｏｌｅ⁃ｅｘｏｍｅａｎａｌｙｓｉｓ［Ｊ］．ＣＥＮＣａｓｅＲｅｐ，２０２０，９（１）：５９－６４．［１１］ＭｏｒｇａｎＡ，ＬｅｎａｒｄｕｚｚｉＳ，ＣａｐｐｅｌｌａｎｉＳ，ｅｔａｌ．ＧｅｎｏｍｉｃｓｔｕｄｉｅｓｉｎａｌａｒｇｅｃｏｈｏｒｔｏｆｈｅａｒｉｎｇｉｍｐａｉｒｅｄＩｔａｌｉａｎｐａｔｉｅｎｔｓｒｅｖｅａｌｅｄｓｅｖｅｒａｌｎｅｗａｌｌｅｌｅｓ，ａｒａｒｅｃａｓｅｏｆｕｎｉｐａｒｅｎｔａｌｄｉｓｏｍｙ（ＵＰＤ）ａｎｄｔｈｅｉｍｐｏｒ⁃ｔａｎｃｅｔｏｓｅａｒｃｈｆｏｒｃｏｐｙｎｕｍｂｅｒｖａｒｉａｔｉｏｎｓ［Ｊ］．ＦｒｏｎｔＧｅｎｅｔ，２０１８，９：６８１．［１２］ＨａｎＪＪ，ＮｇｕｙｅｎＰＤ，ＯｈＤＹ，ｅｔａｌ．Ｅｌｕｃｉｄａｔｉｏｎｏｆｔｈｅｕｎｉｑｕｅｍｕｔａ⁃ｔｉｏｎｓｐｅｃｔｒｕｍｏｆｓｅｖｅｒｅｈｅａｒｉｎｇｌｏｓｓｉｎａＶｉｅｔｎａｍｅｓｅｐｅｄｉａｔｒｉｃｐｏｐｕ⁃ｌａｔｉｏｎ［Ｊ］．ＳｃｉＲｅｐ，２０１９，９（１）：１６０４．［１３］ＺｏｕＳ，ＭｅｉＸ，ＹａｎｇＷ，ｅｔａｌ．Ｗｈｏｌｅ⁃ｅｘｏｍｅｓｅｑｕｅｎｃｉｎｇｉｄｅｎｔｉｆｉｅｓｒａｒｅｐａｔｈｏｇｅｎｉｃａｎｄｃａｎｄｉｄａｔｅｖａｒｉａｎｔｓｉｎｓｐｏｒａｄｉｃＣｈｉｎｅｓｅＨａｎｄｅａｆｐａｔｉｅｎｔｓ［Ｊ］．ＣｌｉｎＧｅｎｅｔ，２０２０，９７（２）：３５２－３５６．［１４］Ｓｌｏａｎ⁃ＨｅｇｇｅｎＣＭ，ＢｉｅｒｅｒＡＯ，ＳｈｅａｒｅｒＡＥ，ｅｔａｌ．Ｃｏｍｐｒｅｈｅｎｓｉｖｅｇｅｎｅｔｉｃｔｅｓｔｉｎｇｉｎｔｈｅｃｌｉｎｉｃａｌｅｖａｌｕａｔｉｏｎｏｆ１１１９ｐａｔｉｅｎｔｓｗｉｔｈｈｅａｒｉｎｇｌｏｓｓ［Ｊ］．ＨｕｍＧｅｎｅｔ，２０１６，１３５（４）：４４１－４５０．［１５］ＮａｚＳ，ＩｍｔｉａｚＡ，ＭｕｊｔａｂａＧ，ｅｔａｌ．Ｇｅｎｅｔｉｃｃａｕｓｅｓｏｆｍｏｄｅｒａｔｅｔｏｓｅｖｅｒｅｈｅａｒｉｎｇｌｏｓｓｐｏｉｎｔｔｏｍｏｄｉｆｉｅｒｓ［Ｊ］．ＣｌｉｎＧｅｎｅｔ，２０１７，９１（４）：５８９－５９８．［１６］ＡｈｍｅｄＺＭ，ＪａｗｏｒｅｋＴＪ，ＳａｒａｎｇｄｈａｒＧＮ，ｅｔａｌ．ＩｎｆｒａｍｅｄｅｌｅｔｉｏｎｏｆｈｕｍａｎＥＳＰＮｉｓａｓｓｏｃｉａｔｅｄｗｉｔｈｄｅａｆｎｅｓｓ，ｖｅｓｔｉｂｕｌｏｐａｔｈｙａｎｄｖｉｓｉｏｎｉｍｐａｉｒｍｅｎｔ［Ｊ］．ＪＭｅｄＧｅｎｅｔ，２０１８，５５（７）：４７９－４８８．［１７］Ｓｌｏａｎ⁃ＨｅｇｇｅｎＣＭ，ＢａｂａｎｅｊａｄＭ，ＢｅｈｅｓｈｔｉａｎＭ，ｅｔａｌ．ＣｈａｒａｃｔｅｒｉｓｉｎｇｔｈｅｓｐｅｃｔｒｕｍｏｆａｕｔｏｓｏｍａｌｒｅｃｅｓｓｉｖｅｈｅｒｅｄｉｔａｒｙｈｅａｒｉｎｇｌｏｓｓｉｎＩｒａｎ［Ｊ］．ＪＭｅｄＧｅｎｅｔ，２０１５，５２（１２）：８２３－８２９．［１８］ＲｉｃｈａｒｄＥＭ，Ｓａｎｔｏｓ⁃ＣｏｒｔｅｚＲＬＰ，ＦａｒｉｄｉＲ，ｅｔａｌ．ＧｌｏｂａｌｇｅｎｅｔｉｃｉｎｓｉｇｈｔｃｏｎｔｒｉｂｕｔｅｄｂｙｃｏｎｓａｎｇｕｉｎｅｏｕｓＰａｋｉｓｔａｎｉｆａｍｉｌｉｅｓｓｅｇｒｅｇａｔｉｎｇｈｅａｒｉｎｇｌｏｓｓ［Ｊ］．ＨｕｍＭｕｔａｔ，２０１９，４０（１）：５３－７２．［１９］ＷａｎｇＲ，ＨａｎＳ，ＫｈａｎＡ，ｅｔａｌ．ＭｏｌｅｃｕｌａｒａｎａｌｙｓｉｓｏｆｔｗｅｌｖｅＰａｋｉ⁃ｓｔａｎｉｆａｍｉｌｉｅｓｗｉｔｈｎｏｎｓｙｎｄｒｏｍｉｃｏｒｓｙｎｄｒｏｍｉｃｈｅａｒｉｎｇｌｏｓｓ［Ｊ］．ＧｅｎｅｔＴｅｓｔＭｏｌＢｉｏｍａｒｋｅｒｓ，２０１７，２１（５）：３１６－３２１．［２０］ＢａｒｔｌｅｓＪＲ，ＷｉｅｒｄａＡ，ＺｈｅｎｇＬ．Ｉｄｅｎｔｉｆｉｃａｔｉｏｎａｎｄｃｈａｒａｃｔｅｒｉｚａｔｉｏｎｏｆｅｓｐｉｎ，ａｎａｃｔｉｎ⁃ｂｉｎｄｉｎｇｐｒｏｔｅｉｎｌｏｃａｌｉｚｅｄｔｏｔｈｅＦ⁃ａｃｔｉｎ⁃ｒｉｃｈｊｕｎｃ⁃ｔｉｏｎａｌｐｌａｑｕｅｓｏｆＳｅｒｔｏｌｉｃｅｌｌｅｃｔｏｐｌａｓｍｉｃｓｐｅｃｉａｌｉｚａｔｉｏｎｓ［Ｊ］．ＪＣｅｌｌＳｃｉ，１９９６，１０９（Ｐｔ６）：１２２９－１２３９．［２１］ＢａｒｔｌｅｓＪＲ．Ｐａｒａｌｌｅｌａｃｔｉｎｂｕｎｄｌｅｓａｎｄｔｈｅｉｒｍｕｌｔｉｐｌｅａｃｔｉｎ⁃ｂｕｎｄｌｉｎｇｐｒｏｔｅｉｎｓ［Ｊ］．ＣｕｒｒＯｐｉｎＣｅｌｌＢｉｏｌ，２０００，１２（１）：７２－７８．［２２］ＬｏｏｍｉｓＰＡ，ＺｈｅｎｇＬ，Ｓｅｋｅｒｋｏｖ Ｇ，ｅｔａｌ．Ｅｓｐｉｎｃｒｏｓｓ⁃ｌｉｎｋｓｃａｕｓｅｔｈｅｅｌｏｎｇａｔｉｏｎｏｆｍｉｃｒｏｖｉｌｌｕｓ⁃ｔｙｐｅｐａｒａｌｌｅｌａｃｔｉｎｂｕｎｄｌｅｓｉｎｖｉｖｏ［Ｊ］．ＪＣｅｌｌＢｉｏｌ，２００３，１６３（５）：１０４５－１０５５．［２３］ＺｈｅｎｇＬ，Ｓｅｋｅｒｋｏｖ Ｇ，ＶｒａｎｉｃｈＫ，ｅｔａｌ．Ｔｈｅｄｅａｆｊｅｒｋｅｒｍｏｕｓｅｈａｓａｍｕｔａｔｉｏｎｉｎｔｈｅｇｅｎｅｅｎｃｏｄｉｎｇｔｈｅｅｓｐｉｎａｃｔｉｎ⁃ｂｕｎｄｌｉｎｇｐｒｏｔｅｉｎｓｏｆｈａｉｒｃｅｌｌｓｔｅｒｅｏｃｉｌｉａａｎｄｌａｃｋｓｅｓｐｉｎｓ［Ｊ］．Ｃｅｌｌ，２０００，１０２（３）：３７７－３８５．［２４］ＤｏｎａｕｄｙＦ，ＺｈｅｎｇＬ，ＦｉｃａｒｅｌｌａＲ，ｅｔａｌ．Ｅｓｐｉｎｇｅｎｅ（ＥＳＰＮ）ｍｕｔａ⁃ｔｉｏｎｓａｓｓｏｃｉａｔｅｄｗｉｔｈａｕｔｏｓｏｍａｌｄｏｍｉｎａｎｔｈｅａｒｉｎｇｌｏｓｓｃａｕｓｅｄｅｆｅｃｔｓｉｎｍｉｃｒｏｖｉｌｌａｒｅｌｏｎｇａｔｉｏｎｏｒｏｒｇａｎｉｓａｔｉｏｎ［Ｊ］．ＪＭｅｄＧｅｎｅｔ，２００６，４３（２）：１５７－１６１．［收稿日期㊀２０２３－０５－１５］［本文编辑㊀吕文娟㊀余㊀军］本文引用格式刘㊀燕，钟鸣骏，熊文羽，等．ＥＳＰＮ基因罕见纯合突变导致常染色体隐性遗传耳聋的基因诊断及人工耳蜗康复效果评价［Ｊ］．中国临床新医学，２０２３，１６（５）：４３２－４３６．。

EFNS GUIDELINES/CME ARTICLEEFNS guidelines for diagnosis,therapy and prevention of Wernicke encephalopathyR.Galvin a,G.Bra˚then b,A.Ivashynka c,M.Hillbom d,R.Tanasescu e and M.A.Leone fa Department of Neurology,Cork University Hospital,Wilton,Cork,Ireland;b Department of Neurology and Clinical Neurophysiology, Trondheim University Hospital,Trondheim,Norway;c Department of Neurology,National Neurology and Neurosurgery Research Center, Minsk,Belarus;d Department of Neurology,Oulu University Hospital,Oulu,Finland;e Department of Neurology,Colentina Hospital, University of Medicine and Pharmacy Carol Davila,Bucharest,Romania;and f Clinica Neurologica,Azienda Ospedaliero-Universitaria Maggiore della Carita`,Novara,ItalyKeywords: alcoholism,diagnosis, guidelines,prevention, thiamine,treatment, Wernicke encephalopathy Received20April2010 Accepted14June2010Background:Although Wernicke encephalopathy(WE)is a preventable and treat-able disease it still often remains undiagnosed during life.Objectives:To create practical guidelines for diagnosis,management and prevention of the disease.Methods:We searched MEDLINE,EMBASE,LILACS,Cochrane Library. Conclusions and recommendations:1The clinical diagnosis of WE should take into account the different presentations of clinical signs between alcoholics and non alcoholics(Recommendation Level C); although prevalence is higher in alcoholics,WE should be suspected in all clinical conditions which could lead to thiamine deficiency(good practice point–GPP).2The clinical diagnosis of WE in alcoholics requires two of the following four signs;(i)dietary deficiencies(ii)eye signs,(iii)cerebellar dysfunction,and(iv)either an altered mental state or mild memory impairment(Level B).3Total thiamine in blood sample should be measured immediately before its administration(GPP).4MRI should be used to support the diagnosis of acute WE both in alcoholics and non alcoholics(Level B).5Thiamine is indicated for the treatment of suspected or manifest WE.It should be given,before any carbohydrate,200mg thrice daily,preferably intravenously(Level C).6The overall safety of thiamine is very good(Level B).7After bariatric surgery we recommend follow-up of thiamine status for at least 6months(Level B)and parenteral thiamine supplementation(GPP).8Parenteral thiamine should be given to all at-risk subjects admitted to the Emergency Room(GPP).9Patients dying from symptoms suggesting WE should have an autopsy(GPP).IntroductionWernicke encephalopathy(WE)is a devastating acute or subacute neurological disorder due to thiamine (Vitamin B1)deficiency.Although vitamins were dis-covered at the beginning of the20th century and we learned to treat thiamine deficiency some decades later, WE remains the most important encephalopathy due to a single vitamin deficiency.The disease we now recog-nise as wet beriberi caused by thiamine deficiency from eating polished rice was probably recognized1000years ago in China[1]but WE and the associated Korsakoffamnestic syndrome were not described until the late 19th century[2–4].The classical clinical triad of signs of WE comprises ocular signs,cerebellar dysfunction and confusion.Correspondence:Dr.M.Leone,Clinica Neurologica,Ospedale Maggiore della Carita,C.Mazzini18–28100Novara,Italy(tel.:+390321/3733218;fax:+390321/3733298;e-mail:maurizio.leone@ maggioreosp.novara.it).This is a Continuing Medical Education article,and can be found with corresponding questions on the Internet at /EFNS Continuing-Medical-Education-online.301.0.html.Certificates for correctly answering the questions will be issued by the EFNS.1408Ó2010The Author(s) European Journal of NeurologyÓ2010EFNSEuropean Journal of Neurology2010,17:1408–1418doi:10.1111/j.1468-1331.2010.03153.xThe reported prevalence of WE in autopsy studies ranges from0.4%to2.8%,accounting on average for 1.3%of all autopsies(Table1),and seems to be much higher in alcoholics than in non alcoholics.WE is tra-ditionally regarded as a condition related to alcohol abuse.Interestingly,one of Carl WernickeÕs index cases was a young woman with repeated vomiting following the ingestion of sulphuric acid and we now increasingly recognize that WE can arise in many situations other than alcohol abuse.The disease is rare,catastrophic in onset,clinically complex and often delayed in diagnosis.We lack con-trolled studies on its management although the litera-ture abounds with small series and individual case reports.Because of ethical problems in conducting controlled trials in a disease with a high mortality and an established therapy,new controlled data are also unlikely to be published in the future.Evidence is scarce for many aspects concerning the diagnosis and treat-ment of WE but we consider guidelines to be important because it is potentially preventable and treatable and frequently