抗NMDAR受体脑炎课件
抗nmda受体脑炎-PPT课件
延伸知识4 畸胎瘤
畸胎瘤是一种被膜包覆的肿瘤，在肿瘤中可以看到许多 类似于正常器官的组织混杂其间，如毛发、软骨、腺体等 ，这些组织可能源自三个胚层，而在正常的器官中，并不 会有这种情形，故此乃是诊断畸胎瘤的一大依据。畸胎瘤 中发现的各个组织，尽管他们本身看似正常，但经常与周 围的组织无关（比如在软骨的周围形成角质）。 畸胎瘤 属于非精母细胞性生殖细胞肿瘤(nonseminomatous germ cell tumor)。在这个分类下的肿瘤，是由异常增殖 的多功能生殖干细胞及胚胎干细胞发展而来。发生的位置 因人而异；而来自生殖细胞的畸胎瘤，在男性发生于睾丸 ，在女性发生于卵巢，其来源仍不明朗。胚胎细胞源的畸 胎瘤在以往的报告中，曾出现于脑、颅、鼻、颈、舌及舌 下；纵隔、腹膜后及尾椎，但畸胎瘤却很少出现在实质器 官（肝、心等）及管道器官（消化道、膀胱）。
抗NMDA受体脑炎诊断：
对于年轻女性患者, 出现特征性临床表现：不明原因的 精神症状伴痫性发作、不自主运动，记忆丧失、意识 水平降低、运动障碍甚至出现中枢性通气不足, 特别是 伴有卵巢畸胎瘤者, 脑脊液和或血清抗NMDA受体抗 体阳性即可诊断。
1 手术治疗 发现肿瘤并尽早切除是治疗该病的关键。 2 免疫治疗 去除抗原，阻止进一步免疫调节引起的神经损伤。 一线免疫疗法，包括肾上腺皮质激素、丙种球蛋白或血浆 置换； 二线免疫疗法，包括利妥昔单抗和（或）环磷酰胺的单独 使用与联合使用。
头部MRI对边缘叶脑炎有特异性，FLAIR/T2高信号， 累及一侧或双侧海马，没有强化 典型的受累部位为海马、杏仁体，颞叶、基底节、下 丘脑、脑干、额叶及顶叶的病灶少见； 可以出现局灶性脑萎缩、脑膜强化等； 可以表现为正常； PET-CT可以出现脑叶代谢的增高； 80%病人脑脊液为轻到中度淋巴细胞增多； 30%病人脑脊液为轻到中度蛋白增多； 50-60%出现寡克隆带；
抗nmda脑炎ppt课件
预防措施与注意事项
预防措施 提高公众对NMDAR脑炎的认识，了解其早期症状。
保持良好的生活习惯，增强免疫力。
预防措施与注意事项
• 避免接触可能的诱发因素，如某些药物或化学物 质。
预防措施与注意事项
01
注意事项
02
03
04
如有疑似NMDAR脑炎症状， 应及时就医。
在治疗过程中，严格遵循医生 的建议和指导。
抗NMDAR脑炎的症状与表现
记忆障碍
表现为记忆力减退 、健忘等症状。
运动障碍
表现为肢体无力、 肌肉萎缩等症状。
精神异常
表现为情绪波动、 易怒、焦虑、抑郁 等。
言语障碍
表现为言语不清、 表达困难等症状。
其他症状
如睡眠障碍、食欲 不振等。
02
抗NMDAR脑炎的诊断与鉴 别诊断
诊断标准与流程
诊断标准
特点
多发于年轻女性，通常表现为精 神异常、记忆障碍、言语障碍等 症状，病情严重时可出现昏迷甚 至死亡。
抗NMDAR脑炎的发病机制
免疫系统异常
抗NMDAR脑炎的发生是由于人体免 疫系统将NMDAR误认为是外来物质 ，从而产生抗体攻击NMDAR，导致 神经元功能障碍。
遗传因素
研究表明，抗NMDAR脑炎可能与某 些基因突变有关，这些基因可能影响 免疫系统的正常功能。
01 问题1
抗NMDAR脑炎的诊断标准是 什么？
02
解答1
抗NMDAR脑炎的诊断标准主 要包括临床特征、脑影像学检 查结果和实验室检查结果，其 中临床特征包括精神行为异常 、癫痫发作等。
03
问题2
04
抗NMDAR脑炎与其他脑炎有何 不同？
儿童抗NMDAR脑炎
脑电图
更具体的检查 自免脑炎相关抗体
肿瘤筛查 认知评估 PET-CT
Tania C, et al. Neurol Neuroimmunol Neuroinflamm .2020 Mar; 7(2): e663.
双侧枕叶代谢明显减低 伴额叶与基底节代谢升高
诊断
①精神行为异常或者认知障碍
初步检查 血液 尿液
脑脊液 头颅MRI
脑电图
辅助检查
更具体的检查 自免脑炎相关抗体
肿瘤筛查 认知评估 PET-CT
• 抗NMDAR抗体阳性 • 以脑脊液CBA法抗体阳性为准
Tania C, et al. Neurol Neuroimmunol Neuroinflamm .2020 Mar; 7(2): e663.
脑电图
更具体的检查 自免脑炎相关抗体
肿瘤筛查 认知评估 PET-CT
血常规 血沉 C反应蛋白 铁蛋白 病原体筛查 维生素B12 维生素D 乳酸 甲状腺功能 甲状腺自身抗体 自身抗体谱 免疫球蛋白 血清补体
Tania C, et al. Neurol Neuroimmunol Neuroinflamm .2020 Mar; 7(2): e663.
