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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
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
Seroepidemiology JCV and BKV
Egli JID 2009
Hirsch APMIS 2013Knowles 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%!
JCV in body compartments
Egli JID 2009
N=400 blood donors
JCV IgG: 58%
JCV DNA in urine: 19%
(32% of seropositives)
n=75
•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
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)
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 diseaseDarbinyan Acta Neurop Comm 2016
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,
often subcortical involvement of u-fibers, sometimes involvement adjacent
gray matter
• High mortality (>20%)
MRI axial flare T2
Monaco Front Immun 2015
PML: patients at risk
Long term suppression of cellular immunity
Loss of immune surveillance in CNS
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: ?
Pathogenesis of PML
Ferenczy CMI 2013
• Transformation of JC virus:
• recombination NCCR
• VP1 mutations
(altered receptor specificity)
e.g. L55F and S269F
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
Paul 2007 Nature Reviews Neuroscience
Explanation for bilateral lesions
Wharton et al Plos One 2016
JCV may spread via myelin sheets
MRI scan
12 11 10 9 8 7 6 5 4 3 2 1 0
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!
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!
Case history
Woman, 64 years oldmarried, 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:(enhancing lesion
with contrast)
MRI scan:lesions associated with
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 protocolPsorinovo 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 careof 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
CD8 CD20CD4CD3
SV40T
Diagnosis post mortem
Brain tissue: PCR JC virus positiveSV40 staining positive
bizarre oligodendrocytes & astrocytesInflammatory 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)
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)
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 infiltratesMRI 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
Viscidi CID 2011
Different
Units than
STRATIFY
Antibody
Index!
Higher titre in cases
before PML
IgG anti-JC virus titre in HIV patients +/- PML
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?
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
PCR or serology?
• 70% natalizumab PMLReiber index >1.5 = intrathecal antibody production
• 0% of control group
Warnke Ann Neur 2014
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
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
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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