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MR Imaging of Multiple Sclerosis: Review and Update

Aditya Bharatha MD FRCPC

NeuroradiologySt Michael’s HospitalUniversity of Toronto

MRI in MSMRI in MS

DISCLOSURES

• Participant (speaker, panel member) in MS-related educational activities sponsored by EMD Serono.

Objectives

• Review conventional MR imaging features of Multiple Sclerosis

• 2010 McDonald Criteria• Advanced MR Imaging• Imaging “Mimics” of MS

MRI in MSMRI in MS

Epidemiology

• Canada has one of the highest rates of MS in the world

• Approximately 50,000 people have MS• Prevalence 1:500-1000

• Female: male 2:1

• Average age of onset 30 years

• Most common neurological disease of young adults

MRI in MSMRI in MS

• Chronic neurological disease characterized by inflammatory activity that causes localized areas of demyelination and axonal degeneration in the central nervous system (CNS)

• Lesions can occur virtually anywhere in the CNS, leading to a wide range of neurological signs and symptoms:– Typical lesion locations include supratentorial white

matter, optic nerves, brain stem and spinal cord

• Symptoms can occur alone or in combination, as isolated attacks or part of a steady progression

O’Connor P, et al., 2002; Paty DW, Ebers, GC (eds), 1997.

Definition

MRI in MSMRI in MS

Pathogenesis

Myelin

Axon

Noseworthy et al. NEJM 2000,343(13):938-952

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MRI in MSMRI in MS

MS Plaques

Chronic plaqueShadow plaque - remyelination

Acute plaque Noseworthy et al. NEJM 2000,343(13):938-952

MRI in MSMRI in MS

Terms• Clinically Isolated Syndrome (CIS): First clinical episode of

symptoms typical of MS, requires “further confirmation” Common clinical scenario

• Relapsing-remitting MS (RRMS): Repeated, clearly defined acute attacks (relapses), each followed by full or partial recovery and lack of progression between attacks

• Progressive forms Can be primary (progression from onset), or secondary (progression after initial relapsing-remitting course)

MRI in MSMRI in MS

MS Disease Classification

Relapsing -remitting

Primary progressive

Secondary progressive

Progressive relapsing

or

or

or

or

MRI in MSMRI in MSCertain clinical features seen in CIS are

typical of those seen in confirmed MS

Courtesy of Dr. Dan Selchen Adapted from Miller DH, et al., 2008.

CIS features typically seen in MS Less common CIS features which may be seen in MS

Atypical CIS features not expected in MS

Optic nerve•Unilateral optic neuritis RAPD•Pain on eye movement •Partial and mainly central visual blurring •Normal disc or mild disc swelling

•Bilateral simultaneous optic neuritis •No pain •No light perception •Moderate to severe disc swelling with no hemorrhages •Uveitis (mild, posterior)

•Progressive optic neuropathy •Severe, continuous orbital pain• Persistent complete loss of vision •Neuroretinitis (optic disc swelling with macular star) •Uveitis (severe, anterior)

Brain stem/cerebellum•Bilateral internuclear ophthalmoplegia•Ataxia and multidirectional nystagmus•Sixth nerve palsy •Facial numbness

•Unilateral internuclear ophthalmoplegia, facial palsy, facial myokymia•Deafness•One-and-a-half syndrome •Trigeminal neuralgia •Paroxysmal tonic spasms

•Complete external ophthalmoplegia; vertical gaze palsies•Vascular territory syndrome, e.g., lateral medullary•Third nerve palsy •Progressive trigeminal sensory neuropathy •Focal dystonia, torticollis

Spinal cord•Partial myelopathy•Lhermitte’s symptom •Deafferented hand•Numbness•Urinary urgency, incontinence, erectile dysfunction•Progressive spastic paraplegia (asymmetrical)

•Complete transverse myelitis•Radiculopathy, areflexia •Segmental loss of pain and temperature sensation •Partial Brown-Sequard syndrome (sparing posterior columns) •Fecal incontinence•Progressive spastic paraplegia (symmetrical)

