SCLEROZA MULTIPLA SI ALTE

BOLI DEMIELINIZANTE

1
 Multifocal zones of inflammation due to focal T-
lymphocytic and macrophage infiltrations, and
oligodendrocyte death are the primary causes of
myelin sheath destruction that result in the
formation of CNS plaques composed of
inflammatory cells and their products,
demyelinated and transected axons, and
astrogliosis in both white and gray matter.

Multiple Sclerosis: Pathogenesis, Symptoms, Diagnoses and Cell-Based

Therapy
Nazem Ghasemi, Ph.D,1 Shahnaz Razavi, Ph.D,1,* and Elham Nikzad, B.Sc
2
Reprinted from Neuroimaging Clinics of North America, Vol. 10, Ludwin SK,
et al. Neuropathology of multiple sclerosis, pp. 625-648, © 2000, with
permission from Elsevier (9). 3
 INFLAMATIE/ DEMIELINIZARE-puseu

NEURODEGENERARE

CICATRICE /SCLEROZA Progresie

PIERDERI AXONALE de
ATROFIE CEREBRALA disabilitate

DISABILITATE PROGRESIVA
B.CRONICA CU EVOLUTIE CU PUSEE(85%)
4
VECHEA PARADIGMA:

• AXON RELATIV RESPECTAT

• LEZIUNI EXCLUSIV FOCALE

• LOCALIZARE EXCLUSIV IN W.M.

• CLINICA SPECIFICA

5
ACTUAL:

• AFECTARE DIFUZA/FOCALA

• SI W.M. SI G.M

• AFECTARE SI PE REGIUNI APARENT

HETEROGENITATE
NORMALE(NAWM lesions) • PATOLOGIE
• CLINICA
• AXONI LEZATI TIMPURIU • IMUNOPATOGENEZA
• TERAPIE
• INFLAMATIE/NEURODEGENERARE

6
 PATOLOGIE. NEUROPATOLOGIE.
IMUNOPATOGENEZA

Olaf Stüve, M.D., Ph.D.

Neurology Section VA North
Texas Health Care System
Dallas VA Medical Center
Departments of Neurology and
Neurotherapeutics University of
Texas Southwestern Medical
Center at Dallas
7
SM Suspiciune autoimunitate
Cel. T mielin specifice CD4+ si
CD8+ penetreaza SNC si initiaza
inflamatia

8
CELULARITATE:
1. MACROFAGUL – celula din placa acuta /activa-semn histopatologic
patognomonic

2. MICROGLIA

3. CELULA T : CD4+ si CD8+ autoreactive cu Ag mielinici ( determinat

genetic) Ag mielinici: MOG ,MAG, PBM, PLP. Th 17 ce secreta IL17.
CD 8+ distruge OG efect deleter pe remielinizare.

1. CELULA B - Ig

2. LEUCOCIT

3. OLIGODENDROCIT

4. CELULA PREZENTATOARE DE Ag : celula B, macrofag, microglie,cel.

dendritica etc
9
Determinism genetic
Raspuns
Factori de mediu imun
anormal
Agenti infectiosi

10
 FACTORII AMBIENTALI:

1. VIRUSI- herpes, EB, mycoplasma

2. expunerea la UV
3. Latitudinea Nordica
4. deficit de vit D-rol in imunitate

Multiple Sclerosis: Pathogenesis, Symptoms, Diagnoses and Cell-Based Therapy

Nazem Ghasemi, Ph.D,1 Shahnaz Razavi, Ph.D,1,* and Elham Nikzad, B.Sc

11
Multiple Sclerosis: Pathogenesis, Symptoms, Diagnoses and Cell-Based
Therapy
Nazem Ghasemi, Ph.D,1 Shahnaz Razavi, Ph.D,1,* and Elham Nikzad, B.Sc 12
Cresterea expresiei molec de supraf: integrine(VLA4/alfa4,ICAM-1, VCAM-1:
aderare,transport ,penetrare. MMPs

MMPs

Molecule de costimulare

Multiple Sclerosis
Updated: May 04, 2017
Author: Christopher Luzzio, MD; Chief Editor: Jasvinder Chawla, MD, MBA more... 13
Th 1: IL 2,12, INF gama,TNFalfa-proinflamatie