remains undiagnosed particularly in non alcoholic situations.Search strategyWe searched MEDLINE with the following string: (i)*Wernicke Encephalopathy/OR(ii)(ÔThiamine Deficiency/complicationsÕ[Mesh]ORÔThiamine Defi-ciency/diagnosisÕ[Mesh]ORÔThiamine Deficiency/drug therapyÕ[Mesh]ORÔThiamine Deficiency/epidemiologyÕ[Mesh]ORÔThiamine Deficiency/etiologyÕ[Mesh]OR ÔThiamine Deficiency/prevention and controlÕ[Mesh])OR (iii)KorsakoffSyndrome/NOT Wernicke Encephalo-pathy/).We also searched EMBASE,LILACS(Wer-nicke Encephalopathy OR Thiamine),and the Cochrane Library.All searches were done from data-base incep-tion up to May31,2009.All papers published in European languages were considered.Titles and abstracts were double checked by two blinded panel members and relevant papers were fully read.Secondary searching was performed using the bibliography of rel-evant articles.Congress abstracts were not searched. Methods for reaching consensusArticles were graded for evidence according to the revised EFNS scientific task force guidance for guide-lines[5]by two members of the panel;in case of disagreement,grading was discussed in a panel meeting. Each successive guideline draft was circulated among panellists and modified after their comments.All members of the task force agreed to all recommen-dations unanimously;where there was lack of evidence, but consensus was clear,we have stated our opinion as a good practice point(GPP).Table1Frequency of Wernicke encephalopathy in series of consecutive autopsiesAuthor [reference]Years ofsurvey Area SourceAlcoholics and nonalcoholics Alcoholics Non alcoholicsN WE%N WE%N WE%Cravioto[38]1957–60USA,New York H160028 1.7Jellinger[39]NS Austria H100911 1.1Victor[40]1963–66USA H153929 1.9Torvik[41]1975–79Norway H8735750.9713709.8Harper[42,43]1973–81Australia,Perth H+CO4677131 2.8Hauw[44]1952–83France H8200111 1.4Harper[45]NS Australia,Sydney H+CO2856 2.1Lindboe[46]1983–87Norway H6964520.760440 6.66360120.2 Pollak[47]NS Germany H154138.4Skullerud[48]1984–87Norway CO1271814.2Naidoo[49]1988–89South Africa H291758.6Riethdorf[50]1983–86Germany H2372140.622314 6.3Vege[51]1988Norway H2794 1.4Lana-Peixoto[52]1978–90Brazil H165536 2.2Boldorini[53]NS Italy H3806517.1 Harper[54]1989–94France H+CO25610.4Sheedy[55],Harper[56]1996–97Australia,Sydney CO221225 1.1Bleggi-Torres[57]1987–98Brazil H18010 5.6 Bertrand,[58]2001–06France CJD nationalregister65719 2.9 Total39783523 1.318501729.3692087 1.3 NS,not specified;H,hospital series;CO,Coroner series;WE,Wernicke encephalopathy.EFNS guidelines for Wernicke encephalopathy1409Ó2010The Author(s)European Journal of NeurologyÓ2010EFNS European Journal of Neurology17,1408–1418FindingsHow often is WE diagnosed in life?Autopsy studies indicate that WE is frequently undi-agnosed during life.Table 2lists the autopsy studies reporting the percentage of alcoholic and non alco-holic patients with WE diagnosed ante mortem.All were Class IV studies.WE was suspected during life in only about one-third of alcoholic and 6%of non alcoholic patients.These series are likely to be biased towards more severe cases and the number of patients remaining undiagnosed before death is probably higher.These observations would suggest that thia-mine deficiency and its consequences are likely to remain undiagnosed during life in significant numbers of cases.We are probably underestimating the real incidence of the disease and it seems reasonable to recommend that an autopsy has to be performed when patients die in situations with a suspicion of thiamine deficiency.RecommendationPatients dying from symptoms suggesting WE should have an autopsy (GPP).When should we suspect WE in non alcoholic subjects?We found more than 600cases of WE reported in clinical settings other than alcohol use (Table 3).Among the most frequent settings were malignant disease,gastrointestinal disease and surgery,and vomiting due to hyperemesis gravidarum.Other causes included fasting,starvation,malnutrition and the use of unbalanced diets.Systematic reviews have been published for bariatric surgery [6,7]and hyperemesis gravidarum [8].After bariatric surgery,i.e.the surgical procedures for obesity (gastric banding,gastric by-pass,bilio-pancreatic diversion,etc.),the risk for WE is long-lasting.According to one report,94%of WE cases were seen within 6months after surgery [6].Whenever a pregnant subject with persistent vomiting develops neurological signs or symptoms,WE should be considered [8].Prevalence studies of WE among non alcoholics have not been done and we can only speculate about the real prevalence of the disease in at-risk situations.Some conditions,such as bariatric surgery,may increase in the future,whereas others may disappear.RecommendationThe level of suspicion for WE should be high in all clinical conditions that could lead to thiamine defi-ciency in the absence of alcoholism (GPP).AfterT a b l e 2N u m b e r o f c a s e s o f W e r n i c k e e n c e p h a l o p a t h y d i a g n o s e d a n t e m o r t e m i n a u t o p s y s e r i e sA u t h o r s [r e f e r e n c e ]Y e a r s o f t h e s u r v e yA r e aE v i d e n c e c l a s sS o u r c eA l c o h o l i c sN o n a l c o h o l i c sN o .o f a u t o p s i e sN o .o f d i a g n o s e d a n t e m o r t e m%N o .o f a u t o p s i e sN o .o f d i a g n o s e d a n t e m o r t e m%V i c t o r [40]1950–61U S A I V H 534584.9T o r v i k [41]1975–79N o r w a y I V H 1915.3H a r p e r [42,43]1973–81A u s t r a l i a ,P e r t h aI V H +C O 1312619.8H a r p e r [45]N S A u s t r a l i a ,S y d n e y I V H +C O 6233.3L i n d b o e [46]1983–87N o r w a y I V H 11436.47N a i d o o [49]1988–89S o u t h A f r i c a I V H 1700R i e t h d o r f [50]1983–86G e r m a n y I V H 14321.4V e g e [51]1988N o r w a y I V H 3133.31S h e e d y [55]H a r p e r [56]1996–97A u s t r a l i a ,S y d n e yI V C O18422.2O g e r s h o k [59]1984–99U S A I V H 11100.03133K u o [60]N S U S A I V H 5120B e r t r a n d [58]2001–06F r a n c eI V C J D n a t i o n a l r e g i s t e r190T o t a l2738731.93525.7N S ,n o t s p e c i fie d ;H ,h o s p i t a l s e r i e s ;C O ,C o r o n e r s e r i e s .a >90%a l c o h o l i c s .1410R.Galvin et al.Ó2010The Author(s)European Journal of Neurology Ó2010EFNS European Journal of Neurology 17,1408–1418bariatric surgery we recommend follow-up of the thi-amine status for at least6months(Recommendation Level B).Which clinical features accurately identify WE?Table4lists the studies comparing autopsy series (including‡3cases)with clinical features of patients with acute WE.Most patients were alcoholics.Con-secutive autopsies were collected without knowledge of clinical data.However,it is unknown whether the clinical data evaluation was blinded to autopsy results; thus all these studies are considered Class IV.The classical diagnostic triad(eye signs,cerebellar signs and confusion)was reported only in8%of patients with clinical details.Although it should be considered as a minimum estimate due to a possible reporting bias,thisfigure prompts the need to reconsider diagnostic criteria for in-life diagnosis of WE.Caine et al.