异基因造血干细胞移植后合并自身免疫性脑炎的再生障碍性贫血患者1例临床分析并文献复习

Clinical analysis of a case of aplastic anemia combined with autoimmune encephalitis after allogeneic hematopoietic stem cell transplantation and literature review

目的探讨对再生障碍性贫血(AA)进行异基因造血干细胞移植(allo-HSCT)后,合并自身免疫性脑炎(AE)患者的临床特征、诊断、治疗及预后,并进行相关文献复习。方法选择2020年12月28日第九四〇医院血液科收治的1例因AA接受单倍体造血干细胞移植(haplo-HSCT)后发生AE患者(患者1)为研究对象。患者1为男性、30岁。采用回顾性研究方法,对其病史、临床表现、实验室及影像学检查结果与诊疗结果等临床资料进行分析。对患者1的随访,截至2023年9月30日。以"造血干细胞移植""脑炎""脑膜炎""自身免疫性脑炎""hematopoietic stem cell transplantation""encephalitis""meningitis""autoimmune encephalitis"为中、英文关键词,在万方数据服务知识平台、中国知网数据库及PubMed数据库中,检索血液病患者接受allo-HSCT后发生AE的相关研究文献。文献检索时间设定为以上数据库建立至2023年12月。本研究遵循的程序符合2013年修订的《世界医学会赫尔辛基宣言》的要求,并且与受试者签署临床研究知情同意书。结果患者1因"allo-HSCT后42+个月,肌无力1+个月"于2020年12月28日第九四〇医院血液科入院治疗。①患者1入院实验室检查结果如下。脑脊液压力为350 mmH 2O(1 mmH 2O=9.81 Pa);脑脊液生化检查:Cl-浓度为129.4 mmol/L,葡萄糖水平为2.85 mmol/L,蛋白定量为879.0 mg/L;脑脊液常规检查:白细胞计数(WBC)为15×106/L,蛋白定性呈阳性;外周血感染相关检测:降钙素原(PCT)水平为0.047 ng/mL,白细胞介素(IL)-6水平为2.0 pg/mL;外周血血培养、血清及脑脊液病毒系列检查、脑脊液墨汁染色、脑脊液细菌及真菌培养结果均呈阴性;脑脊液及血清AE相关抗体均呈阴性。②患者1影像学检查结果如下。头颅MRI检查结果提示,双侧大脑半球、中脑、小脑中脚见大致呈对称分布的片状稍长T2信号影,弥散加权成像(DWI)提示双侧大脑半球、中脑、小脑中脚高信号。③临床诊断:患者1于2021年1月14日被确诊为自身抗体呈阴性AE。④治疗及转归:对患者1采取镇静、输注大剂量甲泼尼龙、静注人免疫球蛋白(IVIG)、抗癫痫、脱水降颅压、抗感染及呼吸机辅助呼吸等治疗后,体温逐渐正常,可脱离呼吸机自主呼吸,提示治疗有效。3月3日,患者1出院时可在家属搀扶下行走,四肢肌张力、腱反射正常,一般情况好转,病情稳定。⑤随访及预后:患者1于随访期内规律复诊,9月30日复诊结果显示,AE后遗症症状明显,表现为反应迟钝、记忆力减退、精神行为异常等。⑥按照本研究设定的文献检索策略,检索到3篇关于allo-HSCT后发生AE的相关研究文献,共计4例患者(患者2~4),包括患者1在内的5例allo-HSCT后合并AE患者被纳入以下研究。这5例患者allo-HSCT后,均出现中枢神经系统(CNS)症状,经头颅MRI、脑脊液AE相关抗体检测,最后均被诊断AE。对其均采取糖皮质激素、CD20单克隆抗体、IVIG等治疗后,其CNS症状均有所改善。结论血液肿瘤患者在接受allo-HSCT后免疫重建过程中,若出现CNS症状,需尽早完善头颅MRI、脑脊液抗体检测排查AE可能。一旦患者被诊断为allo-HSCT后合并AE,应立即采取糖皮质激素联合IVIG等治疗,以挽救其生命。