Th 2: IL 4,10,13, TGFbeta- antiinflamatie

Th 17: IL 17,6,TNFalfa-inflamatie

14
Tipuri de placi(perivenular/vascular):

• placa acuta activa

• placa activa cronica cu centrul hipo/acelular cu

cicatrice( cresc OGD remielinizare incipienta
doar in placi recente-placi in semiton/umbroase)

• placa “linistita” cronica-

scleroza,pierdere/degenerare axonala

15
 Unitatea OGD-mielina-axon
Na Ca - injurie axonala , degenerare: glutamat,NO,proteaze
Na RO,citokine,CD8+, activare:
lipaze
proteaze
NOS
ca Ca

Na

Cumulul de pierderi axonale datorita inflamatiei/demielinizarii/transectiei

se coreleaza cu disabilitate progresiva(insuficienta energetica)
Flux persistent de Na depolarizare.
16
Patternurile demielinizante in SM:

1. Pattern I : macrofag activat, cel T autoreactiva, citokine

inflamatorii,NO)-placi clasic perivenular.

2. Pattern II: anticorpi antiMOG, Ig, complement, CIC-

plasmafereza.

3. Pattern III: putina inflamatie, pierdere de MAG, apoptoza

OGD,remielinizare minima.

4. PatternIV: fara CIC,putina inflamatie clasica,

distrofie/degenerare OGD.

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Clinica : conceptul DIS si DIT

varsta tanara

evolutie in pusee-85%

puseu: o disfunctie neurologica

acuta/subacuta ce dureaza cel putin 24 de ore ce
reflecta un eveniment demielinizant/inflamator
focal/multifocal in SNC; primul puseu-CIS

intre pusee: minim 30 de zile

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Criteriile MAGNIMS radiologice(2016):

• periventricular: cel putin 3 leziuni

• cortico-sub(juxta)cortical: cel putin 1 leziune (trei

tipuri de placi)

• spinal: cel putin 1 leziune

• infratentorial: cel putin 1 leziune

DIS
• nerv optic: cel putin 1 leziune

CEL PUTIN 2
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DIT ??
• prezenta simultana oricand pe acelasi
MRI de leziuni Gd+ si Gd- SAU

• o leziune noua T2 sau T1 Gd+pe MRI de

urmarire in raport cu MRI bazal.

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DE CE CRITERIILE DE DG
Mc DONALD ????
• NU pt dg. dif. cu alte boli ci pt dg pozitiv sau de mare
probabilitate la pacienti cu CIS tipic la care alte dg nu
sunt plauzibile.
• Integrarea datelor de
istoric,clinica,imagistica,laboratorul este cruciala pt
acuratetea dg.
• evitarea erorilor de dg la cei cu CIS atipic, varsta >50
ani, nonalbi, copii, evolutie progresiva de la inceput,
imagerie si laborator atipice.
• solicitarea de LCR si MRI spinal oricand in situatiile
atipice
21
 Criteriile actualizate McDonald 2010

CLINICA LEZIUNE CLINICA CRITERII

TOPOGRAFIE SUPLIMENTARE
CEL PUTIN 2 ATACURI CEL PUTIN 2 LEZIUNI NU
( DIT) SEPARATE(DIS)

CEL PUTIN 2 ATACURI 1 LEZIUNE DIS: cel putin 1T2 pe cel

( DIT) putin 2 regiuni clasice pt
SM sau alt atac cu alta
localizare.
1 ATAC 2 LEZIUNI(DIS) DIT: simultan Gd+ si Gd-
asimptomatice sau T2 lez
noua sau T1 Gd+ pe MRI
control sau alt atac.

DIS: cel putin 1 T2 pe cel

1 ATAC
CIS-sindrom clinic izolat
putin 2regiuni tipice sau
alt atac
1 LEZIUNE Impreuna cu
DIT:simultan Gd+ si Gd-
asimptomatice sau T2 lez
noua sau T1 Gd+ pe MRI
control sau alt atac 22
 ACTUALIZAREA CRITERIILOR
Mc DONALD 2017
LA VARIANTELE : 1 atac clinic si 2 leziuni obiective si la
1 atac si 1 leziune obiectiva, DIT poate fi substituita de
LCR cu benzi oligoclonale.

Mai este o varianta: cel putin 2 atacuri clinice cu o

leziune obiectiva si cu o evidenta documentata de o alta
leziune intr-o regiune anatomica distincta

23
RATIUNILE REVIZUIRII CRITERIILOR
2017

1. Diferentierea SM de NMOSDs
2. Dg pozitiv la cei cu CIS atipic
3. Benzile oligoclonale din LCR-parametru
surogat pt DIT
4. frecventa mare a erorilor dg.

