mri in ms: the radiologist perspectiveunidad de resonancia magnética servicio de radiología...
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Unidad de Resonancia MagnéticaServicio de RadiologíaHospital Vall d’Hebron.
Barcelona. [email protected]
Àlex Rovira
“MRI in MS: the radiologist perspective”
MS Preceptorship - Updating Knowledge in Multiple Sclerosis -June, 1-3 2010
Barcelona
Increased water content (edema, acute demyelination, tissue disruption)Increased BBB permeability (acute inflammation)
T2-weighted Post-contrastT1-weighted
Conventional MRI measuresT2 and CE T1-WI
• Highly sensitive for detecting MS plaques• Provide quantitative assessment of inflammatory activity and lesion load• Most important paraclinical tool for diagnosing and monitoring MS
Preclinical Relapsing-Remitting MS Secondary Progressive MS
Lesion LoadT2
Brain Volumeatrophymeasures
EDSS (clinical deficit)
Time
Inflammation Degeneration/ nervoussystem damage
Two Overlapping Pathogenetic Components of MS
Antiinflammatory/immunomodulatory
therapiesMyelin/neural repair/
neuroprotection
Modified from Roland Martin
Clinico-radiological paradoxDiscrepancy between cMRI and clinical measures
Non specificity of the underlying lesion substrate
Insensitivity to quantify extent of damage in NAWM and spinal cord, which
substantially contribute to disability
Insensitivity to reveal cortical lesions
Inability to assess cortical adaptive reorganization
How can we overcome limits of conventionalbrain MRI in MS ?
Application of MR techniques that selectively detect specificpathological substrates (lesions and NABT)
Putative markers of matrix destruction: axonal density,myelination
•T1 Black holes•MTR•Atrophy•MRS
Outcome measures in clinical trials (neuroprotective agents for myelin repair)
1997 2002 20031995 2005
IMAGING IRREVERSIBLE TISSUE DAMAGET1 Black holes
Van Waesberghe et al. Ann Neurol. 1999
2
50%
2
2: mildly hypointense
1
Axonal density40%
1
1: strongly hypointense
3
90%
3
3: slightly hypointense
IMAGING IRREVERSIBLE TISSUE DAMAGET1 Black holes
• Chronic black hole lesions: T1 hypointense lesions (SE sequences)persisting 6 months or longer indicate
– Significant demyelination– Axonal loss
• This tissue damage is irreversible• Correlation with disability is strong
IMAGING IRREVERSIBLE TISSUE DAMAGET1 Black holes
Gd + (90%)New T2 lesion
T2 +
T1 + (80%)
Evolution of lesion appearance over time
Modified from R. Zivadinov Neurology 2007
Timet10
t26 -12 months
Gd + (90%)New T2 lesion
T2 +
T1 + (80%)
T2 + / T1 +(20-40%)
T2 + / T1 -(60-80%)
T2 - / T1 -(3-5%)
Evolution of lesion appearance over time
remyelination
Modified from R. Zivadinov Neurology 2007
demyelinationremyelination
severe tissuedestruction
Timet10
t26 -12 months
Ring-enhancing lesionsLarge lesionsPV lesions
baseline 12 months
Tracking individual lesion evolution
80% of gad-enhancing lesions are hypointense on T1Most became isointense
Interferon beta reduces the frequency of new BH formationRR MS patients
Bagnato et al. Arch Neurol. 2005
Natural history
Therapy phase
ProsT1 Black holes
Specific marker of severe tissue destruction
T1W sequences easy to obtain, not time-consuming
Improve correlations with disability
Sensitive to changes over time (disease progression
under treatment)
Biomarker of neuroprotective effect
ConsT1 Black holes
Definition is arbitrary and highly operatordependent
Do not provide quantitative assessment
No graded information about intrinsic pathology (invivo MRS extremely variable)
Difficult to detect in the brainstem, spinal cord andoptic nerve
MTRT1PD
•Quantitative measure•Marker of demyelination (significant correlation between myelin content and MTR)•Focal and global tissue assessment
Magnetization Transfer Ratio (MTR)MTR = 40-50%
MTR = 37%
MTR = 21%
MTR = 0%
•Decreases with demyelination (reduced proton exchange)•Increases with remyelination
Schmierer et al. Arch Neurol 2004
Demyelination / RemyelinationPostmortem MTR
remyelinated
demyelinated
T2 MTR
LFB
LFB
MTR / Myelin contentr = -0.84 p <0.001
Magnetization Transfer RatioSequential analysis in acute/chronic MS plaques
