LA SCLEROSI MULTIPLA OGGI: DALLA DIAGNOSI ALLA TERAPIA PERSONALIZZATAProf. Massimiliano Calabrese

Professore Associato di Neurologia Dipartimento di Neuroscienze, Biomedicina e MovimentoUniversità di Verona

Università di Padova Università di Verona

In Collaborazione con

150/100.000

La Sclerosi Multipla Oggi in Veneto

7.000 pazienti

110.000.000 €SM – COSTI DIRETTI

250.000.000 €SM – COSTI COMPLESSIVI

History of Multiple Sclerosis

Multiple sclerosis is a complex genetic disease associated with inflammation in the CNSwhite matter thought to be mediated by autoreactive T cells. Clonal expansion of B cells,their antibody products, and T cells, hallmarks of inflammation in the CNS, are found inMS.

A French neurologist at the Salpetrière in Paris, Jean MartinCharcot, first described multiple sclerosis (MS) in 1868,noting the accumulation of inflammatory cells in aperivascular distribution within the brain and spinal cordwhite matter of patients with intermittent episodes ofneurologic dysfunction. This led to the term sclérose enplaques disseminées, or multiple sclerosis.

David A. Hafler, J Clin Inv 2004

Charcot, J., Histologie de la sclerose en plaques in Gazette des hopitaux, Paris, vol. 41, 1868, pp. 554–5.

Le tipiche “Placche”

White matter pathology and cortical pathology in MS:a history of “poor” corelations and contradictory findingsWM T2 lesion load showed low or no correlation with:

– Clinical disability (EDSS)– Disease progression– Cognitive impairment (Rao’s BRB)– Paroxysmal symptoms (i.e., epilepsy)– Cortical atrophy

A

B

EDSS: 5.5CI

EDSS: 2.5CN

Il Paradosso Clinico- Neuroradiologico

Extensive demyelination is apparent subpially (inset 1) and around numerous vessels(inset 2) within the cerebral cortex. Subpial demyelination in targeted cortical EAE lesions is

highly reminiscent of subpial demyelination found in MS autopsyMerkler et al. Brain 2006

Subpial demyelination in a rat model of EAE

CONCLUSION: MR imaging with 3D DIR enables increased intracortical lesiondetection in the multiple sclerosis brain, as well as improved distinction betweenjuxtacortical and white matter–gray matter lesions

Gains with DIR were 538% and 152% compared with SE and FLAIR, respectively.

• Migliorare l’accuratezza e la velocità nel porre la diagnosi• Identificare le forme aggressive e quelle Benigne• Personalizzare la terapia: la terapia giusta per il paziente giusto

Concetti base della Ricerca nella Sclerosi Multipla

Una nuova tecnica di Risonanza Magnetica per studiare la Sostanza Grigia

Type IIIWedge-shaped CLs, with a sub-phial base and the apex towards the white matter.

Calabrese et al Archives Neurol 2007

Calabrese et al., Nature Reviews, 2010

Calabrese et al, Neurology 2010

Individuiamo una relazione traPatologia Corticale e Disabilità

Calabrese et al, Brain 2012

r=0.59p<0.001

Epilepsy in Multiple Sclerosis:the role of temporal lobe damage

M. Calabrese, M. Castellaro, A. Bertoldo, A. De Luca, F.B. Pizzini, G.K. Ricciardi,M. Pitteri, S. Zimatore, R. Magliozzi,, M.D. Benedetti, P. Manganotti,

S. Montemezzi, R. Reynolds, A. Gajofatto and S. Monaco

Regional analysis revealed that hippocampus was the brain region most affected by GMLs (14.7%) followed by lateral temporal lobe (13.2%), cingulate (10.2%), and insula (8.1%).

Compared to RRMS patients, RRMS/E showed more severe damage to temporal lobe

Multiple Sclerosis Journal 2016

BRAIN ATROPHY

– Tissue Loss = Atrophy

PatientNormal

Sub-Cortical Tissue Loss

Cortical Tissue Loss

White Matter Tissue Loss VentricularEnlargement

FREESURFERSegmentation: 1) Start with high quality MRI scan 2) Classify tissue types

Volumetric Image WM GM CSF

HV CIS p-MS RR SP1,50

1,75

2,00

2,25

2,50

2,75

3,00

Mean

CTh (m

m)

Multiple Sclerosis withoutcognitive impairmentMultiple Sclerosis with cognitive impairment

Widespread cortical thinning characterizes patients with MS with mild cognitive impairment.