24
FORME EVOLUTIVE: Fr.silentioasa

1. RRMS Fr. benigna

2. SPMS CIS

RRMS
3. PRMS
FR progresive
4. PPMS
Maligna Marburg
gravitate
25
 PPMS CRITERII:

Evolutie insidioasa progresiva de 1 an

- cel putin 1-2 lez.T2 localizari tipice
- cel putin 2 lez focale spinale
- LCR: index IgG>0.7 sau benzi
oligoclonale prezente.

2 din 3 prezente.
La fel si in 2017 cu exceptia: fara distinctie intre
leziunile de pe MRI simptomatice si asimptomatice
IgG INDEX= IgG lcr/IgG ser/albumina
26
lcr/albumina ser <0.7 normal
FORME DE CIS:
CLASICE/TIPICE

• NO unilaterala
• sy. supratentorial focal-hemiparestezii
• lez de focar infratentoriala: cerebel,
trunchi, peduncul –ataxie, mers titubant, Romberg
• mielopatie parcelara(Lhermitte sy.)
• nevralgie trigeminala/alte nevralgii/parestezii
• paralizie de nVII

27
 CIS- NEUROPATIA OPTICA-risc
conversie SM

Optic neuritis
A.Prof Frank Gaillard◉ et al. Radiopaedia

28
SEMNE CLINICE NEUROPATIE OPTICA

• ambliopie
• discromatopsie
• scotom central
• dureri la mobilizarea globilor ocular
• FO- edem papilar inflamator –papilita- dilatatii
venoase,exsudate,hemoragii, pseudostaza. In papilite dispare
de la inceput vederea. In HIC vederea dispare tardiv
postatrofie optica.
• NO retrobulbara FARA semne doar tardiv zona decolorata

29
Optic neuritis
A.Prof Frank Gaillard◉ et al. Radiopaedia

30
Majda Thurnher and Robin Smithuis
Department of Radiology of the Medical University of Vienna, Austria and Rijnland hospital in
Leiderdorp, the Netherlands Radiology Assistant

NMO DEVIC disease

31
Dg dif:
1. AION –deficit altitudinal brusc nedureros
2. Neuropatia optica secundara compresiei: adenom
hipofizar,meningiom,anevrism
3. NO infectioasa:tbc, sifilis,Lyme +/- uveita,coroidita
4. NO inflamatorii: NMOSDs (Ig anti aquaporina-4),
ADEM. Coafectarea spinala!
5. Genetice –Leber
6. Toxic
7. Sarcoid
8. lupus, Wegener, Sjogren,Behcet, vasculite retiniene
9. Glaucom atac
10. Tromboza vena centrala retina
11. Tromboza ACR.
12. Uveita/edemul macular la cei cu fingolimod
13. atentie fenomenul Uhthoff-pseudopuseu
32
Tratament cf. ONTT

250 mg iv MP X4 3 zile plus 11 zile de

Prednison 1mg/Kgc

Riscul de conversie la SM

33
 Mielita CIS
Sy.Lhermitte

Majda Thurnher and Robin Smithuis

Department of Radiology of the Medical University of Vienna, Austria and Rijnland hospital in Leiderdorp, the
Netherlands Radiology Assistant
34
Majda Thurnher and Robin Smithuis
Department of Radiology of the Medical University of
Vienna, Austria and Rijnland hospital in Leiderdorp, the
Netherlands Radiology Assistant

35
 Patternul captarii Gd in mielitele din MS

Majda Thurnher and Robin Smithuis

Department of Radiology of the Medical University of Vienna, Austria and
Rijnland hospital in Leiderdorp, the Netherlands Radiology Assistant
36
SEMNE CLINICE MIELITA:

• aspect de mielita transversa

• sy. Brown -Sequard

Deficit motor piramidal

37
Dg dif:
1. NMO SDs
2. Mielite transverse(infectii! HIV,Lyme ,granuloame
paraziti)
3. Astrocitom
4. Ischemia
5. MAV cu hemoragie
6. ADEM mai frecvent la varste f tinere
7. Compresiunile medulare
8. Lupus

38
NMOSDs: trebuie avuta in vedere la copii
Ig anti AQP4 poz
La cei seronegativi- anti MOG
Nu se trateaza cu interferon !!!
Clinica sugestiva: NO bilaterala,implicare TRCsevera,
mielita lunga, leziuni cerebrale mari.

