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ObjectiveTo 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.MethodsAnalysis 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.ResultsOf 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.ConclusionsJC 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.