van Waesberghe et al. Am J Neuroradiol 1998
.48
.46
.44
.42
.40
.38
.36
.34
.32–1 0 1 3 5 7
Months of Follow-Up
NAWMNAWMPattern A
Pattern DPattern B
Isointense
36%5%
15%
Chronicblack holespermanent
Initiallyisointense
20%
Hypointense80%
Acute blackholes
Pattern C 44%
Mean MTR
remyelination
demyelination
Chen et al. Ann Neurol 2008
Quantitave and continuous measure
Related to axonal loss and degree of demyelination
Proposed as a surrogate marker of remyelination
Information of the entire brain
Correlated with the degree of disability and cognitive
impairment
Sensitive to changes over time
ProsMTR in MS
ConsMTR in MS
Time consuming
Variability
Optimization and standarization across multiplesites and over time is challenging
Technical demands have limited its use intherapeutic trials to single centers
Edema (dilution effect) and T1 relaxation influenceMT effect
IMAGING IRREVERSIBLETISSUE DAMAGE
Brain atrophy
1997 2002 20031995 2005
Loseff et al. Brain 1996
No definite change in EDSSp <0.05 by 18 months
-1.8mL/year
Definite change in EDSSp <0.05 by 6 months
-6.4mL/year
Months
basal 1 y 2 y 3 y 4 y
Effect of DMT on brain atrophy prevention in MS
Zivadinov et al. J Neurol 2008
Untreated
Low dose INF
Natalizumab
GA
High dose INF / Chemotherapeuthics
Year 0 – Year 5 Year 0 – Year 1(Pseudoatrophy)
Year 1 – Year 5
Khan O. et al., AAN 2008.
-3,8
-2,2-1,83
-1,48
-4
-3
-2
-1
0
Control IFNß-SC IFN ß-IM GAn = 34 91 47 102
-0,95 -1,01
-0,79 -0,79
-1,5
-1
-0,5
0
-4,75
-3,21-2,62
-2,27
-5
-4
-3
-2
-1
0
Control IFNß-SC IFN ß-IM GAn = 34 91 47 102
Control IFNß-SC IFN ß-IM GAn = 34 101 53 121
•• All therapies areAll therapies aresignificantly better thansignificantly better thancontrols (p < 0.001)controls (p < 0.001)
•• All therapies areAll therapies aresignificantly better thansignificantly better thancontrols (p < 0.001)controls (p < 0.001)
p<
0.00
01
p=
0.00
36
p < 0.0001
p=
0.02
01
p=
0.00
56
p < 0.0001
p<
0.00
01
Brain Atrophy in MSEffect of Therapies on Brain Volume Change (%)
1 monthbaseline 3 months 1 year6 months
Brain volume changes in ADEMEffect of steroids
Hoogervorst et al. Mult Scler 2002
• Pseudoatrophy– Resolving inflammation– Loss of inter/intracellular water– Changes in electrolyte balance
• Atrophy– Natural history
• Demyelination– Partially reversible (remyelination)
• Loss of glial cells– Partially reversible (recruitment,
differentiation)• Axonal loss
– Irreversible– DMA related
• Protein catabolism• Chemotoxicity• Inhibition of good inflammation
– DMA induced• Resolving inflammation• Loss of inter/intracellular water• Changes in electrolyte balance
Mechanisms that may decrease brain volume in multiple sclerosis
Reversible Irreversible
Modified from Zivadinov et al. Neurology 2008
• MS results in tissue loss of Regional brain atrophy, both GM and WM, but at differentrates
(Chard 2002; Dalton 2004; Valsasina 2005)
• GM and WM atrophy relate differently to disability / cognitive impairment(Sanfilipo 2005;Tedeschi 2005; Amato 2007; Fisniku 2008)
Rudick RA, et al. J Neurol Sciences 2009
(n=29) (n=34)
Fisher, et al, Ann Neurol 2008
Regional brain atrophy- Rationale
2.23.1 3.43.5 3.2
8.1
5.24.4
12.4
5.8
3.3
14.0
-2
0
2
4
6
8
10
12
14
16
?BPF ?WMF ?GMF
HC (n=17)
CIS (n=7)
CIS->RRMS(n=8)
RRMS (n=28)
RRMS->SPMS(n=7)
SPMS (n=19)
Fold
Incr
ease
(rel
ativ
eto
cont
rols
)
6.3
14.2
3.82.8
MS Prog MS Stable
Fol
dIn
crea
seO
verH
Cs
+S
EGM Atrophy WM Atrophy
-0.46% (Dalton, 2004)
-0.58% (Paolillo, 2004)
-1.06% (Hardmeier, 2003)-1.84% (Saindane, 2000)
-0.61% (Rudick, 1999)
-1.88% (Inglese, 2004)
-0.88% (Kalkers, 2002)
-0.7% (Kalkers, 2002)
-1% 0%-2%
-0.5% (Kalkers, 2002)
-0.9% (Fox, 2000)
-0.8% (Fox, 2000)
-0.6% (Fox, 2000)
-1.33% (Sormani, 2004)
-1.23% (Tiberio, 2004)
CIS
RR MS
PP MS
SP MS
Whole brain(yearly atrophy estimates)
-0.4% (Filippi, 2000)
-0.28% (Stevenson, 2002)
-2.0% (Ge, 2000)
-1.5% (Ge, 2000)
-1.17% (Zivadinov, 2001)
Healthypopulation
Jaume Sastre-Garriga. Institute of Neurology, University College London, Queen Square
Variaciones anuales
Courtesy of Jaume Sastre-Garriga.
