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Two cases of CNS JC Virus Disease
Yonah Ziemba, MS4Dept. of Pathology, TJUH
August, 2016
Comparing the common to anextremely rare disease manifestation
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Polyomaviridae virus family• Polyomaviridae are non-enveloped ds DNA viruses, with
circular DNA capsid and Icosahedral structure. • Widely present in healthy individuals in latent state.
Associated with disease in immunocompromised host. • Members include JC, BK, Merkel cell and SV40• JC virus: PML. • BK virus: Nephropathy. • SV40 virus: subclinical infection• Merkel cell virus: Merkel cell carcinoma • Murine polyomavirus: oncoviruses (extensively studied)
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Why does a virus that infects 80% of the world’s population cause disease in so few?
And why does the same pathogen cause such different pathologies?
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Patient A: First Admission• 52 yo woman with history of lupus nephritis presents with four weeks
of headache and nausea.• Current medications include Cortisol, Mycophenolic acid (CellCept),
Hydroxychloroquine (Plaquenil) and Rituximab. • Lumbar puncture showed opening pressure of 26 (slightly elevated) . • Diagnosed with pseudotumor cerebri (idiopathic intracranial
hypertension) and treated with Diamox and Reglan.• Discharged before CSF viral studies are available.
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Patient A: Second Admission•Presents to ER two days after discharge reporting
worsening of symptoms.•Now CSF studies for JCV are available:
Positive for JC virus, 104,000 copies per mL. •Diagnosis: JC Virus meningitis
Rare to present without PML•Only treatment for JCV is to stop suppressing immune
system.•Mycophenolic acid (CellCept) is discontinued.
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• WBCs 10 (48% PMNs, 52% Lymph)• RBCs: 5; Glucose 60, Protein: 45.• Negative for HSV, HHV6, CMV, EBV, Lyme
and cryptococcus. • JC virus: 104,000 copies per mL• PCR sensitivity, specificity and assay range.
Patient A: JCV Workup
CSF Studies:
MRI:
No visible lesion
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In which cell type does the virus replicate when it is causing Meningitis?
Leptomeninges and underlying GM:
Long arrow: leptomeningeal cellsShort arrow: meningeal vessels
High mag of Leptomeninges
Short arrow = Brown = JCV T Ag Long arrow = Blue = LCV VP1 protein
( Ann Neurol. 2014 Jul; 76(1): 140–147)
epithelial cells of the choroid plexus
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Patient A: Response to treatment
796596
453763
10194
JCV in serum
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Patient A: Response to treatment
104829
39045
2331
JCV in CSF
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• August 13: 104,000 copies/ml CSF,
- Headache, photophobia, nausea, weakness
• August 20: discontinue Mycophenolic acid (CellCept)
• August 25: 39,000 copies/ml CSF.
- Normal eating habits with relief of nausea and weakness.
- Some headache and photophobia persist.
Patient A: Response to treatment
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Pt B: HIV and PML
• 54 year old gentleman complains of fevers, chills and left sided weakness. • Diagnosed with HIV/ AIDS two weeks prior to presentation. • CD4 count 15, HIV viral load of 160,000.•When AIDS patient has neurological complaint, CNS infection such
as toxo or crypto must be ruled out with brain imaging and lumbar puncture.• Imaging was positive for PML• Lumbar Puncture Positive for JCV w 45,000 copies/ml CSF
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MRI features differentiate PML from other lesions:
• Focal white matter hypodensity.• Absence of mass effect. • Cortical preservation.
Pt B: HIV and PML
13 Credit Dr. Mark Curtis MD PhD , TJUH
• enlarged oligodendrocytes with intranuclear inclusions• loss of oligodendrocytes• macrophage infiltration of
white matter • breakdown and phagocytosis of
myelin• “Bizarre” astrocytes.
PML Features
14 Credit Dr. Mark Curtis MD PhD , TJUH
• enlarged oligodendrocytes with intranuclear inclusions• loss of oligodendrocytes• macrophage infiltration of
white matter • breakdown and phagocytosis of
myelin• “Bizarre” astrocytes.
PML Features
15 Credit: Mark Cohen MD, Case Western University
Immunohistochemical Staining
Black/brown cells are infected with JCV
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black arrows: oligodendrogcytes
white arrow: astrocytes
Credit: Mark Cohen MD, Case Western University
In Situ hybridization for JC virus
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Innumerable areas of degenerative change within the subcortical white matter
Credit: Mark Cohen MD, Case Western University
PML Gross section
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PML Epidemiology National Data
Source: N Engl J Med. 2004;350(18).