39
Spine – Myelopathy The Radiology assistant
Majda Thurnher and Robin Smithuis
Department of Radiology of the Medical University of Vienna, Austria and Rijnland hospital in
Leiderdorp, the Netherlands
40
Spine – Myelopathy The Radiology
assistant
Majda Thurnher and Robin Smithuis
Department of Radiology of the Medical
University of Vienna, Austria and Rijnland
hospital in Leiderdorp, the Netherlands

NMOSDS

41
Diplopia CIS

Atentie orice tanar cu debutul brusc al unei

diplopii FARA DURERE aproape sigur SM.
Trebuie exclusa miastenia.

By Gregory M. Notz, DO 42
Dr. Timothy Hain
 Cortex frontal aria 8

Horizontal eye movement pathways.

43
(From Bajandas FJ, Kline LB: Neuro-Ophthalmology Review Manual. Thorofare, NJ, Slack, 1988 .
 Clinica OIN
From Wikipedia, the free encyclopedia 44
 Clinica oculomotricitatii:
-diplopie, nistagmus: gaze evoked
pendular
down/up beat
see-saw

OIN uni/bilat
One and a half Scaderea fixatiei
skew deviation Imbalanta vestibulara
Leziuni nn oculomotori

Opsoclonus, flutter , sacade hipo/hipermetrice

45
 Paraclinic : MRI

Multiple Sclerosis Radiology Assistant

Frederik Barkhof, Robin Smithuis and Marieke Hazewinkel
From the MR Center for MS Research, Radiology Department of the 'Vrije Universiteit' Medical Center,
Amsterdam and the Rijnland Hospital, Leiderdorp, the Netherlands 46
 vascular MS

Multiple Sclerosis Radiology Assistant

Frederik Barkhof, Robin Smithuis and Marieke Hazewinkel
From the MR Center for MS Research, Radiology Department of the 'Vrije Universiteit' Medical Center, Amsterdam and the Rijnland Hospital,
Leiderdorp, the Netherlands
47
Multiple Sclerosis Radiology Assistant
Frederik Barkhof, Robin Smithuis and Marieke Hazewinkel
From the MR Center for MS Research, Radiology Department of the 'Vrije
Universiteit' Medical Center, Amsterdam and the Rijnland Hospital,
Leiderdorp, the Netherlands

48
Multiple Sclerosis Radiology Assistant
Frederik Barkhof, Robin Smithuis and Marieke Hazewinkel
From the MR Center for MS Research, Radiology Department of the 'Vrije
Universiteit' Medical Center, Amsterdam and the Rijnland Hospital,
Leiderdorp, the Netherlands
49
 Tipic Dawson finger

Black holes

Gd+
edem

Multiple Sclerosis Radiology Assistant

Frederik Barkhof, Robin Smithuis and Marieke Hazewinkel
From the MR Center for MS Research, Radiology Department of the 'Vrije
Universiteit' Medical Center, Amsterdam and the Rijnland Hospital,
Leiderdorp, the Netherlands 50
 Dinamica evolutiei: leziuni noi pe T2

Multiple Sclerosis Radiology Assistant

Frederik Barkhof, Robin Smithuis and Marieke Hazewinkel
From the MR Center for MS Research, Radiology Department of the 'Vrije
Universiteit' Medical Center, Amsterdam and the Rijnland Hospital,
Leiderdorp, the Netherlands
51
 MS maligna /tumorala

Multiple Sclerosis Radiology Assistant

Frederik Barkhof, Robin Smithuis and Marieke Hazewinkel
From the MR Center for MS Research, Radiology Department of the 'Vrije
Universiteit' Medical Center, Amsterdam and the Rijnland Hospital, 52
biopsie Leiderdorp, the Netherlands
 ADEM versus MS

