JC virus granule cell neuronopathy onset two months after chemotherapy for low-grade lymphoma

JC virus granule cell neuronopathy onset two months after chemotherapy for low-grade lymphoma:

Abstract

Background

Granule cell neuronopathy (GCN) is a rare disease caused by the JC virus, leading to degeneration of cerebellar granule cell neurons. Primarily described in patients with AIDS, it has also been diagnosed in patients with lymphoproliferative diseases and after long-term treatment with immune-suppressing medications such as natalizumab.

Case presentation

A 69 year old woman presented with progressive ataxia which began 2 months after initiation of treatment for follicular low-grade B cell lymphoma with rituximab/bendamustine, and progressed for 2 years prior to admission. Extensive prior evaluation included MRI that showed atrophy of the cerebellum but normal CSF analysis and serum studies. Neurologic exam on admission was notable for severe appendicular ataxia and fatigable end-gaze direction-changing horizontal nystagmus. FDG-PET/CT scan was unremarkable and repeat lumbar puncture revealed 2 WBCs/mm³, 148 RBCs/mm³, glucose 70 mg/dL, protein 37.7 mg/dL and negative flow cytometry/cytopathology. Standard CSF JC virus PCR testing was negative, but ultrasensitive TaqMan real-time JC virus PCR testing was positive, consistent with JC virus-related GCN.

Conclusions

Because of the diagnostic challenges in identifying GCN, a high threshold of suspicion should be maintained in patients with an immune-suppressing condition such as lymphoma or on immune-suppressing agents such as rituximab, even shortly after initiation of therapy.

Πολυόμα ιός JC

Επιστημονική ονομασία: JC polyomavirus

Κατάταξη: Είδος

Υψηλότερη κατηγορία ταξινόμησης:Polyomavirus

JC virus

From Wikipedia, the free encyclopedia

JC virus
Immunohistochemical detection of JC virus protein (stained brown) in a brain biopsy (glial cellsdemonstrating progressive multifocal leukoencephalopathy(PML))
Virus classification
Group:	Group I (dsDNA)
Family:	Polyomaviridae
Genus:	Polyomavirus
Species:	JC polyomavirus

The JC virus or John Cunningham virus (JCV, not to be confused with Jamestown Canyon virus that bears the same initials) is a type of human polyomavirus (formerly known as papovavirus) and is genetically similar to BK virus and SV40. It was identified by electron microscopy in 1965 by ZuRhein and Chou,^[1] and by Silverman and Rubinstein, and later isolated in culture and named using the two initials of a patient, John Cunningham, with progressive multifocal leukoencephalopathy (PML).^[2] The virus causes PML and other diseases only in cases of immunodeficiency, as in AIDS or during treatment with drugs intended to induce a state of immunosuppression (e.g. organ transplant patients).^[3]

Contents

  [hide] 

• 1Epidemiology
• 2Infection and pathogenesis
• 3Drugs associated with reactivation
• 4References
• 5External links

Epidemiology[edit]

A map of the genome of JC virus, indicating the position of the tumor antigen genes (red), the three capsid protein genes (green and blue), theagnogene (yellow), and the non-codingcontrol region (NCCR).^[4]

The virus is very common in the general population, infecting 70% to 90% of humans; most people acquire JCV in childhood or adolescence.^[5][6][7] It is found in high concentrations in urban sewage worldwide, leading some researchers to suspect contaminated water as a typical route of infection.^[8]

Minor genetic variations are found consistently in different geographic areas; thus, genetic analysis of JC virus samples has been useful in tracing the history of human migration.^[9] 14 subtypes or genotypes are recognised each associated with a specific geographical region. Three are found in Europe (a, b and c). A minor African type—Af1—occurs in Central and West Africa. The major African type—Af2—is found throughout Africa and also in West and South Asia. Several Asian types are recognised B1-a, B1-b, B1-d, B2, CY, MY and SC.

An alternative numbering scheme numbers the genotypes 1–8 with additional lettering. Types 1 and 4 are found in Europe and in indigenous populations in northern Japan, North-East Siberia and northern Canada. These two types are closely related. Types 3 and 6 are found in sub-Saharan Africa: type 3 was isolated in Ethiopia, Tanzania and South Africa. Type 6 is found in Ghana. Both types are also found in the Biaka Pygmies and Bantus from Central Africa. Type 2 has several variants: subtype 2A is found mainly in the Japanese population and Native Americans (excluding Inuit); 2B is found in Eurasians; 2D is found in Indians and 2E is found in Australians and western Pacific populations. Subtype 7A is found in southern China and South-East Asia. Subtype 7B is found in northern China, Mongolia and Japan Subtype 7C is found in northern and southern China. Subtype 8 is found in Papua New Guinea and the Pacific Islands.