辅助检查
初步检查 血液 尿液
脑脊液 头颅MRI
脑电图
更具体的检查 自免脑炎相关抗体
肿瘤筛查 认知评估 PET-CT
• 超90%患者有弥漫或多灶慢波
• 偶尔可见癫痫波
• 异常δ刷是较特异性的改变， 多见于重症患者
Tania C, et al. Neurol Neuroimmunol Neuroinflamm .2020 Mar; 7(2): e663.
Qianyi H, et al.Brain Research.. 2020 Jan 15;1727:146549.
自身免疫性脑炎诊治护理课件
心理护理
心理护理原则
心理护理注意事项
关注患者的心理状态，提供心理支持 和情绪疏导，促进患者的心理健康。
了解患者的心理需求，尊重患者的隐 私和人格，避免伤害患者的自尊心。
心理护理方法
包括倾听、沟通、鼓励、支持等，以 及必要的心理疏导和干预。
CATALOGUE
预防与预后
预防措施
疫苗接种
鼓励接种流感和肺炎等疫苗，以 降低感染风险，减少自身免疫性
脑炎的发生。
健康生活方式
保持健康的生活方式，包括均衡 饮食、适量运动、规律作息和减 轻压力等，有助于提高免疫力，
预防疾病发生。
早期筛查与诊断
对于有自身免疫性疾病家族史的 人群，应定期进行相关筛查和诊
断，以便早期发现和治疗。
预后情况
恢复期护理 定期复查 长期管理
注意事 项
关注心理健康 避免诱发因素 与医生保持沟通
病因
发病机制
临床表现
症状 病程
CATALOGUE
诊断与鉴别诊断
诊断标准
临床表现
脑脊液检查 神经影像学检查
鉴别诊 断
其他病因引起的脑炎 神经系统其他疾病
辅助检查
CATALOGUE
治疗与护理
药物治疗
01
药物治疗原则
02 常用药物
03 药物治疗注意事项
康复治 疗
康复治疗原则
康复治疗方法
康复治疗注意事项
自身免疫性脑炎诊 治护理课件
目录
• 自身免疫性脑炎概述 • 诊断与鉴别诊断 • 治疗与护理 • 预防与预后
CATALOGUE
自身免疫性脑炎概述
定义与分类
定义
分类
根据病因和发病机制的不同，自身免 疫性脑炎可分为抗NMDA受体脑炎、 抗LGI1受体脑炎、抗GABABR抗体相 关性脑炎等多种类型。
《nmda脑炎》课件
山西医科大学第一医院 神经内科 王洁
入院时情况
❖患者，女性，23岁 ❖主述：发热、头痛9天，精神行为异常4天
入院时情况
现病史
2012年6月20日开始出现发热，体温在37°C左右，伴头痛、头晕、恶心 3天后出现多睡
5天后出现言语混乱，幻觉、妄想 8天后出现癫痫发作 来我院就诊
入院时情况
❖辅助检查 头部MRI改变不显著 脑电图（EEG）常提示广泛不正常 脑脊液呈轻度淋巴细胞性炎症 NMDA受体抗体（+）---血、脑脊液
诊断
脑炎
抗NMDA 自身免疫性脑炎
治疗及效果
北京协和医院
静脉用丙种球蛋白（3个疗程）
激素
抗感染
对症支持
❖意识较前清晰
❖口唇及四肢不自主动作减少
❖体温基本恢复正常
❖脑电图：中度异常
既往史
既往体健 ❖否认高血压、糖尿病史 ❖否认肝炎、结核、伤寒、猩红热等传染病史 ❖否认手术、外伤史 ❖否认食物药物过敏史
入院时情况
神经系统查体
❖一般情况：意识朦胧，表情淡漠，反应迟钝 ❖颅神经：双侧瞳孔等大约3mm，对光反射（+），余查体欠合作 ❖肌容积：未见肌萎缩 ❖肌力、肌张力：正常 ❖共济运动：不配合 ❖步态及姿势：不配合 ❖反射：正常 ❖病理反射：阴性 ❖脑膜刺激征：阴性
辅助检查 （2012.6.29~2012.7.14）
压力增高 淋巴细胞为主
压力：290mmH2O 白细胞：20×10^6/L
淋巴细胞：18×10^6/L 葡萄糖：2.5 mmol/L 氯化物：128 mmol/L 蛋白：406 mg/L
辅助检查 （2012.6.29~2012.7.14）
广泛重度异常
抗NMDAR受体脑炎ppt课件
24
诊断
患儿尤其女性患儿出现急性精神行为异常、语言、睡眠、 运动障碍及频繁的自主神经功能紊乱、通气障碍等时需 要考虑该病。
MRI正常或在海马、额叶等出现短暂异常高信号影。 排除其他感染性、中毒性、代谢性、自身免疫性和其他
类型副肿瘤性边缘叶脑炎。 血清和脑脊液中检测到抗NMDAR抗体可以确诊。 所有患者均应检测可能存在的肿瘤，尤其是卵巢畸胎瘤，
抗NMDAR抗体的检测。
27
鉴别诊断
自身免疫性脑炎 包括其他副肿瘤性边缘性脑炎及神经细胞自身抗体相关
性脑炎，如抗AMPA受体抗体相关性脑炎、抗GABA受体 抗体相关性脑炎，依赖于肿瘤的检出及相应抗体的检测。
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鉴别诊断
自身免疫性疾病相关性脑炎 多与一些自身免疫性抗体有关，如系统性红斑狼疮与抗
18
辅助检查
影像学检查 主要是磁共振成像(MRI)检查。 一半患者无明显变化。 另一半可伴有T2像或FLAIR像以下区域的异常高信号：海
马、额叶、基底节、岛叶、小脑、大脑皮层、脑干，极 少数发生于脊髓。 病变轻微、短暂、轻度强化，且随着疾病进展加重，影 像学检查并无变化或者变化轻微。
19
抗NMDAR抗体脑炎的确切发病机制目前不详。
9
发病机制
抗NMDAR抗体主要在蛛网膜下腔合成 ，能够选择性、 可逆性地减少突触后膜表面的NMDAR密度，且与抗体滴 度呈正相关，不影响突触后其他受体的密度(如AMPA、 GABA等)。
选择性的降低NMDAR的突触电流，在补体不参与的情况 下与NMDAR耦联且导致NMDAR的封闭及内化。
效至少维持治疗1年以上。 目前存在的问题是如何进一步优化GCH治疗，最佳剂量、
最佳疗程以及应用二线免疫治疗时GCH的应用等尚未达成 共识。 长期应用GCH治疗，有可能出现严重不良反应，剂量越 大、时间越长、不良反应也就越大，如高血压、高血糖、 骨质疏松、感染和电解质紊乱等，应密切观察，及时处 理，以免加重病情。
抗nmda受体脑炎-PPT课件
炎症
具有血管系统的活体组织对损伤因子所发生的防御 反应。 在炎症过程中，一方面损伤因子直接和间接造成组织 和细胞的破坏，另一方面通过炎症充血和渗出反应， 以稀释、杀伤和包围损伤因子。同时通过实质和间质 细胞的再生使受损伤的组织得以修复和愈合。因此可 以说炎症是损伤的抗损伤的统一过程。
炎症的原因
5.免疫反应各型变态反应均能造成组织和细胞损伤而导致 炎症： Ⅰ型变态反应； Ⅱ型变态反应； Ⅲ型变态反应； Ⅳ型变态反应； 此外还有某些自身免疫性疾病如甲状腺炎、溃疡性结肠 炎等
延伸知识1 变态反应
Ⅰ型变态反应 即速发型，又称过敏反应，是临床最常见的一种，其特 点是：由IgE介导，肥大细胞和嗜碱粒细胞等效应细胞 以释放生物活性介质的方式参与反应；发生快，消退 亦快；常表现为生理功能紊乱，而无严重的组织损伤 ；有明显的个体差异和遗传倾向。 Ⅱ型变态反应 即细胞毒型，抗体（多属IgG、少数为IgM、IgA）首先 同细胞本身抗原成分或吸附于膜表面成分相结合，然 后通过四种不同的途径杀伤靶细胞
延伸知识3:常见自身免疫性脑炎
抗NMDA受体脑炎
2019年由Vitaliani R首先发现报道的一种免疫性脑炎，但 当时并未发现抗NMDA受体抗体。 2019 年Dalmau等首先报道了在病人的血清及脑脊液中发 现了抗NMDA受体抗体，才将其定义为一种新型脑炎 。 2019年Dalmau J报道了3年内100例病人，说明该病不是 一种罕见疾病。 调查显示抗NMDA受体脑炎占所有脑炎患者的4%，在免 疫相关脑炎中占第2位，仅次于播散性脑脊髓炎。 抗NMDA受体脑炎常发生于伴有卵巢畸胎瘤的年轻女性， 其临床表现包括精神异常、意识障碍、不自主运动和自 主神经功能紊乱、癫痫发作等。
抗NMDAR脑炎 PPT
抗神经抗体
病因
2007年Dalamau在此类患者体内发现了海马和前额叶 神经细胞膜的抗NMDAR抗体，并首次命名了抗 NMDAR脑炎
该病是一种自身抗体特定作用于NMDAR的NRl亚基， 通过免疫介导而产生的炎症
个人史：间断吸烟3年。
一般资料：
婚育史：未婚未育。
家族史：父母体健，1哥体健，否认家族遗传病史。
一般情况： 因患者呈昏迷状，不能主观配合检查，余检查未见明显异常。
神经内科查体： 1.不合作、神志模糊、呈浅昏迷状、高级智能不配合、不能 言语。 2.颅神经：对光反射灵敏、余检查均不能配合， 3.颈抵抗阳性
抗NMDAR脑炎
一般资料：
患者青少年男性，17岁，亚急性起病。 代主诉：抽搐3月，精神行为异常2月，意识障碍1月，加重3天入
院。 现病史：3月前无诱因出现四肢抽搐，无大小便失禁，约4~5分钟
缓解，期间意识不清，后感头痛，未诊治，在外院按癫痫发作治 疗，后出现尿失禁、言语不能、不能行走、反应差等症状。
抗 NMDAR 抗 体介导的免疫 反应类似于 NMDAR 拮 抗 剂 （ PCP ） 引 起的反应
