河源市源城区人民医院-冬令瘙痒症-专家在线问诊-京东健康互联网医院

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源城区人民医院是源城区唯一的集医疗、教学、康复和保健功能于一体的综合性医院和直属医疗机构，位于河源市大桥路南26号，地处市中心，为二级甲等医院、爱婴医院、文明单位、巾帼文明示范岗、医保定点单位，承担着全区30多万人口的医疗、保健、科研、教学任务。源城区人民医院由院本部、高新区门诊部、高塘门诊部等组成，医院开放床位100多张。年门诊量6万多人次，年住院病人4000多人次。现有干部职工200余人，其中高级职称7人，中级职称32人。源城区人民医院学科齐全设有：急诊科、门诊部、外科、内科、儿科、老干科、妇产科、中医科、理疗科、五官科、眼科、皮肤科、痔疮科、口腔科、医技科、防保所、体外震波碎石室、高压氧舱治疗室、婚前检查门诊等科室，急诊24小时应诊，危重病人抢救成功率达90%以上。源城区人民医院现有美国GE公司的CT机、500AmX光机、日立彩超诊断仪、东芝B超诊断仪、富士电子胃镜、脑电地形图、经颅多普勒、全自动生化仪、三分类血细胞分析仪、电解质分析仪、尿液分析仪、血凝仪等一大批先进医疗设备。冬季瘙痒症又称皮脂缺乏性湿疹裂隙性湿疹,冬令湿疹。主要见于老年人皮肤,特别是小腿、前臂和手部发生以干燥和发裂为突出的湿疹样皮炎。，皮肤中皮脂缺乏及水分丢失可能是主要的原因而造成皮脂缺乏的因素很多,有皮肤自然干燥伴明显皮脂缺乏、年龄(老年者)、疾病营养不良、皮肤萎缩、硬化、缺汗、内分泌功能减退、环境湿度、角层贮藏水分的完整性破坏等。，皮肤,特别是小腿、前臂和手部，寻找病因,避免诱发因素是防治的关键。避免用搔抓、摩擦及热水烫洗等方法止痒。生活应规律,衣着松软,不要沐浴过勤。避免饮酒、喝浓茶及食用辣椒、胡椒及芥末等辛辣刺激食品。精神紧张及情绪不安的患者应注意休息,适当改变不良的生活环境。，与湿疹、虫咬皮炎、虱病、疥疮、异位性皮炎、神经性皮炎和结节性痒疹等病鉴别。，1.忌吃容易诱发过敏的食物；2.忌吃干燥的食物；3.忌吃刺激性的食物。，相关检查：尿常规皮损皮疹阴道病原体皮肤试验，。

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本人从事妇产科临床工作30多年，擅长于本专业常见病、多发病、少见病、疑难病的诊治。对子宫内膜异位症，月经不调，复发性流产，生殖道炎症等疾病的诊疗，有着丰富的临床经验，并能独立完成本科的相关手术操作，对免疫性不孕，多囊卵巢综合症，排卵障碍及输卵管性，子宫性疾病等引起的不孕不育的诊治有丰富的经验

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内科医师，从事内科工作近20年，临床医学专业，本科学历。曾在广东省第二人民医院进俢学习，拥有扎实的理论基础，并在多年的工作中积累了丰富的临床经验。对内科常见病及多发病的诊断和治疗拥有独特见解，对各种疑难杂症具有较高的诊治能力。尤其擅长糖尿病、高血压，骨质疏松，心脑血管疾病及老年病科的诊断与治疗，目前全科医学科，在工作中认真负责，深受广大患者的认可和信任。

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擅长妇产科常见病，多发病的诊治及妇产科手术等，独立开展剖宫产、宫腔镜、腹腔镜、阴道镜、leep刀等手术；对妇科内分泌如多囊卵巢综合征、闭经、痛经、卵巢早衰、青春期及更年期月经病，子宫脱垂等有丰富的临床治疗经验。

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儿科常见病，多发病，对儿童慢性咳嗽，喘息性疾病有丰富经验。

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一直致力于内科疾病的诊治及研究，特别擅长于呼吸系统疾病的诊治

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2024-10-31 13:17:50

科普文章

冬季皮肤保健之道

又是一年冬来到，很多人在冬天皮肤会出现干燥、脱屑，甚至是顽固性瘙痒或是冻疮等症状，那么在寒冷的冬天，我们该怎样注意皮肤保健呢？

1. 减少清洁，注重保湿

冬季，空气干燥，皮肤容易缺水，新陈代谢较为迟缓，皮脂腺和汗腺分泌也都会减少。这些会导致皮肤表面的皮脂膜屏障非常脆弱，如这时过度清洁加之使用一些碱性的肥皂沐浴乳等，会破坏皮肤的皮脂膜及皮肤屏障功能，导致皮肤干燥瘙痒等发生。

建议：冬季每周洗澡 1-2 次，尽可能减少肥皂沐浴乳的使用次数。如每天洗澡，需注意减少每次洗澡的时间，最好是 5 分钟快速淋浴，避免用力洗搓皮肤。洗澡后需使用较温和的保湿霜涂抹在皮肤上。

2. 冷水洗脸，按摩肌肤

冷水洗脸，美容保健。冬季气温低下，肌肤裸露在寒冷的空气中，容易受到低温的侵害。加之冬季人体血流减缓，血管及循环功能减低，易出现冻疮等情况。

建议：冷水洗脸。洗冷水脸的过程中，冷水的刺激既可改善面部的血液循环，又可改善皮肤组织的营养结构，增强皮肤的弹性，消除或减轻面部皱纹。另外需经常按摩面部、手部皮肤，促进血液循环，增加皮脂分泌，预防或减少冻疮的发生。

3. 合理穿着，保温防寒

冬季穿衣较多，如不注意穿着，衣服与衣服之间摩擦产生静电，静电会刺激皮肤引起皮肤瘙痒。同时需注意皮肤裸露部位的保暖工作，注意保温防寒。

建议：冬季应选择穿着纯棉、真丝之类不易产生静电的材质的内衣、内裤、衬衫等。同时还需要注意衣服搭配，穿了涤纶衬衫就不要再传腈纶毛衣，里面穿了合成纤维的衣服，外面就不宜再传绝缘性的涤纶外衣。外出时需要皮肤保暖，注意戴手套，带口罩帽子，围围巾。注意保护裸露的皮肤。

4. 科学饮食，适当锻炼

当人体缺乏维生素时，皮肤会变得干燥，严重时会出现色素异常。皮肤瘙痒时进食辛辣刺激性食物时易加重瘙痒症状。冬季皮肤角质代谢减缓，油脂分泌减少，皮肤含水量下降。

建议：多喝开水，多吃水果、蔬菜、牛奶、肉皮、银耳、香菇、南瓜等食物。定量吃鸡、鱼、猪肝等含脂类的食物。如皮肤瘙痒，或是皮炎湿疹等易过敏人群建议鱼虾、海鲜、牛羊肉等避免进食。另外，冬季适当锻炼，可以增强血液循环，增加皮肤含水量及皮脂分泌，减少皮肤干燥的发生，促进皮肤健康。

如皮肤已经出现干燥，皮疹及瘙痒等症状时，建议您及时去医院皮肤科就诊。

瘙痒症的病因与治疗进展

北京医院皮肤科葛蒙梁

瘙痒症是指临床上无原发皮肤损害，主要为皮肤瘙痒的一组皮肤病。因引起瘙痒的原因和机制不同，可将瘙痒症分为不同类型，采取不同的治疗措施。

瘙痒是一种能引起搔抓欲望的皮肤粘膜感觉。长期以来，人们对于瘙痒的了解大多来自对疼痛的研究，并认为强刺激引起痛，弱刺激引起痒。然而痒是皮肤黏膜特有的感觉，切除皮肤表皮后痒感消失，而疼痛仍然存在；瘙痒引起搔抓反应，而疼痛则引起肢体退缩反应；椎管内注射止痛的阿片类药物可以诱发瘙痒。这充分表明瘙痒与疼痛是两种绝然不同的感觉。因此，在1990年斯德哥尔摩召开的世界皮肤科大会上，与会专家一致同意将瘙痒从疼痛中独立出来。这使得近十几年来瘙痒的研究取得了飞速发展，并发现了传导痒觉的C神经纤维。

六周以内的瘙痒称急性瘙痒，瘙痒持续六周或六周以上为慢性瘙痒。急性瘙痒是肌体的防御反应，可能对机体有益。而慢性瘙痒则影响睡眠，影响生活与工作，加重心脑血管疾病病情甚至导致自杀。

【发病机制】

【病因】

1.皮肤干燥：皮肤干燥是瘙痒最常见原因之一。

2.药物：许多药物可以引起皮肤瘙痒，而不出现皮疹。

3.内脏疾病：肝脏胆汁淤积、尿毒症、甲状腺功能亢进或减退。

4.感染：艾滋病、寄生虫病等。

5.恶性肿瘤：霍奇金淋巴瘤、非霍奇金淋巴瘤等。

6..精神因素：精神紧张、抑郁，部分抑郁症、精神分裂症、寄生虫恐怖妄想症等患者可有轻中度的瘙痒。

【病理】

外周感觉神经的无髓细纤维（C纤维）的终末在表皮与真皮交界处形成游离神经末梢。这些游离神经末梢就可能就是痒感受器。痒感受器呈点状分布，痒感觉信号沿 C纤维通路至背根神经节进入脊髓，在胶质细胞轴突组成的Lissauers束上升1至6个节段，并在脊髓灰质后角的第二级神经元终止，再由后角细胞发出的轴突经灰质前联合交叉至对侧的腹外侧索，通过脊髓丘脑束上升至丘脑，再由丘脑传递到大脑皮层从而产生痒觉。在痒觉的末梢至中枢的传导过程中，任何伤害和病理该变都有可能产生瘙痒。

瘙痒是一个复杂的感觉过程，其产生、传导以及参与的相关介质不完全明了。瘙痒的主要介质有胺类（如组胺、5-羟色胺等）、脂类（如前列腺素、血小板激活因子）、蛋白质/多肽（如血管舒缓素、细胞因子(IL-2，IL-6，IL-31)、蛋白水解酶(胰蛋白酶、番木瓜酶、黏液酶)、血管舒缓素-激肽(P物质、降钙素相关基因肽、血管活性肠肽)、类鸦片肽(β-内啡肽、亮氨酸脑磷脂、蛋氨酸脑磷脂)等。

