Progressive multifocal leukoencephalopathy (PML) is a rare, life-threatening disease that is characterized by focal neurological deficits. It is caused by the John Cunningham virus (JC virus), which is usually contracted during childhood but is asymptomatic until the virus is reactivated later in life due to weakened immune status. The clinical manifestations are consistent with findings on brain imaging or biopsy. Since this disease is fatal, early diagnosis and prompt treatment are imperative.
The clinical course of PML is gradual and progressive as it develops over several weeks to months . The features of this disease include visual deficits, aphasia, gait ataxia, motor impairment, and possibly headaches and seizures. Patients also suffer from cognitive function decline that may result in dementia. If left untreated, PML is associated with high rates of morbidity and mortality.
It is important to consider the risk factors. This viral infection is most prevalent in patients with HIV/AIDS. Additionally, it may manifest in immunocompromised individuals with leukemia, Hodgkin's disease, organ transplant, or genetic immunodeficiencies. Patients receiving treatment with natalizumab  and other monoclonal antibodies , long-term steroid therapy, methotrexate, cyclosporine, and other immunosuppressants are also at increased risk for developing PML .
Remarkable findings on the neurological exam include ataxia, hemiparesis, limb apraxia, and possibly head tremor. Altered mental status is also observed. Visual assessment may be notable for conjugate gaze deficits and other abnormalities.
The workup consists of a careful assessment of the clinical picture, history, risk factors as well as a detailed physical exam and appropriate tests. Immunosuppressed patients with worsening manifestations and progressive deterioration should raise suspicion for PML.
Brain magnetic resonance imaging (MRI) in patients with PML reveals unifocal or multifocal lesions that are hypointense on T1 images but hyperintense on T2 and FLAIR (fluid attenuated inversion recovery) sequences. Moreover, these foci are likely to develop in the parietooccipital white matter although white matter changes may also appear in the cerebellum, brain stem or peduncles.
Computed tomography (CT) brain scan is another imaging modality that can be used to evaluate these patients. However, it is usually less sensitive than MRI .
Confirmation of PML is through detection of the JC virus in cerebrospinal fluid, which is obtained through a lumbar puncture (LP). Polymerase chain reaction (PCR) analysis of the sample requires technical expertise since testing for the JC virus is complex. Since DNA PCR may be negative in the initial phases of PML, LP should be repeated in patients with progressive clinical and radiographic signs suggestive of PML.
A brain biopsy can definitively establish the diagnosis as well, in which immunohistochemistry and in situ hybridization analysis of the tissue demonstrates the presence of the JC virus. This test is associated with a sensitivity as high as 95% and 100% specificity.
Postmortem brain examination also confirms the diagnosis.