[9](Class II)studied clinical features of28 autopsy-proven alcoholic patients with WE that were well-evaluated during life.They divided signs and symptoms into eight clinical domains(see Table4for definitions):dietary deficiencies,eye signs,cerebellar signs,seizures,frontal lobe dysfunction,amnesia,mild memory impairment,and altered mental state. Reproducibility and validity of the criteria were then tested on106autopsied alcoholic patients.Clinical records of the patients were blindly reviewed by three researchers:sensitivity of each domain(recalculated from the paper)ranged from20%(seizures)to75%Table3List of cases of Wernicke encephalopathy reported in nonalcoholic subjects aClinical condition No.%Cancer11318.1Gastrointestinal surgery10516.8Hyperemesis gravidarum7612.2Starvation/Fasting6410.2Gastrointestinal tract diseases487.7AIDS31 5.0Malnutrition26 4.2Dialysis and renal diseases24 3.8Parenteral nutrition24 3.8Vomiting15 2.4Psychiatric diseases15 2.4Stem cell/marrow transplantation14 2.2Infections9 1.4Intoxication9 1.4Thyroid diseases8 1.3Unbalanced diet6 1.0Iatrogenic50.8Hypoxic encephalopathy20.3Others12 1.9Unknown etiology19 3.0Total625100.0a Search performed in Medline,Embase,LILACS from data-baseinception through May31,2009.Table4Clinical features of patients with an autopsy proved diagnosis of Wernicke encephalopathyAuthors [reference]EvidenceclassTotalno.ofpatientsDietarydeficienciesNauseaandvomitingAnyeyesignCerebellarsigns SeizuresAmnesia,mild memoryimpairmentAlteredmentalstate TriadCravioto[38]IV281495264 Grunnet[61]IV2419344170 Torvik[41]IV1940180 Harper[62]IV972836294116 Lindboe[46]IV1830110 Naidoo[49]IV17180290 Vege[51]IV421001230 Ogershok[59]IV434141 Bleggi-Torres[63]IV83060 Harper[56]IV1803360 Bertrand[58]IV192151910 Total N(%)25621(8.2)9(3.5)62(24.2)65(25.4)8(3.1)60(23.4)136(53.1)21(8.2)Empty cell=not mentioned;0=specified as absent.Definition of domains[9]Domain6and7are combined in the table.Domain5was sporadically mentioned in the papers and it is not included here.(i)dietary deficiencies(a body mass index lower than2SD below normal as evidence of undernutrition,a history of grossly impaired dietary intake, or an abnormal thiamine status);the column including nausea and vomiting is added here,but they were not considered by Caine et al.(ii)eye signs (oculomotor abnormalities such as ophthalmoplegia,nystagmus,or gaze palsy);(iii)cerebellar signs(ataxia,unsteadiness,abnormalities of past pointing,dysdiadokokinesia,impaired heel-shin testing);(iv)seizures(either as part of a withdrawal syndrome or in isolation,or a longstanding history of anticonvulsant medication);(v)frontal lobe dysfunction(abnormalities in planning,insight,or abstraction with formal neuropsychological testing or when neurological examination elicited these characteristics);(vi)amnesia(a stable and persisting inability to form new memories);(vii)mild memory impairment(failure to remember two or more words in the four item memory test,or impairment on more elaborate neuropsychological tests of memory function);(viii)altered mental state(disorientation in two of threefields,confused,an abnormal digit span,or comatose).EFNS guidelines for Wernicke encephalopathy1411Ó2010The Author(s)European Journal of NeurologyÓ2010EFNS European Journal of Neurology17,1408–1418(cerebellar signs).Sensitivity of the classic triad was 23%,but rose to85%if the patients had at least two of the four following features:dietary deficiencies,eye signs,cerebellar signs,and either mild memory impairment or an altered mental state.Thiamine deficiency may also result in other mani-festations such as dry beriberi(neuropathy),wet beri-beri(neuropathy with high-output congestive heart failure),gastrointestinal beriberi(abdominal pain, vomiting and lactic acidosis)and coma followed by Marchiafava-Bignami syndrome[10,11].Heart failure with lactic acidosis is an important syndrome to be noted,because several papers have reported favourable outcome after thiamine treatment[12,13]. RecommendationThe clinical diagnosis of WE in alcoholics requires two of the following four signs;(i)dietary deficiencies, (ii)eye signs,(iii)cerebellar dysfunction,and(iv)either an altered mental state or mild memory impairment (Level B).It is reasonable to apply the same criteria to non alcoholic patients(GPP).Are clinical features of alcoholic WE different from non-alcoholic WE?Table5lists case series(including‡3cases)published after CaineÕs criteria and compares clinical features of alcoholic and non alcoholic patients with WE.All but two were Class IV studies.In most studies,the MRI investigations were not performed blind to clinical evaluation and vice versa.Although these studies cannot give reliable information on the frequency of clinical features,they allow a comparison of the clinical features in alcoholics and non alcoholics. There is evidence that clinical features were unevenly distributed;dietary deficiency and vomiting were more frequent among non alcoholics(P<0.0001), whereas eye and cerebellar signs were more frequent among alcoholics(P<0.0001).The classical triad was significantly more frequent in alcoholics than in the non alcoholics(P<0.005).Reasons for the dif-ference are unclear,but may be due to the fact that WE in non alcoholics usually presents as a dramatic acute syndrome,whereas WE in alcoholics may moreTable5Clinical features of alcoholic and non alcoholic patients with Wernicke encephalopathyAuthors [reference]EvidenceclassTotal no.of patientsDietarydeficienciesNauseaandvomitingAnyeyesignCerebellarsigns SeizuresAmnesia,mild memoryimpairmentAlteredmentalstate TriadAlcoholicsGallucci[64]IV555433 Antunez[19]II151412109 Park[65]III121110154 Varnet[66]IV2520221911 Ogershok[59]IV616363 Weidauer[67]IV1111105109 Chung[68]IV110110 Halavaara[69]IV21122222 White[70]IV11111111 Zuccoli[71]IV2422172013 Total N(%)1024(3.9)7(6.9)92(90.2)82(80.4)0(–)9(8.8)77(75.5)55(53.9)Non alcoholicsShikata[72]IV333131 Merkin-Zaborsky[73]IV312330 Park[65]III32222132 Ogershok[59]IV6635262 Weidauer[67]IV1111111 Chung[68]IV3101331 Halavaara[69]IV33233122 Zhong[74]IV662226White[70]IV22222111 Sun[75]IV41330140 Unlu[76]IV666666 Fei[77]IV12129332 Kirbas[78]IV25257141094 Francini-Pesenti[80]IV7736776 Zuccoli[71]IV32211122133011 Total11696(82.8)36(31.0)82(70.7)58(50.0)0(–)13(11.2)78(67.2)39(33.6)Empty cell=not mentioned;0=specified as absent.See Table4for the definition of domains.1412R.Galvin et al.