Taking a Closer Look at Each Patient: Exploring Novel Biomarker and Imaging Strategies in MS

Co-Chairs, Amit Bar-Or, MD, FRCPC, and Jiwon Oh, MD, PhD, FRCPC, prepared useful Practice Aids pertaining to multiple sclerosis for this CME/NCPD/CPE/IPCE activity titled “Taking a Closer Look at Each Patient: Exploring Novel Biomarker and Imaging Strategies in MS.” For the full presentation, downloadable Practice Aids, and complete CME/NCPD/CPE/IPCE information, and to apply for credit, please visit us at https://bit.ly/3IyZJQh. CME/NCPD/CPE/IPCE credit will be available until June 29, 2025.

1. Selected Emerging Biomarkers in Multiple Sclerosis
Full abbreviations, accreditation, and disclosure information available at PeerView.com/UCT40 Emerging MRI Biomarkers in MS
White matter lesions in MS are the result of immune cell infiltration from the
periphery into the CNS via small penetrating veins; these inflammatory
lesions result in oligodendrocyte and myelin damage as well as
neuroaxonal degeneration
Chronic active lesions in MS can be identified pathologically by an
iron rim at the lesion edge that contains iron-laden macrophages
and microglia as well as activated astrocytes
Paramagnetic Rim Lesions
1
Central Vein Signs
2
3T SWI and FLAIR
images showing
examples of rim
lesions in
periventricular
(a, d), juxtacortical
(b, e), and
infratentorial (c, f)
regions
T1 and FLAIR
appearance of an
SWI rim lesion
Axial 3T FLAIR images
showing central vein sign
in the three orthogonal
planes
Axial 1.5T T2 echo-planar
images in the three orthogonal
planes for central vein assessment
SWI T1 FLAIR
SWIFLAIR

2. Selected Emerging Biomarkers in Multiple Sclerosis
Full abbreviations, accreditation, and disclosure information available at PeerView.com/UCT40 Main MRI Sequences Used for Detecting Each Biomarker
3
Disease Activity/PrognosisDiagnosis/ClassificationCompartment
SWI
SWI
QSM
Phase 2
GRE/EPI
SWI
SWI
T2
GRE/EPI
FLAIR
QSM
Phase 2
GRE/EPI
T2
GRE/EPI
Paramagnetic Rim Central Vein Sign
With or without a contrast agent
7T
3T
MRI (Field Strength and Image Modalities)

3. Selected Emerging Biomarkers in Multiple Sclerosis
Full abbreviations, accreditation, and disclosure information available at PeerView.com/UCT40 Emerging Fluid Biomarkers for MS Disease Activity and Prognosis
4
Disease Activity/PrognosisDiagnosis/ClassificationCompartmentBiomarker
• Serum: ↑ CIS or RIS that converts to MS
• ↓ with DMT in RMS or PMS
• ↑ disease activity in RMS
• ↑ risk of new MRI lesions
• ↑ risk of brain/spinal cord atrophy
• CSF and serum: ↑ in RMS and PMS
vs HC
• ↑↓ in PMS vs RMS (conflicting results)
CSF, serum,
plasma; good
correlation
NfL
• Serum: ↑ risk of worsening EDSS
• ↑ lesion progression on MRI
• Serum: ↑ in active RMS vs NIND and HC
• ↑↓ in PMS vs RMS (conflicting results)
• ↑ in NMOSD vs MS or HC
CSF, serum,
plasma; good
correlation
GFAP
• CSF: ↑ CIS that converts to MS
• ↑ likelihood of disability progression
• ↓ with DMT
• ↑ risk of new MRI lesions
• CSF: ↑ in RMS vs HC
• ↑ in PMS vs RMS and SPMS
CSF; CSF levels
do not correlate
with serum
CHI3L1/YKL-40
• ↑ increased cortical lesion number
• ↑ cortical thinning
• ↑ cognitive impairment
• CSF: ↑ PMS vs HCCSFParvalbumin
• ↑ lower risk of developing MS
• ↓ neonatal vitamin D increased risk of developing MS
• ↑ lower degree of brain atrophy
• ↑ less clinical progression at year 5
• ↓ increased relapse risk
Serum —Vitamin D
• CSF: ↑ CIS that converts to MS
• ↑ disease activity in RMS
• CSF > serum: ↓ with DMT
• Serum: predict response to fingolimod
• CSF: ↑ RMS and PMS vs NIND
and OIND
CSF; serum
does not
correlate
with CSF
CXCL13

