Advances in the Use of MRI in the Management of MS. The Role of MRI in MS Management. Jack H. Simon Portland, Oregon

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1 Advances in the Use of MRI in the Management of MS The Role of MRI in MS Management Jack H. Simon Portland, Oregon

2 Disclosures Dr. Simon has nothing to disclose. This continuing education activity is managed and accredited by Professional Education Services Group in cooperation with the Paralyzed Veterans of America. Neither PESG nor PVA nor any accrediting organization supports or endorses any product or service mentioned in this activity. PESG Staff and the Program Planning Committee have no financial interest to disclose. Commercial Support was not received for this activity.

3 MRI in the Individual Patient As Opposed to the MS Patient Population

4 The Role of MRI in MS Management MRI in Diagnosis/Differential Diagnosis McDonald-International Criteria/CIS/RIS Technique Standardized Imaging New Techniques/Technologies Measures of Disease & Disease Activity Monitoring Sub-Clinical Change Over Time Evaluating Treatment Outcome-Responding? Detecting Complications of Treatment

5 Why Conventional MRI in (MS) Clinical Practice? Advantages Sensitive to early and subclinical disease Measure of pace of disease Objective, Informative, Predictive Detects concurrent pathology - complications of therapy Limitations T2- lesions Non-specific with regard to pathology Gd lesions Only a subclass & fraction of inflammation Indirect sensitivity to neurodegeneration (atrophy) Blind to details of axons, myelin, cells, chemistry But -qmri is not (yet) effective in individuals

6 Number Lesions The Disease is Largely Subclinical MR Event Rate >>>>>>Clinical Attack Rate CIS Time (months) Zero Attacks

7 Baseline-CIS 12 month 18 month No Clinical Event over 5 years - Cognitive Deficits The Focal Sub-Clinical Changes Are Relevant

8 Example--What we cannot see What we can see

9 Pre-Imaged Stage Group avg MTR or 1/T2 etc Lesion Image Stage Gd+ / T2 + Follow-up Imaging T2 + T2 Footprint Goodkin et al, 1998

10 The T2 Footprint is Stable Over Time time A Strong Measure of Sub-Clinical Activity Within a Given Interval

11 Problem Gd-enhanced MRI in an Individual is only a Snapshot in Time Monthly MRI s over a year Goodkin, Rooney, Sloan, et al Neurol. 98

12 Enhancing Lesion Counts After a CIS Fred Barkhof et al Amsterdam

13 Enhancing lesion number Enhancing Lesion Count in Untreated MS Patient CEL month Courtesy of Nancy Richert

14 Atrophy as a Measure of Neurodegeneration Baseline Two Years Later BPF Fisher et al, 2002

15 Example Case 12 Years of Data July Atrophy Pattern: Decelerating Male RRMS Symptom duration: 13.4 years Baseline (July 2000) Last Visit (Sept 2012) Age: EDSS: 1 3 MSFC: BPF courtesy Beth Fisher Sept 2012

16 BPF in Individual Patients Over 12 months Courtesy E. Fisher & R. Rudick

17 BPF Change Over 12 Years in 4 MS Patients 49 F; RRMS; EDSS F; RRMS; EDSS F; RRMS; EDSS 3 65 M; SPMS; EDSS 4 courtesy Beth Fisher

18 Classic Spinal Cord Pathology in MS Vertically oriented A few segments (remember 2 or fewer) Multicentric - Multiple lesions May enhance Partial cross-sectional involvement Dorsal-lateral surfaces Cord can be enlarged in acute stages Atrophy

19 Spinal Cord --- Classic Appearance

20 Spinal Cord --- MS Proton/T2 Proton density

21 Spinal Cord Atrophy

22 Spinal Cord MRI for Differential Diagnosis MS Non-specific Non-specific T2-hyperintensities are very rare in normal spinal cord (including from aging and in patients with cardiovascular risk factors) From Bot et al., 2002

23 Presents with episode of severe myelopathy Brain MRI negative Courtesy Tony Traboulsee, UBC

24 Neuromyelitis Optica NMO IgG Seropositivity Antibody Against Aquaporin-4 Water Channel AQP-4 receptors reside on the astrocyte foot-processes

25 Patient with severe bilateral optic neuritis

26 3 months later - after spinal cord symptoms develop

27 Monitoring Therapy in The Individual MS Patient Art Becoming Science

28 Enhancing lesion number 1 Lesion Counts Proof of Concept - Monitoring Therapy T2LL (cc) IFN CEL T2LL month Courtesy of Nancy Richert

29 Evaluating Treatment Response by MRI? But MONTHLY MRI IMPRACTICAL Good Response Continue Rx Initiate Therapy MRI or Clinical Criteria? Poor Response (Non- Responder) Consider Change in Therapy Second Line Therapy Are there objective criteria for non-responder?

