MRI in MS: the radiologist perspective

Transcription

1 MS Preceptorship - Updating Knowledge in Multiple Sclerosis - June, Barcelona MRI in MS: the radiologist perspective Àlex Rovira Unidad de Resonancia Magnética Servicio de Radiología Hospital Vall d Hebron. Barcelona. Spain alex.rovira@idi-cat.org

2 Conventional MRI measures T2 and CE T1-WI T2-weighted Post-contrast T1-weighted Increased water content (edema, acute demyelination, tissue disruption) Increased BBB permeability (acute inflammation) Highly sensitive for detecting MS plaques Provide quantitative assessment of inflammatory activity and lesion load Most important paraclinical tool for diagnosing and monitoring MS

3 Modified from Roland Martin Two Overlapping Pathogenetic Components of MS Preclinical Relapsing-Remitting MS Secondary Progressive MS EDSS (clinical deficit) Lesion Load T2 Brain Volume atrophy measures Time Inflammation Antiinflammatory/ immunomodulatory therapies Degeneration/ nervous system damage Myelin/neural repair/ neuroprotection

4 Clinico-radiological paradox Discrepancy 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

5 How can we overcome limits of conventional brain MRI in MS? Application of MR techniques that selectively detect specific pathological 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)

6 IMAGING IRREVERSIBLE TISSUE DAMAGE T1 Black holes

7 IMAGING IRREVERSIBLE TISSUE DAMAGE T1 Black holes 2 Axonal density 40% % 1 1: strongly hypointense 2: mildly hypointense 3: slightly hypointense Van Waesberghe et al. Ann Neurol % 2 3

8 IMAGING IRREVERSIBLE TISSUE DAMAGE T1 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

9 Evolution of lesion appearance over time T2 + New T2 lesion Gd + (90%) T1 + (80%) Time t1 0 t months Modified from R. Zivadinov Neurology 2007

10 Evolution of lesion appearance over time T2 - / T1 - (3-5%) remyelination T2 + New T2 lesion Gd + (90%) T2 + / T1 - (60-80%) demyelination remyelination T1 + (80%) T2 + / T1 + (20-40%) Ring-enhancing lesions Large lesions PV lesions severe tissue destruction Time t1 0 t months Modified from R. Zivadinov Neurology 2007

11 Tracking individual lesion evolution 80% of gad-enhancing lesions are hypointense on T1 Most became isointense baseline 12 months

12 Interferon beta reduces the frequency of new BH formation RR MS patients Natural history Therapy phase Bagnato et al. Arch Neurol. 2005

13 T1 Black holes Pros 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

14 T1 Black holes Cons Definition is arbitrary and highly operator dependent Do not provide quantitative assessment No graded information about intrinsic pathology (in vivo MRS extremely variable) Difficult to detect in the brainstem, spinal cord and optic nerve

15 Magnetization Transfer Ratio (MTR) MTR = 40-50% MTR = 37% MTR = 21% MTR = 0% PD T1 MTR Quantitative measure Marker of demyelination (significant correlation between myelin content and MTR) Focal and global tissue assessment Decreases with demyelination (reduced proton exchange) Increases with remyelination

16 Demyelination / Remyelination Postmortem MTR remyelinated LFB demyelinated MTR / Myelin content r = p <0.001 LFB T2 MTR Schmierer et al. Arch Neurol 2004

17 Magnetization Transfer Ratio Sequential analysis in acute/chronic MS plaques.48 Initially isointense 20% NAWM Pattern A Pattern C Isointense 15% 44% Hypointense.36 80%.34 Mean MTR.32 1 Pattern D Pattern B Acute black holes Months of Follow-Up % 5% Chronic black holes permanent van Waesberghe et al. Am J Neuroradiol 1998

18 remyelination demyelination Chen et al. Ann Neurol 2008

19 MTR in MS Pros 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

20 MTR in MS Cons Time consuming Variability Optimization and standarization across multiple sites and over time is challenging Technical demands have limited its use in therapeutic trials to single centers Edema (dilution effect) and T1 relaxation influence MT effect

21 IMAGING IRREVERSIBLE TISSUE DAMAGE Brain atrophy

22 basal 1y 2y 3y 4y No definite change in EDSS p <0.05 by 18 months -1.8mL/year Definite change in EDSS p <0.05 by 6 months -6.4mL/year Months Loseff et al. Brain 1996

23 Effect of DMT on brain atrophy prevention in MS GA Low dose INF Natalizumab Untreated High dose INF / Chemotherapeuthics Zivadinov et al. J Neurol 2008

24 Brain Atrophy in MS Effect of Therapies on Brain Volume Change (%) -3-2, ,5-2,27-3, Control IFNß-SC IFN ß-IM n = ,5-4,75 GA ,79-0,95-1,01 0 Control IFNß-SC IFN ß-IM n = ,79-1,83 GA 102 p = GA 121 Year 1 Year 5 p = p = p < Control IFNß-SC IFN ß-IM n = Year 0 Year 1 (Pseudoatrophy) p < Year 0 Year 5-1,48-2, ,8 p < p < All therapies are significantly better than controls (p < 0.001) All therapies are significantly better than controls (p < 0.001) Khan O. et al., AAN 2008.

