哈尔滨医科大学附属第一医院-早熟性巨睾症-专家在线问诊-京东健康互联网医院

简介:

哈尔滨医科大学附属第一医院始建于1949年，是黑龙江省最大的医疗中心，集医疗、教学、科研和预防保健等为一体的大型综合性临床医学院。1992年被评为“三级甲等”医院，2010年再次以全省最高分通过三级甲等医院复审。1998年获全国“百佳医院”称号，2014年荣获“全国百姓放心示范医院”称号，2016年荣获“全国百姓放心示范百佳医院”称号。医院承担着副省级以上领导、党和国家领导人及重要外宾的保健、诊疗任务，医疗辐射周边国家和地区。医院现有员工5669人，卫生技术人员5195人，副高职以上专业人员1755人。设南岗院区和群力院区两个院区，54个临床科室，117个病区，开放床位6073张。 2020年极不平凡，面对突如其来的新冠肺炎疫情，医院传承哈尔滨医科大学“红色基因”，发扬伍连德博士抗疫精神，在龙江抗疫斗争中医院群力院区成为“主战场”，在支援全国和国际抗疫斗争中哈医大一院成为“主力军”，坚决打赢疫情防控阻击战和歼灭战，为抗疫取得巨大成果、作出重大贡献，发挥了决定性作用，得到中央指导组和各级政府充分肯定，获得人民群众高度赞扬。医院坚持统一思想、凝聚力量。2020年初新冠肺炎疫情发生后，班子坚决同党中央决策部署保持一致，跟踪研判疫情演变形势，发出倡议号召7份、吹响抗疫集结号，各党总支、支部充分发挥战斗堡垒作用，组织党员百分之百请战、发挥先锋模范作用。班子成员身先士卒战在一线，与党员群众一同抗疫，让党旗在抗疫一线高高飘扬。援鄂一线建立5个临时党支部，省新冠重症救治中心建立临时党委并建立13个临时党支部。发展预备党员75人、转正党员2人、确定入党积极分子178人。医院坚持同舟共济、共克时艰。全院坚持“人民至上、生命至上”理念，白衣为甲、逆行出征，舍生忘死、挽救生命。驰援武汉派出两批205名医务人员，救治危重患者300余名，取得“医护零感染、患者零死亡”优异成绩；保卫龙江、守卫国门，群力院区作为省新冠肺炎重症救治中心三次启用，收治全省90%的重型和98%的危重型新冠肺炎患者，救治成功率达98.4%，并驰援俄罗斯和新疆等地，充分彰显了医院医疗救治的能力和水平。医院抗疫工作受到国务院副总理孙春兰同志和省委书记、省人大主任张庆伟同志的认可和表扬。医院抗疫成效显著、业绩突出。群力院区获批国家发改委“平战结合”重大疫情救治基地项目，获全国抗疫先进个人4人、全国抗疫优秀共产党员1人；获省抗疫先进个人4人、省优秀共产党员3人、省五一劳动奖章2人、省五一劳动奖状1个、省工人先锋号1名、省先进基层党组织2个；获全国五四红旗团支部、全国优秀团支部、省五四奖章集体、省青年五四奖章各1个，组织抗疫捐款共计948763.43元。医院统筹兼顾常态化疫情防控与百姓正常医疗需求。借助信息化技术平台，实现了平诊100%预约制、完成全省首家互联网医院建设；通过优化就诊流程、分时段检查检验、弹性工作时间等措施，进一步提高医疗服务效率。用新模式、新技术、新手段，为患者提供看病就医的新体验。医院在全省首家通过国家医疗健康互联互通标准化成熟度测评四级甲等，为区域、医疗机构之间的医疗信息交换、整合和共享，实现业务协同提供了技术保障。医院有17个专科是国家临床重点专科建设项目，24个专科为省医疗质量控制中心。医院突出优势，提升疑难罕见、急危重症诊疗能力。打破学科壁垒，推进MDT诊疗模式，借助“疑难病症诊治能力提升工程项目”，积极建设“国家呼吸系统疾病临床医学研究中心病毒诊断研究和推广区域平台”、黑龙江省罕见病协作网、黑龙江省泛血管病急危重症救治中心、黑龙江省心血管专病大数据平台等项目，发挥医院疑难罕见病、急危重症诊疗水平在全省乃至东北区域的引领和辐射作用，积极提升医院的品牌声誉和影响力。通过优化学科资源、调整学科布局，积极推动优势学科申报国家级区域医疗中心，大力扶持五大中心建设，加快医疗技术创新及成果转化应用。2021年4月《医院蓝皮书：中国医院竞争力报告（2020-2021）》中医院位居第四十四名。医院重视护理专业发展，临床护理专业是国家重点专科建设项目、中国护理质量促进联盟单位、中华护理学会科普教育基地、中国心血管病专科护理及技术培训基地，2020年获批六个中华护理学会京外培训基地、黑龙江省护理培训基地、国家卫健委“优质护理服务示范工程”活动重点联系医院、护士岗位管理试点医院，优质护理服务覆盖率100%，截止到2021年共有专科护士811名、兼职教师200余人，不断加强护理内涵建设，实现护理工作贴近患者、贴近临床、贴近社会，为患者提供优质、安全、高效、温馨的护理服务。