Diagnosis of PML requires having a high index of suspicion, particularly among patients with impaired cellular immunity who present with progressive neurologic deficits. Clinicians should utilize a combination approach based on patient's symptoms, MRI, and CSF analysis. CSF-PCR for JCV DNA is the method of choice for diagnosing PML. Importantly, in patients receiving natalizumab, viral loads in the CSF may be low. Up to 50% of patients with natalizumab-associated PML have an initial viral load less than 500 copies/ml, and thus a high sensitivity analysis detecting less than 50 copies/ml should be used. A negative CSF-PCR result does not exclude PML, often requiring repeat CSF analysis and reliance on clinical presentation and imaging. The use of JCV- specific IgG CSF antibodies and serum antibodies can be used to determine an antibody index. An antibody index greater than 1.5 indicates intrathecal synthesis, even when CSF-PCR is negative. Serum and urine JCV PCR is not reliable for screening or diagnosis of PML.
MRI is a sensitive test to screen suspected patients for PML, and has been useful in preclinical detection of asymptomatic cases. As clinical manifestations of PML can be subtle, diagnosis can be delayed from days to months. In these cases, MRI screening may be a useful tool to offer patients. PML lesions appear as single or multiple hyperintense areas on T2-weighted imaging, which become confluent and large as the disease progresses. Lesions typically involve subcortical white matter and arcuate fibers, but may also involve adjacent gray matter. Lesion asymmetry and limited mass effect is common in PML. Figure 1 displays characteristic MRI findings in a patient with PML. Brainstem and cerebellar involvement is more common in HIV-infected patients; however, this pattern has been reported in natalizumab-associated PML. Importantly, MRI patterns in patients treated with natalizumab may exhibit contrast enhancement in up to 40% of patients at the time of diagnosis. This is strikingly different than PML associated with other immunosuppressive conditions in which contrast enhancement is exceedingly rare. Contrast enhancing lesions should not be assumed to be multiple sclerosis exacerbations in patients on natalizumab therapy. In those cases in which the diagnosis of PML cannot be made by CSF analysis or MRI, brain biopsy may be considered.
Axial MRI displaying the typical appearance of progressive multifocal leukoencephalopathy (PML). (a) T2-weighted image shows nonsymmetrical geographic confluent subcortical hyperintensities that affect subcortical U-fibers but not the overlying cortex. Mass effect is not seen in this case. (b) Fluid-attenuated inversion recovery (FLAIR) image again reveals the findings described in (a), and also makes more conspicuous the multiple sites of involvement, with sites at the posterior vertex on the left and at the anterior portion of the left superior frontal gyrus and adjacent left frontal convexity. (c) T1-weighted image shows the typical hypointensity of the PML lesions without mass effect. (d) Gadolinium contrast enhanced T1-weighted image reveals a small amount of linear enhancement at the gray matter–white matter interface in the dominant left posterior frontal lesion, with additional subtle enhancement farther anteriorly in the left frontal lobe.