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Case Report/Case Series |

JC Polyomavirus Granule Cell Neuronopathy in a Patient Treated With Rituximab FREE

Louis Dang, MD, PhD1; Xin Dang, PhD2; Igor J. Koralnik, MD2; Peter K. Todd, MD, PhD1
[+] Author Affiliations
1Department of Neurology, University of Michigan, Ann Arbor
2Division of Neurovirology, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
JAMA Neurol. 2014;71(4):487-489. doi:10.1001/jamaneurol.2013.4668.
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Published online

Importance  Progressive multifocal leukoencephalopathy results from lytic infection of the glia by the JC polyomavirus (JCV); JCV granule cell neuronopathy is caused by infection with a mutated form of JCV, leading to a shift in viral tropism from the glia to cerebellar granule cells. This shift results in a clinical syndrome dominated by progressive cerebellar dysfunction that might elude standard diagnostic workup strategies for ataxia.

Observations  We present the case report of a patient receiving long-term rituximab therapy who developed progressive cerebellar ataxia and marked isolated cerebellar degeneration. This syndrome resulted from JCV granule cell neuronopathy associated with a novel JCV mutation.

Conclusions and Relevance  New onset or worsening of isolated cerebellar ataxia in patients being treated with rituximab or natalizumab warrants early assessment for JCV infection.

Figures in this Article

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease that occurs in the setting of severe immunosuppression and results from lytic infection of glia by the JC polyomavirus (JCV). In rare cases, mutations in JCV can trigger a change in tropism, leading to involvement of other cell types.

An older man presented with an 8-month history of progressive cerebellar ataxia. Eleven years before presentation, the patient was diagnosed as having non-Hodgkin lymphoma and treated with 6 cycles of the CHOP (cyclophosphamide, doxorubicin hydrochloride [hydroxydaunorubicin], vincristine sulfate [Oncovin], and prednisone) regimen, with a good response. He started maintenance therapy consisting of rituximab with infusions initially every 6 months. Five years before presentation, the frequency of rituximab infusions was increased to every month because of persistent lymphadenopathy.

Eight months before presentation, the patient noted the gradual onset of gait instability. Magnetic resonance imaging of the brain demonstrated early vermian atrophy in the cerebellum but no significant white matter changes (Figure, A-C). A lumbar puncture 2 months after symptom onset showed a white blood cell count of 12/mm3 with 44% lymphocytes and 56% monocytes, an elevated protein level at 102 mg/dL, and a glucose level within the reference range at 68 mg/dL, without malignant cells on cytopathologic analysis.

Place holder to copy figure label and caption
Figure.
Brain Magnetic Resonance Imaging (MRI) in a Case of JC Polyomavirus Granule Cell Neuronopathy

At symptom onset, no significant cerebellar or white matter abnormalities were observed (A-C). One year after symptom onset, T1-weighted image demonstrates significant cerebellar atrophy (D). In addition, abnormal T2-weighted fluid-attenuated inversion recovery (FLAIR) signal involved the white matter tracts of the dorsal midbrain (E) and pons (F) and the cerebellar peduncles (F). The supratentorial white matter remained relatively spared.

Graphic Jump Location

Four months before presentation, he gradually developed slurred, slowed speech without word-finding difficulties. His gait worsened, requiring use of a walker. His hand coordination worsened to the point that he could no longer write legibly. He occasionally would choke and cough when drinking.

At presentation, the neurological examination demonstrated normal cognition and moderate ataxic dysarthria. The patient displayed saccadic ocular pursuits, square wave jerks, and rebound and gaze-evoked nystagmus. He had marked titubation when sitting upright and appendicular dysmetria, worse on the right side, with dysdiadochokinesia. He had a wide-based gait with short strides and could not ambulate without assistance. He had visual field defects in the inferior hemifield of the right eye and lateral hemifield of the left eye, and results of an ophthalmologic evaluation revealed retinal degeneration. Results of motor and sensory examinations and deep tendon reflexes were otherwise normal.

Results of an extensive laboratory workup (including erythrocyte sedimentation rate; levels of ceruloplasmin, α-fetoprotein, thyrotropin, vitamins E and B12, fluorescent treponemal antibody, rheumatoid factor, anti–double-stranded DNA, antinuclear antibody, antineutrophil cytoplasmic antibody, Sjögren syndrome A antibody, ribonuclear protein antibody, Smith/ribonuclear protein antibody, glutamic acid decarboxylase antibody [65 kDa], antithyroglobulin antibody, antigliadin, transglutaminase, and endomysial antibody; heavy metal screening; serum protein electrophoresis; and paraneoplastic antibody panel) were within the reference range. Analysis of cerebrospinal fluid (CSF) showed a white blood cell count of 3/mm3, red blood cell count of 1/mm3, protein level of 81 mg/dL, and glucose level of 67 mg/dL. Results of screening for oligoclonal bands, fungal and acid-fast bacterial cultures, and polymerase chain reaction (PCR) for herpes simplex virus, Epstein-Barr virus, and cytomegalovirus were negative. However, the CSF PCR findings were positive for JCV at 109 000 copies/mL, consistent with active infection. After consultation with the patient’s oncologist, rituximab infusions were stopped.

