Neuroimaging Christopher Bever, MD, MBA (MODERATOR) Use of MRI in Diagnosing and Monitoring MS Jack H. Simon, Portland, OR

Transcription

1 Neuroimaging Christopher Bever, MD, MBA (MODERATOR) Use of MRI in Diagnosing and Monitoring MS Jack H. Simon, Portland, OR What MRI Taught Us about Neurodegeneration and MS Matilde Inglese, NewYork

2 MRI in the Diagnosis of Multiple Sclerosis and MRI For Monitoring Disease Activity Jack H. Simon Portland, Oregon

3 Disclaimer The speaker has received research support from Biogen-Idec and Genentech, and has been a consultant and/or received honoraria for speaking from Biogen-Idec, Genentech, Serono, Teva, Genzyme. Recent research support is reviewed by the Portland VA Research Oversight committee.

4 Outline MS Diagnosis And Diagnostic Criteria Standardized Imaging Integrating New Techniques Following Sub-clinical Disease Is Treatment Effective? Complications of Treatment

5 MRI in the Individual Patient (As Opposed to the Population)

6 MRI in MS Clinical Trials and Natural History Studies Interferon dosing Natural History Data From Li et al From Fisniku et al Question - The Relevance of Population Studies to the Individual?

7 FROM SIMPLE TO COMPLEX T2-Lesions Gd-Enhancing Lesions T1-Black Holes Atrophy Magnetization Transfer Diffusion Tensor Myelin Water Functional MRI MR Spectroscopy Long Experience, Validated - Secondary Measures in Trials Increasing Relevance to Care of the Individual Patient

8 Lesion Overview

9 Gadolinium Enhancing Lesions Cell Trafficking Leaky Blood-Brain-Barrier Inflammation

10 Problem - MRI in Individual is a Snapshot in Time Jan Feb Mar Apr May Jun Jul Aug PD difference (Dec-Jan) Sep Oct Nov Dec Goodkin, Rooney, Sloan, Bacchetti, Gee, Vermathen, Abundo, Majumbdar, Nelson, Weiner Neurol. 98

11 T2 Lesions Non-Specific Pathology Including Edema, Demyelination Acute Weeks later

12 The T2 Footprint is Stable Over Time

13 Distribution--Periventricular >> Peripheral White MS-Mostly Periventricular- Minimial, Early Non-Specific Peripheral other WMD MS-Peripheral- Juxtacortical-Cortical

14 Brainstem/Cerebellum

15 T1 Black Holes A subset of T2 lesions with more damage Chronic T1- Black Holes- Lesions of more severe pathology Some Association with greater disability

16 Atrophy Strongest MRI - disability correlations but still only modest

17 Spinal Cord Proton/T2 Proton density

18 Why MRI? MS Is Largely Subclinical That is--most current and new pathology is not known or detected by the patient or the clinician

19 Number Lesions Most of the Disease is Subclinical Time of CIS Time (months)

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

21 MRI in Diagnostic Criteria

22 MRI Criteria for Diagnosis (& earlier diagnosis) of MS Historical ( clinical) criteria for MS: Dissemination in time and space New Criteria Quantitative (counts of specific T2 lesions) to document dissemination in space MRI used as substitute (& strong) criteria for dissemination in time (second attack)

23 Accurate Prediction of Earliest MS After First Clinical Event A positive MRI is a good predictor of a second clinically event which indicating MS

24 MRI Predictors of Second Clinical Event (MS) after a Clinically Isolated Syndrome N= 39 (max) From F. Barkoff

25 Barkoff Combined Criteria More Accurate Prediction of Second Clinical Event 1 Enhancing or 9 T2 1 Juxtacortical-Cortical 3 Periventricular 1 Infratentorial

26 Validation of Barkoff Criteria

27 McDonald Criteria Annals of Neurology 2001 MRI Dissemination in Space 3 of the 4 Barkoff Components 1 Enhancing or 9 T2 1 Juxtacortical-Cortical 3 Periventricular 1 Infratentorial + MRI Dissemination in Time Enhancing lesion or New T2 lesion

28 Classical Diagnosis of MS Clinically Isolated Syndrome Clinical Obvious Classic MS

29 Earlier Diagnosis of MS with MRI Event Clinically Isolated Syndrome MS Classic MS

30 MS (Diagnostic Criteria) After a CIS Polman et al revisions Spinal cord lesions can be utilized to substitute for brain lesions

31 The Criteria are Imperfect Vigilance is Required PD T2 December 1997 CIS 3 periventricular lesions-doesn t meet criteria

32 December year follow-up Strong evidence for ongoing demyelination despite not meeting formal criteria initially

33 Both criteria highly specific (>90%) Modified criteria more sensitive (77% v 46%) Modified criteria more accurate (86% v 73%) Swanton et al. JNNP 2005

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35 Presentation ---Visual symptoms Infratentorial- none Enhancing or 9 T2-no Juxtacortical - not sure Periventricular

36 2003 Cortical Lesions only in retrospect 2004 Improved Technique, Improved Diagnoses

