LE PML IN HIV E IN CORSO DI

TERAPIE BIOLOGICHE :

IL PARERE DEL

NEURORADIOLOGO

Prof.ssa Anna Pichiecchio

Dott.ssa Federica Lucev

Neuroradiology Department

National Neurological Institute IRCCS “C.Mondino”

Pavia

Natalizumab and PML/IRIS

PML MRI features in HIV

PML MRI features in HIV post-HAART

PML in MS and disease modifying drugs (DMDs)

Which MRI study protocol?

What is PML-IRIS (immunorecostitution inflammatory syndrome)?

PML in primary immunodeficiency disorders

Differential diagnosis

What is progressive multifocal leukoencephalopathy (PML)?

• Opportunistic CNS demyelinating disease caused by

a neurotropic mutant strain of the JC virus

• Causes benign infection in >50% of adults worldwide

• Very rarely causes PML, following reactivation

• Associated with immunosuppressed states

(AIDS, transplant pts, hematologic malignancies,

mAb therapies, primary immunodeficiency disorders)

• JCV infection and damage of oligodendrocytes

leads to severe demyelination

PML time course

O Major Lancet Neurology 2018

PML – Why MRI?

“[…] MRI detects PML lesions even several months before

clinical symptoms occur and JCV DNA may become detectable

in the CSF”

“[…] clinicians and radiologist should be aware that clinical

symptoms are not required to make the diagnosis of PML in

natalizumab-treated MS patients; such requirement could delay

timely diagnosis and intervention”.

(Yousry et al. 2012, Wattjes MP et al. 2013, Dong-Si et al. 2014)

• Relevance of MRI in the early diagnosis

• asymptomatic PML at diagnosis (confirmed by detection of JCV in

CSF) : 100% survival rate (69% in symptomatic)

Delayed diagnosis

Younger age

Low physical impairment

Low JCV copy number in CSF

Localized brain involvement

PML – Why MRI?

Poor prognosis

Better prognosis

Vermersch et al. Neurology 2011;

Dong-S et al. J Neurovirol 2015

Early diagnosis of PML: results from the Italian cohort

77% of PML lesions was noticeable at the pre-diagnostic MRI

Lesion volume change diagnostic volume/pre-diagnostic volume = 13,91

Mean interval time between pre-diagnostic and diagnostic = 5 months

Scarpazza C et al. 2017 submitted

Each month of diagnostic delay, the lesion triplicate its volume

Natalizumab and PML/IRIS

PML MRI features in HIV

PML - HIV

Large lesions in subcortical white matter, most commonly parieto-occipital regions

Less frequent gray matter involvement (> basal ganglia and thalamus)

No mass effect

No contrast enhancement

Augusto L, et al; Acta Med Port 2015

Natalizumab and PML/IRIS

PML MRI features in HIV

PML MRI features in HIV post-HAART

PML in MS and disease modifying drugrs (DMDs)

PML – Disease modifying drugs

frontal (48%)> occipital (20%)>parietal (12%)

Deep white matter with involvement of subcortical WM and U fibers, as well as occasionally the

adjacent cortical GM

Large> 3cm

PML – MRI features

MS

UNILOBAR

(42%)

WIDESPREAD

(multiple noncontiguous lobes or

bilateral

(35%)

MULTILOBAR

(more than one contiguous

lobes)

(19%)

Linda H et al, Front in Neurology 2013

Kleinshmidt-De Masters,

J Neuropath Exp Neurol 2012

PML – MRI features

MS

Fills the gyrus (heart of the girus)

Borders are ill defined toward the white matter and rather sharply delineated

toward the cortical gray matter.

no mass effect.

Phan Ba R, Neurology 2012

PML – MRI features

MS

Posterior fossa

occurs in <10% of cases at presentation

during follow-up is frequently observed

the brainstem

the pons

middle cerebellar peduncles (as HIV-PML)

the cerebellar hemispheres

dentate nucleus

Leukoencephalopathy…and gray matter ?

Healthy MS PML

Moll et al, Neurology 2008

Leukocortical: involving the

juxtacortical white matter and the

adjacent deep cortical GM

not involving the subpial cortical layer

Cortical gray matter manifestation

Phan Ba R, Neurology 2012

Asymptomatic PML

Contrast-enhancing lesions during

natalizumab treatment are more likely

inflammatory PML lesions than

asymptomatic MS plaques

Natalizumab and PML/IRIS

PML MRI features in HIV

PML MRI features in HIV post-HAART

PML in MS and disease modifying drugrs (DMDs)

Which MRI study protocol?

Wattjes MP et al, Mult Scler J 2013

MRI study protocol

…how to get through the matter?