根据发生瘙痒的原因不同以及瘙痒的外周和中枢可能机制，Twycross等提出将瘙痒分为以下四个临床类型。

1.皮肤源性瘙痒：是指由于炎症、感染、干燥或其它皮肤损伤导致的皮肤瘙痒，如荨麻疹及蚊虫叮咬引起的反应。

2.神经病理性瘙痒：在痒觉传入途径中任何疾病所引起的瘙痒称为神经性瘙痒。如带状疱疹后遗神经痛。

3.神经源性瘙痒：是指外周神经通路未受累的中枢性瘙痒。例如胆汁淤积引起的瘙痒就是由于阿片样神经肽作用于μ-阿片样受体所致。

4.精神性瘙痒: 由抑郁症、精神分裂症、寄生虫恐怖妄想症等引起的瘙痒。

【诊断】

【病史要点】

1.皮肤瘙痒持续时间较长，一般大于六周。

2.无明显原发皮肤损害，可有抓痕、血痂及苔藓化等表现。

3.部分患者伴有严重肝肾疾病、缺铁性贫血、甲状腺功能亢进或减退、淋巴瘤等。

4.有的为药物引起无皮疹的瘙痒，有明确的用药史及瘙痒与用药的时间关系。

【症状要点】

1.局部或全身皮肤瘙痒。

2.无明显原发皮肤损害，可有抓痕、血痂及苔癣化等表现。

【查体要点】

详细询问病史，尤其是系统疾病史、瘙痒前数天至数月的用药情况。仔细查体，重点注意瘙痒的部位、瘙痒最常发生的时间以及诱发和加重因素。排除引起瘙痒的皮肤病（尤其是疥疮）。

【辅助检查】

【实验室检查】

1.血尿便常规查看有无贫血、外周嗜酸细胞水平、有无尿糖与尿蛋白、大便虫卵等

2.血生化检查查肝肾功能，了解瘙痒与肝肾疾病的相关性。

3.血清铁检测伴有贫血和血清铁低的老年人，可发生瘙痒。

4.甲状腺功能检测甲状腺亢进和甲状腺功能低下可发生瘙痒。

5.肿瘤标志物检测筛查相应的恶性肿瘤。

【影像学检查】

B超、X线、CT及核磁检查肝肾疾病及恶性肿瘤的可能。

【临床类型】

临床上一般将瘙痒症分为全身性瘙痒症和局限性瘙痒症。

1.全身性瘙痒症常由皮肤干燥、药物、胆汁淤积、尿毒症、恶性肿瘤、神经精神因素等引起。

（1）冬季瘙痒症：发生部位多为下肢，尤其是小腿伸侧，还有大腿内侧、背部、腹部甚至全身。在我国北方，在湿度低的冬季、浴后尤其是热水浴、就寝时容易发病或加重。是老年人最常见的瘙痒症。

（2）药物性瘙痒：药物引起的瘙痒在临床上并不少见，约12%的药物性瘙痒不伴有皮疹。瘙痒可以发生在用药的第一天，也可发生在用药数周后。停用致痒药物后，瘙痒可以迅速消退，也可持续数周才消退。

（3）胆汁淤积性瘙痒：虽然肝脏疾病引起的老年瘙痒症不多见，但慢性胆汁淤积的确可引起严重的瘙痒。全身瘙痒可能是原发性胆汁性肝硬化的早期表现。瘙痒也可以是药物所致的肝内胆汁淤积的早期症状。胆汁淤积引起瘙痒的机制还不清楚，早期认为与胆酸盐特别是与胆盐沉积于神经末梢有关。抗组胺H1受体药物治疗慢性胆汁淤积引起的严重瘙痒症无明显效果，提示组胺可能不是胆汁淤积症瘙痒的主要介质。最近研究表明，内源性鸦片肽在胆汁淤积性瘙痒中起重要作用。慢性胆汁淤积患者血浆鸦片样肽水平常常增加，而且鸦片样肽拮抗剂可改善其瘙痒。

（4）尿毒症瘙痒：全身瘙痒是老年尿毒症的一个最常见且难治的皮肤表现。有研究表明尿毒症患者的瘙痒程度与其三年生存率显著相关，瘙痒越严重，死亡率越高。全身瘙痒约占尿毒症的25-30%，局部瘙痒以面部、颈部、胸背部、前臂常见。瘙痒多呈阵发性发作，可自行缓解。往往夏季加重。尿毒症瘙痒发生率在血透前约为36%，血透后可达60-90%。慢性肾衰血透病人瘙痒发生率已由上世纪80年代的60-90%下降到现在的25-30%被认为与血透技术的改进，优质材料应用有关。

尿毒症瘙痒发生机制尚不完全清楚。皮肤干燥可能是尿毒症瘙痒的主要原因之一，见于84.6%尿毒症病人，病人的瘙痒与皮肤干燥的程度相关，应用润肤剂可明显减轻瘙痒。这可能是由于干燥的皮肤导致表皮神经纤维数目以及神经纤维传导活性显著增加。尿毒症血中阿片样物质增加，周围神经病变、皮肤中二价离子浓度增高（Ga++，Mg++，P++）、表皮中VitA水平升高、继发性甲状旁腺功能亢进、血浆组胺5-羟色胺水平升高、以及透析过程中接触致敏物质（包括用于消毒的碘、高锰酸钾、消毒防腐药、环氧树脂、环氧乙烷及甲醛等）有关。

（5）恶性肿瘤性瘙痒何杰金淋巴瘤瘙痒发生率达30%，可以在任何其它临床症状出现前就长期存在。全身性瘙痒也常常发生于蕈样肉芽肿而不伴任何皮肤表现、慢性白血病和真性红细胞增多症的患者。恶性肿瘤瘙痒的发病机制仍不清楚。

（6）水源性瘙痒(Aquagenic pruritus， AP)

AP是一种罕见的瘙痒性疾病,在接触水后发生顽固的皮肤瘙痒，且无任何皮损，患者除有痒感外，还有刺痛或烧灼感。只有温水和热水才能诱发瘙痒，而痒感直接与皮肤的干燥程度成正比，冬季更严重。

AP常发生于真性红细胞增多症的老年病人。水源性瘙痒的机制还不清楚。可能是与水接触后，经皮肤吸收的一种未知物，被吸收的物质或者皮肤内部的结构变化直接和间接的激活交感神经末梢释放乙酰胆碱，后者又引起组胺和其他肥大细胞介质释放。具有瘙痒而无皮肤体征是真性红细胞增多症患者常见的特征。该病的瘙痒实际上开始于热浴后，持续15-60分钟。其瘙痒的原因还不清楚。真性红细胞增多症患者的在接触水之前，血清组胺水平正常，接触水后血清组胺水平升高，提示组胺水平增加可能与真性红细胞增多症的瘙痒发作有关。5-羟色胺拮抗剂和阿斯匹林可抑制真性红细胞增多症的瘙痒，提示5-羟色胺和前列腺素可能是真性红细胞增多症的瘙痒介质。

（7）内分泌疾病的瘙痒：甲状腺功能亢进可伴有瘙痒和荨麻疹样皮疹。而甲状腺功能减退其皮肤干燥也可以出现瘙痒。糖尿病病人常出现局限性瘙痒，如肛门瘙痒、阴部瘙痒，但研究表明糖尿病人瘙痒发生率并不比对照组高。

（8）精神性瘙痒（心源性瘙痒）：因精神因素，如精神紧张、情绪激动、抑郁焦虑、条件反射等引起或加重瘙痒也较常见。一般主诉瘙痒明显，但实际上很少抓痕，也较少影响生活和睡眠。但精神性瘙痒的诊断要在排除其他原因之后才能确立，并且要和神经科医生协作诊治。

2.局限性瘙痒症根据瘙痒部位不同分为以下类型。

（1）肛门瘙痒症：男女均可发病，多伴有外痔、肛裂等影响肛门清洁卫生的疾病。因搔抓使肛门及其周围皮肤表皮剥脱、苔藓化。儿童多见于蛲虫患儿。

（2）阴囊瘙痒症：与局部湿热或精神因素关系密切，多局限于阴囊，也可累及阴茎、会阴。因搔抓使阴囊皮肤增厚、苔藓化。

（3）女阴瘙痒症：瘙痒主要位于大小阴唇，因搔抓使阴唇部皮肤增厚、糜烂。

（4）头部瘙痒症：可单独发生或与全身瘙痒同时发生，可有抓痕、血痂。

（5）小腿瘙痒症：常与皮肤干燥有关，老年人、秋冬季、洗浴后、北方地区容易发病。

【分期】

无

【鉴别诊断】

1.人工荨麻疹：皮肤瘙痒，抓后出现红色条状风团，口服抗组胺药有效。

2.疥疮：夜间剧痒，有传染接触史或家中有类似病人，指间可见丘疹丘疱疹，男性患者阴囊和阴茎可见疥疮结节，丘疹丘疱疹处可查见疥虫。

【治疗】

【治疗原则】

寻找病因对因治疗，联合治疗，保护皮肤屏障功能。目前还没有特异的抗瘙痒药物，也没有某一种药物对所有瘙痒都有效。确定引起瘙痒的潜在疾病并进行治疗非常重要。

【一般治疗】

瘙痒病人应该有充足睡眠。不吃辛辣食物。不用或少用碱性洗涤用品。不过度洗浴。保持室温凉爽、湿度适宜。穿宽松柔软内衣。及时修剪指甲。避免摩擦、挤压、搔抓患处。外用保湿润肤霜保护皮肤屏障功能。

【药物治疗】

1.外用药物治疗

根据不同类型瘙痒可以选择外用保湿润肤霜、抗组胺药物、薄荷、樟脑制剂、他克莫司软膏、辣椒素软膏、中药制剂等。

2.系统治疗

当一般治疗和局部外用治疗效果不佳时，可考虑选择系统治疗。包括抗炎及免疫抑制剂（糖皮质激素、环孢素A、硫唑嘌呤），抗组胺药物，复方甘草苷酸，葡萄糖酸钙，硫代硫酸钠，维生素C，沙利度胺，抗抑郁药（多虑平），抗惊厥药物（加吧喷丁、普瑞巴林），阿片受体拮抗剂，中药等。

3.几种慢性瘙痒治疗方案

（1）冬季瘙痒症：充足睡眠。不吃辛辣食物。不用或少用碱性洗涤用品。不过度洗浴。保持室温凉爽、湿度适宜。穿宽松柔软内衣。每天尤其浴后外用保湿润肤霜。

（2）药物性瘙痒：停用可疑致痒药物，瘙痒可逐渐减轻或消退。瘙痒严重者可10%的葡萄糖酸钙注射液10ml或硫代硫酸钠0.64g加入注射用水10ml，每天一次，静脉注射。口服抗组胺药。

（3）尿毒症性瘙痒：要排除甲状旁腺功能亢进；优化透析方法光疗；外用润肤霜和辣椒碱乳膏；口服加巴喷丁（100-300mg每次透析后）、普瑞巴林（75mg，bid）

（4）肝病/胆汁淤积性瘙痒：考来烯胺口服，4-16g/d；纳曲酮口服，25-50mg/d；帕罗西汀20mg或舍曲林70-100mg/d。

（5）原因不明型瘙痒（PUO）：一般治疗（同前）；润肤剂；局部外用抗炎剂（糖皮质激素、他克莫司）；口服镇静药或抗组胺药物；UVB；米氮平口服，7.5-15mg，睡前服（夜间瘙痒、老年瘙痒）；加巴喷丁口服，1800mg/d或普瑞巴林75-150 mg bid；纳曲酮，50mg/d；要坚持不定期做进一步随访和检查，找出瘙痒原因，对因治疗。