25 Brain volume changes in ADEM Effect of steroids baseline 1 month 3 months 6 months 1 year Hoogervorst et al. Mult Scler 2002

26 Mechanisms that may decrease brain volume in multiple sclerosis Reversible Pseudoatrophy Resolving inflammation Loss of inter/intracellular water Changes in electrolyte balance Irreversible Modified from Zivadinov et al. Neurology 2008 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

27 Regional brain atrophy- Rationale MS results in tissue loss of Regional brain atrophy, both GM and WM, but at different rates (Chard 2002; Dalton 2004; Valsasina 2005) 16 (n=17) CIS (n=7) Fold Increase (relative to controls) HC RRMS CIS->RRMS (n=8) (n=28) RRMS->SPMS (n=7) 2 0 SPMS -2?BPF?WMF (n=19)?gmf Fisher, et al, Ann Neurol 2008 Fold Increase Over HCs + SE GM and WM atrophy relate differently to disability / cognitive impairment (Sanfilipo 2005;Tedeschi 2005; Amato 2007; Fisniku 2008) MS Prog (n=29) MS Stable (n=34) GM Atrophy WM Atrophy Rudick RA, et al. J Neurol Sciences 2009

28 Brain volume loss in multiple sclerosis Variaciones anuales Whole brain -0.6% (Fox, 2000) (yearly atrophy estimates) -0.8% (Fox, 2000) -0.9% (Fox, 2000) CIS -0.5% (Kalkers, 2002) -1.17% (Zivadinov, 2001) RR MS -0.7% (Kalkers, 2002) SP MS -0.88% (Kalkers, 2002) -0.28% (Stevenson, 2002) PP MS -0.61% (Rudick, 1999) -2.0% (Ge, 2000) -1.33% (Sormani, 2004) -0.58% (Paolillo, 2004) -1.88% (Inglese, 2004) -1.23% (Tiberio, 2004) -1.84% (Saindane, 2000) -0.46% (Dalton, 2004) -1.06% (Hardmeier, 2003) -0.4% (Filippi, 2000) -1.5% (Ge, 2000) -2% -1% Healthy population 0% Courtesy of Jaume Sastre-Garriga. Jaume Sastre-Garriga. Institute of Neurology, University College London, Queen Square

29 Brain atrophy Pros 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)

30 Brain atrophy Cons Pathologic basis still unclear Non-specific brain response: drug use, aging, and different neurodegenerative diseases Small changes over time Confounding effect: Gliosis/ inflammation prevents atrophy Fluctuations of tissue water (paradoxal therapeutic effect) Prednisolone Immunomodulatory drugs

31 IMAGING IRREVERSIBLE TISSUE DAMAGE 1H-MRS and MS NAA Simmons et al., 1991 NAA immunohistochemical staining Decrease in brain NAA/Cr ratio has been shown to be indicative of irreversible axonal dysfunction and reduced cerebral volume Reports have shown an annual decline of 4% to 6% in NAA/Cr ratio in MS patients De Stefano et al., Brain 1998

32 Role of advanced MR techniques: controversial Proton MR spectroscopy T2 T1 gad Cholin map Grade III astro Acute MS

33 Glioma Pseudotumor Majós et al. Am J Neuroradiol 2009

34 NAA/Cr ratio progressively increased, and relapse rate, disability, and T2W and T1W lesion load progressively decreased in treated patients over 4 yrs 2,4 Mean NAA/Cr 2,3 +9.6% P =.04 2,2 VOI NAWM HC 2,1 2 VOI = Volume of Interest NAWM = Normal-Appearing White Matter HC = Healthy Control +12.7% P =.03 1,9 BL Y1 Y2 (n = 18) Y3 Y4 (n = 15) Khan O et al. J Neuroimaging 2008

35 MRS in MS Pros 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

36 MRS in MS Cons Time consuming Quantification relies on ratios (NAA/creatine) Optimization and standarization across multiple sites and over time is challenging Technical demands have limited its use in therapeutic trials to single centers with conflicting results generally reported from small patient cohorts Guidelines for using proton MR spectroscopy in multicenter clinical MS studies De Stefano et al. Neurology 2007

37 Conclusions MRI provides information of the inflammatory and neurodegenerative components of MS MRI should be considered as a marker of neurodegeneration in clinical trials Not enough evidence to support the use of MRI for monitoring the neurodegenerative component of the disease in individual patients

38 Neuroimmunology Unit (Dr. Montalban) MRI Neuro Unit

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40 Magnetization Transfer Ratio Sequential analysis in acute MS plaque % MTR T1 gad Flair MTR baseline 2w 2 mo 1 year 15 baseline 2w 2 mo 1 year

41 Voxel-wise changes in magnetization transfer ratio A sensitive method for identifying focal demyelination and remyelination in patients with multiple sclerosis Dwyer et al. J Neurol Sci 2009

42 Misclassification of MS Lesions as GM GM / WM volume in RR MS SPM 52% of lesion voxels misclassified as GM (Chard, et al. Brain 2002) GM volume in RR MS WM volume in RR MS Mask Mask No mask No mask T2 lesion volume Effect: Lesion volume GM volume Trials: Could under-estimate a treatment effect on GM atrophy Research: Could obscure correlations