Brain volume loss in multiple sclerosis
Brain atrophyPros
Quantitative and continuous measure
Marker of irreversible tissue damage
Information of the entire brain
Regional measure (gray / white matter)
Correlated with the degree of disability and cognitive impairment
Sensitive to changes over time (disease progression under treatment)
Brain atrophyCons
Pathologic basis still unclearNon-specific brain response: drug use, aging, and different neurodegenerativediseasesSmall changes over timeConfounding effect:
Gliosis/ inflammation prevents atrophyFluctuations of tissue water (paradoxal therapeutic effect)
PrednisoloneImmunomodulatory drugs
NAA immunohistochemicalstaining
Sim
mon
set
al.,
1991
NAA
IMAGING IRREVERSIBLE TISSUE DAMAGE1H-MRS and MS
•Decrease in brain NAA/Cr ratio hasbeen shown to be indicative ofirreversible axonal dysfunction andreduced cerebral volume
•Reports have shown an annualdecline of 4% to 6% in NAA/Cr ratioin MS patients
De Stefano et al., Brain 1998
Grade III astro
Acute MS
T2 T1 gad Cholin map
Role of advanced MR techniques: controversialProton MR spectroscopy
Majós et al. Am J Neuroradiol 2009
Glioma
Pseudotumor
NAA/Cr ratio progressively increased, and relapse rate, disability,and T2W and T1W lesion load progressively decreased in treated
patients over 4 yrs
1,9
2
2,1
2,2
2,3
2,4
BL Y1 Y2 Y3 Y4
Mea
nN
AA
/Cr
VOINAWMHC
+9.6%P = .04
+12.7%P = .03
(n = 18) (n = 15)
VOI = Volume of InterestNAWM = Normal-Appearing White MatterHC = Healthy Control
Khan O et al. J Neuroimaging 2008
ProsMRS in MS
Quantitative and continuous measure related to neuroaxonal loss
/dysfunction
Assessment of normal appearing brain tissue
Information about tissue injury in a large segment of brain tissue
Sensitive to disease changes over time
Correlated with disability
ConsMRS in MS
Time consuming
Quantification relies on ratios (NAA/creatine)
Optimization and standarization across multiple sites andover time is challenging
Technical demands have limited its use in therapeutic trialsto single centers with conflicting results generally reportedfrom small patient cohorts
Guidelines for using proton MR spectroscopy in multicenter clinical MS studiesDe Stefano et al. Neurology 2007
Conclusions
MRI provides information of the inflammatory andneurodegenerative components of MS
MRI should be considered as a marker of neurodegenerationin clinical trials
Not enough evidence to support the use of MRI formonitoring the neurodegenerative component of the diseasein individual patients
Neuroimmunology Unit (Dr. Montalban) MRI Neuro Unit
T1 gad
Flair
MTR
baseline 2 w 2 mo 1 year
% MTR
15
17
19
21
23
25
27
29
31
15
17
19
21
23
25
27
29
31
33
baseline 2 w 2 mo 1 year
Magnetization Transfer RatioSequential analysis in acute MS plaque
Voxel-wise changes in magnetization transfer ratioA sensitive method for identifying focal demyelination and
remyelination in patients with multiple sclerosis
Dwyer et al. J Neurol Sci 2009
Misclassification of MS Lesions as GM
Effect:
Lesion volume GM volume
Trials:
Could under-estimate a treatment effecton GM atrophy
Research:
Could obscure correlations
SPM52% of lesion voxels misclassified as
GM(Chard, et al. Brain 2002)
GM / WM volume in RR MS
GM volume in RR MSMask
No mask
WM volume in RR MSMask
No mask
T2 lesion volume