【手术治疗】

肝病/胆汁淤积性瘙痒药物及物理治疗效果不佳时，可以与肝胆病专家合作，考虑外科手术解决胆道梗阻；尿毒症性瘙痒经血液透析仍然剧痒者可考虑肾移植手术。

【其他治疗】

1.光疗

一些非炎症性皮肤瘙痒如尿毒症性瘙痒、真性红细胞增多症瘙痒、原因不明性瘙痒等，光疗有效。常用光疗仪器为窄波UVB（NB-UVB），也可用BB-UVB、UVA1、PUVA 。光疗治疗瘙痒的可能机制可能与抗炎/免疫抑制作用、减少表皮与真皮神经纤维、增加痒阈值等有关。

2.心理治疗

顽固的慢性瘙痒对患者的生活和工作甚至心理会造成严重的影响，医生、家人或朋友从感情上的支持与帮助极为重要。可以帮助患者改变不良习惯（见一般治疗），避免搔抓，阻断因搔抓引起的恶性循环。

身上没有什么表现，就是感觉痒痒痒

今天我们来聊一下瘙痒症，一个没有明显皮疹表现，但自觉瘙痒的皮肤病。

瘙痒症多发于老年人，又称为老年皮肤瘙痒症，多是由于皮肤油脂分泌少，干燥引起的瘙痒。此病好发于秋冬季节。

瘙痒症要排除一些基础疾病，比如糖尿病，尿毒症，胆汁性肝硬化以及生活环境的改变和精神神经因素等。

老年性的瘙痒症以夜间明显(别问为什么，晚上没事注意力全集中在痒这上面)，呈慢性病程，没有原发皮疹，可见抓痕以及色素沉着。

生活上要注意，避免局部刺激，搔抓热水烫洗，酒和辣椒少吃。可加强外用保湿剂。

罹患双癌，依然有办法治疗！“海外二诊”为客户快速链接全球权威专家资源！

病症：胃癌恶性黑色素瘤

患者：李女士

年龄：70岁

罹患癌症，毫无疑问对每个人都是重大打击。而如果一位患者不幸同时罹患两种癌症，我们可以想象得出他的心情会是怎样的沉重。

但时至今日，癌症早已不再是什么“不治之症”，很多良好的治疗方法，可帮助患者迈过重重困境，预后得到极大提升。

不仅如此，在医疗全球化的今天，中国患者也能通过“海外二诊”服务，快速触达到国际权威专家资源，为自己的治疗保驾护航！

今天的案例主人公李女士，正是一位“海外二诊”的受益者。我们来一起看看她的故事。*为保护隐私，文中患者个人信息均已经脱敏处理。

70岁的李女士在去年年底，因脚底疼痛去医院看病，结果发现脚后跟有一个1厘米的黑色肿物。医生判断是冻疮，于是开了点外用药，李女士也就没有再放在心上。

大概4个月后，真正的噩梦降临：李女士通过影像检查，被诊断为胃癌，而且有了淋巴结转移。她还出现了多次呕血，病情非常危急。很快,医生为她实施了全胃切除。令人意想不到的是，几天后通过检查，医生发现李女士后脚跟的肿物竟然也是癌症——恶性黑色素瘤。于是大概2个月后，医生又切除了她的足底肿瘤。

为了降低复发风险，李女士开始了3个周期的化疗联合免疫治疗（替吉奥联合纳武单抗）。

虽然该做的都已做完，但对于李女士来说，恐惧感还远未被消除。因为癌症最令人恐惧的，是其具有“复发转移”的能力。一旦癌症再次袭来，李女士不知道自己该如何应对。另外，两种癌症的治疗以及术后辅助药物治疗，也让李女士遭遇了一些副作用。比如腹泻、味觉障碍还有体重明显下降的问题。这些对于已经70岁的李女士来说，都很影响生活质量，所以迫切需要解决。

在本次的国际专家“海外二诊”服务中，李女士预约的是来自日本某知名综合性医院肿瘤中心的外科部长医生，他的专长领域既包括肿瘤外科，又包括各类癌症药物疗法、姑息治疗，是一位“内外兼修”的权威专家。在充分了解了李女士既往的病情和治疗经过后，医生很快通过远程会诊的方式，为患者详细解答了当前她的所有问题。

1、未来如果转移或复发了该怎么办？

医生：假如您未来不幸出现转移或复发，那么化疗是核心治疗手段。对于单发的孤立转移灶，可以选择手术、放疗来进行局部治疗。

具体化疗方案选择，我按使用的先后顺序列出了3类，当前面的方案失效后，可更换为后面的方案。

一类方案：化疗联合/不联合免疫方案

CAPOX (卡培他滨+奥沙利铂)±O药（即免疫药物纳武单抗）

SOX (替吉奥+奥沙利铂)±O药

FOLFOX (5-FU+奥沙利铂)±O药

二类方案：化疗联合/不联合抗血管药物方案

Taxane (紫杉醇/白蛋白结合型紫杉醇/多西紫杉醇)±雷莫芦单抗

三类方案：化疗方案

曲氟尿苷/盐酸替吡嘧啶

伊立替康

2、N K细胞疗法是否对我有帮助？副作用是否可控？ X医生：目前尚没有证据表明NK细胞疗法对癌症有效，因此不予推荐。

3、口服替吉奥会腹泻，是否需要调整方案？ II/III期胃癌患者术后采用辅助治疗方案，分别为：

替吉奥口服 1 年（口服 4 周，停药 2 周，共 8 个疗程或口服 2 周，停药 1 周，共 16个疗程）

CAPOX (卡培他滨+奥沙利铂) 共半年（每 3 周一次，共 8 个疗程）

SOX (替吉奥+奥沙利铂) 共半年（每 3 周一次，共 8 个疗程）

这三种方案中，替吉奥方案和CAPOX方案等效，但SOX要优于替吉奥。另外，胃癌术后直接使用纳武单抗免疫治疗无意义。

替吉奥确实会出现腹泻等代表性不良反应，患者可以考虑对症治疗，比如调节肠道的药物、止泻药等缓解副作用。如果副作用太严重，那么可以考虑减少药物剂量。

替吉奥的标准用药剂量为120mg，但用量低于80mg无法达到预期效果。如果当前患者用药为100mg，那么为了降低副作用，可以减少剂量到80mg；但如果目前剂量已经是80mg，则无法进一步降低剂量，此时考虑更换方案为CAPOX方案替代。如果不良反应严重到干扰日常生活，则患者可以选择停药，持续观察病情变化。

对于无淋巴结转移的II期B和II其C的患者，可选择使用1年帕博丽珠单抗免疫治疗。

4 、术后患者很瘦，味觉障碍，如何调理改善？通常，手术后患者体重会减轻20%左右。这是患者消化吸收能力低下、促食欲的胃肠激素减少引起的。大约6个月到1年时间，患者可以恢复正常。

味觉障碍可能是抗癌药的副作用引起的，也可能是饮食减少导致缺乏锌等微量元素引起的。建议患者采用少食多餐的方式饮食，每天分5-6次吃饭。在日本，我们有时也会给患者用一些营养补充剂。

另外，也可以考虑采用中草药的对症治疗，改善症状，比如十全大补汤、六君子汤。会诊结束后，李女士的心情得到了极大的平复。她对自己未来要走的路更清晰了，也对日本专家的细致指导和会诊的快速响应非常满意。

高龄+多基础病，该手术还是姑息治疗？日本专家为7旬胃癌患者一锤定音！

中国是消化道癌症发病数量较多的国家，根据国家癌症中心发布的《2022年中国恶性肿瘤疾病负担情况》数据，2022年我国胃癌新发病例约为35.87万例，死亡人数26.04万人。

总体来说，胃癌属于严重威胁我国国民生命健康的蕞常见癌症之一。胃癌如能在早、中期发现，还是有很大机会通过手术实现根治的，患者仍有一定机会得到临床治愈（术后5年不复发即为临床治愈）。

但在胃癌患者中，一部分人会因为【年龄较高】、伴有诸多【基础病】等问题，对手术存有疑虑，担心“下不来手术台”，甚至会放弃手术机会，选择吃药等姑息治疗。这样的选择真的正确吗？现如今的技术能否支持这类老年患者安全手术呢？接下来，我们一起看一个真实案例。

01七旬老人遭遇中期胃癌

一位七十多岁的“老胃病”项女士，因短时间体重骤降（8斤）前往就医。血液检测显示，她有一项指标异常升高。进一步检查发现，她的食道和胃连接的地方（贲门）以及胃的“外墙”（胃壁）都变得异常的厚，而且形状不均匀——这正是胃癌常见的表现。

医生随后通过胃镜检查和病例活检（取一小块组织观察上面的细胞），确诊了老人患有胃癌。由于还没有出现胃以外的远处其他器官的转移，也没有附近淋巴结转移，因此项女士的胃癌分期为中期。虽不是早期，但中期胃癌通常是可以手术的。为项女士提供诊疗的医生也表示，可以通过全胃切除手术实现根治。

但一来项女士已经七十多岁，二来她有20多年的糖尿病（手术伤口会更慢愈合、感染风险高、术后并发症风险高）、右肺还有一枚1.2厘米的肺结节。种种问题让老人和家人们都比较犹豫，担心扛不住治疗，最终“越治越糟”。在这样的背景下，项女士决定找一位足够权威的外科专家，来为自己进行全面评估，看看能不能兼顾好肿瘤根治以及手术的安全性。

不久后，项女士预约了来自日本癌研有明医院消化中心胃外科部长布部创也医生为自己提供指导。

02日本专家咨询内容分享

在充分了解了项女士的病情信息和全部资料后，布部创也医生给出了如下指导建议：首先，患者此前接受的是普通CT而非增强CT，胃镜也没有清晰展示食道上肿瘤具体侵犯的程度，因此很难得出精准的分期判断。

后面患者来癌研有明医院就医时，医疗团队会在治疗前为她做一套非常精细、全面的检查，此后就可以明确肿瘤情况了。届时如果发现患者的分期、肿瘤侵犯的范围确实和现在的结果相同，那么可以通过一个腹腔镜微创手术实现根治，损伤会非常小；如果届时发现肿瘤侵犯食道过多，则需要消化道联合食道外科共同进行胸腔镜手术治疗。

但无论是哪一种情况，患者都可以耐受手术，并且保留一部分胃。癌研有明医院是一家极为擅长肿瘤微创手术的知名癌症专科医院。在胃癌方面，2005年，医院开始导入腹腔镜，2019年又引入了达芬奇手术机器人，患者术后并发症更少了。如今，癌研有明医院98%的外科手术都采用微创。

