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Published: 7 September 2017

JC Virus — More than PML

Prescriber Update 38(3): 34-36
September 2017

Key Messages

  • In immunocompromised patients infected with JC virus, mutation of the virus can lead to neurological infection causing clinically distinct entities: PML, granule cell neuronopathy, encephalopathy and meningitis.
  • PML and granule cell neuronopathy have been diagnosed in patients treated with immune-suppressing medicines, particularly natalizumab and rituximab.
  • Clinicians should be aware of JC virus-granule cell neuronopathy and should consider this in cases of progressive cerebellar syndrome of unknown origin in immunosuppressed patients.

JC Virus

The etiologic agent of progressive multifocal leukoencephalopathy (PML) is a small ubiquitous polyomavirus, the JC virus (JCV). At least 50% of the general population is seropositive to JCV1.

It is believed that initial infection with JCV results in a transient viraemia before the virus establishes as a latent or persistent infection in the kidney, tonsils and gut1,2. JCV reactivation can occur particularly in the setting of cellular immune suppression2.

Mutations in the JCV genome can allow JCV to infect other cell types, such as oligodendrocytes, astrocytes, neurones and meningeal cells. Clinically distinct entities occur depending on the location of infection including:

JCV meningitis, JCV encephalopathy, JCV-GCN and PML may occur separately or co-exist on a continuum as the virus mutates and spreads from one location to another3. These new features of JCV infection provide challenges for clinicians taking care of affected patients (Table 1)3,4.

Table 1: Clinical presentation of JC virus infection (adapted from Tan)4

  Classic PML PML–IRIS JCV–GCN JCV encephalitis JCV meningitis
Onset Subacute Immune recovery Chronic Subacute Acute
MRI findings Asymmetric well demarcated non-enhancing subcortical white matter lesions Contrast enhancement and mass effect Cerebellar atrophy Cortical lesions No defined brain lesions, ventricular dilation
Neurological symptoms Based on location Based on location and inflammation Cerebellar syndrome Encephalopathy Headache, stiff neck, fever
Diagnosis JC virus detection in the CSF, brain biopsy, MRI findings and symptoms JC virus detection in the CSF, brain biopsy, MRI findings and symptoms Cerebellar biopsy, JC virus in CSF, radiological findings and symptoms Brain biopsy, JC virus PCR in the CSF, radiographical findings and symptoms JC virus in the CSF and exclusion of other viruses
Treatment Decrease immunosuppression, plasma exchange for natalizumab-treated patients Similar to PML, steroids in cases with notable worsening Similar to classic PML Similar to classic PML Similar to classic PML

PML

PML has been described in previous Prescriber Update articles, PML: a rare but serious disease (www.medsafe.govt.nz/profs/PUArticles/PMLSept2012.htm) and Reminder: immunomodulatory medicines and risk of progressive multifocal leukoencephalopathy (www.medsafe.govt.nz/profs/PUArticles/March2016/ReminderImmunomodulatoryMedicinesAndRiskProgressiveMultifocalLeukoencephalopath.htm).

Initially PML was mostly associated with HIV infection, but is now increasingly being associated with medicine-induced immune suppression. For example, in patients taking natalizumab, who have JCV antibodies and prior immunosuppressant use, the frequency of PML is 1%5. The features of PML are summarised in Table 1.

PML-Immune Reconstitution Inflammatory Syndrome (PML-IRIS)

A cellular immune response directed against JCV is beneficial in classic PML. However, a rapid global recovery of the immune system may not always be favourable. It can trigger an immune reconstitution inflammatory syndrome (IRIS).

IRIS is an inflammatory response to clinically apparent or subclinical pathogens associated with recovery of the immune system after a period of immunosuppression. Immune reconstitution is inferred by an increase in T lymphocyte counts. This can occur after starting combination anti-retroviral therapy in HIV positive patients or with stopping immunosuppressive therapy, for example with natalizumab4.

Natalizumab has a biological activity of three months following discontinuation, during which time either PML can progress or the resulting return of lymphocytes in the CNS may lead to IRIS. Plasma exchange/immunoadsorption reduces the serum concentration of natalizumab more quickly. The rapid restoration of the immune system increases the risk of precipitating a severe IRIS reaction up to three weeks later. Aggressive use of corticosteroids has been recommended in this situation to reduce the risk of a fatal outcome4.

Granule Cell Neuronopathy (JCV-GCN)

In JCV-GCN, JCV infects the granule cell layer of the cerebellum, but spares Purkinje cells3. Symptoms include ataxia, tremor, dysarthria, dysdiadochokinesia (inability to perform rapid alternating movements), dysmetria (lack of coordination) on finger to nose and heel to shin testing, incoordination and nystagmus4.

MRI typically shows cerebellar atrophy suggestive of neurodegeneration3,4. The diagnosis is established by cerebellar biopsy showing a lytic infection of granule cell neurons by JCV4.

JCV-GCN has mainly been reported in patients with HIV infection, but also in patients treated with natalizumab and rituximab2,3.

JCV-GCN can occur in isolation or concomitantly to PML. A histologic survey of archival PML samples indicated that infection of granule cell neurons may be found in up to half of patients with PML3. It is unclear whether JCV-GCN should be considered as a separate entity of JCV related disease or a PML subtype2.

The reversal of the immunocompromised status is the only way to stop the disease evolution of JCV-GCN. Motor function can remain impaired, but the illness itself, unlike PML does not appear to be life-threatening6.

Clinicians should be aware of this entity. JCV-GCN should be considered in cases of progressive cerebellar syndrome of unknown origin in immunosuppressed patients6.

JCV Encephalitis

JCV encephalitis occurs when JCV infects cerebral pyramidal neurons and astrocytes in the cortical grey matter and grey-white junction. The pathology of JCV encephalitis is characterised by the infection and lysis of cortical grey matter1,3,4.

JCV Meningitis

JCV meningitis has been associated with findings of JCV in the CSF of patients presenting with meningeal symptoms only4. Several studies have documented JCV as the only pathogen present in the CSF of patients with typical meningeal signs and symptoms such as neck stiffness and diplopia. Whether these cases result from JCV primary infection or reactivation is unclear3.

Healthcare professionals should be aware that JCV infection can result in clinically distinct entities depending on the location of infection. JCV-GCN, in addition to PML, has been reported in patients with medicine-induced immune suppression.

References
  1. Adang L, Berger J. 2015. Progressive multifocal leukoencephalopathy. F1000Research 4: 1424.
  2. Wijlburg MT, van Oosten BW, Murk J-L et al. 2015. Heterogeneous imaging characteristics of JC virus granule cell neuronopathy (GCN): a case series and review of the literature. Journal of Neurology 262: 65–73.
  3. Miskin DP, Kroalnik IJ. 2015. Novel syndromes associated with JC virus infection of neurons and meningeal cells: no longer a gray area. Current Opinion in Neurology 28: 288–94.
  4. Tan CS, Koralnik IJ. 2010. Beyond progressive multifocal leukoencephalopathy: expanded pathogenesis of JC virus infection in the central nervous system. Lancet Neurology 9: 425–37.
  5. Biogen NZ Biopharma Limited. 2016. Tysabri Data Sheet. 11 November 2016. URL: medsafe.govt.nz/profs/Datasheet/t/Tysabriinf.pdf (accessed 3 July 2017).
  6. Henry C, Jouan F, De Brouker T. 2015. JC virus granule cell neuronopathy: a cause of infectious cerebellar degeneration. Journal of the Neurological Sciences 354: 86–90.
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