Ó2010The Author(s)European Journal of NeurologyÓ2010EFNS European Journal of Neurology17,1408–1418frequently present as a subclinical syndrome.Fur-thermore,alcoholics may develop thiamine deficiency several times during their life span,whereas non alcoholics are not likely to do so.Magnesium defi-ciency could also contribute to the poor recovery from WE in alcoholics[14].RecommendationThe clinical diagnosis of WE should take into account the different presentations of clinical signs between alcoholics and non alcoholics and the higher prevalence of the disease in alcoholics(Level C).Is there any laboratory test that accurately identifies patients with thiamine deficiency?The erythrocyte transketolase activity assay including thiamine pyrophosphate effect has been replaced by direct measurement of thiamine and its phosphate esters in human blood by high-performance liquid chromatography(HPLC)[15,16].This thiamine assay is now commercially available in many countries.Adult normal range(60–220n M)and the lowest detectable level(3–35n M)are given.The sample(2ml EDTA blood)should be taken before administration of thia-mine and should be protected from light.However, normal thiamine levels do not necessarily exclude WE in exceptional cases,i.e.in the presence of thia-mine transporter gene mutations[17].The concentration of thiamine and thiamine mono-phosphate and diphosphate in plasma and whole blood samples were assessed in six healthy subjects for12h and in urine for24h following either intravenous or oral bolus dose of50mg thiamine HCl.Unphosphor-ylated thiamine increased rapidly in plasma after intravenous administration and then decreased to its initial value within12h.The half-life was96min. Thiamine mono and diphosphate increased moderately (56%),and decreased slowly;the half-life of diphos-phate was664min.Within24h,53%of the adminis-tered dose was recovered in the urine,indicating a restricted distribution[18].RecommendationWhenever WE is suspected a blood sample for mea-surement of total thiamine should be drawn immedi-ately before administration of thiamine and sent for HPLC analysis(GPP).Does radiology accurately identify patients with WE?CT scanning is not a reliable test for WE[19](Class II). Table6lists MRI series including‡3cases of WE. Seven compare alcoholics to non alcoholics and one additional paper alcoholics with acute WE to controls and asymptomatic alcoholics without WE.In this Class II retrospective study alcoholics with and without WE were compared and MRIs were randomly and blindly assessed by two neuroradiologists[19].The sensitivity and specificity of MRI were53%and93%.Positive predictive value was89%.Pooled data in Table6showed that among alcoholics with a clinically verified acute WE,conventional MRI revealed lesions in nearly two-thirds of the subjects. Little additional information was obtained by using fluid-attenuated inversion recovery(FLAIR)images and diffusion-weighted imaging(DWI).In non alco-holics,the available data showed a higher yield of lesions varying from97%(DWI),99%(conventional) and100%(FLAIR).Location of lesions was more frequently atypical among non alcoholic than alcoholic patients whereas contrast enhancement of the thalamus and mamillary bodies was observed to associate more frequently with alcohol abuse[20].Typically,the lesions were symmetrical and seen in the thalami,mamillary bodies,tectal plate and periaqueductal area.Atypical lesions were located in the cerebellum,vermis,cranial nerve nuclei,red nuclei,dentate nuclei,caudate nuclei, splenium and cerebral cortex.Reversible cytotoxic edema was considered the most distinctive lesion of WE [20].The heterogeneity of MRI lesions may result from disease severity,acuteness of the disease and timing of imaging.We cannot say which of the MRI techniques used is most useful.RecommendationMRI is a powerful tool which should be used to support the diagnosis of acute WE both in alcoholics and non alcoholics(level B).It could also be used to follow the recovery of patients.What is the efficacy of thiamine treatment in WE?The efficacy of thiamine for WE has been assessed in only one double-blind randomized clinical trial[21]. Due to several methodological shortcomings it is in our opinion a class III study.Thiamine hydrochloride was given to107patients in doses of5,20,50,100and 200mg im daily for2days,with assessment of effect on the third day by a single neuropsychological test,sug-gested to be sensitive to cognitive impairment.The authors concluded that the200mg dose was superior to the mean result of all the other dosages.This study was evaluated in a Cochrane review concluding that in comparison to the5mg dose200mg was significantly more effective[22].In another randomized double-blind study10mg thiamine or placebo were given to elderly people with subclinical thiamine deficiency[23].These EFNS guidelines for Wernicke encephalopathy1413Ó2010The Author(s)European Journal of NeurologyÓ2010EFNS European Journal of Neurology17,1408–1418people did not have WE.Quality of life was enhanced by providing thiamine supplements.There is no consensus on the optimal dose of thi-amine,its preparation form,duration of treatment,or the number of daily doses.Pharmacokinetic studies show a blood half-life of free thiamine of only96min [18]so it can be speculated that giving thiamine in two or three daily doses might achieve better pene-trance to the brain and other tissues than a single daily dose[24].According to many case reports,treatment with either100or200mg thiamine given intravenously has cured the disease in non alcoholics.On the other hand,this has not always been the case in alcoholics. Alcoholic patients with WE may need higher daily doses and500mg three times daily has been recom-mended[25,26].The reason for the discrepancy is unclear.Alcoholics may have had previous subclinical episodes of the disease leading to permanent damage in the brain before admission to hospital with WE or the often coexistent severe alcohol withdrawal syn-drome may have resulted in permanent damage of the brain tissue due to excess glutamate liberated in the brain[27].Experimental[18]and clinical data[28–30]indicate that orally administered thiamine hydrochloride is inef-fective in increasing blood thiamine or curing WE.The critical blood concentrations of thiamine for treating WE have not been determined.It could be speculated that patients in a catabolic state and alcoholics have reduced ability to store thiamine because the enzymes depending on thiamine are down regulated or protein binding is altered by the influence of alcohol.In such patients even high doses of thiamine might not cause a sufficient increase of thiamine stores unless a balanced diet has been instituted at the same time.Thus,normalization of diet might be an important factor in the acute treatment of suspected or manifest WE.As the unwanted side-effects to B vitamins are most commonly seen after multiple administrations, and the necessary dose of thiamine amounts to a rather painful volume when given intramuscularly,weTable6MRI features of alcoholic and non alcoholic patients with Wernicke encephalopathyEvidence class Type ofMRIConventionalMRIMRI-Gadoliniumenhancement FLAIR MRI DWR MRI Totalno.Positiveno.(%)Totalno.Positiveno.(%)Totalno.Positiveno.(%)Totalno.Positiveno.(%)AlcoholicsGallucci[64]IV0.5T55Antunez[19]II 1.5T15820Park[65]III 2.0T88Varnet[66]III 1.0/1.5T2516253Ogershok[59]IV?20Chung[68]IV 1.5T11 Weidauer[67]IV 1.5T112114113Halavaara[69]IV 1.5T22202222 White[70]IV?111111 Zuccoli[71]IV 1.0/1.5T241718172417Total9359(63.4)5824(41.4)3823(60.5)44(100)Non alcoholicsMascalchi[79]IV?3321Park[65]III 2.0T33Ogershok[59]IV?11Chung[68]IV 1.5T11111111 Weidauer[67]IV 1.5T101111Halavaara[69]IV 1.5T33303333 White[70]IV?222222 Zhong[74]IV 1.5T6666Unlu[76]IV 1.0T66656666 Fei[77]IV 1.5T121233101043 Francini-Pesenti[80]IV?777777 Zuccoli[71]IV 1.0/1.5T32322393232Total7776(98.7)4322(51.0)7272(100)2928(97.0) FLAIR,fluid-attenuated inversion recovery.1414R.Galvin et al.