Neuroimaging Christopher Bever, MD, MBA (MODERATOR) Use of ...

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

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

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.

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

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

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 ?

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

Lesion Overview

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

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

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

The T2 Footprint is Stable Over Time

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

Brainstem/Cerebellum

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

Atrophy
Strongest MRI - disability correlations but still only modest

Spinal Cord
Proton/T2
Proton density

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

Number Lesions
Most of the Disease is Subclinical
70
60
50
40
30
20
10
0
Time of CIS
0 6 12 18
Time (months)

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

MRI in Diagnostic Criteria

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)

Accurate Prediction of Earliest MS
1991-1995
After First Clinical
Event
A positive MRI is a
good predictor of a
second clinically
event which
indicating MS

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

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

Validation of Barkoff Criteria

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

Classical Diagnosis of MS
Clinically Isolated Syndrome
Clinical Obvious
Classic MS

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

MS (Diagnostic Criteria) After a CIS
2005 - Polman et al
revisions
Spinal cord lesions can be
utilized to substitute for
brain lesions

The Criteria are Imperfect – Vigilance is Required
PD
T2
December 1997 – CIS
3 periventricular lesions-Doesn’t meet criteria

December 2002 - 5 year follow-up
Strong evidence for ongoing demyelination despite not meeting formal criteria
initially

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

Presentation ---Visual symptoms
Infratentorial- none
Enhancing or 9 T2-no
Juxtacortical - not sure
Periventricular - 3
2003
2004

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

Even Earlier Diagnosis?
Radiologically Isolated
Syndrome

Okuda et al. Neurology 2009;72:800

WiFi
Worrisome Imaging Follow-up Indicated

Use of MRI to Follow Subclinical
Disease

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

1
4
7
10
13
16
19
22
25
28
37
40
43
46
50
Enhancing lesion number
Untreated MS Patient
16
14
12
10
8
6
4
2
0
CEL
month
Courtesy of Nancy Richert – NIH

1
6
11
16
21
26
31
36
41
46
51
56
67
74
79
84
89
94
Enhancing lesion number
T2LL (cc)
Resumption of Disease Activity after IFN Discontinued
(CEL and T2LL)
30
25
IFN
14
12
20
10
15
10
5
0
8
6
4
2
0
CEL
T2LL
month
Courtesy of Nancy Richert

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

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

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

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

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

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

Treated Patients with 2 or more lesions at 6 months after treatment
Are Non-Responders- Hazard Ratio 4.99 (p < 0.0001)
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

Odds Ratio 8.96 (p

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

2005

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

PML

Yousry et al. NEJM;2006 354:924-933

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

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

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, 2006 - updated 2008 @
www.mscare.org/cmsc/images/pdf/MRIprotocol2003.pdf
taboulsee update???? MR Imaging in Diagnosing and Monitoring
MS
Don Paty

Standardized MRI Guidelines
PD optional
Recommended

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

Update
T. Traboulsee et al
In 2009
Mscare.org

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?

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

Sicotte et al, 2003

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

3D FLAIR - 1mm partitions
3T MRI

3D FLAIR - 1mm partitions reconstructed to axial projection

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

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)

Very High Field Imaging
7T Human Scanner

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

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

MS, Fe Permeability Study
OHSU 7T, Bill Rooney

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

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)

The End
Thank You