受益于此，很多在别的医院需要胃全切的胃癌患者，到癌研有明后可以保留一部分胃，还能兼顾临床治愈。这对于术后患者的长期营养摄入和体重维持都很有帮助。布部创也医生所在科室的主要目标之一，正是在做到根治性切除的前提之下，将原本的胃全切术式变为次全胃切除术，尽可能为患者保留一些胃，让他们未来的生活质量得到提升。

那么项女士的糖尿病问题，会不会影响到手术呢？对此，布部创也医生认为完全不必担心，因为对于这类患者，癌研有明医院会进行详细的术前评估，并且有专业团队介入，从生活方式调整和专业治疗入手，帮助患者控制好血糖，让血糖水平达到符合手术的标准，从而降低术后愈合不良风险。

关于肺部的1.2厘米结节，布部医生认为可以暂不处理，无论它到底是良性还是恶性。因为这枚结节属于纯磨玻璃结节，即便是恶性，进展也非常缓慢，并不会快速出现转移扩散。而胃癌根治手术虽然会采用微创方式，但依然会给患者带来一定的负担，如果同时处理肺结节，会导致负担过重、患者难以承受。所以当前蕞好的处理办法，是先集中精力解决胃癌肿瘤，术后安排呼吸科专家为患者进行肺结节诊断，给出随访或手术或根治性放疗的建议。

03项女士术后，是否需要化疗来降低复发风险、争取更大治愈希望？

对此，布部创也医生表示，是否化疗现在还不能判断。因为术后患者能获得蕞精准的分期判断，有可能患者术前被认为是2期，但实际上术后成了1期（无需化疗）；有时也可能患者术前是1期，但术后成了2-3期。假如是2-3期，则患者术后需要坚持1年的辅助化疗，大概可以降低10%的复发风险。

有效减少不良反应，AD新药改良给药方案来了

当地时间10月29日礼来宣布了Ⅲb期临床试验（TRAILBLAZER-ALZ 6）的积极结果，对于早期症状性阿尔茨海默病成人患者，用改良滴定方案接受donanemab治疗的患者在24周主要终点时，伴水肿/积液的淀粉样蛋白相关影像学异常（ARIA-E）有所减少。

donanemab这个新药在今年7月获批于美国，又在之后获日本厚生劳动省、英国药品和医疗产品监管局批准，用于轻度阿尔茨海默病、轻度认知功能障碍的治疗。donanemab在国内2023年取得突破性治疗药物认定，并纳入优先审评审批程序，目前还在审评审批过程中。

CDE官网截图

但在FDA说明书中有黑框警告，大意是应用该药时应注意淀粉样蛋白相关影像学异常（ARIA），表现为ARIA-E和ARIA伴含铁血黄素沉积（ARIA-H），通常发生在治疗早期，且无症状，很少发生严重和危及生命的事件。本次试验的积极结果和这个黑框警告相关。一起来看详情。

FDA说明书截图

给药方式有哪些改变？会不会影响效果？

TRAILBLAZER-ALZ 6是一项多中心随机双盲Ⅲb期研究，主要研究donanemab的不同给药方案对早期症状性AD患者ARIA-E和淀粉样蛋白清除率的影响，这里的早期AD指的是轻度认知障碍（MCI）和轻度痴呆疾病阶段。

给药方式和既往不同，既往标准给药方案是在前三次输注时接受2瓶（700mg）donanemab，然后再接受4瓶（1400mg）；改良滴定方式是患者第一次输注1瓶（350mg），第二次输注2瓶（700mg），第三次输注3瓶（1050mg），此后每次输注4瓶（1400mg）。

研究的主要终点是第24周时患者出现ARIA-E占总参与者的比例，结果显示接受改良滴定方式的患者ARIA-E发生率为14%，而标准给药方案为24%，相对风险降低41%。载脂蛋白E（APOE）是已知的阿尔茨海默病遗传风险因素的携带者，在这些患者中，19%患者在改良滴定时患有ARIA-E，而标准给药方案中为57%，相对风险降低67%。

看到这里你或许也有疑问，虽然ARIA-E的发生风险降低了，但改良滴定方案会不会影响疗效？答案是不会。

与接受标准给药方案的患者相比，改良滴定患者淀粉样斑块和p-tau217减少。改良滴定的患者的淀粉样斑块水平较基线平均降低 67%，而标准给药组患者为69%。

参考来源

1.Modified Titration of Donanemab Demonstrated Reduction of ARIA-E in Early Symptomatic Alzheimer's Disease Patients in Phase Ⅲb study.

2.CED官网.

3.A Study of Different Donanemab (LY3002813) Dosing Regimens in Adults With Early Alzheimer's Disease (TRAILBLAZER-ALZ 6).

重磅！白血病一线新药获FDA加速批准

当地时间10月29日，阿西米尼（asciminib）获美国食品药品管理局（FDA）加速批准^[1] ，用于慢性期新诊断的费城染色体阳性慢性粒细胞白血病（Ph+CML）成年患者。CML是一种骨髓和血细胞癌症，通常由费城染色体的异常染色体引起。在一线治疗中，约1/3的患者会出现下列问题：由于不良反应或者治疗无效而停止酪氨酸激酶抑制剂（TKI）治疗。

为了解决这一问题，需要开发新的药物，asciminib就是解决这一困境的新药。早在2022年8月，加拿大药物和卫生技术局（CADTH）建议^[2] ：“若满足条件，可通过公共药物计划报销asciminib用于治疗费城染色体阳性慢性粒细胞白血病。”

asciminib为何得到FDA的青睐？

本次获批基于一项III期多中心随机研究，研究目的是比较每日80mg的asciminib与TKI治疗的疗效。TKI治疗是接受伊马替尼、尼洛替尼、达沙替尼或博舒替尼任意一种治疗。

共有405名患者被随机分配（1:1）进两组治疗。主要疗效结局指标是48周时的主要分子反应（MMR）率。这个指标是慢性髓性白血病的关键指标，这个比例越高，说明该治疗在基因水平上对疾病的控制效果越好，能够更有效地抑制疾病相关基因的表达，进而有望更好地控制疾病的进展、改善患者的症状和预后。

研究结果显示，48周时MMR率方面，asciminib组中为68%（95% CI: 61, 74)，TKI组为49%（95% CI: 42, 56），二者相差19%。细看具体的TKI，入组伊马替尼和其他TKI药物入组比例为1:1；asciminib组的MMR率为69%（95% CI: 59, 78），而伊马替尼组为40%（95% CI: 31, 50），相差近30%（95% CI: 17, 42）。

这个新药安全吗？每周需要打几次药？

根据FDA数据显示，在新诊断和既往接受过治疗的患者，应用新药最常见的不良反应（≥20%）是肌肉骨骼疼痛、皮疹、疲劳、上呼吸道感染、头痛、腹痛和腹泻。若只看新诊断的患者，最常见的实验室异常（≥40%）是淋巴细胞计数降低、白细胞计数降低、血小板计数降低、中性粒细胞计数降低等。

根据FDA已批准的asciminib说明书，用药期间还需要注意一下事项：

1.骨髓抑制：用药期间可能因出现骨髓抑制，发生血小板减少症、中性粒细胞减少症和贫血。用药应在治疗的前3个月，需要每两周进行一次全血细胞计数，此后每月进行一次检测，从而判断患者有无骨髓抑制症状。根据严重程度，咨询医生是否需要停药。

2.胰腺毒性：患者可能出现血清脂肪酶和淀粉酶无症状升高，每月需评估血清脂肪酶和淀粉酶水平，如果您有胰腺炎，则注意主动告知医生，需要进行频率更高的检测。

3.高血压风险：可能出现3级或4级高血压风险，应注意检测血压。

4.超敏反应：可能出现3级或4级超敏反应，包括皮疹、水肿和支气管痉挛。如果出现这些症状，需及时反馈医生，医生会根据超敏反应的体征和症状，开始适当的治疗。

5.心血管毒性：如果您有心血管病史，需要告知医生；对于3级或更高级别的心血管毒性，医生会考虑暂停用药、减少剂量或永久停药。

6.胚胎/胎儿毒性：若您在怀孕期间用药或在服用药物期间怀孕，可能对孩子有潜在风险。这个新药是口服药，需要根据不同的给药剂量（80mg或40mg）每天/或每两天用药。

近些年来，还有哪些白血病药物获批FDA？

根据FDA肿瘤学/血液系统恶性肿瘤批准通知，白血病相关新药整理如下表。

另外可以看出21年时asciminib已获批白血病治疗，但限定既往接受过两种或更多TKIs治疗，本次获批属于扩大适应证。

参考来源：

1.FDA grants accelerated approval to asciminib for newly diagnosed chronic myeloid leukemia. 2.Asciminib(Scemblix):CADTHReimbursementRecommendation:Indication:ForthetreatmentofadultpatientswithPhiladelphiachromosome-positivechronicmyeloidleukemia(Ph+CML)inchronicphase(CP)previouslytreatedwith2ormoretyrosinekinaseinhibitors.Ottawa(ON):CanadianAgencyforDrugsandTechnologiesinHealth;2022Aug.PMID:38713779. 3.AStudyofOralAsciminibVersusOtherTKIsinAdultPatientsWithNewlyDiagnosedPh+CML-CP. 4.Product information：SCEMBLIX-asciminibtablet,filmcoated.UpdatedAugust7,2024. 5.Oncology(Cancer)/HematologicMalignanciesApprovalNotifications.

病例31-2023：一名79岁男性，身体不自主运动，一过性反应迟钝

以下内容来源于新英格兰医学杂志。

Presentation of Case

Dr. Carrie Chui (Neurology): A 79-year-old man was admitted to this hospital because of involuntary movements on the left side and transient unresponsiveness.

The patient had been in his usual state of health until 9 months before admission, when involuntary movements of the left shoulder and left side of the face developed. The movements were described by the patient as twitching, were not associated with a change in the level of consciousness, and resolved after 1 to 2 minutes. During the next 6 months, the patient had similar episodes approximately once per month, but the episodes increased in duration, lasting 5 to 6 minutes.

Three months before admission, the episodes of involuntary movements increased in frequency, and the patient was evaluated by his primary care physician. The physical examination was normal. Results of kidney-function tests were normal, as were blood levels of glucose and electrolytes, except for the sodium level, which was 129 mmol per liter (reference range, 135 to 145). There was a history of inappropriate antidiuretic hormone secretion, and the sodium level was similar to levels obtained during the past 4 years. Magnetic resonance imaging (MRI) of the head (Figure 1A), performed before and after the administration of intravenous contrast material, revealed a focus of enhancement in the right middle frontal gyrus that was thought to be a small vascular anomaly. Electroencephalography (EEG), performed with the patient in awake and drowsy states, revealed rare, brief, focal slowing in the left temporal lobe during drowsiness; no epileptiform abnormalities were present.

Figure 1

MRI of the Head and CT Angiogram of the Head and Neck.