或尖形慢波散发，睡眠期右侧中央、顶、颞区偶见尖波发放 头颅MRI：1，轻微脑白质脱髓鞘，余未见异常。
头颅MRI
TI
大家应该也有点累了，稍作休息
大家有疑问的，可以询问
TI像
侧脑室旁可见轻微脑白质脱髓 鞘
MRI
T2
DWI 像
诊断-定位
定位：症状、查体
★皮层
→精神行为异常 →惊厥及/或CNS局灶体征 →意识障碍 ★辅助检查：EEG、MRI
抗NMDA受体脑炎通用课件
寻找生物标志物
寻找能够用于早期诊断和病情监测 的生物标志物，提高诊断的敏感性 和特异性。
个体化治疗方案
研究不同患者的免疫特点和基因变 异，为个体化治疗方案提供依据， 提高治疗效果。
治疗前景与期待
开发新型免疫疗法
01
期待通过深入研究，发现新的免疫治疗靶点，开发更为高效、
低副作用的新型免疫疗法。
临床症状与诊断
研究者们已经明确了抗NMDA受体脑炎的典型症状，包括认知障碍 、运动障碍、自主神经功能紊乱等，并提出了相应的诊断标准。
治疗策略
当前治疗策略主要包括免疫治疗，如使用糖皮质激素、免疫抑制剂等 ，以及对症治疗和支持治疗。
未来研究方向
深入研究发病机制
进一步揭示抗NMDA受体脑炎的 发病机制，探讨自身免疫反应是 如何产生的，以及抗体与NMDA
康复训练
心理支持
针对患者出现的运动障碍，制定个性化的 康复训练计划，帮助患者恢复运动功能。
对患者进行心理疏导，帮助患者调整心态 ，积极面对疾病，减轻精神压力。
患者的教育与自我管理
疾病知识普及
向患者及家属普及抗NMDA受 体脑炎相关知识，提高患者对
疾病的认知程度。
生活方式调整
建议患者保持良好的作息习惯 ，充足睡眠，合理饮食，适当 锻炼，以增强身体免疫力。
临床表现与诊断方法
临床表现：抗NMDA受体脑炎的症状 多样，包括认知障碍、精神行为异常、 运动障碍、自主神经功能紊乱等。病情
严重者可出现昏迷。
诊断方法：诊断抗NMDA受体脑炎需 要结合临床表现、脑脊液检查（显示抗 体存在）以及脑部影像学检查（如MRI
排除其他病因）。
请注意，以上信息仅为概述，并不能替 代医学诊断和治疗。在实际医疗实践中 ，请咨询专业医生并依据患者的具体情
抗NMDAR脑炎：一种可治疗的严重精神病
Anti-NMDA-receptor encephalitis:A severe,multistage,treatable disorder presenting with psychosisKlaus-Peter Wandinger a ,⁎,Sandra Saschenbrecker a ,Winfried Stoecker a ,Josep Dalmau ba Institute of Experimental Immunology,af filiated to Euroimmun,Seekamp 31,23560Luebeck,GermanybDivision of Neuro-Oncology,Department of Neurology,University of Pennsylvania,3400Spruce Street,Philadelphia,PA 19104,USAa b s t r a c ta r t i c l e i n f o Keywords:Limbic encephalitisAnti-NMDA-receptor encephalitisAnti-glutamate receptor (type NMDA)antibodyAnti-glutamate receptor (type AMPA)antibodyAnti-VGKC antibodyRecombinant immuno fluorescence assayAnti-NMDA-receptor encephalitis is a severe,treatable and potentially reversible disorder presenting with memory de ficits,psychiatric symptoms and seizures.Initially described in young patients with ovarian teratoma,the disease is meanwhile increasingly recognized also in women without tumours,in men and in children.The presence of anti-glutamate receptor (type NMDA)autoantibodies in serum or cerebrospinal fluid is speci fic for this novel and widely underdiagnosed disorder.Early recognition is crucial since prognosis largely depends on adequate immunotherapy and,in paraneoplastic cases,complete tumour removal.Indirect immuno fluorescence using NMDA-type glutamate receptors recombinantly expressed in human cells is a highly competent method for diagnosing anti-NMDA-receptor encephalitis.©2010Elsevier B.V.All rights reserved.1.Limbic encephalitisLimbic encephalitis (LE)is an in flammatory process predominant-ly affecting the medial temporal lobes (hippocampus,amygdalae)and orbitofrontal cortex.Patients typically present with rapidly progres-sive memory de ficits,psychiatric disturbances and seizures.If differential diagnosis excludes an infection with neurotropic viruses such as HSV,an autoimmune paraneoplastic or non-paraneoplastic cause may be assumed (Tuzun and Dalmau,2007).Autoimmune-mediated LE is commonly characterized by MRI,EEG and CSF abnormalities as well as by the presence of circulating antineuronal antibodies (Graus et al.,2010).The latter can be directed against intracellular onconeuronal targets (e.g.Hu,CV2/CRMP5,Ma2,amphiphysin),providing speci fic diagnostic markers for paraneoplas-tic syndromes in almost 100%of cases if present.The associated syndromes are largely mediated by cytotoxic T-cell mechanisms and affected individuals are only poorly responsive to treatment (Dalmau et al.,1992,2004;Dalmau and Rosenfeld,2008;Graus et al.,2001;Gultekin et al.,2000;Honnorat et al.,2009).More recent studies revealed a substantial number of LE patients diagnosed as ‘encephalitis of unknown origin,’all of them lacking evidence of known infectious or autoimmune aetiologies and showing absence of classical