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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.
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