医院具有较强的科研实力，通过ISO医学实验室质量和能力评估认证，也是全国首批“医疗机构抗菌药物管理评价研究基地”。荣获2020未来科学大奖“生命科学奖”、“吴阶平-保罗?杨森”医学药学奖。2020年获聘“长江学者”特岗教授、“长江学者”青年学者各1人、获“2020年百千万人才工程有突出贡献中青年专家”称号1人。获批7个黑龙江省首批临床研究中心。教育部肝脾外科实验室、卫生部细胞移植实验室、国家卫健委干细胞临床研究机构、省心血管病生光电磁诊疗实验室、省血液与造血系统实验室、省眼科基础及临床转化研究实验室、省普通高校神经外科实验室等重点实验室均设在医院。1949年完成全国首例角膜移植手术，劈裂脾移植和同种异体双前臂移植等手术处于国际领先地位，多项新技术为国际、国内首例。医院发明的亚砷酸注射液被评为国家二类新药，在中国科学院2000年《科学发展报告》中被称为20世纪中国十大科技发明之一。医院研制的双黄连制剂获省政府优秀成果奖。医院现有临床医学、口腔医学、儿科学专业，设有26个教研室、5个教研组，医院承担五年制、“5+3”一体化、留学生、研究生、成人教育等临床教学任务，在院学生3000余人，年均接收进修医师500余人。临床医学及口腔医学为一级学科博士、硕士授予点，现有博士生导师147人、硕士生导师377人。获得国家级教学成果一等奖1项、二等奖3项，拥有4门国家级精品资源共享课、3门国家本科一流课程、1门国家级课程思政示范项目，是国家级临床技能实验教学示范中心和国家级虚拟仿真实验教学中心，是首批国家临床教学培训示范中心和国家住院医师规范化培训示范基地。获得全国医学生临床技能大赛一等奖、中国国际“互联网+”大学生创新创业大赛铜奖、全国医学院校青年教师讲课竞赛一等奖、黑龙江省高等教育教学成果特等奖、黑龙江省教材建设特等奖。医院配有PET-MR、PET-CT、3.0T核磁共振、高端领航CT、直线加速器、射波刀、睿平台系统血管造影机、回旋加速器、达芬奇手术机器人、体外模肺（ECMO）等一系列大型诊疗设备，有国际标准手术室113间，配备一流的物流传输系统、耗材智能配送系统、医疗设备及手术器械，可开展植入类、介入杂交类、机器人、脏器移植等高尖端手术，日均外科手术400余台，每年有近百项先进技术应用于临床。医院持续创新优化门诊预约体系、多学科联合会诊、全科门诊、日间手术流程等医疗服务模式；在成人活体肝脏移植、角膜移植、心脏及肾脏移植等多个领域处于国内领先水平。医院大力弘扬总书记提出的“敬佑生命、救死扶伤、甘于奉献、大爱无疆”职业精神，秉承“团结、奉献、敬业、创新”的院训，以“教书育人、为人师表、服务病人、诚信为本”为办院宗旨，以技术创新为源动力，实施“专科有特色、专家有特长”发展战略，坚持以病人为中心，以高尚的医德、精湛的医术和严谨的医风，为建设国内一流、国际有影响的社会主义现代化强院而努力奋斗。医院的愿景与使命：进入新时代，医院坚持以新时代中国特色社会主义思想为指导，认真落实党中央、国务院决策部署，深入贯彻落实健康中国战略，坚持贯彻落实2021年全国卫生健康工作会议和2021年全国医疗管理工作会议精神和指示；牢牢把握公立医院高质量发展的战略机遇期，以改革创新为动力推进公立医院高质量发展，发挥绩效考核、评审评价的“指挥棒”作用，推动公立医院“三转变、三提高”；坚持新时期卫生与健康工作方针，坚持以人民健康为中心，坚持公立医院公益性，加强党的领导，持续深化改革创新，努力形成维护公益性、调动积极性、保障可持续性的运行新机制，建立医院决策、执行、协调、监督相互协调、相互制衡、相互促进的治理机制，健全权责清晰、管理科学、治理完善、运行高效、监督有力的现代医院管理制度。重视社会主义核心价值观教育，着力加强基层党组织、精神文明、医德医风和医院文化建设。弘扬“敬佑生命、救死扶伤、甘于奉献、大爱无疆”的医疗卫生职业精神，发扬“生命至上，举国同心，舍生忘死，尊重科学，命运与共”的伟大抗疫精神，激发员工爱院兴院强院、担当敬业奉献的热情，不断增强员工凝聚力，努力建设国内一流、国际有影响的社会主义现代化强院。肾上腺皮质功能亢进是指一个或一个以上肾上腺皮质激素分泌过多产生的不同临床综合征。过度产生雄激素导致肾上腺雄性化；糖皮质激素过高分泌产生库欣综合征；过度醛固酮产生导致醛固酮增多症，肾上腺皮质功能亢进，全身，手术治疗,药物治疗，不确定，控制钠盐的摄入,限制饮酒,维持钾的摄入,忌高糖饮食,，X线或超声波定位作小针穿刺吸取生物活检，。