paraneoplastic antibodies.However,all these patients were found to have seroreactivity against targets located inthe cell membrane of neurons,as demonstrated by immunostaining of the neuropil of the molecular layer of rat hippocampus (Dalmau et al.,2008;Graus et al.,2008).Among the so far identi fied antigens of anti-neuropil antibodies are voltage-gated potassium channels (VGKC)(Pozo-Rosich et al.,2003;Tuzun and Dalmau,2007),GABA B receptors (Lancaster et al.,2009),AMPA-type glutamate receptors (Lai et al.,2009)as well as NMDA-type glutamate receptors (Dalmau et al.,2007),with a tumour being diagnosed in 20–70%of antibody-positive cases,depending on the target autoantigen.These LE entities appear to be antibody-mediated and represent severe,potentially lethal syndromes (Lai et al.,2009;Tuzun et al.,2009).However,the response of numerous patients to therapeutic intervention substanti-ates the importance of early and reliable diagnosis.2.Anti-NMDA-receptor encephalitis2.1.Identi fication and pathogenicity of anti-glutamate receptor (type NMDA)antibodiesAnti-NMDA(N-methyl-D -aspartate)-receptor encephalitis was firstly described in 2007in a cohort of twelve women presenting with a severe neuropsychiatric syndrome,ovarian teratoma and autoantibodies targeting glutamate receptors (type NMDA)(Dalmau et al.,2007).Localized in post-synaptic membranes,these receptors serve as ligand-gated cation channels with major signi ficance for synaptic transmission and plasticity (Bliss and Collingridge,1993;Lau and Zukin,2007;Yashiro and Philpot,2008).Conventional NMDA-receptors are tetrameric complexes composed of glycine-binding NR1subunits and glutamate-binding NR2(NR2A –NR2D)subunits,which assemble heteromerically to form receptor subtypes with distinctJournal of Neuroimmunology 231(2011)86–91⁎Corresponding author.Tel.:+49451585525321;fax:+494515855591.E-mail address:kp.wandinger@euroimmun.de (K.-P.Wandinger).0165-5728/$–see front matter ©2010Elsevier B.V.All rights reserved.doi:10.1016/j.jneuroim.2010.09.012Contents lists available at ScienceDirectJournal of Neuroimmunologyj o u r n a l h om e p a g e :w w w.e l s ev i e r.c o m /l o c a t e /j ne ur o i msynaptic localization,physiological and pharmacological properties (Fig.1)(Dingledine et al.,1999;Ishii et al.,1993;Lynch et al.,1995;Qiu et al.,2005).Autoantibodies in the serum or cerebrospinal fluid (CSF)of patients with anti-NMDA-receptor encephalitis were shown to bind speci fically to an epitope located in the extracellular domain of the NR1subunits (Dalmau et al.,2008).Immune-mediated pathogenesis of anti-NMDA-receptor enceph-alitis is likely because patients frequently improve with immuno-therapeutic treatment or tumour resection.A pathogenic role was ascribed to the antibodies based on the finding that they cause a reversible reduction in glutamate receptors (type NMDA)on the cell surface of neurons,and due to immunopathological findings (Dalmau et al.,2008;Hughes et al.,2010;Tuzun et al.,2009).Furthermore,a pharmacological blockade of the receptors with NMDA antagonists in animals causes clinical symptoms similar to those of anti-NMDA-receptor encephalitis (Manahan-Vaughan et al.,2008;Stone et al.,2007).2.2.Disease course,treatment,prognosisSince the first patients with anti-NMDA-receptor encephalitis were diagnosed in 2007,the number of documented cases has increased manifold,suggesting that this disorder is not rare.Initially described mainly in young women with ovarian teratoma,diagnosis has been reported in the meantime also for older patients,women without teratoma,men and children (some with teratoma).Noteworthy,in a recent study the diagnosis was made in a panel of patients comprising 40%adolescents