MS Speaks

1: 10,000 Is Not Zero. Lessons Learned from a Natalizumab-Related PML Case with Repeated Negative Anti-JCV Antibody Testing

Marie-Sarah Gagne Brosseau, MD , Neurology, University of Washington, Seattle, WA
Gary Stobbe, MD , Neurology, University of Washington, Seattle, WA
Deb Cramer, RN , Neurology, University of Washington, Seattle, WA
Hillary Lipe, A.R.N.P. , Neurology, University of Washington, Seattle, WA
Annette Wundes, MD , Neurology, University of Washington, Seattle, WA
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Background:

Progressive multifocal leukoencephalopathy (PML) is a severe brain infection caused by the JC virus (JCV) that leads to lysis of oligodendrocytes. Natalizumab is known to be associated with PML. Clinical presentation varies; most common symptoms are cognitive impairment, weakness and language deficit. Natalizumab-related PML has a mortality rate of 22% and many survivors have a poor functional outcome, which makes it natalizumab’s most serious complication.

50-60% of adults have detectable serum antibodies against JCV. Seropositivity for anti-JCV antibodies is a PML risk factor and periodic testing is recommended. Previously, 2 natalizumab-treated multiple sclerosis PML patients were classified as anti-JCV antibody negative, but testing dated from 8 and 9 months before diagnosis.

Objectives:

To describe a case of natalizumab-associated PML in which the last anti-JCV antibody testing 2 weeks before onset of symptoms was negative.

Methods:

Case presentation.

Results:

A 70-year-old woman with multiple sclerosis (MS) treated with natalizumab for 4.5 years developed PML symptoms of right hand weakness 2 weeks after last negative anti-JCV antibody testing. She had never received immunosuppressants. Brain MRI showed 4 new nonenhancing lesions which were surmised due to MS. A course of intravenous methylprednisolone for a presumed relapse was given but her weakness worsened. Short-term repeat MRI was suggestive of PML and CSF JCV PCR came back positive. While 4 prior quantitative anti-JCV antibody tests every 3 months had been negative, including 2 weeks prior to onset of symptoms (index 0.19), at time of diagnosis the result was positive (index 2.56). Evolution and management of the present case will be presented.

Conclusions:

Initial misdiagnosis of MS relapse may delay the diagnosis of PML. Clinicians should be wary that a natalizumab-treated patient with new MRI findings and/or neurological symptoms could have PML, including those with negative anti-JCV antibody. 2 weeks is currently the shortest interval reported between last negative anti-JCV antibody testing and onset of PML symptoms. In negative patients, risk can be due to a false negative test result reported as 3%, or to de novo infection. In our case, de novo infection with seroconversion is more plausible given the repeatedly negative testing. If PML is suspected, anti-JCV antibodies should be repeated even if recently negative. Moreover, short-term repeat MRI and CSF testing warrant consideration.