免疫检查点抑制剂相关神经系统不良反应的临床诊治建议

免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)可引起神经系统的不良反应,发生率在0.1%-12%,80%发生在应用前4个月内。可以引起神经系统各部位的病变,包括无菌性脑膜炎,脑膜脑炎,坏死性脑炎,脑干脑炎,横贯性脊髓炎等中枢神经系统病变,也可引起颅神经周围神经病、多灶性神经根神经病、格林巴利综合征、脊神经根神经病、重症肌无力、肌病等周围神经病变。对于神经系统的这些并发症,均需要症状体征,并结合影像学、脑脊液细胞学、脑电图或肌电图等检查,除外感染或恶性肿瘤后获得诊断。治疗中,在严重病例需停用ICIs,并用大剂量糖皮质激素或丙种球蛋白治疗和对症支持治疗。在出现神经系统不良反应后,严重病例预后较差。

Dysregulated N6-methyladenosine modification in peripheral immune cells contributes to the pathogenesis of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis(ALS)is a progressive neurogenerative disorder with uncertain origins.Emerging evidence implicates N6-methyladenosine(m6A)modification in ALS pathogenesis.Methylated RNA immunoprecipitation sequencing(MeRIP-seq)and liquid chromatography–mass spectrometry were utilized for m6A profiling in peripheral immune cells and serum proteome analysis,respectively,in patients with ALS(n=16)and controls(n=6).The single-cell transcriptomic dataset(GSE174332)of primary motor cortex was further analyzed to illuminate the biological implications of differentially methylated genes and cell communication changes.Analysis of peripheral immune cells revealed extensive RNA hypermethylation,highlighting candidate genes with differential m6A modification and expression,including C-X3-C motif chemokine receptor 1(CX3CR1).In RAW264.7 macrophages,disrupted CX3CR1 signaling affected chemotaxis,potentially influencing immune cell migration in ALS.Serum proteome analysis demonstrated the role of dysregulated immune cell migration in ALS.Cell type-specific expression variations of these genes in the central nervous system(CNS),particularly microglia,were observed.Intercellular communication between neurons and glial cells was selectively altered in ALS CNS.This integrated approach underscores m6A dysregulation in immune cells as a potential ALS contributor.

The Gold Coast criteria increases the diagnostic sensitivity for amyotrophic lateral sclerosis in a Chinese population

Objectives:The aim of this study was to assess and compare the diagnostic utility of a new diagnostic criteria for amyotrophic lateral sclerosis(ALS),abbreviated as the‘Gold Coast Criteria’,with the revised El Escorial(rEEC)and Awaji criteria.Methods:Clinical and electrophysiological data of 1185 patients from January 2014 to December 2019 in the Peking Union Medical College Hospital ALS database were reviewed.The sensitivity of the Gold Coast criteria was compared to that of the possible rEEC and Awaji criteria(defined by the proportion of patients categorized as definite,probable,or possible ALS).Results:A final diagnosis of ALS was recorded in 1162 patients.The sensitivity of the Gold Coast criteria(96.6%,95%confidence interval[CI]=95.3%-97.5%)was greater than that of the rEEC(85.1%,95%CI=82.9%-87.1%)and Awaji(85.3%,95%CI=83.2%-87.3%).In addition,the sensitivity of the novel criteria maintained robust across subgroups,and the advantage was more prominent in limb-onset ALS patients and those who completed electromyographic tests.In those who did not achieve any of the rEEC diagnostic categories,the sensitivity of Gold Coast criteria was 84.4%.Conclusions:The current study demonstrated that the Gold Coast criteria exhibited greater diagnostic sensitivity than the rEEC and Awaji criteria in a Chinese ALS population.The application of the Gold Coast criteria should be considered in clinical practice and future therapeutic trials.