Ó2010The Author(s)European Journal of NeurologyÓ2010EFNS European Journal of Neurology17,1408–1418suggest an intravenous infusion of thiamine diluted with100ml of normal saline or5%glucose,given over30min.It is also important to give thiamine before any car-bohydrate,because it is well known that glucose infu-sion precipitates WE in thiamine deficiency[26]. RecommendationThere is sufficient evidence that thiamine is indicated for the treatment of suspected or manifest WE(level C). Since studies of sufficient quality to warrant a formal recommendation are lacking,there is no evidence to support conclusions as to dosage,route of administra-tion,and treatment time.However,we recommend that thiamine should be given200mg three times daily and preferably via intravenous instead of intramuscular route(level C).Thiamine should be given before any carbohydrate,and a normal diet should be instituted immediately after thiamine(GPP).Treatment should be continued until there is no further improvement in signs and symptoms(GPP).Is thiamine therapy safe?The overall safety of intravenous thiamine is very good. In a prospective study of989patients receiving100mg thiamine hydrochloride as a single intravenous injection over10s or less,one patient reacted with generalized pruritus and11had transient local irritation[31](Class II).In a retrospective survey Wrenn and Slovis[31] identified no cases of significant adverse reactions to thiamine in more than300.000treatments.Sporadic anaphylactic reactions have been reported,but it is not documented that thiamine was the cause in all cases. However,it has been suggested that thiamine should be given in circumstances where facilities for resuscitation are available[25].This is preferable,but because a delay in treatment may cause irreversible brain damage and is life-threatening we recommend to start treatment immediately,even in the absence of facilities for resus-citation.RecommendationThe overall safety of thiamine is very good,regardless of route of administration(level B).Thiamine should be given without delay in all circumstances irrespective of whether facilities for resuscitation are immediately available or not(GPP).Is there a place for prophylactic thiamine therapy? Studies from several countries show a thiamine defi-ciency in the elderly population[32].Thiamine has been added to foods in many countries[33].Some observa-tional studies from Australia[33,34]suggest that this preventive effort has resulted in a decrease of the occurrence of the disease,although no controlled studies have been performed on this matter and are unlikely to be done in the future.Supplementation of thiamine to alcoholic beverages has been suggested too [32].However,the mechanisms via which alcohol ingestion predisposes to thiamine deficiency suggest that adding thiamine into alcoholic beverages is a use-less strategy.First,alcohol inhibits the absorption of thiamine from the intestine;second,during alcohol metabolism thiamine will neither be phosphorylated nor incorporated to enzymes in body tissues[35].Thi-amine ingested together with alcohol will be excreted in urine as free thiamine.Thiamine deficiency is frequently not clinically apparent and WE can easily be worsened or precipi-tated if the treating physician gives glucose to a patient unaware that there is thiamine deficiency.In many countries emergency ward guidelines include recom-mendations to administer parenteral thiamine,e.g.,to patients who are in status epilepticus[36]before any infusion of carbohydrates is started.There are also other conditions(Table3)in which administration of thiamine in food or oral preparation is inefficient(e.g.vomiting).Such conditions require parenteral administration of thiamine.In hunger strikers there is evidence from one cohort study(Class IV)[37]that up to600mg.thiamine orally together with one tablespoon of sugar daily did not prevent the development of WE.We did notfind any other studies evaluating the prophylactic administration of thiamine in other risk conditions in alcoholics or in non alco-holics.Administration of multivitamin pills has been recommended following bariatric surgery.However, parenteral administration of vitamins may be a better strategy to prevent vitamin deficiency,because these patients frequently vomit[7].RecommendationSupplementation of thiamine to food may prevent the development of WE(GPP).There is no evidence that supplementation to beverages may be useful.We recommend prophylactic parenteral administration of 200mg thiamine before carbohydrates are started in all subjects with a risk condition managed at the Emergency Room(GPP).After bariatric surgery we recommend parenteral thiamine supplementation (GPP).We think that hunger strikers should be carefully informed of the risk of WE and persuaded to accept a parenteral administration of thiamine followed by glucose(GPP).However,in both these situations we do not have any evidence of an effective dosage.EFNS guidelines for Wernicke encephalopathy1415Ó2010The Author(s)European Journal of NeurologyÓ2010EFNS European Journal of Neurology17,1408–1418。

恒河猴听觉脑干反应的测定王振民;杨智君;王博;赵赋;渠沛然;王兴朝;李朋;刘丕楠【期刊名称】《中国现代医学杂志》【年(卷),期】2015(025)010【摘要】目的探索实施恒河猴听觉脑干反应的测定方法及其波形特点.方法成年恒河猴8只,在基础联合持续静脉麻醉下以美国Bio-logic电生理检测仪行测定听觉脑干反应.测试完毕后,分别测量双侧耳的Ⅰ、Ⅱ和Ⅳ潜伏期和振幅,以及Ⅰ～Ⅱ、Ⅰ～Ⅳ和Ⅱ～Ⅳ波间期,并行双耳对比.结果测试顺利,过程中动物生命体征平稳.恒河猴ABR波Ⅰ、Ⅱ和Ⅳ波分化良好,波形重复性好,并以Ⅱ波最为显著.动物双耳的阈值介于0～15dB nHL.80 dB nHL时恒河猴双耳Ⅰ、Ⅱ和Ⅳ波的平均潜伏期为(1.201±0.112)、(2.239±0.127)和(2.239±0.127)ms;平均振幅为(0.186±0.160)、(0.521±0.314)和(0.138±0.159)μV.除Ⅰ波潜伏期右耳较左耳长(t=-3.986,P＜0.05),其余各波的潜伏期、振幅双耳比较均差异无统计学意义.结论恒河猴听觉脑干反应操作简便,可行性强,波形重复好.ABR各波潜伏期、波间期等为后续研究及其他相关研究提供了参考与借鉴.【总页数】4页(P6-9)【作者】王振民;杨智君;王博;赵赋;渠沛然;王兴朝;李朋;刘丕楠【作者单位】首都医科大学附属北京天坛医院神经外科,北京100050;首都医科大学附属北京天坛医院神经外科,北京100050;首都医科大学附属北京天坛医院神经外科,北京100050;北京市神经外科研究所,北京100050;首都医科大学附属北京天坛医院神经外科,北京100050;首都医科大学附属北京天坛医院神经外科,北京100050;首都医科大学附属北京天坛医院神经外科,北京100050;首都医科大学附属北京天坛医院神经外科,北京100050【正文语种】中文【中图分类】R76;R-332【相关文献】1.恒河猴七氟烷血/气和组织/气分配系数的测定 [J], 张鹏;庄菁;李鹏2.人工耳蜗植入术后电诱发听觉脑干反应和复合动作电位测定 [J], 王亮;董明敏3.恒河猴促黄体激素生物测定法及应用研究 [J], 王训立4.安徽野生和自繁恒河猴血液生化指标的测定与分析 [J], 徐玉蕊;李进华;孙丙华;夏东坡;朱勇;王希5.恒河猴、食蟹猴毛发氨基酸和微量元素测定分析 [J], 李鹤龄;王宏;陈智岗;宗发梁因版权原因，仅展示原文概要，查看原文内容请购买。

Experimental investigation and numerical simulation for weakening the thermal fluctuations in aT-junctionK.Gao a ,P.Wang b ,T.Lu a ,⇑,T.Song caCollege of Mechanical and Electrical Engineering,Beijing University of Chemical Technology,Beijing 100029,China bSchool of Energy and Power Engineering,Dalian University of Technology,Dalian 116024,China cChina Nuclear Power Technology Research Institute Co.,Ltd,Shenzhen 518124,Chinaa r t i c l e i n f o Article history:Received 25August 2014Received in revised form 17November 2014Accepted 4January 2015Available online 17January 2015Keywords:Experimental investigation Numerical simulation Tee junctionThermal fluctuationa b s t r a c tIn this work,the mixing processes of hot and cold fluids with and without a distributor are predicted by experiments and numerical simulations using large-eddy simulation (LES)on FLUENT platform.Temperatures at different positions of the internal wall and mixing conditions caused by T-junctions at different times are obtained,then the simulated normalized mean and root-mean square (RMS)temperature,velocity vector and temperature contour for the two structures,namely with and without a distributor,are compared.The results show that,compared with the a T-junction without a distributor,the mixing region of hot and cold water in the T-junction with distributor moves to the middle of the pipe,and the inclusion of the distributor reduces the temperature fluctuations of internal wall noticeably and makes the mixing of hot and cold water more efficient.