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Feb 15, 2023 223 likes •721 views

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

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Progressieve multifocale leukencefalopathie en alternatieve neurologische presentaties van polyomavirus infecties

Jean-Luc Murk, MD PhD Arts-microbioloog / viroloog ETZ Tilburg, the Netherlands

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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

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Peretti J Gen Virol 2015

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Wollebo Ann Neur 2015

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Seroepidemiology JCV and BKV

Egli JID 2009 Hirsch APMIS 2013 Knowles J Med Vir 2003

  • 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%!

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JCV in body compartments

Egli JID 2009 N=400 blood donors JCV IgG: 58% JCV DNA in urine: 19% (32% of seropositives)

n=75

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  • JCV DNA present in the brains of each case!
  • Many studies with similar results. See White and Khalili JID 2011

Perez-Liz Ann Neur 2008

JCV in the brains of non-immunocompromised

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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)

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JC virus associated diseases

Miskin Curr Opin Neur 2015

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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

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PML

Wattjes MS journal 2013

  • 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,
  • ften subcortical involvement of u-fibers, sometimes involvement adjacent

gray matter

  • High mortality (>20%)

MRI axial flare T2

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Monaco Front Immun 2015

PML: patients at risk

Long term suppression of cellular immunity Loss of immune surveillance in CNS

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Mills MS Journal 2018

PML in MS patients

*Schwab Neurology 2017: Risk for JCV IgG pos >24 months natalizumab after IS: 1:31 Medication Treatment Cases, n Incidence rate Rituximab (often in combination therapy) Autoimmune diseases / cancer >500 RA: ~1:25.000 CLL/NHL: ~1:10.000 SLE: 1:4000 MS: ?

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Pathogenesis of PML

Ferenczy CMI 2013

  • Transformation of JC virus:
  • recombination NCCR
  • VP1 mutations

(altered receptor specificity) e.g. L55F and S269F

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JCV NCCR rearrangements

Ferenczy CMI 2013

NCCR is binding site for:

  • T-antigen
  • SPI-B
  • NF-κß
  • C/ERPß
  • Egr-1
  • NFAT4
  • Oct-6
  • AP-1
  • HIF-1α
  • YB-1/Purα
  • HIV tat
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Paul 2007 Nature Reviews Neuroscience

Explanation for bilateral lesions

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Wharton et al Plos One 2016

JCV may spread via myelin sheets

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JCV may spread via myelin sheets

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MRI scan

12 11 10 9 8 7 6 5 4 3 2 1 Months

No pre-PML lesions on MRI Early PML lesions on MRI MRI at PML diagnosis*

At 6–12 before PML diagnosis no lesions could be identified that were associated with PML lesions 1–6 months prior to diagnosis, small PML lesions were often seen

PML cases: retrospective identification on MRI

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.

From small lesion to symptomatic PML may take 6 months!

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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

  • natalizumab

median time after 1st infusion = 26 months (range 8-91 months)

  • rituximab

median time after 1st infusion = ~15 months 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!

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Case history

Woman, 64 years old married, 2 adult children

  • lung embolism (1987)
  • migraine
  • psoriasis
  • Alcohol –
  • smoking +
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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
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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
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CT scan: (enhancing lesion with contrast) MRI scan: lesions associated with cerebral arteries?

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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
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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)

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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
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CT scan MRI scan

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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

  • f 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
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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
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CD8 CD20 CD4 CD3 SV40T

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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

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Total lymphocytes: 880 x10E9 cells/ml CD4: 270 x10E9 cells/ml; CD8: 40x10E9 cells/ml

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Protection against PML (simplified)

JC virus replication, evolution & dissemination PML Cellular immune system

  • CD4+ T cells
  • CD8+ T cells
  • B-cells

Immune surveillance in brain HIV DMF Rituximab Natalizumab Efalizumab Fingolimod Many drugs (PML-IRIS)

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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

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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

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JCV ANTIBODIES AND PML RISK

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Viscidi CID 2011

Different Units than STRATIFY Antibody Index! Higher titre in cases before PML

IgG anti-JC virus titre in HIV patients +/- PML

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JCV IgG index in natalizumab treated patients

*

*See also Schwab Neurology 2017: Risk for JCV IgG pos >24 months NTZ after IS: 1:31

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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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Laboratory diagnosis of PML

  • Detection of JC virus in brain tissue
  • Immunohistochemistry, viral culture, PCR etc
  • Detection of JC virus DNA in CSF
  • Not very sensitive! 65% in first CSF tap in published cases
  • Detection of intrathecal antibody production to JCV
  • Not diagnostic:
  • Detection of JC virus DNA in blood/urine/other fluids
  • Detection of JC virus miRNA’s in CSF/ blood/urine/other

fluids

Maas J Neur 2016

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Wijburg JAMA Neurol 2018

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PCR or serology?

  • 70% natalizumab PML

Reiber index >1.5 = intrathecal antibody production

  • 0% of control group

Warnke Ann Neur 2014

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PCR or serology?

Warnke Ann Neur 2014 Warnke J NNP 2017

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Therapeutic options for PML Approaches:

  • Inhibition of viral replication / lifecycle
  • Stimulation of immune system

NO CONVINCING EVIDENCE FOR ANY SPECIFIC TREATMENT

See Pavlovic Ther Adv in Neur Dis 2015

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Prognosis PML Depends on underlying disease / condition!

  • HIV / AIDS:
  • before cART:

~90% mortality

  • since / with cART:

~20-45% mortality

  • MS + natalizumab:
  • Symptomatic PML:

~25% mortality

  • Asymptomatic PML:

~3% mortality

  • Transplant pts (SCT, organ):

~40% mortality

  • SLE:

~60% mortality

  • Malignancies:

~80% mortality

  • Rituximab associated:

~90% mortality

Maas J Neurol 2016; Zhai & Brew Neurol of HIV Infection 2018

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Take home

  • JCV infections persist for life
  • Cellular immunity is essential for control of JCV infection:

CD4, CD8 and B cells are all important

  • PML: takes long time to develop
  • CSF is not same compartment as brain tissue
  • PML diagnosis can be improved by testing

CSF for JCV DNA with PCR & by intrathecal antibodies BKV may also cause PML like illness (but this is rare) Therapy for PML:

  • Nothing proven / benefit seems unlikely for many candidates
  • Improve function of cellular immune system a.s.a.p!

(G-CSF? Cytokines?)

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QUESTIONS?