and children aged below 18years with the youngest being 23months old (Dalmau et al.,2008;Florance et al.,2009;Schimmel et al.,2009).A stereotypical clinical course occurring in phases is typical for anti-NMDA-receptor encephalitis.A non-speci fic flu-like prodrome (subfebrile temperature,headache,fatigue)is always followed by a psychotic stage with bizarre behaviour,disorientation,confusion,paranoid thoughts,visual or auditory hallucinations and memory de ficits.Because of these features a large proportion of patients end up in psychiatric therapy,and in many cases a drug-induced psychosis is initially diagnosed.In the following phase,decreased consciousness,hypoventilation,lethargy,seizures,autonomous instability and dyskinesias develop.Due to the severity of this disease (coma,status epilepticus,etc.)affected individuals must often undergo treatment in intensive care units for long periods of time (Fig.2)(Dalmau et al.,2007,2008;Ferioli et al.,2010;Gable et al.,2009;Iizuka et al.,2008;Niehusmann et al.,2009;Sansing et al.,2007).About half of patients show irregularities in cerebral MRI.The EEG is pathologically altered in over 90%of persons with the disease.Investigation of CSF reveals mild lymphocytic pleocytosis in more than 90%of cases,intrathecal protein increase in 33%and oligoclonal bands in about 25%.On average,60%of patients have tumours,in which the presence of nervous tissue was proven.The probability of an associated neoplasm is dependent on age and gender.In women,the frequency of predominantly ovarian teratoma amounted to about 62%,while only 22%of men were affected (testicular teratoma and small cell lung cancer)(Dalmau et al.,2007,2008).In young females (b 18years)and children (b 14years),tumours were diagnosed in 31%and 9%,respectively (Florance et al.,2009).Prognosis of patients depends on early diagnosis,implementation of appropriate immunomodulatory therapy and,in paraneoplastic cases,complete tumour removal.Current immunotherapeuticstrategiesFig.1.Glutamate receptors (type NMDA).The receptors are located in the post-synaptic membrane and form heteromeric ligand-gated cation channels composed of NR1and NR2subunits.Anti-glutamate receptor (type NMDA)antibodies are directed against a main epitope located in the extracellular domain of the NR1subunit.Fig.2.Clinical characteristics of patients with anti-NMDA-receptor encephalitis.Dalmau et al.,2008.87K.-P.Wandinger et al./Journal of Neuroimmunology 231(2011)86–91include steroids,plasmapheresis,intravenous immunoglobulins and rituximab.In around 75%of cases a substantial regression of symptoms can be achieved.However,25%of patients suffer from severe neurological de ficits or die.Upon recovery,there is amnesia for the duration of the illness,and there is a risk of relapses of the encephalitic syndrome,the latter in particular when the tumour is removed too late or not at all or if no tumour could be found (Breese et al.,2010;Dalmau et al.,2007,2008;Iizuka et al.,2008;Wong-Kisiel et al.,2010).The gradual process of clinical recovery may take a long time (up to years)but can,in some patients,even be associated with improvement of frontotemporal brain atrophy (Iizuka et al.,2010).Moreover,it has been demonstrated recently that severe anti-NMDA-receptor encephalitis may occur during pregnancy but can have a good outcome for both the mother and the newborn (Kumar et al.,2010).2.3.Differential diagnosisDiagnosis of anti-NMDA-receptor encephalitis is based on the characteristic clinical symptoms and supporting results from brain MRI,EEG and CSF.Infectious encephalitides (especially HSV)and other autoimmune aetiologies (limbic encephalitis with autoantibo-dies against Hu,Ma2,CV2and amphiphysin)must