true 刘岚副主任医师

三级甲等哈尔滨医科大学附属第一医院

好评率：99% 接诊量：2224 平均响应：15分钟

肝脏疾病、乙型肝炎、丙型肝炎、脂肪肝、自身免疫性肝病、肝硬化、酒精性肝病、肝癌、药物性肝病，布鲁菌病，感染性发热

true 远健主治医师

三级甲等哈尔滨医科大学附属第一医院

好评率：99% 接诊量：2208 平均响应：30分钟

肿物切除、瘢痕修复、微创腋臭、个性化双眼皮、内眼角开大术、睑周年轻化、女性器官整形等手术。注射除皱、瘦脸、瘦小腿、隆鼻、隆下颏等微创注射项目。

true 汤占斌副主任医师

三级甲等哈尔滨医科大学附属第一医院

好评率：100% 接诊量：6 平均响应：-

脑梗死。肌无力，吉兰芭蕾，脑炎，面神经炎，脑出血。周围神经病

true 王婷副主任医师

三级甲等哈尔滨医科大学附属第一医院

好评率：100% 接诊量：193 平均响应：15分钟

擅长呼吸系统疾病的诊治，如上呼吸道感染，咳嗽，发热，咯血，肺部结节，慢阻肺等

true 樊瑛主任医师

三级甲等哈尔滨医科大学附属第一医院

好评率：99% 接诊量：505 平均响应：19小时

高血压、冠心病、心力衰竭等心血管慢病诊治

true 夏永华主任医师

三级甲等哈尔滨医科大学附属第一医院

好评率：99% 接诊量：2.1万平均响应：30分钟

牙疼、牙齿矫正、龋齿、灼口综合征、牙髓病、根尖病、牙周病、智齿问题等常见口腔疾病，尤其擅长儿童的根管治疗、龋齿充填、口腔正畸矫正牙齿。

true 谢荣盛主任医师

三级甲等哈尔滨医科大学附属第一医院

好评率：99% 接诊量：702 平均响应：1小时

心律失常（早搏、房颤、室上速、房室传导阻滞），冠心病，心绞痛，心力衰竭，心肌炎，高血压病，高脂血症，肺栓塞、肺动脉高压。尤其擅长心律失常的介入治疗，如室上速、室性早搏、房颤的射频消融治疗和起搏器植入。

