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

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)

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 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

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

JCV ANTIBODIES AND PML RISK

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

Wijburg JAMA Neurol 2018

PCR or serology?

• 70% natalizumab PMLReiber index >1.5 = intrathecal antibody production

• 0% of control group

Warnke Ann Neur 2014

PCR or serology?

Warnke Ann Neur 2014

Warnke J NNP 2017

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?)

QUESTIONS?