Progressieve multifocale leukencefalopathie en alternatieve neurologische presentaties ... ·...
Transcript of Progressieve multifocale leukencefalopathie en alternatieve neurologische presentaties ... ·...
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?)