Ó2015Elsevier Ltd.All rights reserved.1.IntroductionTee junction is a familiar structure that is universally used in pipeline systems of power plants,nuclear power plants and chemi-cal plants,it is often applied to mix hot and cold fluid of main and branch pipes.The fluctuations of fluid temperature are transported to the solid walls by heat convection and conduction.This can cause cyclical thermal stresses and subsequent thermal fatigue cracking of the piping (Lee et al.,2009).So far,leakage accidents took place in several light water and sodium cooled reactors due to thermal fati-gue.In 1998,a crack was discovered at a mixing tee in which cold water from a branch pipe flowed into the main pipe in the residual heat removal (RHR)system in a reactor in Civaux,France.Metallur-gical studies concluded that the crack was caused by a high degree of cycle thermal fatigue (Eric Blondet,2002).In 1990,sodium leak-age happened in the French reactor Superphenix (Ricard and Sperandio,1996).It has been established that mixing hot and cold sodium can induce temperature fluctuations and result in thermal fatigue (IAEA,2002).Therefore,it is significant to study how to weaken thermal fatigue of the piping wall to ensure the integrity and safety of the piping system in a nuclear power plant.In the analysis of thermal fatigue,temperature fluctuation is a very important evaluation parameter.A reliable lifetime assess-ment of these components is difficult because usually only thenominal temperature differences between the hot and cold fluids are known,whereas the instantaneous temperatures and heat fluxes at the surface are unknown (Paffumi et al.,2013).Kamaya and Nakamura (2011)used the transient temperature obtained by simulation to assess the distribution of thermal stress and fati-gue when cold fluid flowed into the main pipe from a branch pipe.Numerical simulation of flow in the tee has been carried out Simoneau et al.(2010)to get temperature and its fluctuation curves,and the numerical results were in good agreement with the experimental data.Through the analysis on thermal fatigue stress,it draw the conclusion that the enhanced heat transfer coef-ficient and the temperature difference between hot and cold fluids were primary factors of thermal fatigue failure of tees.Many numerical simulations and experiments have been carried out to evaluate the flow and heat transfer in a mixing tee junction (Metzner and Wilke,2005;Hu and Kazimi,2006;Hosseini et al.,2008;Durve et al.,2010;Frank et al.,2010;Jayaraju et al.,2010;Galpin and Simoneau,2011;Aulery et al.,2012;Cao et al.,2012).Turbulent models such as Reynolds-averaged Navier–Stokes (RANS),Unsteady Reynolds averaged Navier Stokes (URANS),Scale-Adaptive Simulation (SAS),Reynolds stress model (RSM),detached eddy simulations (DES),and LES have all been used in industrial applications.As one of the choices of turbulent model for predicting the mixing flow in tee junctions,the RSM can bemused to describe the momentum conservation of the mixing (Durve et al.,2010;Frank et al.,2010).Turbulent mixing phenomena in a T-junction have been numerically investigated using the k $x/10.1016/j.anucene.2015.01.0010306-4549/Ó2015Elsevier Ltd.All rights reserved.Corresponding author.based baseline Reynolds stress model(BSL RSM)(Frank et al.,2010) for two different cases.Durve et al.(2010)applied the RSM to pre-dict the velocityfield of three non-isothermal parallel jetsflowing in an experiment setup used to simulate theflow occurring at the core outlet region of a fast breeder reactor(FBR),with a Reynolds number of1.5Â104.Theflow in tube of different Reynolds numbers (Re)andflow velocity ratio were studied experimentally with three-dimensional scanning using particle image velocimetry(3D-SPIV) (Brücker,1997).Large-eddy simulation(LES)is an alternative turbulence model with different subgridscale models often employed to predict velocity and temperaturefluctuations.Indeed many numerical studies have shown the capability of LES to model thermalfluctu-ations in turbulent mixing.LES was performed(Lee et al.,2009)to analyze temperaturefluctuation in the tee junction and the simu-lated results were in good agreement with the experimental data. Thermal striping phenomena in the tee junction had been numer-ically investigated using LES(Hu and Kazimi,2006)for two differ-ent mixing cases,and the simulated normalized mean and root-mean square(RMS)was consistent with experimental results. LES in a mixing tee were carried out(Galpin and Simoneau, 2011)in order to evaluate the sensitivity of numerical results to the subgrid scale model by comparing the experimental results, and to investigate the possibility of reducing thefluid computa-tional domain at the inlet.Another simulation that mixing of a hot and a coldfluid stream in a vertical tee junction with an upstream elbow main pipe was carried out with LES(Lu et al., 2013).And the numerical results show that the normalized RMS temperature and velocity decrease with the increases of the elbow curvature ratio and dimensionless distance.In the meantime,many scholars have studied how to weaken the thermalfluctuation.Experiments and simulation were con-ducted(Wu et al.,2003)on a tee junction geometry with a sleeve tube in it.Theflow is divided into three types of jets by theflow velocity ratio in main and branch pipes.Through the analysis of flowfield and velocityfield of various jets types,it indicate that the addition of sleeve tube relieve the thermal shock caused by the coldfluid injection rge-eddy simulation have been used(Lu et al.,2010)to evaluate the thermal striping phe-nomena in tee junctions with periodic porous media,the temper-ature and velocityfield inside the tubes are obtained.The research revealed that the addition of a porous reduces the tem-perature and velocityfluctuations in the mixing tube.As mentioned above,experiments and numerical simulations for both tee junction geometry with a sleeve tube in it(Wu et al., 2003)and for a mixing tee with periodic porous media in it(Lu et al.,2010)have been carried out.The results of previous researches provide a good reference value for this work that anal-yses the role of distributor in weakening the thermalfluctuation of internal piping wall,and this structure has not been studied to date,to the best of our knowledge.In this work,mixing processes have been studied by the experiment and numerically predicted with LES.Then the simulated normalized mean and root-mean square(RMS)temperature,velocity vector and temperature con-tour of the two tees are compared.2.Experiment systemThe Experimentflowchart is presented in Fig.1.The experimen-tal system consists of four main components,a cold water supply line,a hot water supply line,a test section,and a data acquisition unit.The experiment device is shown in Fig.2.Experimentfluid was adjusted to the desired temperature by the heater and chiller, and then was pumped to the test section.After mixing thefluid is returned to the heater for recycling,some of the excessfluid is dis-charged through the overflow pipe.During