be excluded ascause of the symptoms.Final diagnosis is based on the detection of anti-glutamate receptor (type NMDA)antibodies in the patients'serum or CSF.When a positive serological result is obtained,thorough investigations in order to detect an underlying teratoma need to be undertaken.boratory diagnosis and follow-upSo far,criteria for the presence of anti-glutamate receptor (type NMDA)antibodies included serum or CSF reactivity (i)with the hippocampal tissue on rat brain sections,(ii)cell-surface labelling of cultured hippocampal neurons,and (iii)reactivity with NR1/NR2-transfected human embryonic kidney (HEK)cells (Dalmau et al.,2008).The recombinant cell substrate proved best suitable for highly sensitive and monospeci fic antibody detection.In particular,recom-binant expression of NMDA-type glutamate receptors on the surface of human cells copes well with the challenge of this membrane-bound antigen to require synthesis and presentation in a largely authentic environment for optimal exposition of conformational epitopes.However,this approach has so far been restricted to only a few research laboratories worldwide since it necessitates sophisticated molecular biological and immunological techniques.In addition,the necessity of long-term cell line maintenance and of transfecting cells prior to each testing is labour-intensive,time-consuming and might also affect assay reproducibility.In order to generate transfected cell substrates in a standardized manner,cDNA encoding the glutamate receptor (type NMDA;subunits NR1/NR1and NR1/NR2,respectively)was inserted into eukaryotic expression vectors as described (Dalmau et al.,2008).Plasmids were transfected into HEK293cells seeded on cover glasses using polyethylenimine.48hours after transfection,the cells were fixed with acetone.Coated cover glasses were then cut automatically into millimetre-sized fragments (biochips)and used side by side with non-transfected cells in a mosaic which contained additionally frozen sections of rat hippocampus and cerebellum.Table 1Reactivity of patients and control subjects with glutamate receptor (type NMDA)expressed on the surface of recombinantly transfected HEK293cells.PanelsnNo.of samples reactive with recombinant glutamate receptor (type NMDA)Anti-NMDA-receptor encephalitis 6666Sensitivity66100%Other autoimmune encephalopathies 31–Multiple sclerosis100–Systemic lupus erythemadodes 50–Healthy blood donors 200–Speci ficity 381100%Fig.3.Serum reactivity of a patient with anti-NMDA-receptor encephalitis as detected by indirect immuno fluorescence.(A)Positive reaction with transfected HEK293cells expressing the glutamate receptor (type NMDA;subunit NR1).(B)Non-transfected HEK293cells (negative reaction).(C)Neuropilic staining of the molecular layer on rat hippocampus.(D)Staining of the granular layer on rat cerebellum.88K.-P.Wandinger et al./Journal of Neuroimmunology 231(2011)86–91Expression and reactivity of the recombinantly expressed antigens was con firmed using antibody preparations speci fically reactive with the receptor subunits NR1and NR2,respectively.The potential of the NR1/NR2substrate to detect anti-NR2antibodies is insofar of relevance since these antibodies were suggested to be involved in manifestations of neuropyschiatric lupus (NPSLE)(DeGiorgio et al.,2001).In a clinical study aimed at evaluating the diagnostic potential of the assay,serum or CSF samples from 66clinically characterised patients with anti-NMDA-receptor encephalitis were subjected to antibody determination.Among these patients,39were serologically con firmed cases previously examined at the Center for Paraneoplastic Disorders at the University of Pennsylvania,USA (Dalmau et al.,2008);samples