JC virus (JCV) causes lytic infection of oligodendrocytes, leading to demyelinating disease of the brain called progressive multifocal leukoencephalopathy (PML). In addition, JCV may infect cerebellar granule cell neurons resulting in JCV granule cell neuronopathy (GCN). JCV GCN is associated with mutations in the C terminus of the JCV VP1 gene, coding for the major capsid protein.
The objective of this paper is to describe the clinical, neuroimaging, immunologic, and virologic characteristics of JC virus–associated granule cell neuronopathy in a natalizumab-treated patient with multiple sclerosis (MS) who developed immune reconstitution inflammatory syndrome (IRIS) after natalizumab withdrawal.
After 63 infusions of Natalizumab, a 32-year-old man with MS and JCV-seropositive presented with changes in his handwriting, speech, and gait. As progressive cerebellar symptoms increased, he underwent a CSF analysis which confirmed the diagnosis of JCV GCN. Natalizumab was discontinued and he received plasma exchange (PLEX) for five days. MRI showed progressive cerebellar atrophy without any confluent white matter lesions.
About four weeks after PLEX, he developed vertigo, headaches, and dysphonia and an MRI scan was suggestive of IRIS. Molecular analysis of CSF JCV strains revealed mutations in the C terminus of the VP1 gene, consistent with GCN-type JCV strains. MRI and proton magnetic resonance spectroscopy (1H-MRS) obtained eight months after onset of symptoms showed near resolution of cerebellar enhancement. Eleven months after initial presentation, ataxia, nystagmus, and dysarthria persisted. Spasticity from his cervical MS lesions and the cerebellar ataxia restrict him to a wheelchair for most of the time.
The authors obtained longitudinal clinical data as well as MRI and proton magnetic resonance spectroscopy from this patient with MS. They measured JCV-specific cellular immune response in his peripheral blood by intracellular cytokine staining and sequenced a fragment of JCV VP1 capsid gene detected in his CSF. Treatment with corticosteroids resulted in resolution of IRIS, as demonstrated by proton magnetic resonance spectroscopy.
The patient had a strong JCV-specific T-cell response in his peripheral blood and remains alive after 15 months from onset of symptoms, although with significant disability. He did not have MS relapse on glatiramer acetate.
The authors also contrasted their findings with the first reported case of JCV GCN in a natalizumab-treated patient with MS. Both patients received more than 50 doses of natalizumab monotherapy and had progressive cerebellar symptoms without white matter changes suggestive of PML on initial MRI. They were both treated with PLEX and survived with significant morbidity. In the absence of a definite treatment against JCV, early withdrawal of natalizumab followed by PLEX constitutes the only hope for the immune system to contain JCV GCN and avoid irreversible cerebellar damage. IRIS should be expected as a complication of this treatment, and timing of corticosteroid administration may be guided by 1H-MRS.
Agnihotri SP, Dang X
: Neurology. 2014 Jul 18. pii: 10.1212/WNL.0000000000000713. [Epub ahead of print]
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