Kira Blankenbach1, Nicholas Schwab1, Benjamin Hofner1, Ortwin Adams1, Brigitte Keller-Stanislawski1, Clemens Warnke2. 1. 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. 2. 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. clemens.warnke@uk-koeln.de.
Abstract
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: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.
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