from the remaining 27subjects were sent for diagnostic workup to the authors'laboratory (Luebeck,Germany).In addition,31samples from patients with other autoimmune encephalopathies (including anti-VGKC and anti-AMPA receptor encephalitis),100with multiple sclerosis,50with SLE (including 29patients with NPSLE)as well as 200healthy blood donors were analysed.Slides were incubated with patient samples at a starting dilution of 1:10(serum)or undiluted (CSF).After incubation for 30min at room temperature,the slides were rinsed with a flush of PBS-Tween and incubated in PBS-Tween for at least 5min.Bound IgGwas labeled using Fluorescein-conjugated goat anti-human IgG antibody for 30min and washed as described before.Samples were classi fied as positive or negative based on the intensity of surface immuno fluorescence of transfected cells in direct comparison with non-transfected cells and control samples.As a result,all samples from patients with anti-NMDA-receptor encephalitis were tested positive with the transfected cells (100%sensitivity),while all disease controls and healthy blood donors proved negative (100%speci ficity;Table 1,Fig.3).Thus,the results obtained by this assay showed a 100%correlation with the original protocol for detection of anti-glutamate receptor (type NMDA)antibodies (Dalmau et al.,2008).All anti-glutamate receptor (type NMDA)antibody-positive samples showed staining of the neuropil of the molecular layer on rat hippocampus and staining of the granular layer on rat cerebellum in a highly characteristic,although less speci fic manner (Fig.3).Moreover,the tissue substrates allowed the identi fication of further autoantibodies (i.e.antibodies directed against VGKC and AMPA-type glutamate receptors)in 23%of encephalopathy patients that were tested negative for anti-glutamate receptor (type NMDA)antibodies with the monospeci fic cell substrate (Table 2,Fig.4).In 11patients studied serially,a decrease in serum antibody titers was demonstrated in parallel to immunomodulatory treatment and clinical remission (Fig.5).Consequently,the effectiveness of thera-peutic strategies may be assessed individually by quantitative determination of anti-glutamate receptor (type NMDA)antibodies.3.ConclusionsAnti-NMDA-receptor encephalitis is a novel and considerably underdiagnosed disease that mainly affects young females with ovarian tumours,but also occurs in females without neoplasm,in men and in children.It has to be considered in patients with “encephalitis of unknown origin,”“drug-induced psychosis ”and “new onset epilepsy.”Despite the severity of symptoms,the disorderTable 2Reactivity of patients and control subjects with rat hippocampal and cerebellar tissue sections.PanelsnNo.of samples reactive with HippocampusCerebellum Anti-NMDA-receptor encephalitis 6666(100%)66(100%)Other autoimmune encephalopathies 317(23%)7(23%)Multiple sclerosis100––Systemic lupus erythemadodes 50––Healthy blood donors200––Fig.4.Detection of anti-neuropil antibodies by indirect immuno fluorescence on brain tissue.(A,B)Reactivity of a patient serum containing anti-VGKC antibodies,resulting in (A)neuropilic staining of the outer molecular layer on rat hippocampus and (B)staining of the molecular and granular layer on rat cerebellum.(C,D)Reactivity of a patient serum containing anti-glutamate receptor (type AMPA)antibodies with (C)the hippocampal neuropil and (D)the cerebellar molecular and granular layer as well as the Purkinje cells.89K.