JC virus granule cell neuronopathy and GCN–IRIS under natalizumab treatment

Abstract

Progressive multifocal leukoencephalopathy is the most common clinical presentation of JC virus (JCV)-associated central nervous system (CNS) disease and has emerged as a major safety concern in multiple sclerosis patients treated with the monoclonal antibody natalizumab. Here we report clinical, radiological, and histological findings of a case of cerebellar granule cell neuronopathy (GCN), a JCV-associated CNS disease, so far unreported amongst patients treated with natalizumab. GCN should be considered as a JCV CNS manifestation in patients with newly developed, progressive cerebellar signs under natalizumab treatment, especially in cases where cerebellar atrophy can be visualized by magnetic resonance imaging.

MRI pattern in asymptomatic natalizumab-associated PML

“…Fortunately, several histopathological studies have conclusively demonstrated that cortical pathology in terms of neuronal infection and cortical demyelination are important features in PML or JCV infection in general 27–32. This is also reflected by subtypes of JCV infection such as granule cell neuropathy and JCV associated encephalopathy 29 32 33. In other words, PML is not a white matter disease as the term “leukoencephalopathy” might suggest.…”

JC virus granule cell neuronopathy: A cause of infectious cerebellar degeneration

“…Adding our 5 cases leads to a total of 23 reported cases (22 probable and 1 possible). Most cases of JC-GCN were described in HIV-infected patients [15][16][17], but some others were in patients with sarcoidosis [18], congenital CD40 ligand deficiency [19] and rituximab treatment [20] or natalizumab treatment for multiple sclerosis [21,22].…”

“…A unique case of immune reconstitution inflammatory syndrome was reported [21] after natalizumab withdrawal. No gadolinium enhancement was described, but cerebellar biopsy identified an extensive inflammatory reaction associated with JC-GCN.…”

Mechanisms of immune escape in central nervous system infection with neurotropic JC virus variant

“…16,22,30 Importantly, the presence of both CD4 + and CD8 + T cells were described in brain biopsies of PML-IRIS and GCN-IRIS cases, indicating that both subpopulations are relevant for controlling JCV infection in the CNS. 16,22,30 However, several studies reported dominant CD8 + T cell infiltrates in the brain during PML-IRIS However, a recent study on JCV epitope mapping using the same JCV peptide pools revealed that a wide range of different epitopes is recognized, that responses to all JCV peptide pools were detected and that there was high variability of reactivity against single JCV peptide pools between different individuals suggesting that the 15-mer peptides used in this work should be sufficient to uncover variability in epitope specificity. 20 The preferential expression of LTAg in granule cell neurons 32 suggests that CD8 + T cells are the main effector cells for eliminating JCV GCN -infected granule cell neurons.…”