Diffusion weighted image (DWI)

DWI is a useful tool in early diagnosis

Core centrale con DWI e ADC ,

indice di distruzione tissutale

Ring periferico con DWI e ADC ,

indice di demielinizzazione attiva e

danno(edema) degli oligodendrociti

Shah et al. Clinical Radiology 2010;

Honce et al. Mult Scl Int 2015

Diffusion weighted image (DWI): lesion load

Global lesion load in PML

correlates with disease

duration and severity

DWI differentiates central core

lesion vs. peripheral rim

Larger central core

worsened clinical status,

longer disease duration

Diffusion weighted image (DWI)

DD MS plaques and PML lesions

Homogeneous pattern

Susceptibility-weighted imaging (SWI)

Hodel J et al. Am J Neuroradiol 2015

Early diagnosis PML NTZ-associated

SWI in asymptomatic Pts cortical and/or U fibers hypointensity and involving

basal ganglia

75% of asymptomatic Pts had hypointensity in SWI

Susceptibility-weighted imaging (SWI)

Pontillo G et al. Front Neurol 2017

Sinnecker T et al.American Academy of Neurology 2015

…non perivenular distribution

…perivenular distribution

T1-weighted images

Perfusion-weighted imaging (PWI)

rCBV tipicamente ridotto

Magnetic resonance spectroscopy (MRS)

Aspecific profile

Cho

Lac

=/ Naa

PML: variabile NAA, Cho, Lip

IRIS: Cho/Cr e Lip/Lac, NAA

Magnetic resonance spectroscopy (MRS)

Milky way appearance

Within and adjacent to the

main PML lesion, small T2-

lesions with a microcystic

appearance may be

observed with a star-like

distribution pattern

These lesions might

represent an early immune

response in the perivascular

spaces

Wattjes MP et al. Mult Scl Journal 2013

Contrast enhancement

Gd-enhancement 30%−40% pts in the early natalizumab-associated PML stages

Milky way – differential diagnosis

Lee A. ECR 2012

Pesaresi I. et al. Magnetic Resonance Imaging 2013

↑ lesion size, becoming confluent

New lesions appear

Lesion growth and expansion may follow

WM tracts

Lesion evolution/Follow-up multifocal pattern

Cortico-spinal tract

Lesion evolution/Follow-up multifocal pattern

Corpus callosum

Dicembre 2017

Febbraio 2018

Lesion evolution/Follow-up lesion characteristics change over time

↑ lesion size, becoming confluent

Progressive and irreversible demyelination ( ↓SI in T1)

Neurodegeneration with no remyelination

dark

Linda H et al, Frontiers in Neurology 2013

Natalizumab and PML/IRIS

PML MRI features in HIV

PML MRI features in HIV post-HAART

PML in MS and disease modifying drugrs (DMDs)

Which MRI study protocol?

What is PML-IRIS (immunorecostitution inflammatory syndrome)?

Immuno Reconstitution Inflammatory

syndrome (IRIS)

Steiner and Berger ,Update on PML, Curr Neurol Neurosci Rep 2012

Consequence of rapid entry of immune cells into the brain at

the time of immunorestoration

Exuberant inflammatory response to an antigen in an

individual with CNS infection

only a subset of HIV PML patients (17%- 27%) develop IRIS

Paradoxical worsening of existing clinical symptoms in an individual with

CNS infection during immune recovery

PML-IRIS

MRI «new inflammatory changes»

an increase of

PML lesion size

new areas of

contrast

enhancement

edema and

mass effect

Cortical laminar necrosis

DD PML vs PML-IRIS

Wattjes, JNNP 2013 PML 4th week 6th week 13th week

Natalizumab and PML/IRIS

PML MRI features in HIV

PML MRI features in HIV post-HAART

PML in MS and disease modifying drugrs (DMDs)

Which MRI study protocol?

What is PML-IRIS (immunorecostitution inflammatory syndrome)?

PML in primary immunodeficiency disorders

Differential diagnosis

DD PML vs MS in patients treated with natalizumab

new MS lesions

Wattjes MP et al, Mult Scler 2013

Different sintomatology (acute in MS, subacute in PML)

typical MS enhancement patterns (homogeneous or open-ring enhancement)

not observed in any PML lesion

PML and high lesion load MS

4 helpful features:

1. Subcortical location

2. T1 hypointensity

3. DW hyperintensity

4. Number of small

punctate T2 lesions in

the immediate vicinity of

the main lesion

TDL Mass effect

Remyelination over time

ADEM

no or subtle enhancement

T1 isointense

frequently spinal cord

Wattjes MP et al, Mult Scler 2013

Conclusions N-PML

PML represents an heterogeneous disease showing an abundance of inflammatory changes that have been rather neglected in the context of HIV-associated PML.

It is not an exclusive white matter disease as suggested by the term leukoencephalopathy, but remains multifocal

In the early disease stages, PML frequently presents as a focal leucocortical lesion and may be confused with a new MS lesion

(Neuro)Radiologists should be aware of these heterogeneous imaging findings to aid in the early and preferably asymptomatic diagnosis of PML with positive influence on clinical outcome and survival.