Calabrese et al. Neurology. 2010 Jan 26;74(4):321-8.

Normal control

Lateral views of the pial surface 3D representation with cortical thickness map overlaid in a red/green color scale of the typical (mean) case for each group:

Una visione d’insiemeM. Calabrese, R.Magliozzi, O.Ciccarelli, JJ.Geurts, R. Reynolds, R. Martin. Nature Rev Neurosci, 2015

Cominciamo a fare delle previsionisulla disabilità futura dei nostri pazienti

Conclusion: selective cortical atrophy is relevant in patients with CIS whoconvert to MS. The inclusion of GM analysis in the MS diagnostic workupshould be under consideration

Calabrese et al. Neurology 2011

Calabrese et al, Annals of Neurology 2013

Cerchiamo di identificare già al momento della diagnosi i pazienti con forme piu’aggressive

IDENTIFICARE I PAZIENTI CON PATOLOGIE PIU’ AGGRESSIVE

Subarachnoidspace

GMDuraArachnoid

Pia

Cerebral sulcus

WM

CD20

WM lesion

Subpial cortical lesion

MOG

CD20 CD35 CD3 IgA,G,M

Magliozzi et al., Brain 2007; Howell et al., Brain 2011

Grey matter lesionsWhite matter lesions

Plasma cells

IntrathecalIg secretionIntrathecalinflammation

CSF

Tertiary lymphoid-like structures

Grey matter demyelination

HYPOTHESIS:Meningeal inflammation could be strictly associated with:

CSF inflammation and cortical demyelinationTNFIFNGLta

CXCL13CXCL9CXCL10CCL22

IL2IL4IL9IL10IL12p40IL16

MS1:35 MS with low GML load MS2:35 MS with high GML load

Cluster analysis of the levels of 69 inflammatory mediators examined in the CSF of MS patients at disease onset (Immuno-assay Bio-Plex System)

IL-16

CXCL12

LIG

THCCL

19 MIF

Chi

tinase 3

-like 1

CXC

L10CCL

21CXC

L13GM

-CSF

TNF-alp

hasTN

F-R1

sTNF-R

2TW

EAKAPR

ILIL-6 IL-1

0 sIL-

6 alpfa

IL-1

2IL-1

9 sCD

163

IL-22

IL-26

IL-27(p

28)

IL-35

MMP-1

MM

P-2

Osteoc

alcin

Osteop

ontin (

OPN)

Pentrax

in -3

TSLP

CCL2

CCL8

CCL15

CCL23

CXCL16

CCL

20 CX3

CL1CXC

L1IL-8 IFN

-gamm

aCCL

11CCL

24CCL

1BAF

FsCD

30CXC

L9 IFN

-lambda

1 gp1

30IL-2

0 IL-1

1 CXC

L11CCL

26IL-1

2(p40)

IL-32

IL-34

IL-1bet

aIL-2

IL-4 CXC

L5CCL

25INF

-alfa 2

INF-be

ta IFN

lambda

2 CCL

7 CCL

13 CCL

22 CXC

L2CCL

3

MS1

MS2

A B

Una volta identificato il profilo patologico di ogni paziente potremmo dargli la terapia piu’ corretta

Perspectives

RingraziamentiDipartimento di Neuroscienze, Università di Verona

Prof. Salvatore MonacoDr.ssa Roberta Magliozzi

Dr. Marco Pitteri

Neuroradiologia d.O., University Hospital of VeronaDr.ssa Francesca Pizzini

Dr. Sergio ZimatoreDr. Giuseppe Ricciardi

Dr. Stefania Montemezzi

Imperial College, LondonProf. Richard Reynolds

Istituto Superiore di Sanità, RomeDr. Francesco Facchiano

Vu University Medical Center, AmsterdamProf. Jack van Horssen

Gruppo Datamedica, PadovaMaria Paola Belloni Regazzo

Federico RegazzoAlessandro Buriani

Aldo MorraAnna GuglielmoRoberto Cipriani

E tutti I tecnici e le sig.ine di Euganea Medica

Dept. of Information Engineering, University of Padova

Prof. Alessandra BertoldoMarco CastellaroMatteo Tonietto

Enrico Grisan

Biotechnology Centre and Department of Biology, University of Padova

Prof. Chiara Romualdi