the mixing of thefluids, the temperature of the mixingfluid is collected and recorded by the thermocouple probe installed on the tube wall.The experiment requires two different structures of the test sec-tion,Fig.3is the T-junction section without the branch liquid dis-tributor and Fig.4is that with the branch liquid distributor.The addition of this structure has two main functions:(1)changing the mixing position of hot and coldfluids:moving the mixing zone to the middle of the tube,and away from the main pipe wall;(2) increasing the intensity of mixing process:adding the fence near the outlet of distributor enhanced the mixed disturbance and the exacerbatedfluid mixing of the inner tube.For the convenience of observing and adjusting the mixing process,the test section is a round pipe made of plexiglass,and other pipes are made of steel. Fig.5is the physical model of the branch liquid distributor.The test conditions in the present experiment are shown in Table1.We collected the instantaneous temperature data of every measurement points by the data collector.The distribution of sam-pling points are shown in Fig.6,there are total eight thermocou-ples in the circumferential direction at each plane.In the T-junction section without the branch liquid distributor,the number of the collected plane is6(x/d m=1,2,3,4,6,8).That is to say there are48thermocouples in the structure without distributor.And in the T-junction section with the branch liquid distributor,the num-ber of the collected plane is5(x/d m=2,3,4,6,8),which means there are40thermocouples in the structure that with the distrib-utor.In both structures,the distance between measuring point the thermocouple probe and the inner wall is30mm.Since the collect-ing frequency of the collector is limited,we use1Hz as the collect-ing frequency after theflowfield is stable,and the total number of collection is800s.Table1shows the specific parameters of the test conditions.NomenclatureT time(s)Pr Prandtl numberLs mixing length of subgrid grid(m)T temperature(K)G acceleration of gravity(m/s2)K von Karman numberCs Smagorinsky numberS ij subgrid strain rate tensorM R momentum ratio of main pipe and branch pipe TÃnormalized mean temperaturesTÃrms normalized RMS temperaturesR d diameter ratioR v velocity ratiox,y,z axial coordinate(m)Greek symbolsqfluid density(kg/m3)b coefficient of thermal expansionl viscosity(Pa s)ltturbulent viscosity(Pa s)k thermal conductivity(w/(m k))C P heat capacity(J/(kg°C))K.Gao et al./Annals of Nuclear Energy78(2015)180–187181182K.Gao et al./Annals of Nuclear Energy78(2015)180–1871\4\11-thermometers 2\5\10-pressure gauge 3\9-flow meter 6-c ooler 7-heater8-overflow 12-test sec tion 13-thermoc ouple data c ollec torFig.1.Experimentflow chart.Fig.5.Physical model of the branch liquid distributor(a)the whole graph(b)theprofile map.Fig.2.Experiment device of thermalfluctuation.Fig.3.Schematic diagram of the T-junction section without the branch liquid distributor.Fig.4.Schematic diagram of the T-junction section with the branch liquid distributor.3.Numerical simulationFig.7is the numerical model based on the experimental section of T junction.The size of the model,boundary conditions are con-sistent with the experiment.In which,hot water enters from the left of main pipe,and cold water enters from the branch pipe,finally the mixingfluidflow out of the right of the main pipe.Dur-ing the calculation,the steady results offlowfield and heat transfer are obtained by Reynolds stress model(RSM)firstly,and then set @q@tþ@q u i@x i¼0ð1Þ@q u i@tþ@q u i u j@x j¼À@ p@x iÀq0bðTÀT0Þgþ@@x jlþltÀÁ@ u i@x jþ@ u j@x i!ð2Þ@q T@tþ@q Tu j@x j¼@@x jkc p@T@x jÀq T00u00j!ð3ÞIn these equations,q,b,l,l t,k and c p represent the density,ther-mal expansion coefficient,molecular viscosity,turbulent viscosity, thermal conductivity and specific heat capacity,respectively.The Smagorinsky–Lilly model is used for the turbulent viscosity,which is described as:lt¼q L2s j S jð4Þj S jTable1Experimental conditions.Main pipe Branch pipeFlow rate (m3/h)Temperature(K)Flow rate(m3/h)Temperature(K)Without distributor0.645304.650.270287.65With distributor0.645304.650.266287.65Fig.6.The distribution of sampling points on the planes.Physical model of T-junction(a)without the branch liquid distributor;(b)with the branch liquid distributor.K.Gao et al./Annals of Nuclear Energy78(2015)180–187183ij ¼12@ u i@x jþ@ u j@x ið7Þwhere k is the Von Karman constant of0.42;d is the distance to the closest wall;C s is the Smagorinsky constant of0.1;V is the volume of the computational cell.4.Results and discussionThe normalized mean and root-mean square temperature are used to describe the time-averaged temperature and temperature fluctuation intensity.The normalized temperature is defined as:ü1NX Ni¼1TÃið8ÞN is the total number of sample times.TÃi¼T iÀT cT hÀT cð9Þwhere T i is the transient temperature,T c is the coldfluid inlet tem-perature and T h is hotfluid inlet temperature.The root-mean square(RMS)of the normalized temperature is defined as:TÃrms¼ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi1X Ni¼1TÃiÀTÃ2rð10Þ184K.Gao et al./Annals of Nuclear Energy78(2015)180–187parison of experimental and numerical resultsAs can be seen from the Fig.8,the numerical normalized mean temperature distributions at the plane x/d m=1and the plane x/ d m=2are in good qualitative agreement and in adequate quantita-tive agreement,and most of them are within the experimental deviation of±20%.Meanwhile,the lifting trends of the data are the same.In the direction of180°,the mean temperatures are both minimal.And with the angle decrease to0°,the temperatures are gradually increased.Quantitative differences between the experi-ment and numerical results are that the normalized mean temper-atures given by LES are larger than the experimental data.That is because we did not add insulation unit on tube wall in the exper-iment,leading the transfer of some heat into the air.And in the process of numerical simulation,we ignored the convective heat transfer between the wall and the air.As shown in Fig.9,although the numerical results and experi-mental results have a little difference at the plane x/dm=2around the location of225°and the plane x/dm=2around the location of 0°and315°,all of them are within the error range that can be accepted.Both the simulations and experimental results give a lar-ger mean temperature in the top half of the main pipe than in the bottom half.This verifies the validity of the LES model for predict-ing the mixing of hot and coldfluids in a tee junction.The normalized RMS temperature on the plane x/d m=1and plane x/d m=2are shown in Fig.10,respectively.Similar to the nor-malized mean temperature,the normalized RMS temperature lines agree very well with the experiment ones.Both of the maximum values appear at the bottom half of the pipe.This indicates that the maximum temperaturefluctuations of main pipe appear on the opposite of the branch pipe inlet in this condition.As shown in Fig.11,the numerical results and the experimental results have the same trend and the numerical data are agreed well with the experimental ones.By comparison with Figs.4and5,dif-ferent from the temperaturefluctuations distribution which with-out the