Progressieve multifocale leukencefalopathie en alternatieve neurologische presentaties van polyomavirus infecties Jean-Luc Murk, MD PhD Arts-microbioloog / viroloog ETZ Tilburg, the Netherlands
Polyomaviruses Non-enveloped viruses, 42 nm Circular dsDNA ~5100 bp At least 13 different polyomaviruses infect humans Cause life-long persistent infections in humans JC virus: 8 genotypes; probably 1 serotype Infection with more than 1 genotype is possible JC virus has ~72% amino-acid homology and ~75% nucleotide homology with BK virus
Peretti J Gen Virol 2015
Wollebo Ann Neur 2015
Seroepidemiology JCV and BKV - Adults: anual seroconversion rate of 1-5% - There is a negative correlation between antibodies to JCV and BKV - Higher seroconversion rate in natalizumab treated patients: ~5-10%! Egli JID 2009 Knowles J Med Vir 2003 Hirsch APMIS 2013
JCV in body compartments n=75 N=400 blood donors JCV IgG: 58% JCV DNA in urine: 19% Egli JID 2009 (32% of seropositives)
JCV in the brains of non-immunocompromised • JCV DNA present in the brains of each case! Perez-Liz Ann Neur 2008 • Many studies with similar results. See White and Khalili JID 2011
JCV associated diseases • Progressive multifocal leukoencephalopathy (PML) • JCV granule cell neuronopathy (GCN) of cerebellum • JCV meningitis • JCV encephalopathy / encephalitis • JCV polyneuropathy • Kidney transplant patients: nephropathy (<1%) • JCV associated malignancies? (CNS, non-Hodgkin lymphoma, GI-tract)
JC virus associated diseases Miskin Curr Opin Neur 2015
BKV associated neurological diseases • Progressive multifocal leukoencephalopathy (n=~6) (white matter involvement) • BKV (meningo)encephalitis & encephalopathy (n=~12) (periventricular / pia mater / sometimes cortical involvement) Very very rare Underestimated? Similar presentation as JCV disease Darbinyan Acta Neurop Comm 2016
PML MRI axial flare T2 • Subacute onset of neurological symptoms: cognitive / motor / sensory, diverse clinical presentations • Generally no fever, no cells in CSF • Progressive disease which may lead to coma and death (months) • Multifocal, asymmetric white matter demyelinating disease, often subcortical involvement of u-fibers, sometimes involvement adjacent gray matter • High mortality (>20%) Wattjes MS journal 2013
PML: patients at risk Long term suppression of cellular immunity Loss of immune surveillance in CNS Monaco Front Immun 2015
PML in MS patients Medication Treatment Cases, n Incidence rate Rituximab Autoimmune diseases / >500 RA: ~1:25.000 (often in combination cancer CLL/NHL: ~1:10.000 therapy) SLE: 1:4000 MS: ? *Schwab Neurology 2017 : Risk for JCV IgG pos >24 months natalizumab after IS: 1:31 Mills MS Journal 2018
Pathogenesis of PML • Transformation of JC virus: • recombination NCCR • VP1 mutations (altered receptor specificity) e.g. L55F and S269F Ferenczy CMI 2013
JCV NCCR rearrangements NCCR is binding site for: • T-antigen • SPI-B • NF- κ ß • C/ERPß • Egr-1 • NFAT4 • Oct-6 • AP-1 • HIF-1 α • YB-1/Pur α • HIV tat Ferenczy CMI 2013
Explanation for bilateral lesions Paul 2007 Nature Reviews Neuroscience
JCV may spread via myelin sheets Wharton et al Plos One 2016
JCV may spread via myelin sheets
PML cases: retrospective identification on MRI Early PML lesions on MRI MRI scan Months 12 11 10 9 8 7 6 5 4 3 2 1 0 1 – 6 months prior to diagnosis, small PML lesions were often seen No pre-PML lesions on MRI At 6 – 12 before PML diagnosis no MRI at lesions could be identified that were PML diagnosis* associated with PML lesions From small lesion to symptomatic PML may take 6 months! Dong-Si T et al. Ann Clin Transl Neurol 2014;1:755-64.;Richert ND et al. Mult Scler. 2012;18:(S4)27. Yousry TA et al. Ann Neurol . 2012;72:779-787.
PML timing related to triggering condition • allo-SCT median time post SCT = 10 months • auto-SCT median time post auto-SCT = 10 months • Efalizumab median time after start > 36 months median time after 1 st infusion = 26 months • natalizumab (range 8-91 months) median time after 1 st infusion = ~15 months • rituximab median time after last dose = 5.5 months median after 6 doses • DMF median time after start: 31 months median time of lymphocytopenia: 23 months • Fingolimod all cases after > 18 months treatment Probably long ‘incubation’ time / slow development of PML!