Two months before admission, the patient was evaluated in the epilepsy clinic affiliated with this hospital. He reported that the episodes of involuntary movements had increased in both frequency and duration, occurring once or twice per day and lasting approximately 10 minutes. Episodes began with tingling and numbness in the left leg that prompted the patient to voluntarily stomp the left foot to relieve the uncomfortable sensation. Then, the patient had involuntary movements that he described as an uncontrollable invisible force moving the left leg and arm, with hyperextension of the arm backward and pronation of the wrist. There was associated numbness in the distal portions of the left third, fourth, and fifth fingers and involuntary movement of the left cheek. No prodromal symptoms occurred. The patient had awareness during the episodes, and after the episodes, he felt fatigued but had a normal level of consciousness, without confusion. The examination in the epilepsy clinic was normal. A diagnosis of seizure disorder was considered, and treatment with levetiracetam was started.

Three weeks before admission, the patient was again evaluated in the epilepsy clinic. He reported that the episodes of involuntary movements still occurred on a daily basis but had decreased in duration and involved only the left leg, without abnormal movements of the arm or face. Dizziness, headache, and weakness had developed and were attributed to the use of levetiracetam. The patient’s family had recorded a video of one of the episodes of involuntary movements. After reviewing the video, the patient’s neurologist thought that the episodes were less likely to be caused by seizures and more consistent with choreoathetoid movements. Cross-tapering of medications — with the simultaneous administration of levetiracetam in decreasing doses and clobazam in increasing doses — was initiated, and the patient was referred to the movement disorders clinic affiliated with this hospital.

On the morning of admission, an episode of involuntary movements of the left leg and left shoulder occurred and persisted for 1 hour. Several hours after the symptoms abated, the patient’s wife found the patient to be unresponsive; he was sitting in a chair. Emergency medical services were called, and when they arrived, the patient was responsive. The fingerstick blood glucose level was 180 mg per deciliter (10.0 mmol per liter) and the blood pressure 110/80 mm Hg. The patient was transported to the emergency department of this hospital for further evaluation.

In the emergency department, the patient reported dysuria and increased urinary frequency. The patient’s daughter noted that he had been more anxious during the past 3 years and occasionally had trouble with memory. Other medical history included Barrett’s esophagus, benign prostatic hypertrophy, chronic hepatitis B virus infection, eczema, gastroesophageal reflux disease, hypertension, nonischemic cardiomyopathy, and osteoporosis. There was no history of head trauma or extended loss of consciousness. Medications included aspirin, atorvastatin, doxazosin, finasteride, omeprazole, metoprolol, sacubitril, and valsartan. There were no known drug allergies. The patient was a lifelong nonsmoker and drank alcohol rarely; he did not use illicit drugs. His mother had had gastric cancer, and his sister had had esophageal cancer; there was no family history of seizures.

On examination, the temporal temperature was 36.8°C, the blood pressure 152/97 mm Hg, the pulse 65 beats per minute, the respiratory rate 16 breaths per minute, and the oxygen saturation 96% while the patient was breathing ambient air. The body-mass index (the weight in kilograms divided by the square of the height in meters) was 21.7. The blood pressure decreased to 130/63 mm Hg with standing. The patient was alert and interactive. The lower jaw was held to the left, but the nasolabial folds and smile were symmetric with activation. There were nonrhythmic, nonstereotyped, writhing movements of the left arm. Tone was normal, and strength was assessed as 5 out of 5 in the arms and legs. Results of liver-function and kidney-function tests were normal, as were blood levels of glucose and electrolytes, except for the sodium level, which was 125 mmol per liter. The lactate level was 2.1 mmol per liter (19 mg per deciliter; reference range, 0.5 to 2.0 mmol per liter [5 to 18 mg per deciliter]). The urinalysis was normal. Intravenous fluids were administered. Imaging studies were obtained.

Dr. Rajiv Gupta: Computed tomographic (CT) angiography of the head and neck (Figure 1B) revealed extensively calcified plaque with severe stenosis of the distal right common carotid artery (CCA), extending into the proximal right internal carotid artery (ICA), as well as stenosis of the right and left paraclinoid ICAs and the left vertebral artery at its origin. There was no vascular abnormality on the CT angiogram that corresponded to the abnormality in the right middle frontal gyrus seen on the previous MRI.

Dr. Chui: The patient was admitted to the hospital. On the second hospital day, the sodium level had increased to 130 mmol per liter, and the lactate level was normal. Additional imaging studies were obtained.

Dr. Gupta: MRI of the head showed no evidence of acute infarction. The focus of enhancement in the right frontal lobe that had been noted previously was not seen on the current MRI.

Dr. Chui: Blood levels of thyrotropin, cobalamin, and glycated hemoglobin and results of coagulation tests were normal. Screening tests for Lyme disease, tuberculosis, and syphilis were negative, as were tests for antibodies to cardiolipin and β₂-glycoprotein. A test for antinuclear antibodies was positive, at a titer of 1:160 in a homogeneous pattern. During a physical therapy session, the patient had abnormal movements of the left leg, left arm, and left side of the face. The abnormal movements diminished when the patient used distraction techniques, such as thigh tapping, finger snapping, and walking while holding a glass of water.

The transient unresponsiveness that led to the patient’s admission was attributed to a combination of sedation from clobazam and hypovolemia. Treatment with clobazam was stopped, and hydration was encouraged. A diagnosis of functional neurologic disorder was considered; outpatient physical therapy with continued use of distraction techniques was recommended. The patient was discharged home on the third hospital day.

Episodes of involuntary movements continued to occur on a daily basis at home. Two weeks after discharge, when the patient was doing exercises while sitting in a chair and having a conversation with his wife, he suddenly stopped talking. She found him slumped in the chair with his eyes closed, no longer exercising. When she asked him questions, he repeatedly said “yes.” Emergency medical services were called, and when they arrived, the patient was alert, diaphoretic, and nonverbal. He had a facial droop on the left side and a right gaze preference. The fingerstick blood glucose level was 130 mg per deciliter (7.2 mmol per liter) and the blood pressure 120/60 mm Hg. The patient was transported to the emergency department of this hospital for further evaluation.

In the emergency department, the temporal temperature was 36.6°C, the blood pressure 143/63 mm Hg, the pulse 66 beats per minute, the respiratory rate 18 breaths per minute, and the oxygen saturation 98% while the patient was breathing ambient air. He was alert and interactive. There was a facial droop on the left side. There was no effort against gravity in the left arm. The patient was able to lift the left leg off the bed for 1 to 2 seconds. He had a right gaze deviation that could not be overcome and mild dysarthria. The remainder of the examination was normal. A diagnosis of stroke was considered, and emergency CT angiography was performed.

Dr. Gupta: CT angiography showed no evidence of acute territorial infarction and no changes in cerebrovascular disease.

Dr. Chui: On repeat physical examination performed after CT angiography, the gaze deviation and dysarthria had resolved, and strength was normal. Mild facial paralysis was present.

A diagnosis was made.

Differential Diagnosis

Dr. Albert Y. Hung: This 79-year-old man initially presented with involuntary movements of the left shoulder and face without associated loss of consciousness. Diagnosis of an unusual movement disorder, especially one that is present episodically, can be challenging. Videos brought in by the patient can be very useful.¹ Most movement disorders result from abnormal functioning of extrapyramidal circuits involving the basal ganglia, rather than a specific neuroanatomical lesion, and the first step toward diagnosis is to identify the type of abnormal movements.²

Four salient aspects of this patient’s involuntary movements can help in characterizing the movement disorder before generating a differential diagnosis. First, the movements were paroxysmal, lasting for short periods of time with resolution between episodes. Second, the movements were nonstereotyped, appearing randomly and variably. Third, the movements were restricted to the left side of his body throughout the course, localizing the disease process to the right cerebral hemisphere. Finally, the symptoms were progressive, increasing in both duration and frequency.

Movement Disorders

This patient had abnormal involuntary movements, symptoms indicative of a hyperkinetic movement disorder. Tremor, the most common hyperkinetic disorder, is unlikely because the patient did not have rhythmic movements. Dystonia is also unlikely, because he did not have sustained muscle contractions that were causing twisting or abnormal postures of the legs, arms, head, neck, or face. Although the patient initially described the movements as twitching, his later descriptions are not suggestive of myoclonus or tics, which manifest as sudden, rapid, recurrent movements.

This patient’s neurologist described the involuntary movements as “choreoathetoid” after reviewing a video of an episode. Chorea, athetosis, and ballism make up a spectrum of involuntary movements that often occur in combination. Chorea refers to involuntary movements that are “dancelike” — irregular, random, unintended, and flowing from one body part to another. When these movements are slow and writhing (with a lower amplitude) and involve the distal limbs, the term athetosis is used. The presence of both chorea and athetosis in the same patient is referred to as choreoathetosis. When the movements are fast and flinging (with a higher amplitude) and involve the proximal limbs, the term ballism is used. Although the description of this patient’s movements was not clearly suggestive of ballism, hemichorea and hemiballismus often occur together.

The term dyskinesia can refer to any abnormal movements and is often used to describe hyperkinetic disorders that are induced by specific drugs, such as tardive dyskinesia induced by dopamine antagonists or dyskinesia induced by levodopa in patients with Parkinson’s disease. Often, dyskinesia manifests as chorea or choreoathetoid movements, but chorea and dyskinesia are not synonymous. This patient appears to have involuntary dyskinesia with choreoathetosis as the primary phenomenology. Before constructing a differential diagnosis for dyskinesia in this patient, I will consider two conditions that mimic dyskinesia: seizures and functional movement disorder.

Seizures

Various movement disorders may be mistaken for seizures, although these movement disorders are not associated with EEG abnormalities during the episode. Patients with some forms of epilepsy may present with abnormal movements without other features that are typically associated with seizures, such as aura, change in responsiveness, incontinence, or a postictal state.^3,4 Seizures were initially suspected in this patient, and he was referred to the epilepsy clinic. Recurrent focal seizures were probably suspected because of the transient nature of the episodes. Initial MRI had shown a small abnormality in the right middle frontal gyrus, but this finding was not seen on follow-up imaging, which makes it unlikely to be related to the overall presentation. Baseline EEG had shown only brief left temporal slowing, without epileptiform abnormalities. The EEG was an interictal study, so the findings do not rule out seizures. However, the slowing was ipsilateral to the abnormal movements, so it is unlikely to be related to the episodes. In addition, the patient’s involuntary movements were nonstereotyped and nonrhythmic, which makes his presentation unlikely to be due to a seizure disorder.

Functional Movement Disorder

Because this patient’s movements diminished with the use of distraction techniques, a diagnosis of functional movement disorder was considered. Most cases of functional movement disorder begin abruptly after a trigger, such as a mild physical injury or illness; a psychological stressor can be present but is not required for diagnosis. Symptoms are typically most severe around the time of onset and may wax and wane over time. Although distractibility is a finding associated with functional disorders, abnormal movements that occur with nonfunctional syndromes can sometimes be suppressed by action or incorporated into voluntary movements in a manner that may appear distractible. Several clinical features in this patient make a diagnosis of functional disorder unlikely. Functional movement disorder is more common in women than in men, and the average age at onset is 40 years.⁵ In addition, tremor is the most common clinical phenotype seen in patients with functional movement disorder; chorea or choreoathetosis, which was seen in this patient, is very unusual in patients with functional movement disorder. Overall, functional movement disorder is unlikely to explain this patient’s presentation.

