False negative DNA PCR test for JC Virus in Cerebrospinal Fluid Resulting in Delayed Diagnosis of Progressive Multifocal Leukoencephalopathy

Progressive Multifocal Leukoencephalopathy is a rare disease of the Central Nervous System (CNS) caused by reactivation of the JC polyomavirus in an immunocompromised host. It carries a poor prognosis and high mortality rate. Gold standard for diagnosis is brain biopsy however the initial recommend step is to secure diagnosis with PCR showing JC virus in CSF. If negative, PCR is again repeated before attempting brain biopsy as it is the more invasive approach. There have been incidences of delayed diagnosis due to false negative CSF PCR results for JC virus. Here, we present such a case: a 73-year-old man with a recent diagnosis of Chronic Lymphocytic Leukemia on Ibrutinib therapy) who presented with worsening mentation and focal motor deficits. Work up included multiple MRI images of the brain, which demonstrated scattered foci of white matter lesions, with some lesions demonstrating hyperintense Diffusion Weighted Imaging (DWI) signal. Two lumbar punctures were performed, which were negative for infectious etiology (JC Virus negative) and yielded negative cytology. Further workup was negative for drug toxicity, infective endocarditis, primary CNS lymphoma, and primary vasculitis. Brain biopsy was ultimately performed, which demonstrated chronic active viral encephalitis, positive for SV40 by immunohistochemistry consistent with progressive multifocal leukoencephalopathy. This case highlights the importance of obtaining brain biopsy for diagnosis of PML despite negative PCR results for JC virus in CSF, if clinical suspicion remains high.