During the ensuing 4 months, the patient continued to decline. His swallowing difficulties and visual field deficits worsened, and he became nonambulatory. He developed progressive weight loss and fatigue.

He was readmitted 1 year after symptom onset because of several episodes of nonresponsiveness suggestive of seizure. Results of an electroencephalogram and cardiovascular workup were unremarkable. He started empirical therapy with levetiracetam, and these episodes resolved. A second magnetic resonance image of the brain showed progressive cerebellar volume loss with T2-weighted hyperintensity in the dorsal midbrain, pons, and cerebellar peduncles (Figure, D-F). A second lumbar puncture showed a white blood cell count of 1/mm3, red blood cell count of 0/mm3, protein level of 86 mg/dL, and glucose level of 56 mg/dL. Subsequent CSF PCR for JCV demonstrated 18 000 copies/mL. This patient died 17 months after the onset of neurological symptoms. A postmortem examination was not performed.

The JCV from the CSF sample obtained at presentation demonstrated a new granule cell neuronopathy (GCN)–type JCV strain with a 12–base pair in-frame deletion located in the C-terminal of the VP1 gene (RefSeq NC_001699) (2496-2507 in the Mad1 DNA sequence), which we named JCVGCN5. This deletion is different from deletions previously described in other cases of JCV GCN but is localized in the same area of the VP1 gene.1 Using a redesigned PCR method with coamplification at a lower denaturation temperature,2,3 we identified JCVGCN5 in 5% of clones, with wild-type JCV as the predominant species, consistent with a pleiotropic infection.

Human JCV is well known for causing PML, a demyelinating disease that occurs in the setting of severe immunosuppression. Progressive multifocal leukoencephalopathy results from lytic infection of glia by JCV, which typically triggers a leukoencephalopathy predominantly in the posterior supratentorial white matter. In rare cases, mutations in JCV can trigger a change in tropism, leading to involvement of other cell types. This patient had a novel deletion in the same area of the VP1 gene as other cases of JCV GCN identified to date.1 This area is responsible for linking the 72 pentamers of the VP1 protein that form the viral capsid and is not directly exposed to the virion surface.4 Therefore, these mutations are not likely to cause a direct change in receptor binding but rather cause events after entry that may favor replication and assembly in granule cell neurons.1

The JCV GCN entity has been previously reported in immunocompromised hosts in whom the mutated virus is the predominant species.2,5,6 In the case we describe, the clinical presentation and presence of wild-type JCV and JCVGCN5 in the CSF is suggestive of JCV GCN with evolution into the PML spectrum. This patient likely had a coinfection with both strains of the virus before rituximab therapy, and the mutated form was responsible for the JCV GCN phenotype. Subsequently, the development of more classic PML findings likely represented the emergence of the wild-type virus as the dominant feature driving the disease. Consistent with this possibility, repeated magnetic resonance imaging revealed more typical white matter PML lesions in addition to cerebellar atrophy (Figure, E and F). New-onset or worsening cerebellar ataxia in patients receiving rituximab or natalizumab therapy warrants early assessment for JCV infection.79

Accepted for Publication: August 6, 2013.

Corresponding Author: Peter K. Todd, MD, PhD, Department of Neurology, University of Michigan, 109 Zina Pitcher Pl, 4005 BSRB, Ann Arbor, MI 48019 (petertod@umich.edu).

Published Online: February 10, 2014. doi:10.1001/jamaneurol.2013.4668.

Author Contributions: Drs L. Dang and X. Dang contributed equally to this study. Dr Todd had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: All authors.

Analysis and interpretation of data: X. Dang, Koralnik, Todd.

Drafting of the manuscript: L. Dang, Todd.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: X. Dang, Koralnik.

Obtained funding: X. Dang, Koralnik, Todd.

Study supervision: Todd.

Conflict of Interest Disclosures: Dr Todd has received grants from the National Institutes of Health (AG013283), the Veterans Administration (VAMC/BLRD 1I01BX001689), the American Academy of Neurology Foundation, and the National Ataxia Foundation for work unrelated to this project. No other disclosures were reported.

Funding/Support: This study was supported by grants R01 NS 074995, R01 NS 047029, and K24 060950 (Dr Koralnik) and grant K08NS069809 (Dr Todd) from the National Institutes of Health.

Role of the Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank the patient and his family for their participation and consent to research related to this case. Amy Krans, MSc, contributed technical expertise to this project.

Correction: This article was corrected on February 12, 2014, to fix the Author Contributions section.