Infection and pathogenesis[edit]

The initial site of infection may be the tonsils,^[10] or possibly the gastrointestinal tract.^[8] The virus then remains latent in the gastrointestinal tract^[11] and can also infect the tubular epithelial cells in the kidneys,^[12] where it continues to reproduce, shedding virus particles in the urine.

JCV can cross the blood–brain barrier into the central nervous system, where it infects oligodendrocytes and astrocytes, possibly through the 5-HT_2A serotonin receptor.^[13] JC viral DNA can be detected in both non-PML affected and PML-affected (see below) brain tissue.^[14]

JCV found in the central nervous system of PML patients almost invariably have differences in promoter sequence to the JCV found in healthy individuals. It is thought that these differences in promoter sequence contribute to the fitness of the virus in the CNS and thus to the development of PML.^[3]

Immunodeficiency or immunosuppression allows JCV to reactivate. In the brain, it causes the usually fatal progressive multifocal leukoencephalopathy, or PML, by destroying oligodendrocytes. Whether this represents the reactivation of JCV within the CNS or seeding of newly reactivated JCV via blood or lymphatics is unknown.^[15] Several studies since 2000 have suggested that the virus is also linked to colorectal cancer, as JCV has been found in malignant colon tumors, but these findings are still controversial.^[16]

Drugs associated with reactivation[edit]

Since immunodeficiency causes this virus to progress to PML, immunosuppressants are contraindicated in those who are infected.

The boxed warning for the drug rituximab (Rituxan, co-marketed by Genentech BioOncology and Biogen Idec) includes a statement that JC virus infection resulting in progressive multifocal leukoencephalopathy, and death has been reported in patients treated with the drug.^[17]

The boxed warning for the drug natalizumab (Tysabri, marketed by Elan and developed by Biogen Idec) includes a statement that JC virus resulted in progressive multifocal leukoencephalopathy developing in three patients who received natalizumab in clinical trials.

The boxed warning had been included for the drugs Tecfidera and Gilenya, both of which have had incidences of PML resulting in death.

The boxed warning was added on Feb. 19, 2009, for the drug efalizumab (Raptiva, marketed in the U.S. by Genentech, and marketed in Europe by Swiss drugmaker Merck Serono) includes a statement that JC virus, resulting in progressive multifocal leukoencephalopathy, developed in three patients who received efalizumab in clinical trials. The drug was pulled off the U.S. market because of the association with PML on April 10, 2009.

A boxed warning for brentuximab vedotin (Adcetris) was issued by the FDA on January 13, 2011 after two cases of PML were reported, bringing the total number of associated cases to three.^[18]

References[edit]