Case history Woman, 64 years old married, 2 adult children • lung embolism (1987) • migraine • psoriasis • Alcohol – • smoking +
Medication history Topical steroids • 2000-2011: triamcinolone acetonide cream 1mg/g q.d./b.d • 2011: hydrocortisone acetate cream 10 mg/g q.d. • until 2013: on average once per year a course of betamethasone dipropionate cream 50 mcg Systemic therapy • until 2011: incidental triamcinolone acetonide 200 mg i.m. • Psorinovo (compounded dimethylfumarate slow release) • June 2012 – June 2013: 240 mg t.i.d. • July 2013 – July 2014: 240 mg b.i.d
July 17, 2014 Presentation at emergency department • Trouble getting dressed since two weeks • Difficulties to perform basic household chores • Difficulties differentiating between left and right • Repeatedly bumped against objects while walking General exam: no fever / abnormalities Neurologic investigations: • hemianopsia L, no other abnormalities
CT scan: MRI scan: (enhancing lesion lesions associated with with contrast) cerebral arteries?
July 17, 2014 Laboratory investigations: • Blood: • Hb: 7,9 mmol/l (normal) • Thrombocytes: 224 x10E9 cells/ml • Leukocytes: 4x10E9 cells/ml • Lymphocytes: 19,8% (lower limit: 20%) • Normal renal and hepatic function • CSF (July 21): • no abnormalities
July 17, 2014 Differential diagnosis: • Infarction • PML seemed very unlikely • CSF: PCR for JC virus negative Admission for further work-up (July 17 – Aug 5) Stroke protocol Psorinovo stopped Transferred to revalidation clinic (August 5)
August 14, 2014 Sudden decline of cognitive and motor functions: • Hemiparesis L, central n. facialsis paresis L • Dysartria • Headache & somnolence Neurological examination: • Paralysis and hypertonia, hyperreflexia L • Babinsky sign L
CT scan MRI scan
Differential diagnosis • malignant a. cerebri media infarction • ADEM • malignancy (lymphoma) • auto-immune disease • PML / other infectious disease Due to rapid deterioration transferred to intensive care of University Medical Centre Utrecht Administration of: • methylprednisolone 1000 mg q.d. for 5 days • mirtazapine 45 mg q.d • mefloquine 250 mg q.d for 3 days, then once a week
Rapid disease progression • August 17: E1M5V3 • August 20: EEG: epileptic activity respiratory and hemodynamic problems (signs of brain herniation) • August 22: stop treatment • August 26: died
SV40T CD3 CD4 CD8 CD20
Diagnosis post mortem Brain tissue: PCR JC virus positive SV40 staining positive bizarre oligodendrocytes & astrocytes Inflammatory changes (IRIS) PCR CSF: JC virus positive sequencing: typical changes in NCCR CSF/Blood: intrathecal JC virus antibodies
Total lymphocytes: 880 x10E9 cells/ml CD4: 270 x10E9 cells/ml; CD8: 40x10E9 cells/ml
Protection against PML (simplified) PML (PML-IRIS) JC virus replication, evolution & dissemination Cellular immune system Many drugs - CD4+ T cells HIV - CD8+ T cells DMF - B-cells Rituximab Immune surveillance in brain Natalizumab Efalizumab Fingolimod
PML-IRIS • After cessation of immunosuppressive drugs Generally after 4 – 8 wks, may start after 1 wk – 15 wks • HIV pos: after start cART • Mass effect and contrast enhancement may be seen! • PA: T-cell infiltrates in brain tissue, perivascular infiltrates MRI T2 See also Clifford Lancet Neuro 2010
Granule cell neuronopathy of cerebellum • Immunocompromised patients • Sub-acute onset, slowly progressive motor disturbances • Infection of granule cell neurons in cerebellum, sometimes involvement of white matter, sometimes in combination with PML • Cerebellar atrophy, high mortality rate Wijburg J Neurol 2014
JCV ANTIBODIES AND PML RISK
IgG anti-JC virus titre in HIV patients +/- PML Higher titre in cases before PML Different Units than STRATIFY Antibody Index! Viscidi CID 2011
JCV IgG index in natalizumab treated patients * *See also Schwab Neurology 2017 : Risk for JCV IgG pos >24 months NTZ after IS: 1:31
Relationship between JCV IgG and PML? • Antibodies have probably no direct function in controlling JCV infection! • Marker for presence of JCV in the body • Possible explanations for high index value: • Recent primary infection with JCV • Recent primary infection with other polyomavirus • Marker of large JCV reservoir in the body • Marker of increased JCV replication in the body • Perhaps: marker of JCV replication in the brain (stimulation antibody response by antigen presentation in cervical lymph nodes) Is JCV IgG useful for other MS drugs?
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