From the Department Safety of Medicinal Products and Medical Devices (K.B., B.K.-S.), and Section Biostatistics (B.H.), Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines, Langen; Clinic of Neurology with Institute of Translational Neurology (N.S.), University Hospital Muenster, University Muenster; Institute for Virology (O.A.), University of Duesseldorf, Medical Faculty, Duesseldorf; and Department of Neurology (C.W.), University Hospital Koeln, Germany.
Neurology. 2019 May 7;92(19):e2232-e2239. doi: 10.1212/WNL.0000000000007451. Epub 2019 Apr 5.
To evaluate characteristics relevant to diagnosis of JC polyomavirus-associated progressive multifocal leukoencephalopathy (PML), and PML risk stratification in a large national cohort of patients with multiple sclerosis during therapy with natalizumab.
Analysis of 292 adverse drug reaction forms on suspected cases of PML reported to the German national competent authority until July 2017. Patients not fulfilling PML diagnostic criteria or with insufficient information available were excluded.
Of the 142 confirmed patients with PML, 72.3% (95% confidence interval [CI] 64.4%-79.1%) were women, and the median age was 43 years (range 19-69). Of these patients, 7.7% (95% CI 4.3%-13.5%) were clinically asymptomatic at time of PML diagnosis. PML was fatal in 9.1% (95% CI 5.3%-15.1%) of the patients. Infratentorial lesions on imaging were reported in 40% (95% CI 32.0%-48.6%) of the patients. JC polyomavirus DNA in CSF was undetectable at time of first analysis in 23.8% (95% CI 17.3%-31.9%) of the patients. Three patients tested negative for anti-JC polyomavirus antibodies within 6 to 18 months before PML diagnosis, with seroconversion confirmed 5.5 months, 7 months (in a post hoc analysis only), or at time of PML diagnosis.
JC polyomavirus DNA detection in CSF has limited sensitivity in early PML, and clinical and imaging presentation may be atypical. Thus, critical revision of current PML diagnostic criteria is warranted. Negative anti-JC polyomavirus antibodies in sera do not preclude the later development of PML. This emphasizes the need for close and regular serologic, imaging, and clinical monitoring in patients treated with natalizumab.
评估巨细胞病毒（JC）相关多瘤病毒相关进行性多灶性白质脑病（PML）诊断相关特征，并对接受那他珠单抗治疗的多发性硬化症患者进行大型全国队列 PML 风险分层。
分析截至 2017 年 7 月向德国国家主管部门报告的疑似 PML 不良药物反应病例的 292 份药物反应表。排除不符合 PML 诊断标准或资料不全的患者。
在 142 例确诊的 PML 患者中，72.3%（95%置信区间[CI] 64.4%-79.1%）为女性，中位年龄为 43 岁（范围 19-69 岁）。这些患者中有 7.7%（95%CI 4.3%-13.5%）在 PML 诊断时无临床症状。9.1%（95%CI 5.3%-15.1%）的患者 PML 死亡。影像学检查显示 40%（95%CI 32.0%-48.6%）的患者有小脑下病灶。在首次分析时，23.8%（95%CI 17.3%-31.9%）的患者 CSF 中无法检测到 JC 多瘤病毒 DNA。3 例患者在 PML 诊断前 6 至 18 个月内 JC 多瘤病毒抗体检测阴性，5.5 个月、7 个月（仅在后验分析中）或 PML 诊断时出现血清转换。
CSF 中 JC 多瘤病毒 DNA 检测在早期 PML 中的敏感性有限，临床表现和影像学表现可能不典型。因此，有必要对现行 PML 诊断标准进行严格审查。血清中阴性的 JC 多瘤病毒抗体不能排除 PML 的后期发展。这强调了需要对接受那他珠单抗治疗的患者进行密切和定期的血清学、影像学和临床监测。