1. Jump up^ Zurhein, G; Chou, S. M. (1965). "Particles Resembling Papova Viruses in Human Cerebral Demyelinating Disease". Science. 148(3676): 1477–9. PMID 14301897.doi:10.1126/science.148.3676.1477.
2. Jump up^ Padgett BL, Walker DL; et al. (1971). "Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy".Lancet. 1 (7712): 1257–60. PMID 4104715. doi:10.1016/S0140-6736(71)91777-6.
3. ^ Jump up to:^a b Ferenczy, MW; Marshall, LJ; Nelson, CD; Atwood, WJ; Nath, A; Khalili, K; Major, EO (July 2012). "Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain.". Clin. Microbiol. Rev. 25 (3): 471–506. PMC 3416490 . PMID 22763635.doi:10.1128/CMR.05031-11.
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5. Jump up^ Agostini, H.T.; Ryschkewitsch, C.F.; Mory, R.; Singer, E.J.; Stoner, G.L. (1997). "JC Virus (JCV) genotypes in brain tissue from patients with progressive multifocal leukoencephalopathy (PML) and in urine from controls without PML: increased frequency of JCV Type 2 in PML".J. Infect. Dis. 176 (1): 1–8. JSTOR 30107072. PMID 9207343.doi:10.1086/514010.
6. Jump up^ Shackelton, L.A.; Rambaut, A.; Pybus, O.G.; Holmes, E.C. (2006)."JC Virus evolution and its association with human populations".Journal of Virology. 80 (20): 9928–33. PMC 1617318 .PMID 17005670. doi:10.1128/JVI.00441-06.
7. Jump up^ Padgett, B.L.; Walker, D.L. (1973). "Prevalence of antibodies in human sera against JC virus, an isolate from a case of progressive multifocal leukoencephalopathy". J. Infect. Dis. 127 (4): 467–470.PMID 4571704. doi:10.1093/infdis/127.4.467.
8. ^ Jump up to:^a b Bofill-Mas, S., Formiga-Cruz, M., Clemente-Casares, P., Calafell, F. and Girones, R. (2001). "Potential transmission of human polyomaviruses through the gastrointestinal tract after exposure to virions or viral DNA". J. Virol. 75 (21): 10290–9. PMC 114603 .PMID 11581397. doi:10.1128/JVI.75.21.10290-10299.2001.
9. Jump up^ Pavesi, A. (2005). "Utility of JC polyomavirus in tracing the pattern of human migrations dating to prehistoric times". J. Gen. Virol. 86 (Pt 5): 1315–26. PMID 15831942. doi:10.1099/vir.0.80650-0.
10. Jump up^ Monaco, M.C., Jensen, P.N., Hou, J., Durham, L.C. and Major, E.O. (1998). "Detection of JC virus DNA in human tonsil tissue: evidence for site of initial viral infection". J. Virol. 72 (12): 9918–23. PMC 110504 . PMID 9811728.
11. Jump up^ Ricciardiello, L., Laghi, L., Ramamirtham, P., Chang, C.L., Chang, D.K., Randolph, A.E. and Boland, C.R. (2000). "JC virus DNA sequences are frequently present in the human upper and lower gastrointestinal tract". Gastroenterology. 119 (5): 1228–35.PMID 11054380. doi:10.1053/gast.2000.19269.
12. Jump up^ Cornelissen, Cynthia Nau; Harvey, Richard A.; Fisher, Bruce D. (2012). "X. Opportunistic Infections of HIV: JC Virus (JCV)".Microbiology. Illustrated Reviews. 3. Lippincott Williams & Wilkins. p. 389. ISBN 978-1-60831-733-2.
13. Jump up^ Elphick, G.F., Querbes, W., Jordan, J.A., Gee, G.V., Eash, S., Manley, K., Dugan, A., Stanifer, M., Bhatnagar, A., Kroeze, W.K., Roth, B.L. and Atwood, W.J. (2004). "The human polyomavirus, JCV, uses serotonin receptors to infect cells". Science. 306 (5700): 1380–3.PMID 15550673. doi:10.1126/science.1103492.
14. Jump up^ White, F.A., 3rd., Ishaq, M., Stoner, G.L. and Frisque, R.J. (1992)."JC virus DNA is present in many human brain samples from patients without progressive multifocal leukoencephalopathy". J. Virol. 66 (10): 5726–4. PMC 241447 . PMID 1326640.
15. Jump up^ Progressive Multifocal Leukoencephalopathy in HIV at eMedicine
16. Jump up^ Theodoropoulos, G., Panoussopoulos, D., Papaconstantinou, I., Gazouli, M., Perdiki, M., Bramis, J. and Lazaris, ACh. (2005). "Assessment of JC polyoma virus in colon neoplasms". Dis. Colon. Rectum. 48 (1): 86–91. PMID 15690663. doi:10.1007/s10350-004-0737-2.
17. Jump up^ http://ift.tt/2sROzyq
18. Jump up^ "Adcetris (brentuximab vedotin): Drug Safety Communication—Progressive Multifocal Leukoencephalopathy and Pulmonary Toxicity". U.S. FDA. Retrieved 14 January 2012.

• Zu Rhein, G.M.; Chou, S.M. (1965). "Particles Resembling Papova Viruses in Human Cerebral Demyelinating Disease". Science. 148: 1477–9.PMID 14301897. doi:10.1126/science.148.3676.1477.
• Silverman, L.; Rubinstein, L.J. (1965). "Electron microscopic observations on a case of progressive multifocal leukoencephalopathy". Acta Neuropathologica. 5: 215–224. doi:10.1007/bf00686519.

External links[edit]

• JC Brain infection MRI Diagnosis of PML
• Ramirez, B. Vagner; Palacio, V. Castano (2013). "JC virus: A brief review". World J. Neurosci. 3: 126–130. doi:10.4236/wjns.2013.32015.

Taxon identifiers	NCBI: 10632

[show] v t e Human polyomaviruses

[show] v t e Infectious diseases – viral systemic diseases (A80–B34, 042–079)

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