Dyskinesia

Primary paroxysmal dyskinesia refers to a group of heterogeneous syndromes characterized by recurrent involuntary movements that occur episodically and abruptly, without loss of consciousness.⁶ These disorders usually begin in childhood or young adulthood. Both the age of this patient and the described phenomenology make a diagnosis of primary paroxysmal dyskinesia unlikely.

The differential diagnosis in this case is therefore focused on causes of secondary dyskinesia, of which there are many.⁷ MRI ruled out the presence of a mass lesion suggestive of cancer. The patient had no history of acute illness suggestive of a viral or other infectious encephalitis, and there was no history of trauma or exposure to drugs or other toxins. Although his daughter mentioned trouble with memory, there was no compelling history suggestive of a neurodegenerative disease.

A common metabolic cause of secondary dyskinesia is diabetic striatopathy, a syndrome involving the acute-to-subacute onset of chorea and ballism in the context of hyperglycemia.⁸ This syndrome can occur as the initial manifestation of type 2 diabetes mellitus or as a complication of poorly controlled diabetes. Diabetic striatopathy is more likely to develop in women than in men, and the average age at onset is 70 years. Most patients present with hemichorea and hemiballismus, rather than bilateral symptoms. CT shows hyperdensity, and T1-weighted MRI shows hyperintensity, in the contralateral basal ganglia. However, this patient had no history of diabetes and had a normal blood glycated hemoglobin level, features that rule out a diagnosis of diabetic striatopathy.

Choreiform movements can also be a manifestation of autoimmune conditions.⁹ This patient’s initial presentation with unilateral shoulder and face movements would have suggested the possibility of faciobrachial dystonic seizures associated with anti–leucine-rich, glioma-inactivated 1 (anti-LGI1) encephalitis.¹⁰ This condition is often associated with hyponatremia, which was present in this patient. However, as the case evolved, leg involvement and sensory changes developed that would be atypical for anti-LGI1 encephalitis.

One key clue in this case is that the patient did not have an isolated movement disorder. In addition to motor symptoms, he had a variety of sensory symptoms involving both the left arm and the left leg. His first hospital admission was precipitated by an episode of unresponsiveness. The clinical event that led to his second presentation to the emergency department was distinctly different: an acute onset of speech difficulty accompanied by left hemiparesis and right gaze deviation that was worrisome for an acute right middle cerebral artery (MCA) syndrome. The symptoms resolved without intervention, which indicates that he may have had an acute transient ischemic attack (TIA). The most relevant imaging finding was severe cerebrovascular disease, including severe stenosis of the distal right CCA and proximal right ICA. Could this patient’s movement disorder be explained by a vascular lesion?

Limb-Shaking TIAs

Limb-shaking TIAs were first described by C. Miller Fisher in 1962.¹¹ In most case reports, these episodes are associated with high-grade stenosis of the ICA, which was seen in this patient.^12,13 The mechanism is thought to be cerebral hypoperfusion, and changes in posture or head position that decrease cerebral blood flow can precipitate these episodes. In this patient, the first episode of unresponsiveness that led to hospital admission occurred when he was sitting. He then had an acute episode involving right gaze preference that was provoked by exercise and was very suggestive of a TIA in the right MCA territory. These findings are highly suggestive of a diagnosis of limb-shaking TIAs, and I would refer this patient for emergency carotid endarterectomy.

Clinical Impression and Initial Management

Dr. Scott B. Silverman: When I evaluated this patient, his transient right gaze preference and left hemiparesis were consistent with a right MCA syndrome due to a TIA from symptomatic severe stenosis of the right ICA. The mechanism of this event was either artery-to-artery embolism or hypoperfusion. His previous, recurrent episodes of transient choreoathetosis on the left side that had occurred mainly while he was sitting, standing, or exercising were consistent with limb-shaking TIAs from hypoperfusion or low flow.

The pathogenesis of a low-flow state related to severe carotid stenosis resulting in limb-shaking TIAs is described in a small case series.¹⁴ In six out of eight patients, the transient, stereotyped, involuntary movements were eliminated with carotid artery revascularization. Positional cerebral ischemia in patients without orthostatic hypotension has been described.¹⁵

Treatment with atorvastatin was continued, the dose of aspirin was increased to 325 mg per day, and an intravenous heparin infusion was started. The strategy of permissive hypertension was used, with high blood pressure allowed to a maximum systolic blood pressure of 180 mm Hg. The patient was admitted to the stroke service, and carotid artery duplex ultrasonography was performed.

Dr. Gupta: Doppler ultrasonography of the carotid arteries (Figure 2) revealed markedly elevated Doppler flow velocities within the proximal right ICA. There was a parvus et tardus waveform in the distal right ICA, a finding indicative of low flow related to the more proximal high-grade stenosis. The Doppler waveform contours had poststenotic turbulence.

Figure 2

Doppler Ultrasound Image.

Dr. Silverman: The vascular surgery service was consulted, and the patient underwent right carotid endarterectomy.

Clinical Diagnosis

Limb-shaking transient ischemic attacks.

Dr. Albert Y. Hung’s Diagnosis

Limb-shaking transient ischemic attacks due to severe carotid stenosis, with secondary paroxysmal dyskinesia.

Pathological Discussion

Dr. Caroline F. Hilburn: The endarterectomy specimen included the carotid bifurcation and was notable for firm arterial walls, a finding consistent with calcification. On gross examination (Figure 3A), a large plaque was centered at the carotid bifurcation and protruded into the lumen, resulting in a maximal luminal stenosis of 80%. The plaque had an irregular and focally friable surface. On microscopic examination (Figure 3B), the plaque was characterized by extensive calcification. Some regions of the plaque had a smooth, healed fibrous cap, whereas other regions had an irregular surface suggestive of ulceration, which indicated potential sites of plaque rupture. Multiple smaller calcified plaques were present, affecting both branches of the artery.

Figure 3

Endarterectomy Specimen.

Pathological Diagnosis

Complex atherosclerotic plaque with portions of attached media.

Additional Management

Dr. Silverman: After the procedure, the patient had an uneventful recovery and was discharged home on the fifth hospital day. He was seen 1 month after discharge in the stroke prevention clinic. There had been no further episodes of involuntary movements or choreoathetosis and no stroke or TIA. The patient continues to take aspirin, atorvastatin, and antihypertensive medications.

Final Diagnosis

Limb-shaking transient ischemic attacks.

病例28-2024：一名75岁女性，患有水肿、关节炎和蛋白尿

以下内容来源于新英格兰医学杂志。

Presentation of Case

Dr. Christine M. Parsons (Medicine): A 75-year-old woman was evaluated at this hospital because of arthritis, abdominal pain, edema, malaise, and fever.

Three weeks before the current admission, the patient noticed waxing and waning “throbbing” pain in the right upper abdomen, which she rated at 9 (on a scale of 0 to 10, with 10 indicating the most severe pain) at its maximal intensity. The pain was associated with nausea and fever with a temperature of up to 39.0°C. Pain worsened after food consumption and was relieved with acetaminophen. During the 3 weeks before the current admission, edema developed in both legs; it had started at the ankles and gradually progressed upward to the hips. When the edema began to affect her ambulation, she presented to the emergency department of this hospital.

A review of systems that was obtained from the patient and her family was notable for intermittent fever, abdominal bloating, anorexia, and fatigue that had progressed during the previous 3 weeks. The patient reported new orthopnea and nonproductive cough. Approximately 4 weeks earlier, she had had diarrhea for several days. During the 6 weeks before the current admission, the patient had lost 9 kg unintentionally; she also had had pain in the wrists and hands, 3 days of burning and dryness of the eyes, and diffuse myalgias. She had not had night sweats, dry mouth, jaw claudication, vision changes, urinary symptoms, or oral, nasal, or genital ulcers.

The patient’s medical history was notable for multiple myeloma (for which treatment with thalidomide and melphalan had been initiated 2 years earlier and was stopped approximately 1 year before the current admission); hypothyroidism; chikungunya virus infection (diagnosed 7 years earlier); seropositive erosive rheumatoid arthritis affecting the hands, wrists, elbows, and shoulders (diagnosed 3 years earlier); vitiligo; and osteoarthritis of the right hip, for which she had undergone arthroplasty. Evidence of gastritis was reportedly seen on endoscopy that had been performed 6 months earlier. Medications included daily treatment with levothyroxine and acetaminophen and pipazethate hydrochloride as needed for cough. The patient consumed chamomile and horsetail herbal teas. She had no known allergies to medications, but she had been advised not to take nonsteroidal antiinflammatory drugs after her diagnosis of multiple myeloma.

Approximately 5 months before the current admission, the patient had emigrated from Central America. She lived with her daughter and grandchildren in an urban area of New England. She had previously worked in health care. She had no history of alcohol, tobacco, or other substance use. There was no family history of cancer or autoimmune, renal, gastrointestinal, pulmonary, or cardiac disease.

On examination, the temporal temperature was 37.1°C, the heart rate 106 beats per minute, the blood pressure 152/67 mm Hg, and the oxygen saturation 100% while the patient was breathing ambient air. She had a frail appearance and bitemporal cachexia. The weight was 41 kg and the body-mass index (the weight in kilograms divided by the square of the height in meters) 15.2. Her dentition was poor; most of the teeth were missing, caries were present in the remaining teeth, and the mucous membranes were dry. She had abdominal tenderness on the right side and mild abdominal distention, without organomegaly or guarding. Bilateral axillary lymphadenopathy was palpable. Infrequent inspiratory wheezing was noted.

The patient had swan-neck deformity, boutonnière deformity, ulnar deviation, and distal hyperextensibility of the thumbs (Fig. 1). Subcutaneous nodules were observed on the proximal interphalangeal joints of the second and third fingers of the right hand and on the proximal interphalangeal joint of the fourth finger of the left hand. Synovial thickening of the metacarpophalangeal joints of the second fingers was noted. There was mild swelling and tenderness of the wrists. She had pain with flexion of the shoulders and right hip, and there was subtle swelling of the shoulders and right knee. Pitting edema (3+) and vitiligo were noted on the legs. No sclerodactyly, digital pitting, telangiectasias, appreciable calcinosis, nodules, nail changes (including pitting), or tophi were present. The remainder of the examination was normal.

Figure 1

Photograph of the Hands.

The blood levels of glucose, alanine aminotransferase, aspartate aminotransferase, bilirubin, globulin, lactate, lipase, magnesium, and phosphorus were normal, as were the prothrombin time and international normalized ratio; other laboratory test results are shown in Table 1. Urinalysis showed 3+ protein and 3+ blood, and microscopic examination of the sediment revealed 5 to 10 red cells per high-power field and granular casts. Urine and blood were obtained for culture. An electrocardiogram met (at a borderline level) the voltage criteria for left ventricular hypertrophy.