4. Selected Emerging Biomarkers in Multiple Sclerosis
Full abbreviations, accreditation, and disclosure information available at PeerView.com/UCT40 1. Kwong K et al. Neuroradiology. 2022;64:109-117. 2. Maggi P et al. Ann Neurol. 2018;83:283-294. 3. La Rosa F et al. Neuroimage Clin. 2022;36:103205. 4. Gill AJ et al. Eur J Immunol. 2023;e2250228.
Emerging Fluid Biomarkers for MS Disease Activity and Prognosis
4
Central nervous system
Cerebrospinal fluid Peripheral tissuesBlood
Blood
brain
barrier
Peripheral neuron
NfL
Muscle
Parvalbumin
GFAP
?
?
Nonmyelinating
Schwann cell
CHI3L1
ChondrocyteNeutrophilMacrophage
Monocyte
Activated
microglia
Activated
macrophage
CNS-restricted
clonal B cells
CHI3L1
Reactive
astrocyte
GFAP
Clonal
antibodies
Detected as
oligoclonal
bands
Damaged
cortical
interneuron
Degenerating
myelin
and axon
NfL
Parvalbumin
Blood-CSF barrier

5. 2021 MAGNIMS-CMSC-NAIMS Consensus Recommendations on
the Use of MRI in Patients With Multiple Sclerosis
1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/UCT40
a
Isotropic preferred, if over-contiguous (through-plane and in-plane), not >1.5 mm with 0.75-mm overlap.
b
Diffusion-weighted imaging, slice thickness should be <5 mm with a 10%-30% slice gap.
Basic MRI Parameters
Optic NerveSpinal CordBrainMRI Protocols
≥1.5T≥1.5T (3T no added value)≥1.5T (preferably 3T)Field strength
2D or 3D2D or 3D3D (preferred) or 2DAcquisition
≤2-3 mm, no gap
Sagittal ≤3 mm, no gap
Axial ≤5 mm, no gap
3D: 1 mm isotropic
a
2D: ≤3 mm, no gap
b
Slice thickness
≤1 mm x 1 mm≤1 mm x 1 mm≤1 mm x 1 mmIn-plane resolution
Optic nerve and chiasm
Whole cord (cervical,
thoracolumbar
including conus)
Whole brain
(include as much of
cervical cord as possible)
Coverage
Align to optic
nerve/chiasm
orientation
Perpendicular
to sagittal axis of cord
Subcallosal plane
Axial slice orientation

6. 2021 MAGNIMS-CMSC-NAIMS Consensus Recommendations on
the Use of MRI in Patients With Multiple Sclerosis
1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/UCT40
Brain MRI Protocol
Safety MonitoringFollow-UpDiagnostic WorkupBrain Sequences
Recommended
(optional if 3D
FLAIR acquired)
Recommended
(optional if 3D
FLAIR acquired)
Recommended
Axial T2-weighted
(TSE or FSE) sequences
RecommendedRecommendedRecommended
Sagittal T2-weighted FLAIR (preferably
3D; fat suppression is optional)
RecommendedRecommendedRecommended
Axial T2-weighted FLAIR (unnecessary
if a sagittal 3D FLAIR with multiplanar
reconstruction is obtained;
fat suppression is optional)
OptionalOptionalRecommended
Axial (or 3D sagittal) T1-weighted
sequences after contrast
Recommended
(for PML detection)
Optional
(useful for diff Dx)
OptionalDiffusion-weighted imaging
OptionalOptional
Optional
(for cortical lesions)
Double inversion recovery or PSIR for
detecting cortical or juxtacortical lesions
Not RequiredOptional
Optional
(for brain atrophy monitoring)
High-resolution T1-weighted sequences
(isotropic 3D acquisition; for quantitative
assessment of brain volume)
Not RequiredNot Required
Optional
(for central vein sign)
Susceptibility-weighted imaging

