MRI Monitoring In MS. John W. Rose, M.D. Professor of Neurology Division Director: NINV VA Salt Lake City & University of Utah

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1 MRI Monitoring In MS John W. Rose, M.D. Professor of Neurology Division Director: NINV VA Salt Lake City & University of Utah

2 Disclosures Dr. Rose Recieves Research Support from: Biogen, Abbie Vie, Teva, Cumming Foundation, NMSS, VA and NIH Dr. Rose Serves on the Medical Advisory Board for the DECIDE Trial

3 MRI Monitoring in MS Overall Approach Monitoring in Aggressive Disease Monitoring Effects of Immunotherapy Evaluating Special Conditions Advancing Imaging of MS

4 Heterogeneity in MS Disease Course: RR,2P,PP,B,M,CIS Gender: F/M=3:1; Progression M>F Neuropathology: 4 subtypes & Acute Immunogenetic: DR2/OCB+ & DR4/OCB- ON: Better Prognosis MRI: Inflammation and Injury Remyelination: 20% Good, 80% Poor

5 Heterogeneity of MS Lesions Pattern Feature I II III IV T cells Pl. cells μφ/μγ 1, C9neo Oligo # * 55 Remyel Lucchinetti, Ann. Neurol. 47: 707, 2000

6 Oligodendrocyte Death and Demyelination

7 Immune Response: New & Old

8 Clinical Features of Multiple Sclerosis

9 Here at the Rock we have Three Rules 1) Obey all Rules 2) No writing on the walls 3) Order Appropriate MRIs for the Clinical Situation

10 MRI Monitoring In MS Practical Approach Clinical Status & Longitudinal Follow up Patient Report, Neuro Exam & MRI Select Imaging for Clinical Context Interface with Neuroradiology Interpret Imaging in Context of Individual Patient: Course & Rx

11 MRI Monitoring in MS MRI with Standard Protocols Basic Imaging is Most Important: T2/FLAIR, T1, T1 + Contrast Proper Timing of Contrast New T2 or T1 and Enhancing Lesions Atrophy: Brain, Corpus Callosum and Cerebellum Best to Review All Aspects with Neuroradiology

12 Common Problems With MRI Over Interpretation of WM Signal Abnormalities Under Interpretation and Failure to Link Clinical Data to MRI Changes Missing Out on Integration of Brain and Spinal Cord MRIs Missing Lesions in the Brainstem and Cerebellum Difficulty in Comparing MRIs Across Institutions

13 What Type of MS is Being Followed?? RRMS Stable RRMS Active RRMS Aggressive Progressive MS Progressive MS with Relapses 2PMS versus PPMS CIS & RIS

14 How Often Should MRIs Be Performed? Early RRMS: Annual Brain MRI and other MRIs for Specific Relapses Aggressive RRMS: Brain and Cord Imaging Q3 to Q6 months Transitional MS: MRI Brain and/or Cord Q6 months Refractory MS on Advanced Immunotherapy: MRI Brain and/or Cord Q6 months

15 Case II MRIs

16 What Constitutes a Clinically Significant Lesion on MRI? Punctate New T2 or CELs: No CEL < 3mm in diameter: No Occasional New T2: +/- Frequent New T2: Yes CELs > 3mm: Yes Enlarging T2 or T1: Yes

17 Case III: MRIs

18 CASE III: MRIs

19 Importance of Spinal Cord Imaging Go Where The Money Is Follow up for Relapses Longitudinal Studies to Correlate with Evolving Disability Consider Alternate Diagnosis

20 Case V: C-Spine MRI

21 Case V: MRI T1 With Contrast T1 With Contrast

22 MRI In Clinical Studies and Trial Varying Frequency of Testing: Phase I to Phase III New T2 and CELs Volumetric Measurements Brain Atrophy Measures Focal Atrophy (Temporal Lobe) Cortical Imaging

23 Development of Approved Immunotherapies for MS 1970 Prednisone, ACTH, AZA, Disease Model Development 1980 Copolymer 1, IT IFN, Poly ICLC, CTX, PLEX, CSA 1993 Beta Interferon 1b SC 1995 Glatiramer Acetate SC 1996 Interferon Beta 1a IM 2000 Mitoxantrone IV 2002 Interferon Beta 1a SC 2006 Natalizumab IV 2010 FTY 720 (Fingolimod) 2012 Teriflunimide 2012 Dimethyl Fumarate

24 Mab Rx: MRI Effects Rose et al Annals of Neurology 2004, Rojas et al Ther. Adv in Neurol Disorders 2010

25 MRI: Emerging Measures Of Importance Brain DTI Brain Atrophy Higher Resolution ON & Cord Imaging Cord DTI MRS MTR

26 Imaging In Setting of Immunotherapy Control of disease activity Monitoring for PML Evaluate for Viral Encephalomyelitis Diagnosis of Meningitis Detecting Effects of Rx Cessation: IRIS

27 Wide Range of Pathology in MS Cervical Cord Zollinger, Jeong and Rose et al J Magnetic Resonance 2010; Rose, Wood and Carlson et al in prep.

28 Potential For Remyelination In MS Multiple Lesion Types By MRI and Pathology: Myelin and Axons Zollinger, Jeong and Rose et al J Magnetic Resonance 2010; Rose, Wood and Carlson et al in prep.

29 Identification of High Intensity Lesions by DTI Zollinger, Jeong and Rose et al J Magnetic Resonance 2010

30 Questions Can Imaging be Replaced in Progressive MS?? OCT Linked to Brain Atrophy Which DMTs are Neuroprotective or are Promoters of Remyelination?? Candidates: GA, Estriol, Fingolimod, Laquinimod, DMF and Ibudilast

31 Optical Coherence Tomography (OCT) Demonstrates Neurodegeneration and Need for Neuroprotection Fjeldstad, Carlson and Rose 2012

32 Defining the Course Of MS: 2013 Revisions Core Phenotypes: RRMS and ProMS CIS is Added to Core Phenotypes ProMS includes: 2P, PP and PRMS RIS is not a Phenotype/no signs or Sx Modifiers: Active/Worse Confirmed Worsening of Disease International Committee on Clinical Trials in MS. Neurology 83: , 2014

33 Separating Active Inflammatory Clinical Relapses New T2 or CELs Disease Clinical Relapses Correlating with New T2 or CELs

34 Overview of MRI in MS Obey All Rules Choose MRIs Appropriate in Clinical Context Develop Working Relationship with NeuroRadiology Assure Appropriate Protocols Monitor for Adverse Outcomes New Imaging Protocols Should Assist Future Care of MS Patients