Table 1

Laboratory Data.

Dr. Rene Balza Romero: Computed tomography (CT) of the chest, abdomen, and pelvis, performed after the intravenous administration of contrast material, revealed scattered subcentimeter pulmonary nodules (including clusters in the right middle lobe and patchy and ground-glass opacities in the left upper lobe), trace pleural effusion in the left lung, coronary and valvular calcifications, and trace pericardial effusion, ascites, and anasarca. The scans also showed slight enlargement of the axillary lymph nodes (up to 11 mm in the short axis) bilaterally and a chronic-appearing compression fracture involving the T12 vertebral body.

Dr. Parsons: Morphine and lactated Ringer’s solution were administered intravenously. On the second day in the emergency department (also referred to as hospital day 2), the blood levels of haptoglobin, folate, and vitamin B₁₂ were normal; other laboratory test results are shown in Table 1. A rapid antigen test for malaria was positive. Wright–Giemsa staining of thick and thin peripheral-blood smears was negative for parasites; the smears also showed Döhle bodies and basophilic stippling. Antigliadin antibodies and anti–tissue transglutaminase antibodies were not detected. Tests for hepatitis A IgG and hepatitis C antibodies were positive. Tests for hepatitis B core and surface antibodies were negative. A test for human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) was negative.

Findings on abdominal ultrasound imaging performed on the second day (Fig. 2A and 2B) were notable for a small volume of ascites and kidneys with echogenic parenchyma. Ultrasonography of the legs showed no deep venous thrombosis. An echocardiogram showed normal ventricular size and function, aortic sclerosis with mild aortic insufficiency, moderate tricuspid regurgitation, a right ventricular systolic pressure of 39 mm Hg, and a small circumferential pericardial effusion. Intravenous hydromorphone was administered, and the patient was admitted to the hospital.

Figure 2

Imaging Studies of the Abdomen and Hands.

On the third day (also referred to as hospital day 3), nucleic acid testing for cytomegalovirus, Epstein–Barr virus, and hepatitis C virus was negative, and a stool antigen test for Helicobacter pylori was negative. An interferon-γ release assay for Mycobacterium tuberculosis was also negative. Oral acetaminophen and ivermectin and intravenous hydromorphone and furosemide were administered.

Dr. Balza Romero: Radiographs of the hands (Fig. 2C through 2F) showed joint-space narrowing of both radiocarpal joints and proximal interphalangeal erosions involving both hands. Radiographs of the shoulders showed arthritis of the glenohumeral joint and alignment suggestive of a tear of the right rotator cuff. A radiograph of the pelvis showed diffuse joint-space narrowing of the left hip, without osteophytosis, and an intact right hip prosthesis.

Dr. Parsons: Diagnostic tests were performed, and management decisions were made.

Differential Diagnosis

Dr. Beth L. Jonas: This patient is a 75-year-old woman who recently emigrated from Central America. She presented to this hospital with a multisystem disease involving the respiratory, gastrointestinal, renal, and musculoskeletal systems. Her medical history is notable for seropositive erosive rheumatoid arthritis and multiple myeloma, which had been treated with melphalan and thalidomide. Relevant clinical features on presentation include unintended weight loss and cachexia, axillary lymphadenopathy, serositis, cytopenia in two cell lines, hypocomplementemia, and elevated serum free kappa and lambda light-chain levels (with a normal free light-chain ratio) with no monoclonal spike. The white-cell count was elevated, but she had no eosinophilia. CT images of the chest showed scattered subcentimeter pulmonary nodules. With respect to the patient’s anemia, no schistocytes were present, the haptoglobin level was normal, and the iron studies were unremarkable. These findings, in combination with the elevated ferritin level, indicate anemia of chronic inflammation. The renal findings are most salient in the context of the patient’s hypertension, anasarca, elevated cystatin C level, active urinary sediment with proteinuria in the nephrotic range, and small, echogenic kidneys on ultrasonography.

In constructing a differential diagnosis, I will consider medication use, cancer, infectious disease, and autoimmune disease. Medications can be eliminated as the cause of this patient’s illness, since she was taking only levothyroxine, acetaminophen, and the antitussive agent pipazethate.

Cancer

The patient has a history of multiple myeloma, which may manifest with a multisystem disease involving the kidneys, but serum protein electrophoresis showed no monoclonal protein. Given the presence of nephrotic syndrome in the context of multiple myeloma, systemic immunoglobulin light-chain amyloidosis would be highest on the differential diagnosis with respect to cancer; however, the patient’s normal light-chain ratio makes this diagnosis unlikely. The development of myeloid neoplasms, such as acute myeloid leukemia, myelodysplastic syndromes, and myeloproliferative neoplasms, is important to consider in the context of previous treatment with alkylating agents,¹ which this patient had received. However, the peripheral-blood smear showed no findings that would indicate a hematologic cancer, and such a diagnosis would not explain the patient’s acute kidney injury with nephrotic-range proteinuria.

Infectious Disease

Several features of this patient’s case warrant special consideration, including her history of immunosuppression due to rheumatoid arthritis and to previously treated myeloma, along with the fact that she had emigrated from Central America, where certain infections may be prevalent. Infection with hepatitis A virus, hepatitis B virus, hepatitis C virus, HIV-1 and HIV-2, cytomegalovirus, Epstein–Barr virus, H. pylori, and M. tuberculosis can be ruled out on the basis of laboratory studies. A rapid antigen test for plasmodium species was reported to be positive, but this assay has a known cross-reactivity with rheumatoid factor.² Moreover, the thick and thin peripheral-blood smears were negative. Thus, malaria would be an unlikely diagnosis.

The patient has a history of infection with chikungunya virus, an arbovirus transmitted by a mosquito vector that has been responsible for large epidemics in the Americas since 2013.³ Acute symptoms include fever, rash, arthralgia, and myalgia. The development of a chronic arthritis that may meet the classification criteria for rheumatoid arthritis, as defined by the American College of Rheumatology and the European Alliance of Associations for Rheumatology, has been reported in up to 60% of patients infected with chikungunya virus.^4,5 In the context of this discussion, I considered whether chikungunya virus infection could be the cause of this patient’s symptoms, since this infection occurred before the diagnosis of rheumatoid arthritis. However, the degree of erosion and loss of joint space that was visible on radiographs would be most unusual for arthritis associated with chikungunya virus infection and would not explain the renal manifestations.

Strongyloidiasis is a helminth infection (caused by Strongyloides stercoralis) that is widespread in developing countries. Infection usually occurs through contact with soil, and most affected persons are asymptomatic. However, in immunosuppressed persons, strongyloides hyperinfection syndrome or a disseminated infection can develop as a consequence of accelerated autoinfection.⁶ The clinical presentation of strongyloides hyperinfection syndrome can include gastrointestinal symptoms (diarrhea, constipation, nausea, or vomiting), respiratory symptoms (cough, dyspnea, or wheezing), and rash due to migration of larvae through the subcutaneous tissues. Of note, only a minority of patients present with eosinophilia. Several case reports describe the development of nephrotic-range proteinuria, thrombotic microangiopathy, and IgA vasculitis in patients with strongyloides hyperinfection syndrome.^7-9 However, strongyloidiasis would not explain this patient’s cytopenias and hypocomplementemia.

Autoimmune Disease

The patient has a 3-year history of rheumatoid arthritis, although her clinical features of swan-neck deformity, boutonnière deformity, and joint instability suggest a longer duration of disease. We do not know whether she had received previous treatment with disease-modifying antirheumatic drugs or biologic agents, but the possible use of such treatments may be a consideration with respect to her progression of disease and overall degree of immunosuppression. The blood levels of rheumatoid factor and anti–cyclic citrullinated peptide antibodies were elevated, and radiographs of the hands showed erosive disease, although there was a relative paucity of metacarpophalangeal findings. A review of systems was negative for dry mouth, but her physical examination showed poor dentition and dry mouth — findings that make secondary Sjögren’s syndrome a consideration.

Renal disease can occur in patients with Sjögren’s syndrome. The two most typical presentations are tubulointerstitial nephritis and, less commonly, nephritic syndrome (membranoproliferative glomerulonephritis related to cryoglobulinemia). Tubulointerstitial nephritis may manifest with renal disease of varying severity, usually with a bland urinary sediment and often with abnormalities of tubular function such as distal renal tubular acidosis. Membranoproliferative glomerulonephritis caused by cryoglobulinemia is the most common glomerular disease associated with Sjögren’s syndrome. Although nephrotic-range proteinuria can occur with Sjögren’s syndrome, it is relatively uncommon.¹⁰ Renal disease is uncommon in patients with rheumatoid arthritis and is usually related to coexisting cardiovascular conditions. Medications used in the treatment of autoimmune disease — mainly nonsteroidal antiinflammatory drugs — may be associated with renal disease, but I would not expect the presence of an active urinary sediment, as was seen in this patient.

Amyloid A (AA) amyloidosis, a condition that is rare in the era of aggressive management of rheumatoid arthritis, has been described in patients with severe, long-standing seropositive erosive rheumatoid arthritis. Serum amyloid A (SAA) is a protein that is produced in the liver in response to chronic inflammation associated with interleukin-1, interleukin-6, and tumor necrosis factor α (TNF-α) in the context of chronic infections, autoimmune disease (classically rheumatoid arthritis), autoinflammatory disease, and cancers including renal cell carcinoma and non-Hodgkin’s lymphoma.¹¹ Signs and symptoms of AA amyloidosis are related to the deposition of the protein in organs, and patients often present with multisystem signs and symptoms. The kidney is the organ that is most often affected, but deposition can occur in the heart, gastrointestinal tract, nervous system, musculoskeletal system, and lungs. Proteinuria is the first clinical manifestation in almost 95% of patients with AA amyloidosis, and 50% of affected patients present with nephrotic syndrome.¹² The urinary sediment is generally bland, and complement levels in the blood are normal. AA amyloidosis remains on the differential diagnosis in this patient, but it would not completely explain her renal disease.

Hypocomplementemia

The key to this case is understanding the cause of this patient’s hypocomplementemia. Hypocomplementemia can be due to decreased complement production in the context of liver disease, congenital complement deficiency, or increased complement consumption resulting from activation of the innate immune system. This patient has no history of chronic liver disease and her laboratory test results indicated good hepatic synthetic function. Classical complement deficiency (including C4 deficiency) that begins early in life is associated with autoimmune disease, and early C3 deficiency is characterized by severe pyogenic infections. It would be unusual for a patient of this age to be deficient in both C3 and C4 without earlier clinical consequences. I therefore concluded that the hypocomplementemia in this case was related to complement consumption.