Objective To investigate the clinical features,diagnosis,treatment and prognosis of aplastic anemia(AA)patient combined with autoimmune encephalitis(AE)after allogeneic hematopoietic stem cell transplantation(allo-HSCT),and to review the relevant literature.Methods On December 28,2020,one patient(patient 1)who was admitted to Hematology Department of the 940th Hospital,and developed AE after receiving haploidentical hematopoietic stem cell transplantation(haplo-HSCT)for treatment of AA was selected as a study subject.Patient 1 was a 30-year-old male.The clinical data of patient 1,including medical history,clinical manifestations,laboratory and imaging findings,and diagnosis and treatment results were analyzed retrospectively.Patient 1 was followed up until September 30,2023.Using"hematopoietic stem cell transplantation","encephalitis","meningitis",and"autoimmune encephalitis"as keywords in Chinese and English,the relevant literature on the occurrence of AE after receiving allo-HSCT in patients with blood diseases was searched in the Wanfang Data Knowledge Service Platform,China National Knowledge Infrastructure database and PubMed database.The literature search was set for the period from the creation of above databases until December 2023.The procedures followed in this study were in line with the requirements of the Helsinki Declaration of the World Medical Association revised in 2013,and informed consent was obtained from the subject for clinical study.Results Patient 1 was admitted to the Hematology Department of the 940th Hospital on December 28,2020,due to"42+months after allo-HSCT and 1+month of myasthenia".①Admission laboratory examination of patient 1 was as follows.Cerebrospinal fluid pressure was 350 mmH 2O(1 mmH 2O=9.81 Pa).Biochemical examination of cerebrospinal fluid showed that Cl-concentration was 129.4 mmol/L,glucose level was 2.85 mmol/L,and protein quantification was 879.0 mg/L.Routine examination of cerebrospinal fluid showed that white blood cell count(WBC)was 15×106/L and protein qualification was positive.Peripheral blood infection-related test results showed that procalcitonin(PCT)level was 0.047 ng/mL,and interleukin(IL)-6 level was 2.0 pg/mL.The results of peripheral blood culture,serum and cerebrospinal fluid virus series test,cerebrospinal fluid ink staining,cerebrospinal fluid bacterial and fungal culture were all negative.Cerebrospinal fluid and serum autoimmune encephalitis antibody were both negative.②Imaging findings of patient 1 were as follows.Cranial MRI results suggested that bilateral cerebral hemispheres,midbrain,and middle cerebellar peduncles showed a roughly symmetrical distribution of patchy slightly long T2 signals.Diffusion-weighted imaging(DWI)showed high signals in bilateral cerebral hemispheres,midbrain,and middle cerebellar peduncles.③Clinical diagnosis of patient 1 was as follows.Patient 1 was eventually diagnosed as AE with autoantibody-negative on January 14,2021.④Treatment and outcomes of patient 1 were as follows.Patient 1 was treatment with sedation,a large dose of methylprednisolone infusion,intravenous immunoglobulin(IVIG),anti-epilepsy,dehydration to reduce cranial pressure,anti-infection and ventilator assisted breathing,his temperature gradually normalized,and he could breathe on his own off the ventilator,which suggested treatment was effective.On March 3,patient 1 could walk with the support of family members when he was discharged from the hospital.The patient′s muscle tension in limbs and tendon reflexes were normal.His general condition improved and was stable.⑤Follow-up and prognosis of patient 1 were as follows.The patient had regular follow-up visits during the follow-up period,and the results of the follow-up on September 30 showed significant symptoms of AE sequelae in the form of unresponsiveness,memory loss,and mental behavioral abnormalities.⑥According to the literature search strategy established in this study,3 articles related to AE after allo-HSCT were retrieved,totaling 4 patients(patient 2 to 5),and 5 patients including patient 1 with combined AE after allo-HSCT were included in the following study.All 5 patients developed central nervous system(CNS)symptoms after allo-HSCT,and AE was finally diagnosed by cranial MRI and cerebrospinal fluid AE-associated antibody detection.The CNS symptoms of the 5 patients improved after treatment with glucocorticoids,CD20 monoclonal antibody,and IVIG.Conclusions During immune reconstruction process after allo-HSCT,patients with CNS symptoms should be screened for AE.Cranial MRI and cerebrospinal fluid antibody detection should be performed immediately,to rule out AE possibility.Once a patient is diagnosed as AE after allo-HSCT,treatment such as glucocorticoid combined with IVIG should be administered immediately to save the patients′life.