Progressive Multifocal Leukoencephalopathy: Pathogenesis, Diagnostic Tools, and Potential Biomarkers of Response to Therapy

Abstract

JC polyomavirus (JCV) establishes an asymptomatic latent and/or persistent infection in most of the adult population. However, in immunocompromised individuals, JCV can cause a symptomatic infection of the brain, foremost progressive multifocal leukoencephalopathy (PML). In the past 2 decades, there has been increasing concern among patients and the medical community because PML was observed as an adverse event in individuals treated with modern (selective) immune suppressive treatments for various immune-mediated diseases, especially multiple sclerosis. It became evident that this devastating complication also needs to be considered beyond the patient populations historically at risk, including those with hematologic malignancies or HIV-infected individuals. We review the clinical presentation of PML, its variants, pathogenesis, and current diagnostic approaches. We further discuss the need to validate JCV-directed interventions and highlight current management strategies based on early diagnosis and restoring JCV-specific cellular immunity, which is crucial for viral clearance and survival. Finally, we discuss the importance of biomarkers for diagnosis and response to therapy, instrumental in defining sensitive study end points for successful clinical trials of curative or preventive therapeutics. Advances in understanding PML pathophysiology, host and viral genetics, and diagnostics in conjunction with novel immunotherapeutic approaches indicate that the time is right to design and perform definitive trials to develop preventive options and curative therapy for JCV-associated diseases.

Figure 1. Number of Results per Year on PubMed^a (as of December 2022) of Articles Reporting on “Progressive Multifocal Leukoencephalopathy”

^apubmed.ncbi.nlm.nih.gov. A first epoch of research can be noted between 1958 and 1980 (n = 298), a second between 1981 and 2004 (n = 1,544), and a third starting in 2005 (n = 2,849).

Figure 2. Summary of Findings in Progressive Multifocal Leukoencephalopathy

According to current PML diagnostic criteria, for a definitive PML diagnosis, consistent clinical and imaging findings not better explained otherwise in combination with the detection of JCV DNA by PCR in CSF are needed (gray).^e79 Alternatively, biopsy-based diagnosis (blue) requires the histopathologic triad coupled with a technique showing the presence of JCV in tissue.^e80 The figure was designed using biorender. JCV = JC polyomavirus; PML = progressive multifocal leukoencephalopathy.

Figure 3. Magnetic Resonance Imaging Findings in PML

(A) Axial(FLAIR), conventional T2-weighted, gadolinium-enhanced T1-weighted and diffusion-weighted imaging (including ADC mapping) typically used in clinical routine care for detection of PML. Multifocal leukocortical PML lesions involving both hemispheres with a more extensive lesion in the right parietal lobe involving the cortical gray matter, as well as the juxtacortical and deep white matter with multiple punctuate T2 lesions (arrows on the FLAIR and T2-weighted image). Some punctuate lesions show contrast enhancement. Focal areas show already a hypointense signal intensity in the T1-weighted sequence. Areas of high signal intensity on B1000 diffusion-weighted imaging with heterogenous ADC values indicate oligodendrocyte swelling suggestive of active viral replication (arrows). (B) Gadolinium-enhanced T1-weighted and axial FLAIR imaging before and 8 weeks after plasma exchange. Infratentorial PML lesions display more pronounced contrast enhancement on the gadolinium-enhanced T1-weighted image (arrows) and progressive hyperintense T2-FLAIR changes (arrows) partly due to perilesional edema and swelling after accelerated removal of natalizumab using plasma exchange (PLEX) in an individual who developed PML during therapy with natalizumab for MS. In a setting of a proposed reconstitution of the cellular immunity due to enhanced natalizumab drug clearance after PLEX and a more pronounced cerebellar syndrome indicating clinical deterioration, these imaging findings fit with a diagnosis of PML-IRIS. ADC = apparent diffusion coefficient; FLAIR = fluid-attenuated inversion recovery; IRIS = immune reconstitution inflammatory syndrome; MS = multiple sclerosis; PML = progressive multifocal leukoencephalopathy.

Figure 4. Typical PML Lesion Characteristics With Demyelination

(A) Luxol Fast Blue/Periodic Acid-Schiff staining, myelin stained in blue is missing. Only some residual myelin sheaths are present on the left side of the picture. (B) Hematoxylin and eosin staining, enlarged oligodendrocytic nuclei. (C) Anti-VP1, within lesions, numerous virus-replicating glial cells are found. (D) Anti-Glial Fibrillary Acidic Protein, bizarre astrocytes. (E) Anti-CD3, typical for classic PML, only a few T cells are evident. PML = progressive multifocal leukoencephalopathy; VP1 = viral protein 1.