Multiple Sclerosis Radiology Assistant

Frederik Barkhof, Robin Smithuis and Marieke Hazewinkel
From the MR Center for MS Research, Radiology Department of the 'Vrije
Universiteit' Medical Center, Amsterdam and the Rijnland Hospital,
Leiderdorp, the Netherlands 53
Multiple Sclerosis Radiology Assistant
Frederik Barkhof, Robin Smithuis and Marieke Hazewinkel
From the MR Center for MS Research, Radiology Department of the 'Vrije
Universiteit' Medical Center, Amsterdam and the Rijnland Hospital,
Leiderdorp, the Netherlands
54
Multiple Sclerosis Radiology Assistant
Frederik Barkhof, Robin Smithuis and Marieke Hazewinkel
From the MR Center for MS Research, Radiology Department of the 'Vrije
Universiteit' Medical Center, Amsterdam and the Rijnland Hospital, 55
Leiderdorp, the Netherlands
BOALA DE VASE MICI
Multiple Sclerosis Radiology Assistant
Frederik Barkhof, Robin Smithuis and Marieke Hazewinkel
From the MR Center for MS Research, Radiology Department of the 'Vrije
Universiteit' Medical Center, Amsterdam and the Rijnland Hospital, 56
Leiderdorp, the Netherlands
SARCOID Multiple Sclerosis Radiology Assistant
Frederik Barkhof, Robin Smithuis and Marieke Hazewinkel
From the MR Center for MS Research, Radiology Department of the 'Vrije
Universiteit' Medical Center, Amsterdam and the Rijnland Hospital,
Leiderdorp, the Netherlands

LYME 57
Multiple Sclerosis Radiology Assistant
Frederik Barkhof, Robin Smithuis and Marieke Hazewinkel
From the MR Center for MS Research, Radiology Department of the 'Vrije
Universiteit' Medical Center, Amsterdam and the Rijnland Hospital, Leiderdorp,
the Netherlands

58
 TRATAMENT

PUSEU:
Methylprednisolone (Solu-Medrol) can hasten recovery
from an acute exacerbation of MS
Plasma exchange (plasmapheresis) can be used short
term for severe attacks if steroids are contraindicated or ineffective [5]
Dexamethasone is commonly used for acute transverse myelitis and
acute disseminated encephalitis

SECUNDAR : IVIG

Multiple Sclerosis MEDSCAPE

Updated: May 04, 2017
Author: Christopher Luzzio, MD; Chief Editor: Jasvinder Chawla, MD,
MBA more...
59
The DMAMS currently approved for use by the US Food and Drug Administration
(FDA) include the following:
Interferon beta-1a (Avonex, Rebif) reducere rata recidiva cu 29-33% [6]
Interferon beta-1b (Betaseron, Extavia)-scade recidivele cu 34% [7] I linie
Peginterferon beta-1a (Plegridy)- scade RAR cu 36% [8]
Glatiramer acetate (Copaxone)- 20 mg/od 40mg 3z/sapt scade RAR cu 29-
34% [9]

Natalizumab (Tysabri) [10, 11]

Mitoxantrone [12]
Fingolimod (Gilenya)- RA edem macular, bloc AV
Teriflunomide (Aubagio)-TRIALUL TOPIC PT CIShepatotoxicitate,teratogenitate
Dimethyl fumarate (Tecfidera) [15, 16, 17, 18]
Alemtuzumab (Lemtrada)-ANTI CD 52 [19, 20, 21]
Daclizumab (Zinbryta)-anti CD 25 REC. DE IL2
Ocrelizumab - anti CD 20[22, 23]

Multiple Sclerosis MEDSCAPE

Updated: May 04, 2017
Author: Christopher Luzzio, MD; Chief Editor: Jasvinder Chawla, MD, MBA more... 60
DMA SCOPURI
• scaderea ratei de recidiva a atacurilor
• incetinirea disabilitatii progresive( data de
moartea axonala, atrofie)
• scaderea intensitatii atacului
• scaderea nr de leziuni( scaderea
incarcarii cu placi a creierului si maduvei,
mai ales scaderea ratei de aparitie a leziunilor
noi)

61
Interferonii beta:

Impiedica reactia trimoleculara

Scad expresia integrinelor si selectinelor
Activeaza fenotipul antiinflamator

Problemele lor: ac neutralizanti, depresia,hepatita,

flu-like sy,mielosupresie,disfunctie tiroidiana

62
 The following agents are used for treatment
of aggressive MS:
High-dose cyclophosphamide (Cytoxan) has been used
for induction therapy
Mitoxantrone is approved for reducing neurologic disability and/or the
frequency of clinical relapses in patients with SPMS, PRMS, or worsening
RRMS

Multiple Sclerosis MEDSCAPE

Updated: May 04, 2017
Author: Christopher Luzzio, MD; Chief Editor: Jasvinder Chawla, MD,
MBA more...
63