7. 2021 MAGNIMS-CMSC-NAIMS Consensus Recommendations on
the Use of MRI in Patients With Multiple Sclerosis
1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/UCT40
Safety MonitoringFollow-UpDiagnostic Workup
Spinal Cord Sequences
Not requiredOptional
2 sequences
recommended
Sagittal at least 2 of T2 ,
PD, or STIR
Not requiredOptional
Optional
(substitutes for one of above)
Sagittal 3D T1 (PSIR,
MP-RAGE) cervical only
Not requiredOptional
Optional
(through lesions)
Axial T2 or T2
Not requiredOptionalOptionalPre-Gd sagittal T1
Not requiredOptionalRecommendedPost-Gd sagittal T1
Not requiredOptionalOptionalPost-Gd axial T1
Optic Nerve Sequences
Not requiredNot requiredOptional
Axial and coronal
fat-suppressed T2 or STIR
Not requiredNot requiredOptional
Post-Gd axial and coronal
fat-suppressed T1
Spinal Cord and Optic Nerve MRI Protocol

8. 2021 MAGNIMS-CMSC-NAIMS Consensus Recommendations on
the Use of MRI in Patients With Multiple Sclerosis
1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/UCT40
a
Shorter follow-up MRI (ie, 6 months) if substantial isolated MRI activity or isolated clinical activity.
b
Add spinal cord MRI to brain MRI if disability worsening is not explained by brain MRI.
c
Add spinal cord MRI to brain MRI if never done.
d
Longer intervals to be considered in patients treated with disease-modifying treatments (eg, up to 9 months with glatiramer acetate and until completion of the full initial course with induction therapies).
e
Less frequent MRI in clinically stable patients treated with interferon beta or glatiramer acetate.
f
Consider gadolinium administration in patients with highly active disease at baseline or in patients with unexpected clinical activity after treatment initiation. 
Initial
Pretreatment
c
Follow-Ups
a,b
Every year while
on treatment
e
Gadolinium
optional
Second Follow-Up
a,b
24 mo after
treatment onset
Gadolinium
optional
First Follow-Up
a,b
12 mo after
treatment onset
Gadolinium
optional
New Baseline
3-6 mo after
treatment onset
d
Gadolinium usually
not required
f
Gadolinium
recommended
MRI in Pediatrics and Pregnancy
• Brain and full spinal cord with gadolinium
• Optic nerve when MOG/NMOSD under consideration
Pediatrics diagnostic MRI
• Same as adults for follow-up and safety monitoring
• Every 6 months for highly active disease
Pediatric monitoring
• Assessed case by case (unexpected clinical course)
• Gadolinium contraindicated
Pregnancy
• New baseline 2-3 mo post partum
• Gadolinium should only be used judiciously
Post partum and lactation
MRI Timing in Monitoring of Multiple Sclerosis

9. 2021 MAGNIMS-CMSC-NAIMS Consensus Recommendations on
the Use of MRI in Patients With Multiple Sclerosis
1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/UCT40
1. Wattjes M et al. Lancet Neurol. 2021;20:653-670.
Summary of Key Recommendations
• 3D-FLAIR brain MRI most important for diagnosis and monitoring
• Gadolinium use is restricted to diagnosis and early monitoring
• Spinal cord MRI is important for diagnosis and prognosis; dual contrast
• Re-baseline brain MRI after switching treatment (no gadolinium)
• Annual brain MRI while on treatment
• PML monitoring every 3-4 months with abbreviated protocol
• Central vein sign, cortical lesions, and brain volume change quantification
are not recommended