-P.Wandinger et al./Journal of Neuroimmunology 231(2011)86–91is treatable and potentially reversible,with the prognosis crucially depending on early recognition,prompt immunomodulatory therapy and,in paraneoplastic cases,complete tumour removal.Patients present with a characteristic clinical picture and frequently show abnormalities on MRI,EEG and in CSF.Final diagnosis is based on the presence of autoantibodies directed against the glutamate receptor (type NMDA,subunit NR1)in the serum or CSF.Standardized,sensitive and speci fic antibody detection as well as monitoring of disease activity is achieved using recombinant receptor-expressing cell substrates provided on biochips for indirect immuno fluorescene.In biochip mosaics,hippocampal and cerebellar tissue substrates enable the determination of further autoantibody entities implicated in the differential diagnosis of autoimmune encephalopathies,such as antibodies against voltage-gated potassium channels,GABA or AMPA receptors and other yet uncharacterized antigens of the hippocampal neuropil.ReferencesBliss,T.V.,Collingridge,G.L.,1993.A synaptic model of memory:long-term potentiationin the hippocampus.Nature 361,31–39.Breese,E.H.,Dalmau,J.,Lennon,V.A.,Apiwattanakul,M.,Sokol,D.K.,2010.Anti-N-methyl-D -aspartate receptor encephalitis:early treatment is bene ficial.Pediatr.Neurol.42,213–214.Dalmau,J.,Rosenfeld,M.R.,2008.Paraneoplastic syndromes of the ncet Neurol.7,327–340.Dalmau,J.,Graus, 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发病机制
抗NMDAR抗体主要在蛛网膜下腔合成 ，能够选择性、可 逆性地减少突触后膜表面的NMDAR密度，且与抗体滴度 呈正相关，不影响突触后其他受体的密度(如AMPA、 GABA等)。 选择性的降低NMDAR的突触电流，在补体不参与的情况 下与NMDAR耦联且导致NMDAR的封闭及内化。 抗体介导的NMDAR的进行性缺失和在抗体滴度降低后其 功能逐渐恢复可能是抗NMDAR抗体脑炎病情加重和恢复 的机制。
临床表现
有些学者将该病程分为：前驱期、精神症状期、无反应期、 运动过多期和恢复期，但总的来说各阶段并没有明显的 界限。
早期可表现为病毒感染症状，随后出现精神症状、继之出 现意识障碍、抽搐、自主神经功能紊乱等，而后逐渐恢 复。
临床表现
自主神经功能紊乱及通气障碍 心律失常、心动过速、心动过缓、甚至需要应用人工起 搏器均有报道。
儿童相对于成年人较少见且症状较轻。
通气障碍及机械通气的病例也相对成年人少。 唾液分泌过多及尿失禁也较常见。
临床表现
睡眠障碍 往往是令人困扰的主要症状，在使用药物治疗的情况下 患者仍可以连续数日不入睡，或者睡眠一觉醒周期紊乱， 夜间彻夜不眠，睡眠的好转往往提示着疾病的好转。 恢复期患者可表现为睡眠过度或者下丘脑功能障碍的其 他症状。
患儿与肿瘤相关性较成年人低，但部分患儿于发病数月 后或者复发时发现肿瘤。
肿瘤中抗原成分与NMDAR具有相似抗原性，攻击肿瘤组 织的抗体可以导致中枢神经系统的炎症反应。
病因-感染
部分流行性甲型脑炎患者血清及脑脊液中可检测到抗 NMDAR抗体，且多见于肌张力障碍、运动障碍的病例。 部分非肿瘤相关性患者血清中可检等 报道1例3岁男性患儿伴有染色体6p21.32微缺 失，故推断该病与人类白细胞抗原(human leukocyte antigen，HLA)分化以及个人的自身免疫病易患性有关。
部分该病患儿血清中抗核抗体及甲状腺过氧化物酶阳性， 提示该病与遗传因素有关。
发病机制
临床表现
语言障碍 主要表现为进行性语言障碍，由最初的语言效仿减少(常 伴随有动作效仿减少)到后来的缄默，患者常常被认为是 失语，却不符合任何一种类型的失语。
临床表现
抽搐 抽搐往往难以诊断及治疗，在同一患者，可表现为类似 癫痫发作的异常重复动作或者亚临床型的癫痫放电，视 频脑电图有助于及时诊断和治疗。 有些发作不伴有脑电图的变化，提示在脑电图证实之前 有些患者存在假性癫痫发作。
个别H1N1感染患者血清中可检测到抗NMDAR抗体。
多数患者早期有受凉或病毒感染样症状，提示可能存在 病毒感染。
病因-硬脑膜损伤
Suzuki等报道1例硬脑膜损伤的50岁男性患者血清和脑脊 液中检测到抗NMDAR抗体。
SuzukiH，KitadaM，Ueno S，eta1．Anti-NMDAR encephalitis prece—ded by dura mater lesions．Neurol Sci，2013，34(6)：1021-1022．
抗NMDAR受体脑炎
基本概念
儿童抗N-甲基-D-天冬氨酸受体抗体脑炎(anti N-methyl-Daspartate receptor encephalitis，NMDAR)是一种抗NMDA 受体抗体相关性自身免疫性脑炎。
在成年人多与卵巢畸胎瘤相关，称为边缘叶脑炎（LE）。
该脑炎是一种涉及大脑海马、杏仁核、岛叶皮质的炎症 性疾病。
患儿年龄越小肿瘤相关性越小，女性多见，约占81％ ， 发病年龄从23个月～18岁不等。
目前国内尚缺乏相关数据。
病因
肿瘤 感染 硬脑膜损伤 遗传因素
病因-肿瘤
肿瘤与年龄、性别、种族具有相关性，女性发病多于男 性，多见于卵巢畸胎瘤患者，也有报道见于睾丸畸胎瘤、 成神经细胞瘤、霍奇金淋巴瘤及小细胞肺癌患者。
患者可出现烦躁与焦虑状态交替。
临床表现
运动障碍 84％的成年人和儿童会出现运动障碍，尤以口面部运动障碍较为显 著，且具有特征性。
表现为：
亲吻、咀嚼、舌前顶、扮鬼脸、鱼或兔子样动作。 可伴有复杂性或刻板性动作：双手划船样动作、弹钢琴样动作、肢 体旋转样动作，伴有或不伴有上肢异常运动，似癫痫发作。 随着意识程度降低，这些动作可持续存在，有时会造成自我伤害 。 重症患者可出现角弓反张及动眼神经危象，常伴随有心动过速和高 血压。
最早于1997年由Nokura等报道1例19岁卵巢畸胎瘤患者患 有边缘性脑炎，肿瘤切除后好转。2007年Dalmau等 首次 在有类似症状患者的血清和脑脊液中检测到抗NMDAR抗 体。2009年Florance等 报道了首例儿童抗NMDAR抗体脑 炎。
发病率
目前抗NMDAR脑炎确切发病率尚不明确，早期认为该病 主要见于年轻女性，且多具有肿瘤相关性，在儿童及男 性患者中亦有报道。
NMDAR是一种配体调控电压依赖性的非选择性阳离子通 道，是由NR1和NR2两种亚基构成的异四聚体，NR1亚基 结合甘氨酸，NR2亚基结合谷氨酸。 该受体重要作用包括调节突触传递、触发突触重塑和参 与学习记忆等。 NMDAR优先表达于前脑，包括前额叶皮层、海马、杏仁 核以及下丘脑 ，主要位于海马与前脑 J，抗体结合于 NMDAR的NR1亚基的细胞外表位 。 抗NMDAR抗体脑炎的确切发病机制目前不详。
临床表现
抗NMDAR脑炎临床主要表现为逐渐发展的多级症状，早 期出现精神改变，继之表现为语言、睡眠、运动障碍及 频繁的自主神经功能紊乱、通气障碍等。
临床表现
精神症状 大多成年患者最初出现精神症状，如焦虑、烦躁、行为 怪异及妄想等，因此多数患者最先就诊于精神科。
在儿童往往表现为易暴发脾气、多动、易怒等，但多较 难发现，而多以一些非精神症状就诊，如单侧肢体肌张 力异常、语言障碍或者癫痫持续状态。 随着疾病发展，在成年人和儿童均可出现对于外界刺激 的眼神交流及反应减少，对于疼痛刺激无反应。