30 Selected Evidence-Based Studies to Define Treatment Failure Rudick et al (2004) Rio et al (2008) Durelli et al (2008) Kinkel et al (2008) Gd/New T2 /Relapse Active Lesions (N,E,Gd+) Active MRI and NAb Gd+ and T2 Based on different validating outcome measures and classification parameters

31 Can Response to Therapy Be Determined Early and Based on a Single MRI Study? Clinically Isolated Syndrome Positive MRI Evaluate MRI Activity At 6 Month Study Hi Lesion Count Cutpoints Low Count Cutpoints Validation by Outcome Measure (CDMS) By Three Years Kinkel et al, 2008

32 Single MRI Evaluation at Six Months Post Therapy Predicts Outcome in Treated Patients Kinkel et al, 2008 Months after CIS Hi Co Cutpo Low C Cutpo Treated Group Hazard Ratio = 4.99 (p <0.0001)

33 Year 1and Year 2 MRI.15 Year Disability Outcome Bermel et al 2012

34 Worst Quartile of EDSS after 15 Years GD+.Odds Ratio 8.96 (p <0.001) Bermel et al 2012

35 SURVEILLANCE MRI for COMPLICATIONS OF THERAPY of MS

36 Progressive Multifocal Leucoencephalopathy (PML) in MS Treated with Natalizumab Prevalence vs Infusions As of May 3, 2012, approximately 99,600 patients received natalizumab worldwide, with 242 cases of PML reported. Clifford et al, Lancet 2010

37 Progressive Multifocal Leucoencephalopathy (PML) Prognosis for PML has been Poor Discover-Plasmapharese-Antivirals Charil, 2006

38 Difficulty is Detecting PML Within the background of MS Lesions Adapted from Nancy Richert

39 Detecting PML With MS in the Background Slice #1 Slice #1 MS CENTRAL PML PERIPHERAL

40 Slice #1 Slice #2 Adapted from Nancy Richert

41 DWI - Relatively More Positive in PML v MS MS DWI T2 Shine Through PML DWI Greater T2 Shine through? Adapted From Nancy Richert

42 PML Rapid Increase!!!!!!

43 Peripheral, Subcortical; Ill defined borders From Nancy Richer

44 PML Generally no mass effect Ill defined, or linear enhancement possible, not the total lesion area

45

46 Asymptomatic PML Detected Through Surveillance MRI From Demasters et al, 2012

47 VARICELLA-ZOSTER VIRUS ENCEPHALITIS AND VASCULOPATHY IN A PATIENT TREATED WITH FINGOLIMOD Ratchford J N et al. Neurology 2012;79:

48 IMPROVED & STANDARDIZED TECHNIQUE

49 STANDARDIZED MRI in MS Update T. Traboulsee et al In 2009 Mscare.org 3D Acquisition Improves the Interface for Standardized Acquisition and Interpretation

50 Eur Radiol 2008

51 3D SEQUENCES DIR FLAIR T2 MPRAGE

52 Gray Matter Demyelination Double Inversion Recovery- DIR Images from six month follow-up; From Calabrese, Neuroimage, 2008 Geurts, 2005, reported in Radiology a 500% advantage over T2; 150% over FLAIR

53 Counting New T2 Lesions in the Cortex? Calabrese Arch Neurol. 2007

54 3D FLAIR Sagittal Acquisition 1mm partitions 3T MRI

55 Axial Reconstruction From Sagittal Acquisition

56 PD/T2 3D FLAIR

57 Subtraction MRI ---Activity Predicts Atrophy Time 1 Time 2 Subtraction Image Liquori et al

58 Summary -The Role of MRI in MS Management Simple Measures T2, Gd, Atrophy Sensitive to Subclinical Disease Activity Evaluating Response to Therapy Art - Becoming Science Improved Clinical Care MRI in Early Detection of Complications of Therapy Implementing Stronger Technique 3D Acquisition

59 THE END

60

61

62

63 PML Rapid Increase!!!!!!

64 Peripheral, Subcortical; Ill defined borders; From Nancy Richer

65 PML Generally no mass effect Ill defined, or linear enhancement possible, not the total lesion area

66 RRMS- 169 patients classified IFN-beta 1a 3 Classification parameters for non responder Relapses in 2yr cutoff 2 or more Gd+ lesions (yr 1 + yr2) cutoff 2 or more New T2 at yr 2 (versus baseline)- cutoff 3 or more Outcome based on EDSS, MSFC, BPF

67

68

69

70 Correia et al. Neuroimage yo Healthy Control 60 yo Vasc. Cog. Impaired Length & Number of Streamtube based Metrics

71 One Patient Pre/Post-Corpus Callosotomy

72 MRI Signal and Field Strength 3T scanner should have twice SNR of 1.5T scanner 7T should have ~4.7 times SNR of 1.5T. Modified from C.Rorden, www From: F. Fera et.al., J MRI 19:19-26 (2004)

73 7 Tesla MRI - MS T2*W Imaging Advanced Imaging Research Center AIRC, OHSU Courtesy, Dan Pelletier, UCSF

74 Standardized MRI Guidelines PD optional Recommended

75

76 Figure. Examples of double inversion recovery (DIR) images with white matter and cortical lesions. Papadopoulou A et al. Mult Scler 2013; Copyright by SAGE Publications

77 Double Inversion Recovery Images from six month follow-up; From Calabrese, Neuroimage, 2008 Geurts, 2005, reported in Radiology a 500% advantage over T2; 150% over FLAIR

78 Counting New T2 Lesions in the Cortex? Calabrese Arch Neurol. 2007

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