true 滕雷主任医师

三级甲等哈尔滨医科大学附属第一医院

好评率：100% 接诊量：7 平均响应：2小时

擅长胶质瘤5-ALA荧光引导手术及脑恶性肿瘤的个体化综合治疗、脑转移瘤手术、显微外科颅内动脉瘤夹闭手术，年脑肿瘤手术病例近200例。在垂体瘤、脑膜瘤、听神经瘤（保面保听手术）、颅咽管瘤、椎管及脊髓内肿瘤、后颅窝肿瘤（小脑肿瘤）及颅底肿瘤、小脑扁桃体下疝畸形及脊髓空洞症等手术中积累了大量的临床工作经验；同时精通脑出血、颅脑损伤急诊急救手术，以及三叉神经痛、面肌痉挛的微血管减压术等微侵袭神经外科手术。手术中始终秉持“严谨、规范、干净、快速”的风格，始终践行“最大限度地切除肿瘤组织，最大程度地保留患者功能”的手术理念为神经外科患者服务，目前已累计完成各类型颅脑手术1500例，获得了良好的手术效果。所率领的手术团队获得2019年“精艺求菁”神经外科青年医师手术技能大赛，开颅动脉瘤夹闭组—最具风采奖。担任Cancers Review特约审稿人，主要从事神经系统肿瘤发生发展机制的相关研究，主持国家自然科学基金、黑龙江省自然基金、国家教育部留学归国基金、黑龙江省人力资源和社会保障厅留学人员择优资助基金、黑龙江省教育厅海外学人科研资助项目及哈医大一院院基金，发表SCI英语论文多篇，实验论文发表在Neuro-Oncology，British Journal of Cancer，American Journal of Cancer Research，Cancer Science等杂志，最高影响因子为13.028。参编由人民卫生出版社出版的国家卫生健康委员会 “十三五”规划教材《神经外科学》，以及《颅脑肿瘤诊断与治疗精要》、《神经外科危重症诊断与治疗精要》、《脑肿瘤临床病理彩色图谱》等学术专著；并担任美国蓝图双语丛书《急诊医学》副主译，完成了同系列的12本原著医学专著的翻译出版工作。凭借其在胶质瘤发生发展方面的研究，作为主要参与者获得中国抗癌协会科技进步奖一等奖（2014-09-12），黑龙江省人民政府科学技术进步一等奖（2014-08）；2017年所在的胶质瘤基础科研团队获得中华医学会科技奖二等奖（2017-01-03）；第八届中国肿瘤学术大会中国抗癌协会优秀论文奖（2014-09-13）。多次获得哈尔滨医科大学校级优秀医务工作者、哈尔滨医科大学附属第一医院优秀科研工作者，优秀共产党员等称号。

false 朱安龙主任医师

三级甲等哈尔滨医科大学附属第一医院

好评率：- 接诊量：- 平均响应：-

1.胃肠外科疾病，包括胃/肠癌，肠梗阻，2.腹腔镜微创手术，包括胃肠道，胆道手术，胆道镜技术，3.便秘，4.腹股沟疝，切口疝，造口旁疝，5.腹膜后肿瘤，6.普外科复杂疾病

true 马帅男副主任医师

三级甲等哈尔滨医科大学附属第一医院

好评率：100% 接诊量：181 平均响应：15分钟

头晕头痛脑梗死腔隙性脑梗死认知功能障碍癫痫多发性硬化吉兰巴雷综合征神经脊髓炎谱系疾病帕金森病帕金森综合症运动神经元病等

接诊医生：

2024-10-31 12:13:12

科普文章

性早熟科普（下）

4

男孩性早熟有什么表现和特点？

① 男孩的青春期发育进程往往是睾丸增大→阴茎增大→阴毛和腋毛生长→变声、长胡须、长喉结→遗精。

② 男孩在 9 岁以前出现睾丸增大属于性早熟，但是男孩睾丸增大不容易被家长观察到，往往是出现变声、长胡须或者喉结后，家长才知道孩子进入青春期。

③ 男孩整个青春期发育大致经历 3-4 年，如果青春期进展的速度加快也属于性早熟。

5

性早熟有什么危害？

性早熟最主要的危害，也是家长特别关心的，就是对身高的影响了。

大家都知道，孩子在进入青春期后生长加快。一般女孩生长加速的年龄在 10 岁左右，在乳房发育 1-2 年后出现生长突增，一年长 6-12 厘米（速度因人而异），持续 1 年，月经初潮后生长减速。一般月经来潮后还能再长 3-5cm 就达到成年身高了。

一般男孩在 12 岁开始生长加速，大致在变声前后出现生长突增，一年长 7-12cm（速度也是因人而异），持续约 1-1.5 年，遗精后生长减速。

性早熟的孩子会更早出现生长加速，更早停止生长，有可能最终身高低于原本应有的水平。

为什么说“有可能”而不是“肯定”呢？性早熟中会有一部分孩子进展缓慢，例如乳房早发育的女孩，有些到 11 岁左右才来月经，很可能成年身高不易受影响。很多 6 岁后乳房发育的女孩，性早熟进展会比较缓慢。