10. Shared Treatment Decision-Making
in Multiple Sclerosis
1-6
Full abbreviations, accreditation, and disclosure information available at
PeerView.com/UCT40 Yes
Consider
different
MOA and/or
route of
administration
Change therapy?
• Suboptimal response?
• Intolerable adverse events?
• Inadequate treatment
adherence?
• Disease-related factors
(phenotype, activity, severity)
• Patient-related factors
(preference, comorbidities)
• Drug-related factors (efficacy,
safety, route of administration)
• Relapsing or progressive
• Active or not active
• With or without progression
or worsening
Identify the multiple
sclerosis phenotype
• Clinical
• MRI
• Safety
• Biomarkers
MonitorNo
Oral
Self-
injection
Infusion
Choose therapy
in collaboration
with the patient

11. Shared Treatment Decision-Making
in Multiple Sclerosis
1-6
Full abbreviations, accreditation, and disclosure information available at
PeerView.com/UCT40 Please provide your answers to the following questions
2. How do you prefer to take your medicine?
4. What are your thoughts about laboratory monitoring?
3. How much risk are you truly willing to accept?
I prefer to self-inject
I prefer to take a pill
I prefer to have an IV infusion
I have no preference of how I take my medication as long as it can be
taken as infrequently as possible
Risk averse: I am a safety first, benefits second type of person
Moderately risk averse: I am willing to accept a little bit of risk for some
extra benefit
Mildly risk averse: I can accept risks for more benefit, as long as the risks
are not serious
High risk, high reward: I can accept any potential risks if they are
outweighed by the potential benefits
No evidence of disease activity (no attacks, no new findings on my MRI,
no new disability)
Preserve or improve my current level of functioning
Sustain employment and normal daily activities
All of the above
I don’t want to be required to have any laboratory testing during treatment
I am okay with laboratory testing as long I don’t have to do it every month
or after I stop treatment
I have no issues with the frequency or duration of laboratory testing that
may be required during or after treatment
1. What are your goals for treatment?

12. Shared Treatment Decision-Making
in Multiple Sclerosis
1-6
Full abbreviations, accreditation, and disclosure information available at
PeerView.com/UCT40 The Key Components of Engaging Patients
in the Decision-Making Process
2. Describe options
3. Help make decisions
Determine what patient already knows
List and describe options including risks and benefits
Provide decision support such as decision aids, which can help patients
understand their options
List options again and apply teach-back method by asking patient how
they would describe the options to a loved one
Focus on preferences
Check to see if patient is ready to make a decision or if they need more
time or have additional questions
Agree on treatment plan
Ensure patient understands plan can be modified and decisions can be
reviewed at any time
Identify/summarize problem
Offer choices
Emphasize importance of personal preferences
Discuss any uncertainties in treatment
Check reaction
Defer final decision until you are able to discuss options in more detail if
patient asks, “What would you do?”
1. Introduce choice
1. Giovannoni G et al. Curr Opin Neurol. 2012;25(Suppl):S20-S27. 2. Rae-Grant A et al. Neurology. 2018;90:777-788. 3. Lublin FD et al. Neurology. 2014;83:278-286.
4. Gaetani L et al. J Neurol Neurosurg Psychiatry. 2019;90:870-881. 5. Hanson KA et al. Patient Prefer Adherence. 2014;8:415-422. 6. Wilson LS et al. Int J MS Care. 2015;17:74 - 82 .

13. Integrating Serum and CSF NfL With Other
Findings in MS Care: CMSC Algorithm
1
Full abbreviations, accreditation, and disclosure information available at
PeerView.com/UCT40 MRI
CSF/blood
Neuro
exam
CSF or serum NfL
Normal Elevated
Start DMT
MRI, EDSS
Serum NfL
Stable Elevated
Rebaseline blood NfL
Mild or typical for MS
With or without symptoms
consistent with MS
Oligoclonal bands
NfL
T2 hyperintensities
Patient ful fills
McDonald criteria
for MS diagnosis
Relapsing-remitting MS Progressive forms of MS
Baseline evaluation
Determination of severity/prognosis
6-12 month monitoring period
+ MRI and
neuro exam
± other poor
prognostic signs
± other poor
prognostic signs
Continue
current therapy
Switch or
escalate DMT
Repeat CSF-NfL
if needed for clarity
For PMS, use
approved therapies
Start highly
active DMT
1. Freedman MS et al. Int J MS Care. 2021;23(suppl 1):2-7.