Incidence in HIV population: 3.3 → 1.3cases/1000 patient-years at risk [PYR]
Risk factors as % of total PML population• 80%: HIV infection• 13%: Hematologic malignancies• 3%: Autoimmune diseases• ~0%: No apparent immune deficiency
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PML Epidemiology National Data
Source: N Engl J Med. 2004;350(18).
TriNetx has data from July 1st 2008 - last week
• PML cases at Jefferson: 27 (3/year)
• Comorbidities include:• HIV: 21 (78%)• Bone marrow failures: 12 (44%)• Immune suppressants: 1 (4%)
Jefferson Data
Source: TriNetx search of TJUH EMR
Incidence in HIV population: 3.3 → 1.3cases/1000 patient-years at risk [PYR]
Risk factors as % of total PML population• 80%: HIV • 13%: Hematologic malignancies• 3%: Autoimmune diseases• ~0%: No apparent immune deficiency
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Why does a virus that infects 80% of the world’s population cause disease in so few?
And why does the same pathogen cause such different pathologies?
Getting back to our important question….
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Because deficits in Immune function determine manifestation of JCV
Image: Bite sized immunology, British Society of Immunology
• Cytokines are the cellular messengers of the immune system.
• Inflammatory cascade is mediated by cytokines that are released directly into CSF.
• Cytokines analysis of CSF are a window into the current state of the CNS immune activity.
Cytokine Analysis
T cell Monocyte = Effector
Credit: Immense.Immunology.Insight.com
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EGF MCP3 IL-1Ra IL-8FGF-2 IL-12-P40 IL-1a IL-10Eotaxin MDC IL-9 MCP-1/
CCl2TGF-alpha IL-12-P70 Il-1b MIP1aG-CSF PDGF-AA IL-2 MIP1bFractalkine IL-13 IL-3 RANTESINF-alpha PDGF-BB IL-4 TNF-alphaINF-gamma IL-15 IL-5 TNF-beta
GRO sCD40L IL-6 VEGFIL-10 IL-17a IL-7
Cytokine AnalysisIRB-approved translational initiative at TJUH to routinely perform cytokine analysis.
25Nadine Thiel, et al. Viral Interference with Functions of the Cellular Receptor Tyrosine Phosphatase CD45 Viruses 2015, 7(3), 1540-1557; doi:10.3390/v7031540
MyD88 (Myeloid differentiation primary response gene 88): Protein used by most TLRs to activate the transcription of ND-kBTRIF (TIR-domain-containing adapter-inducing interferon-b ): An adaptor in responding to activation of TLRsIRFs (Interferon regulator factors): Master regulators of signaling by TLRs and cytosolic pattern recognition receptors
How are cytokine released in viral CNS infections?
• Viral antigen motif is recognized by toll-like receptors (TLRs)
• MyD88, TRIF and IRFs are released in the cell to stimulate cytokine secretion.
• Effects include• Fever• Leukocyte chemotaxis• T-cell differentiation• Increased I MHC expression• T-cell proliferation
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• Comparison of immune response in our AIDS/PML patient vs our SLE/meningitis patient
• Clearly, the AIDS patient had a less robust immune response than the SLE patient.
• The greater the deficiency of the immune system, the more severe the disease state.
• The immune response in the JC Virus meningitis patient is strong enough to prevent PML, but not robust enough to prevent JC virus meningitis
AIDS /PML
SLE/ JCV Meningitis
Credit: Fortuna, Roberts, Harshyne, Curtis
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Key Learning Points• JC virus can cause meningitis in patients on immunosuppressive
therapy• Clinicians should consider JCV in their DDx for immunosuppressed
patients with changes in mental status.• Disease manifestation of JC Virus is determined by deficits in immune
function which can be of varied severity.• Symptoms of disease are not simply determined by the pathogenic
agent. They are determined by the interplay of pathogen and host immune system status. • PML has increased incidence in the post-HIV era, with 27 recent
admissions at TJUH.
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Acknowledgements Dr. Mark CurtisDr. Stephen PeiperDr. Madalina TulucDr. Jeffrey BaliffDr Joseph DeSimoneDr. Amity RobertsDr. Jack LondonDr. Danielle FortunaDr Estaban GnassAndrew LytleTiffany Morrison