branch liquid distributor,there are two peaks of high fluctuation located at the90°and270°directions along with the tube.This is because the direction is that of the outlet of branch liquid distributor,the coldfluidflowing out from the outlet of branch liquid distributor mixes very fast with the hotfluid,leading to dramatic changes of temperature.In summary,the LES simulation results obtained are generally in good qualitative and quantitative agreement with the experi-mental data for the case of T-junction with/without the branch liquid distributor.Based on this,we analyzed the numerical results further.And the results are reported in the section below.4.2.Numerical results with/without branch liquid distributorThe numerical data were sampled on the inner wall in the plane x/ d m=À1,À0.5,0,0.5,1,2,3,4,6and8.At the same time,the numer-ical data were sampled from points every5mm along the intersec-tional lines of planes of y/d m=0and sections of x/d m=À2,À1,0,1,2, 3,4,5and6,to get the points with the maximum normalized rootK.Gao et al./Annals of Nuclear Energy78(2015)180–187185mean square temperatures in the tee and on the top and bottom walls.Here,the temperature and velocityfields were determined with LES simulations for the case of tee junction with/without branch liquid distributor.The temperature contours and velocity vectors for the T-junction are shown in Figs.12and13,respectively.As can be seen in Fig.12,due to the large branch pipeflow velocity,hot and coldfluid mixing zone is mainly located in both upstream and downstream region of the intersections of the main pipe and the branch pipe.The vigorous mixing offluids in the tube leads to thermalfluctuation on the wall.But in the T-junction with the branch liquid distributor,the mixing region moves to the lower half and downstream region of the main pipe.This indicates that the distributor is advantageous to weaken thermalfluctuations on the wall.The same conclusion can be seen from Fig.13,the dis-tributor weaken thermalfluctuations on the wall of downstream region and the top of the main pipe.186K.Gao et al./Annals of Nuclear Energy78(2015)180–187Fig.14compares the normalized mean temperatures between two tees of different structures.As can be seen,wall temperature changes great in the direction of90°,135°,225°and270°in T-junc-tion with the distributor,because the directions are the distributor outlet directions.This indicates that the coldfluid mixes with hot fluid on the wall afterflows out of the distributor.At the same time,the temperature in the direction of180°also changes dra-matically.That is because the coldfluid moves down in the effects of gravity and buoyancy.As shown in Fig.15,for the tee with distributor,the maximum values of normalized RMS temperature are smaller than that of the tee without distributor in most directions.This indicates that the adding of the distributor can relieve thermalfluctuations on the wall to some extent.And for the T-junction with distributor,tem-perature tends to be stable after the plane of x/d m=6,which indi-cates that twofluids have made a full mixing,while for the initial tee,temperature is still in the dramatic change,and this shows that the improved structure can effectively reduce the mixing length.Fig.16shows the maximum normalized instantaneous temper-aturefluctuations in the tee and on the top and bottom walls in the plane y/d m=0.In the tee,the maximum normalized instantaneous temperaturefluctuations of the case without distributor vary from 0.45to0.8,which means that the hot and coldfluids alternate in this location.However,for the case with distributor,the tempera-turefluctuations in the tee as well as on the top and bottom walls are much smaller than those of the case without distributor.That also implies that the distributor can reduce the temperaturefluctu-ation effectively.The normalized instantaneous temperaturefluctuations cannot describe the relationship between power spectrum density(PSD) and frequency of the temperaturefluctuation.PSD against fre-quency is one of the most important parameter for thermal fatigue analysis,which can directly show how PSD is in a certain fre-quency.The PSDs of the points with maximum temperaturefluctu-ation for the cases with and without distributor against frequency were recorded by fast Fourier transform(FFT)and shown in Fig.17. The temperaturefluctuation of the case without distributor has the highest PSD,at the frequency of0.04Hz,whereas the distributor significantly reduces the PSD of the temperaturefluctuations with the frequency from0.01to0.1Hz.In addition,the PSD of temper-aturefluctuations decreases with the frequency increasing.5.ConclusionsAs thermal stratification can result in thermal fatigue in the pip-ing system of a nuclear power plant,safety and integrity evaluation of the piping system has become an important issue.In this work the temperaturefluctuation has been studied by the experiment and numerically predicted by LES for two types of vertical tee junc-tion:one with distributor in the branch pipe and another without. The numerical results of normalized mean and RMS temperatures for the two structures have been found to be in good qualitative and quantitative agreement with the experimental data,which val-idates the use of LES simulations to evaluate convective mixing in such geometries.At the same time,the simulated normalized mean and root-mean square(RMS)temperature,velocity vector and temperature contour of the two tees are compared.The numerical results show that thefluctuations of temperatures of the tee without the distrib-utor are larger than those of the tee with the distributor,which can be explained by the branch liquid distributor enhancing the mix-ing.Although both tees give the same momentum ratio between the main pipeflow and the branch pipeflow,mixing and convec-tive heat transfer are greatly enhanced by the presence of the branch liquid distributor.These all show that the structure is effec-tive for weakening the thermalfluctuation of tee piping wall when hot and coldfluids mix,and it can make the mixing more sufficient.AcknowledgementsThis work was supported by projects of the National Natural Science Foundation of China(No.51276009),Program for New Century Excellent Talents in University(No.NCET-13-0651),and the National Basic Research Program of China(No.2011CB706900). 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听阈正常耳鸣患者听性脑干反应检测的特点及临床意义冯帅;李晓瑜;罗扬拓;李伟光;王智翔;姜学钧【摘要】目的研究听阈正常耳鸣患者听性脑干反应(auditory brainstem response,ABR)、畸变产物耳声发射(dis-tortion product evoked otoacoustic emissions,DPOAE)客观测试结果的特点,探讨ABR检测在耳鸣中的意义.方法对24例听力正常单侧耳鸣为主诉的患者进行纯音听阈、DPOAE和ABR检测,对比耳鸣侧和健侧的听阈、DPOAE各频率检出率及幅值和ABR各波波幅及潜伏期结果,进行统计分析.结果 24例患者双侧纯音听阈全部≤25dB HL,双侧无显著差异;DPOAE各频率检出率及幅值双侧无显著性差异;ABR结果中I波波幅在耳鸣侧较健侧降低(t=-2.681,P<0.05),而III、V波波幅双侧无显著性差异,各波幅比双侧无显著性差异;I、III、V各波潜伏期及波间期双侧无显著性差异.结论 ABR中I波波幅下降代表听阈正常的耳鸣患者可能已经存在耳蜗早期变化,对耳鸣早期临床诊断有重要意义.【期刊名称】《中华耳科学杂志》【年(卷),期】2019(017)002【总页数】5页(P209-213)【关键词】耳鸣;听性脑干反应;听阈正常【作者】冯帅;李晓瑜;罗扬拓;李伟光;王智翔;姜学钧【作者单位】中国医科大学附属第一医院沈阳110000;济宁医学院附属医院济宁272029;中国医科大学附属第一医院沈阳110000;中国医科大学附属第一医院沈阳110000;中国医科大学附属第一医院沈阳110000;中国医科大学附属第一医院沈阳110000【正文语种】中文【中图分类】R764耳鸣是没有外界声源时感知的声音[1]，已经成为影响人们生活质量的主要耳科症状之一，部分耳鸣患者不伴有听阈下降，但耳鸣感受对其睡眠、情绪及精神心理方面造成严重的干扰。

既往因患者主观感受难以建立测试标准，耳鸣的病理过程及临床诊治尚未得到一致性的客观证实。