37 Even Earlier Diagnosis? Radiologically Isolated Syndrome

38 Okuda et al. Neurology 2009;72:800

39 WiFi Worrisome Imaging Follow-up Indicated

40 Use of MRI to Follow Subclinical Disease

41 Lesion Counts Gadolinium enhancing or T2 Enhancing Lesions over 12 months Courtesy of Bill Rooney (Goodkin et al Neurology 98) Enhancing Lesions 6 months after a CIS Courtesy of Fred Barkhof

42 Enhancing lesion number Untreated MS Patient CEL month Courtesy of Nancy Richert NIH

43 Enhancing lesion number T2LL (cc) Resumption of Disease Activity after IFN Discontinued (CEL and T2LL) IFN CEL T2LL month Courtesy of Nancy Richert

44 Use of MRI to Determine Treatment Response Responders - Non-Responders Complications of Therapy

45 More specifically --- Can we monitor treatment response to disease modifying therapy by MRI in individual patients? In Principle Any Disease Modifying Therapy

46 Evaluating the Therapeutic Response In The Individual Patient Patient Self-Report Physician Global Impression Other More Objective Data MS symptoms, relapses, disability Biological Markers MRI metrics Adapted from R. Rudick, Cleveland Clinic

47 Evidence-Based Studies to Define Treatment Failure Classification Parameters & Outcome Measure 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 Outcome Measure atrophy, disability, clinical event

48 Two year follow-up ; Outcome = Disability Active Lesions at One Year Post Therapy Predicted Disability

49 Durelli et al, 2008 Classification Parameter- Active Scan or NAb Outcome Measure-One or more relapses or confirmed disease progression MRI Activity (any month) and Nab positive status 71% sensitive, 86% specific, 50% PPV, 94% NPV

50 Treated Patients with 2 or more lesions at 6 months after treatment Are Non-Responders- Hazard Ratio 4.99 (p < ) R.P. Kinkel,1 P.W. O Connor,2 J. Simon,3 J. Carulli,4 M. del Carmen Castrillo,4 S. Goelz,4 R. Hyde,4 S. Lanker,4 A. Pace,4 A. Sandrock,4 and H. Zhang4 * non-responder responder Kinkel et al, 2008

51 Odds Ratio 8.96 (p <0.001) for Advancing to Worst Quartile EDSS after 15 Years The results provide rationale for monitoring IFN treated patients with MRI, and for changing therapy in patients with active lesions B

52 New atypical weakness or seizure In a patient with established MS A B

53 2005

54 PML Concern is Detecting PML +MS Limited mass effect No enhancement Follows cortical ribbon Charil, 2006

55 PML

56 Yousry et al. NEJM; :

57 Who would biopsy? Feb 2006 Aug 2006 Mar 2006 From Tony Traboulsee, UBC

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59 Standardized MRI For Improved Care Standardized Ordering Comparisons Possible Standard Terminology Optimal Use of MRI Metrics

60 Consortium MS Centers- Consensus Workshops 2001 Vancouver Consensus workshop 2003 Follow-up meeting update the guidelines and protocol 2008 Follow-up meeting integration of advanced imaging? routine MRI follow-up? Consider the CMSC Consensus Guidelines Simon et al. AJNR 27:455, updated taboulsee update???? MR Imaging in Diagnosing and Monitoring MS Don Paty

61 Standardized MRI Guidelines PD optional Recommended

62 Spinal Cord PD/T2 PD/T2 Sagittal < 3 mm Axial < 4 mm no gap No additional gadolinium required if spinal cord study immediately follows Gad-enhanced brain MRI

63 Update T. Traboulsee et al In 2009 Mscare.org

64 New Issues in Standardized MRI (focal lesions) Effect of Field strength 3T and above New Sequences will the standards remain valid if these are 3D? Cortical MS how do incorporate new findings into clinical care?

65 Field Strength Matters Sicotte, 2003 Wattjes, 2006 Nielsen, 2006

66 Sicotte et al, 2003

67 We Expect 3D Acquisitions to become standard in future Axial Reformats Eur. Radiol. 2008

68 3D FLAIR - 1mm partitions 3T MRI

69 3D FLAIR - 1mm partitions reconstructed to axial projection

70 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

71 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)

72 Very High Field Imaging 7T Human Scanner

73 7T MS MPRAGE 0.8 mm thick AIRC at OHSU, courtesy Bill Rooney

74 7 Tesla MRI - MS T2*W Imaging Courtesy Bill Rooney, Oregon Health Sciences University-AIRC

75 MS, Fe Permeability Study OHSU 7T, Bill Rooney

76 A closer look of MS cortical grey at 7T 3T (IR) SPGR Metcalf et al. Journal of Neuroimaging 2009

77 Summary- And Learning Classical & new diagnostic criteria for MS diagnosis by MRI------From Populations to Individuals MS is largely subclinical What we don t know can hurt us! Monitoring therapy- better experimental criteria for non-responders Standardized MS Exam New considerations (3D, Field strength-image Quality)

78 The End Thank You