6

性早熟分哪些类型？

性早熟可分为中枢性性早熟、外周性性早熟和良性青春期变异。

① 中枢性性早熟：指大脑里分管性发育的中枢“司令部”提前启动，发布青春期发育指令，从而促进青春期发育。导致它的原因可能是特发性因素（即目前找不到病因）或脑内的病变，如肿瘤、脑创伤、脑积水等等，其中 90%的女孩的中枢性性早熟和 60%的男孩的中枢性性早熟都是特发性的。

② 外周性性性早熟：由于性腺或肾上腺分泌的雌激素和/或雄激素过多，或是使用了外源性性激素，例如误服了避孕药等等，是没有大脑里性发育中枢“司令部”的发育指令下达的。

③ 良性青春期变异：指虽然第二性征提前了，但是没有疾病表现，没有进行性的性发育，最终身高也不会受到影响。例如一些 2-3 岁以前出现的乳房发育，也被称为微小青春期。这类孩子不需要治疗，但是需要医生检查患儿有无青春期发育的其他征象，监测生长（如果身高增长加速，提示进行性青春期发育）。如果发现有进行性的青春期发育，这就不属于良性青春期变异的范畴了。

7

发现孩子性早熟，家长该怎么做？

如果发现孩子有性早熟迹象，需要看医生来评估性早熟是中枢性、外周性还是良性青春期变异，以及性发育的进程快不快，判断是不是要排查性早熟的病因，和要不要用药物治疗和干预。

性早熟科普（上）

什么是性早熟？

如果比 95%同性别的人性发育都要早，就叫性早熟。女孩和男孩青春期发动的平均年龄分别约为 9.5 岁和 11.5 岁，如果女孩在 8 岁之前，男孩在 9 岁之前出现第二性征，或者女孩在 10 岁之前出现月经初潮就被定义为性早熟。

什么是第二性征？

孩子一出生就能分辨的男女生殖器的差别是第一性征，青春期开始后出现的男女身体特征区别就叫做第二性征，包括：乳房发育、阴茎变长、睾丸增大、阴毛和腋毛生长、长喉结、长胡须、声音改变等。

女孩性早熟有什么表现和特点？

① 大多数青少年青春期都沿着类似的路径完成整个发育过程。女孩青春期发育进程往往是乳房发育→阴毛生长→外生殖器改变→腋毛生长→外阴白带样分泌物→月经来潮。

② 早期女孩乳房发育多为单侧乳房小硬结，像黄豆或者花生米大小，可伴有轻微的压痛和痒感。若发育继续进展的话，另一侧乳房也会出现发育。

③ 女孩子进入青春期往往更容易被家长发现，而 8 岁以下女孩的性早熟通常是因乳房发育被妈妈发现的。

④ 通常女孩乳房发育 2-3 年后，会月经来潮，但是如果青春期进展太快，例如：虽然是 8 岁以后乳房开始发育，但是 10 岁之前就来月经了，这也属于性早熟。

男孩性早熟有什么表现和特点？

① 男孩的青春期发育进程往往是睾丸增大→阴茎增大→阴毛和腋毛生长→变声、长胡须、长喉结→遗精。

② 男孩在 9 岁以前出现睾丸增大属于性早熟，但是男孩睾丸增大不容易被家长观察到，往往是出现变声、长胡须或者喉结后，家长才知道孩子进入青春期。

③ 男孩整个青春期发育大致经历 3-4 年，如果青春期进展的速度加快也属于性早熟。

早熟的孩子如何长高

早熟的孩子想要长高的话,需要先去医院里测量自己的骨骼线。如果骨骼线没有闭合的话,可以去医院里打生长激素,或者是一些促骨骼生长的物质，这些可以促进骨骼的生长发育,能够使孩子长高。如果说骨骼线已经闭合的话,可以在医生的指导下进行手术,通过手术把骨骼切开，让骨骼进行二次的生长发育，来达到增高的目的。

孩子在生长发育的过程中,一定要补充含营养元素比较丰富的食物，比如说鸡蛋，牛奶，青菜等食物。或者是适当的做一些运动，多蹦蹦跳跳，可以促进骨骼的生长发育。

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.