Dang  X, Vidal  JE, Oliveira  AC,  et al.  JC virus granule cell neuronopathy is associated with VP1 C terminus mutants. J Gen Virol. 2012;93(pt 1):175-183.
PubMed   |  Link to Article
Dang  X, Koralnik  IJ.  A granule cell neuron–associated JC virus variant has a unique deletion in the VP1 gene. J Gen Virol. 2006;87(pt 9):2533-2537.
PubMed   |  Link to Article
Milbury  CA, Li  J, Makrigiorgos  GM.  Ice-COLD-PCR enables rapid amplification and robust enrichment for low-abundance unknown DNA mutations. Nucleic Acids Res. 2011;39(1):e2. doi:10.1093/nar/gkq899.
PubMed   |  Link to Article
Gheuens  S, Wüthrich  C, Koralnik  IJ.  Progressive multifocal leukoencephalopathy: why gray and white matter. Annu Rev Pathol. 2013;8:189-215.
PubMed   |  Link to Article
Koralnik  IJ, Wüthrich  C, Dang  X,  et al.  JC virus granule cell neuronopathy: a novel clinical syndrome distinct from progressive multifocal leukoencephalopathy. Ann Neurol. 2005;57(4):576-580.
PubMed   |  Link to Article
Du Pasquier  RA, Corey  S, Margolin  DH,  et al.  Productive infection of cerebellar granule cell neurons by JC virus in an HIV+ individual. Neurology. 2003;61(6):775-782.
PubMed   |  Link to Article
Vermersch  P, Kappos  L, Gold  R,  et al.  Clinical outcomes of natalizumab-associated progressive multifocal leukoencephalopathy. Neurology. 2011;76(20):1697-1704.
PubMed   |  Link to Article
Clifford  DB, De Luca  A, Simpson  DM, Arendt  G, Giovannoni  G, Nath  A.  Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases [published correction appears in Lancet Neurol. 2010;9(5):463]. Lancet Neurol. 2010;9(4):438-446.
PubMed   |  Link to Article
Schippling  S, Kempf  C, Büchele  F,  et al.  JC virus granule cell neuronopathy and GCN-IRIS under natalizumab treatment. Ann Neurol. 2013;74(4):622-626.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure.
Brain Magnetic Resonance Imaging (MRI) in a Case of JC Polyomavirus Granule Cell Neuronopathy

At symptom onset, no significant cerebellar or white matter abnormalities were observed (A-C). One year after symptom onset, T1-weighted image demonstrates significant cerebellar atrophy (D). In addition, abnormal T2-weighted fluid-attenuated inversion recovery (FLAIR) signal involved the white matter tracts of the dorsal midbrain (E) and pons (F) and the cerebellar peduncles (F). The supratentorial white matter remained relatively spared.

Graphic Jump Location

Tables

References

Dang  X, Vidal  JE, Oliveira  AC,  et al.  JC virus granule cell neuronopathy is associated with VP1 C terminus mutants. J Gen Virol. 2012;93(pt 1):175-183.
PubMed   |  Link to Article
Dang  X, Koralnik  IJ.  A granule cell neuron–associated JC virus variant has a unique deletion in the VP1 gene. J Gen Virol. 2006;87(pt 9):2533-2537.
PubMed   |  Link to Article
Milbury  CA, Li  J, Makrigiorgos  GM.  Ice-COLD-PCR enables rapid amplification and robust enrichment for low-abundance unknown DNA mutations. Nucleic Acids Res. 2011;39(1):e2. doi:10.1093/nar/gkq899.
PubMed   |  Link to Article
Gheuens  S, Wüthrich  C, Koralnik  IJ.  Progressive multifocal leukoencephalopathy: why gray and white matter. Annu Rev Pathol. 2013;8:189-215.
PubMed   |  Link to Article
Koralnik  IJ, Wüthrich  C, Dang  X,  et al.  JC virus granule cell neuronopathy: a novel clinical syndrome distinct from progressive multifocal leukoencephalopathy. Ann Neurol. 2005;57(4):576-580.
PubMed   |  Link to Article
Du Pasquier  RA, Corey  S, Margolin  DH,  et al.  Productive infection of cerebellar granule cell neurons by JC virus in an HIV+ individual. Neurology. 2003;61(6):775-782.
PubMed   |  Link to Article
Vermersch  P, Kappos  L, Gold  R,  et al.  Clinical outcomes of natalizumab-associated progressive multifocal leukoencephalopathy. Neurology. 2011;76(20):1697-1704.
PubMed   |  Link to Article
Clifford  DB, De Luca  A, Simpson  DM, Arendt  G, Giovannoni  G, Nath  A.  Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases [published correction appears in Lancet Neurol. 2010;9(5):463]. Lancet Neurol. 2010;9(4):438-446.
PubMed   |  Link to Article
Schippling  S, Kempf  C, Büchele  F,  et al.  JC virus granule cell neuronopathy and GCN-IRIS under natalizumab treatment. Ann Neurol. 2013;74(4):622-626.
PubMed   |  Link to Article

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