PML With Natalizumab Despite Recent Negative JCV Test Result

January 14, 2016

A case of progressive multifocal leukoencephalopathy (PML) associated with natalizumab (Tysabri, Biogen) therapy has been reported in a patient with multiple sclerosis (MS) who had tested negative for JC virus (JCV) antibodies just 2 weeks before symptoms developed.

The case, published online in Neurology on January 6, was reported by Marie-Sarah Gagne Brosseau, MD, and colleagues from University of Washington, Seattle.

Because the first sign of PML was seen in MRI findings, the authors emphasize the value of surveillance MRIs in patients receiving natalizumab.

"This case exemplifies the risk of delay in PML diagnosis for initial misdiagnosis of MS exacerbation, reiterating that a natalizumab-treated patient with any new MRI lesion or neurologic symptoms could have PML, independent of JCV antibody status," they conclude. "Short-term clinical and MRI reassessment, repeat anti-JCV antibody testing, and CSF [cerebrospinal fluid] testing may be warranted, depending on the level of clinical suspicion."

Commenting on the case for Medscape Medical News, Jeffrey Cohen, MD, Cleveland Clinic, Ohio, said this case illustrates two important points. 

"First, although negative JCV serology is reassuring and lessens the risk of PML, there is a low but finite false-negative rate," he said. "Second, any new MRI lesion or apparent relapse in a patient on Tysabri is suspicious, particularly with prolonged treatment."

The authors note that as of March 2015, Biogen had reported 541 cases of natalizumab-related PML. Of 278 cases with available data, only 2 were negative for anti-JCV antibodies and these patients had tests dating from 8 and 9 months before diagnosis.

"The notable finding in this patient is the 2-week timespan between the most recent negative anti-JCV antibody test result and the onset of PML symptoms," they write.

The patient in this case, a 70-year-old woman with MS, had been taking natalizumab since January 2010, had never received immunosuppressants, and had had several negative JCV antibody test results, the most recent of which was just 2 weeks before the onset of PML symptoms.

The patient was discovered to have new right-hand weakness at an urgent follow-up visit prompted by a routine annual brain MRI in June 2014, which showed two new nonenhancing lesions in the subcortical left precentral gyrus and the left insula. The radiologist thought these represented MS progression.

After two short courses of intravenous methylprednisolone failed to improve the symptoms of weakness in the hand, which had by this time spread to involve the arm, repeat MRI in August 2014 raised concern for PML. The left precentral and insular nonenhancing lesions had progressed, with increasing U-fiber involvement. At this time, natalizumab was stopped and the result of a CSF JCV polymerase chain reaction test proved positive. The result of an anti-JCV antibody test was also now positive.

The researchers note that patients with negative JCV antibody results are still at risk for PML because of the potential for de novo infection as well as the possibility of false-negative test results, which may be as high as 3%.

They say that they cannot exclude de novo infection with seroconversion in this case, although a latent infection with too-low peripheral viral activity to reach threshold is more likely, considering the low viral load in the patient's CSF.

No targeted funding for was reported. Dr Gagne Brosseau has disclosed no relevant financial relationships. Disclosures for coauthors appear in the paper.

Neurology. Published online January 6, 2016. Excerpt


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