Rheumatic diseases that may be associated with prominent renal manifestations include antineutrophil cytoplasmic antibody–associated vasculitis, systemic sclerosis with renal crisis, cryoglobulinemic vasculitis, antiglomerular basement membrane disease, and systemic lupus erythematosus (SLE). Of those conditions, SLE would be the most likely to be manifested by an active urinary sediment and nephrotic-range proteinuria with consumption of both C3 and C4 in the context of fever, thrombocytopenia, and serositis. This patient’s fever, thrombocytopenia, and serositis also fit with this diagnosis.¹³

Because the patient has long-standing seropositive erosive rheumatoid arthritis, a diagnosis of AA amyloidosis is strongly suspected. Moreover, given the presence of thrombocytopenia, hypocomplementemia, and an active urinary sediment, I would recommend a kidney biopsy to evaluate for lupus nephritis and AA amyloidosis.

Dr. Beth L. Jonas’s Diagnosis

Overlap syndrome of rheumatoid arthritis and systemic lupus erythematosus with amyloid A amyloidosis.

Pathological Discussion

Dr. Claire Trivin-Avillach: Testing for autoimmune antibodies was performed. A test for antinuclear antibodies was positive at a titer of 1:5120 with a homogeneous pattern, and a test for anti–double-stranded DNA antibodies was positive at a titer of 1:2560.

The diagnostic procedure in this case was a core-needle biopsy of the kidney. Examination of the specimen with light microscopy revealed 20 glomeruli, 45% of which were globally sclerosed, along with fibrosis involving approximately 60% of the interstitium and tubular atrophy. Diffusely enlarged glomeruli with thickened capillary walls and an expanded mesangium were weakly positive on periodic acid–Schiff staining; the glomeruli stained pale blue on Masson’s trichrome staining. Congo red staining revealed metachromatic salmon-colored deposition involving the glomeruli, the blood-vessel walls, and the interstitium, which was associated with apple-green birefringence when viewed under polarized light (Fig. 3A). In addition, mesangial and endocapillary hypercellularity was identified in approximately 30% of the nonsclerosed glomeruli and was associated with karyorrhexis (Fig. 3B). One cellular crescent was also detected. These features are characteristic of active proliferative glomerulonephritis.

Figure 3

Biopsy Specimen of the Kidney.

Immunofluorescence microscopy revealed prominent granular staining for IgG (4+), IgM (4+), C3 (3+), C1q (3+), IgA (1+), kappa (3+), and lambda (3+) along the glomerular basement membranes and within the mesangium, as well as focal granular deposits of IgG and C3 along the tubular basement membrane (Fig. 3C and 3D). Additional immunofluorescence studies showed strong positivity (4+) for SAA within the glomeruli, the blood-vessel walls, and the interstitium (Fig. 3E), whereas staining for beta₂-microglobulin, transthyretin, and apolipoprotein A1 was faint.

Electron microscopy revealed the presence of subendothelial and mesangial electron-dense deposits (with no substructure identified) adjacent to randomly arranged fibrils (measuring 8.2 to 10.6 nm in diameter) within the glomerular basement membranes and the mesangium (Fig. 3F). Glomerular endothelial cells appeared reactive and contained tubuloreticular inclusions, features that were suggestive of interferon-mediated activation.

The findings on Congo red staining were characteristic of amyloidosis with typical birefringent material. The strong positivity of SAA within the deposits as compared with the faint staining of other reactants identified the type of amyloid as SAA, which is consistent with the patient’s history of rheumatoid arthritis. The biopsy also showed an immune complex–mediated proliferative glomerulonephritis with a “full house” pattern (defined as positivity for the three immunoglobulin classes IgG, IgM, and IgA and the two complement components C3 and C1q, in reference to the “full house” hand in a poker game). Immune complex–mediated proliferative glomerulonephritis has been reported in patients with rheumatoid arthritis who were receiving anti–TNF-α therapy,¹⁴ which was not the case in this patient. The positive test for hepatitis C antibodies prompted consideration of hepatitis C–related membranoproliferative glomerulonephritis. However, taken together, the negative nucleic acid test for hepatitis C virus, the full house pattern on immunofluorescence, the tubular basement membrane deposits, and the positive test for anti–double-stranded DNA antibodies favor a diagnosis of lupus nephritis of at least class III (defined as focal proliferative glomerulonephritis), according to the criteria of the International Society of Nephrology and the Renal Pathology Society, superimposed on AA amyloidosis.

Pathological Diagnosis

Proliferative lupus nephritis of International Society of Nephrology and Renal Pathology Society class III, superimposed on amyloid A amyloidosis.

Discussion of Management

Dr. Pui W. Cheung: On the basis of the finding of echogenic kidneys on ultrasonography and the findings of extensive interstitial fibrosis and tubular atrophy on kidney biopsy, we know that this patient has advanced chronic kidney disease that is unlikely to be reversible. The patient is also noted to have a markedly lower glomerular filtration rate (GFR) than that predicted by the blood creatinine level owing to the presence of cachexia, and this is substantiated by the cystatin C–based GFR and a 24-hour creatinine clearance of 22 ml per minute per 1.73 m² of body-surface area. The typical induction therapy for stage III or IV lupus nephritis consists of high-dose glucocorticoids and either mycophenolate mofetil or cyclophosphamide. Other reasonable alternatives for initial therapy include mycophenolate mofetil in combination with either a calcineurin inhibitor or belimumab, or cyclophosphamide in combination with belimumab.¹⁵ Hydroxychloroquine is also recommended as part of the therapy, since it has shown benefits in improving the response to treatment and reducing disease flare.¹⁶ Mycophenolate mofetil and cyclophosphamide have similar efficacy with respect to clinical response, which includes a reduction in proteinuria and either an improvement in renal function or stabilization of renal function; the risks of infections and adverse events associated with these medications are also similar.^17,18

Given the severity of the lupus nephritis with overlying AA amyloidosis from active rheumatoid arthritis, the treatment options proposed were high-dose glucocorticoids and rituximab with either mycophenolate mofetil or cyclophosphamide.¹⁹ After discussions with multidisciplinary consultants from rheumatology, infectious diseases, and nephrology, lingering concerns were raised about infection and patient frailty; ultimately, the decision was made to initiate high-dose glucocorticoid therapy in combination with mycophenolate mofetil, rituximab, and hydroxychloroquine.

The patient’s mycophenolate mofetil dose regimen was inconsistent owing to gastrointestinal side effects, and the treatment was eventually withheld because of pancytopenia and fever. Unfortunately, her kidney function worsened, and renal replacement therapy was initiated within 3 weeks after the start of the induction therapy. The cause of her renal failure was thought to be disease progression, compounded by hemodynamically mediated tubular injury in the context of infection. While the administration of mycophenolate mofetil was stopped, treatment with rituximab was continued, with slow tapering of the glucocorticoid dose at the direction of the rheumatologist. She remained dependent on dialysis and was deemed to have end-stage kidney disease after 3 months of dialysis.

Dr. Lisa G. Criscione-Schreiber: The patient has SLE with nephritis, seropositive erosive rheumatoid arthritis, and systemic AA amyloidosis. AA amyloidosis is rare owing to the availability of effective therapies for rheumatoid arthritis and is managed through aggressive treatment of inflammation due to rheumatoid arthritis. Reports addressing the management of rheumatoid arthritis–induced AA amyloidosis generally cite stability of end-organ damage caused by AA amyloid as evidence of effective management of the condition (through treatment of the inflammation of rheumatoid arthritis). Methotrexate, the cornerstone of treatment for rheumatoid arthritis, is contraindicated in this case owing to the presence of kidney disease. The alkylating agent cyclophosphamide has been reported to be effective for the treatment of AA amyloidosis from rheumatoid arthritis²⁰ and has known efficacy in patients with lupus nephritis, both of which make it a viable treatment option. Rituximab has also been reported to be effective for managing rheumatoid arthritis–induced AA amyloidosis,²¹ is approved for the treatment of rheumatoid arthritis, and is used for manifestations of SLE, including thrombocytopenia and nephritis. Although anti–TNF-α agents, abatacept, and Janus kinase inhibitors are reported to be effective for the treatment of AA amyloidosis in patients with rheumatoid arthritis,²² recent publications have coalesced on the ability of anti–interleukin-6 therapy to block interleukin-6–induced hepatic production of SAA.^23-25

The overlap of seropositive erosive rheumatoid arthritis and SLE (sometimes termed “rhupus”) usually resembles rheumatoid arthritis more than SLE; manifestations include thrombocytosis, leukocytosis, an elevated erythrocyte sedimentation rate, an elevated blood level of C-reactive protein, and the presence of marginal erosions on radiographs.²⁶ In contrast, SLE without seropositive erosive rheumatoid arthritis characteristically manifests with thrombocytopenia, leukopenia, and an elevated erythrocyte sedimentation rate but usually not an elevated C-reactive protein level; in addition, nonerosive inflammatory arthritis with reversible deformities is commonly observed. This patient had a mixed laboratory profile, on the basis of the results of antinuclear antibody and anti–double-stranded DNA antibody tests. The challenge of treating an overlap syndrome of rheumatoid arthritis and SLE is choosing disease-modifying antirheumatic drugs that are effective and safe in both conditions. This patient’s most severe disease manifestation is lupus nephritis; therefore, the treatment regimen must target nephritis along with the AA amyloidosis and inflammatory arthritis.

As noted earlier, current induction therapy for lupus nephritis includes either mycophenolate mofetil or cyclophosphamide. Mycophenolate mofetil may provide inadequate treatment of the rheumatoid arthritis and amyloidosis, whereas cyclophosphamide would treat the lupus nephritis, has possible efficacy for treatment of the AA amyloidosis, and would treat the rheumatoid arthritis. Rituximab could be added to cyclophosphamide or mycophenolate mofetil to treat the rheumatoid arthritis and resultant AA amyloidosis and could also possibly help treat the lupus nephritis. The addition of anti–interleukin-6 therapy to mycophenolate mofetil or cyclophosphamide is an intriguing option that may effectively treat the rheumatoid arthritis and subsequent AA amyloidosis. The addition of belimumab to mycophenolate mofetil or cyclophosphamide has been reported to improve renal response in patients with lupus nephritis,²⁷ as has the addition of voclosporin to mycophenolate mofetil.²⁸ However, belimumab is ineffective for the treatment of rheumatoid arthritis, and voclosporin has not been studied in patients with rheumatoid arthritis or in those with a GFR of 45 milliliters per minute or less. The high-dose glucocorticoids that are used in induction therapy for lupus nephritis will effectively manage this patient’s inflammatory arthritis and probably also the subsequent AA amyloidosis. Finally, it is important that every patient with lupus nephritis receive hydroxychloroquine, which improves the treatment response to induction therapy.²⁹

Follow-up

Dr. Parsons: The patient’s hospital course was further complicated by suspected immune-mediated thrombocytopenia, for which she received intravenous immune globulin. Her pancytopenia and arthritis ultimately abated. Unfortunately, she did not have renal recovery and continues to receive hemodialysis. After a prolonged hospital course, she was discharged home.

Final Diagnosis

Overlap syndrome of rheumatoid arthritis and systemic lupus erythematosus complicated by proliferative lupus nephritis, superimposed on amyloid A amyloidosis.