JC virus granule cell neuronopathy
JC virus granule cell neuronopathy results from the reactivation of the John Cunningham virus (JC virus), infecting granule cell neurons in the cerebellum, in patients with compromised immune systems.
Immunosuppression is the most significant risk factor :
- immunosuppressive monoclonal antibody therapy (e.g. rituximab, natalizumab)
- congenital CD40 ligand deficiency
- lymphoma with chronic leukopenia
Patients present with progressive subacute or chronic cerebellar and brainstem dysfunction, characterized by signs and symptoms such as :
- gait disturbance
JC virus granule cell neuronopathy is secondary to progressive infection of granule cell neurons in the cerebellum due to the reactivation of the JC virus . It has been postulated that for the JC virus to preferentially infect granule cell neurons instead of glial cells, there must be a mutation, typically involving the C terminus of the VP1 gene, that triggers this change .
There is derangement of the normal laminar cellular organization of cerebellum, with the hallmark histological feature of JC virus granule cell neuronopathy being infection and loss of granule cell neurons in the internal granule cell layer, with sparing of the molecular and Perkinje layers . Additionally, there may also be involvement of nearby glial cells (e.g. oligodendrocytes and astrocytes) .
The most characteristic finding is bilateral, diffuse, symmetric cerebellar atrophy . This is seen in almost all cases reported in the literature .
- T1: normal
- T2/FLAIR: confluent hyperintense regions
- a hot cross bun sign may be noted if the pons is involved
- T1 C+ (Gd): no enhancement
There is conjecture whether these white matter changes are truly due to JC virus granule cell neuronopathy, or due to concurrent infratentorial progressive multifocal leukoencephalopathy . Regardless, supratentorial white matter involvement, on the other hand, is not a feature of JC virus granule cell neuronopathy, and its involvement may be due to other manifestations of the JC virus such as progressive multifocal leukoencephalopathy or immune reconstitution inflammatory syndrome, which are known to manifest concurrently with JC virus granule cell neuronopathy .
One case report describes use of FDG-PET to aid in the diagnosis, showing patchy hypometabolism in the cerebellum, reflective of neuronal cell loss .
Treatment and prognosis
There is currently (as of March 2019) no disease-specific therapy available for JC virus granule cell neuronopathy, and management is therefore supportive.
Longitudinal prognostic data is lacking in the literature; however, small case series suggest that patients will often have a progressive course that will eventually plateau over months with persisting neurological disability .