Novel syndromes associated with JC virus infection of neurons and meningeal cells: no longer a gray area

Abstract

Purpose of review: The availability of a growing number of immunomodulatory medications over the past few years has been associated with various JC virus (JCV)-associated brain syndromes in patients with autoimmune diseases, including multiple sclerosis, Crohn's disease, and psoriasis that had not been previously recognized as predisposing factors for progressive multifocal leukoencephalopathy. This review covers the three novel syndromes discovered in the last decade that are caused by JCV infection of neurons and meningeal cells.

Recent findings: For more than 30 years, JCV was thought to exclusively infect oligodendrocytes and astrocytes in the white matter of the brain of immunosuppressed individuals. We now recognize that JCV-infected glial cells are frequently located at the gray-white matter junction or exclusively within the gray matter causing demyelination in the cortex. Mutations in JCV can trigger a change in tropism leading to involvement of other cell types, such as neurons and meningeal cells, causing clinically distinct entities. These new features of JCV infection provide challenges for clinicians taking care of affected patients and investigators studying the biology of this polyomavirus, its pathogenesis, and tropism.

Summary: We hope that increasing awareness of these syndromes will lead to early diagnosis, and pave the way for new avenues of research to better understand all aspects of JCV pathogenesis and develop efficient therapies for our patients. However, we need to remain vigilant and open to the possibility that additional JC variants or yet unknown polyomaviruses may also be associated with neurological diseases.

Figure 1. JC Virus Granule Cell Neuronopathy (JCV GCN)

MRI demonstrates progressive cerebellar atrophy without intra-parenchymal lesions. (A) Pre-contrast T1 sagittal image illustrating the size of the cerebellum at symptoms onset. (B) Pre-contrast T1 sagittal image done 4 months later and a week after positive CSF JC Virus PCR shows marked cerebellar atrophy (arrow).

Figure 2. JC Virus Encephalopathy (JCVE)

MRI demonstrates multiple cortical lesions with hyperintense signal on fluid-attenuated inversion recovery sequence in the cerebral hemispheres bilaterally (arrows).

Figure 3. JC Virus Meningitis (JCVM)

MRI demonstrates hydrocephalus, abnormal signal in subarachnoid space, and no parenchymal brain lesions. (A) Axial fluid-attenuated inversion recovery sequence shows enlarged ventricles and abnormal hyperintensity in the subarachnoid space, within the sulci of the cerebral hemispheres (arrows). (B) A sagittal T1-weighted sequence demonstrates significant enlargement of the lateral ventricle.

Figure 4. Continuum of CNS syndromes caused by JC Virus (JCV)

The arrows indicate that more than one syndrome may coexist. PML = progressive multifocal leukoencephalopathy; JCVE = JC Virus Encephalopathy; JCVM = JC Virus Meningitis; JCV GCN = JC Virus Granule Cell Neuronopathy; GCL = Granule Cell Layer; PCL = Purkinje Cell Layer; ML = Molecular layer; WM = white matter; = JC virion