PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section

Abstract

Objective: To establish criteria for the diagnosis of progressive multifocal leukoencephalopathy (PML).

Methods: We reviewed available literature to identify various diagnostic criteria employed. Several search strategies employing the terms "progressive multifocal leukoencephalopathy" with or without "JC virus" were performed with PubMed, SCOPUS, and EMBASE search engines. The articles were reviewed by a committee of individuals with expertise in the disorder in order to determine the most useful applicable criteria.

Results: A consensus statement was developed employing clinical, imaging, pathologic, and virologic evidence in support of the diagnosis of PML. Two separate pathways, histopathologic and clinical, for PML diagnosis are proposed. Diagnostic classification includes certain, probable, possible, and not PML.

Conclusion: Definitive diagnosis of PML requires neuropathologic demonstration of the typical histopathologic triad (demyelination, bizarre astrocytes, and enlarged oligodendroglial nuclei) coupled with the techniques to show the presence of JC virus. The presence of clinical and imaging manifestations consistent with the diagnosis and not better explained by other disorders coupled with the demonstration of JC virus by PCR in CSF is also considered diagnostic. Algorithms for establishing the diagnosis have been recommended.

Figure 1. Pathology of progressive multifocal leukoencephalopathy

(A) Luxol fast blue staining with hematoxylin counterstain of the frontal lobe in a patient with progressive multifocal leukoencephalopathy (PML) shows extensive multifocal and confluent areas of demyelination. Small islands of demyelination coalesce to produce large confluent areas resulting in a “ground glass” bright appearance on T2-weighted MRI scan. (B) Enlarged oligodendrocyte with a large inclusion-bearing nucleus is characteristic of PML. No discrete intranuclear inclusion is seen. (C) A large bizarre astrocyte is depicted. (D) Immunostaining with polyclonal antibody to JC virus from Abcam Inc. shows dark brown staining of nuclei of several oligodendrocytes. (E) Electron micrograph of crystalline array of assembled JC virions in nuclei of infected oligodendrocyte in PML brain lesion. Virions measure 40 nm in diameter.

Figure 2. MRI in progressive multifocal leukoencephalopathy

(A) Fluid-attenuated inversion recovery image with large subcortical lesion of right frontal lobe. A smaller lesion is observed posterior to this lesion. (B) T1-weighted image shows hypointense lesion (arrow) in the right frontal lobe. (C) T2-weighted image from another patient with extensive high signal intensity lesions in the white matter sparing the cortex. An area of hyperintensity similar to that of CSF suggests an area of cavitation.

Figure 3. Algorithm for diagnosing progressive multifocal leukoencephalopathy

FLAIR = fluid-attenuated inversion recovery; JCV = JC virus; PML = progressive multifocal leukoencephalopathy; PRES = posterior reversible encephalopathy syndrome; VZV = varicella-zoster virus.