•Anterior spinal artery territory lesion (sparing posterior columns only)•Cauda equina syndrome •Sharp sensory level to all modalities and localized spinal pain •Complete Brown-Sequard syndrome•Acute urinary retention •Progressive sensory ataxia (posterior columns)

Cerebral hemispheres•Mild subcortical cognitive impairment •Hemiparesis

•Epilepsy•Hemianopia

•Encephalopathy (obtundation, confusion, drowsiness)•Cortical blindness

MRI in MSMRI in MS

Principles of diagnosis

• For a diagnosis of MS, there must be:

– No alternate diagnosis

– Evidence of both: • Dissemination in Space (DIS):

• Dissemination in Time (DIT):

McDonald WI, et al., 2001.

MRI in MSMRI in MS

CLINICAL

VEPCSF MRI

PARACLINICAL

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MRI in MSMRI in MS

MS Criteria - History

• Schumacher et al’s (1965) original clinical criteria initiated the concept of dissociation of disease progression in space and time

• Poser et al’s (1983) criteria for MS introduced onto the clinical criteria the use of paraclinical tests, CSF and EP

• During 1990’s various MRI criteria evolved for aiding in the diagnosis of MS

• McDonald Criteria allows for the incorporation of the role of MRI in diagnosing of MS

MRI in MSMRI in MSMR Imaging Protocol

Proton Density T2-Weighted FLAIR DWI

FLAIR T1-Weighted Gado T1-Weighted

MRI in MSMRI in MS

MS Imaging - FLAIR• Fluid attenuated inversion recovery

(FLAIR) • highly T2-weighted images of the

brain• suppression CSF signal• high lesion contrast and conspicuity• Increased sensitivity for

supratentorial lesions (less sensitive for infratentorial and spinal cord)

• Increased detection of cortical lesions (8%)

MRI in MSMRI in MS

MRI Markers - Traditional

• T2 lesion volume• Gd Enhancement• T1 (hypointensity/”black hole”) lesion volume• Atrophy - brain and/or spinal cord

MRI in MSMRI in MS

T2 Hyperintensity – Disease Burden

• Indicates the presence of increased water content in tissue which prolongs T2 relaxation time

• Pulse sequences which are sensitized to T2 relaxation time are T2-weighted, proton density and FLAIR

• Sensitive but not specific indicator of disease activity or response to treatment

• Reflects broad spectrum of pathological changes: inflammation, edema, demyelination, gliosis and axonal loss

Proton Density

T2-Weighted

FLAIR

MRI in MSMRI in MS

Enhancement - Active Lesions

• Active blood-brain barrier breakdown

• Lasts for approximately 1 month

• Some correlation to short term disability

• There is no predilection in the WM

• Best assessed with Gd T1-weighted scans

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MRI in MSMRI in MS

Black Holes and Atrophy

• Late, secondary degenerative phase of the illness

• Extensive demyelination and axonal loss

• Serial decreases in the volume of brain and spinal cord (segmentation analysis)

MRI in MSMRI in MS

MS - typical

MRI in MSMRI in MS MRI in MSMRI in MS

MS - Corpus Callosum

Gean-Morton et al. 1991; Radiology 180:215-221

MRI in MSMRI in MS

Vascular Supply - Corpus Callosum

1 pericallosal artery

2 watershed

3 splenial artery

Gean-Morton et al. 1991; Radiology 180:215-221

Anterior artery of the corpus callosum (A comm)

Pericallosal artery (ACA)

Splenial artery (PCA)

MRI in MSMRI in MS

Corpus Callosum

Palmer et al. Radiology 1999;210:149-153

Ependymitis granularis

Small-vessel disease

Ovoid lesion

Gray matter bridges

Callosal striations

MS

MS

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MRI in MSMRI in MS

MRI is a unique paraclinical test in its ability to give information on both dissemination in space and in time

MRI in MSMRI in MS

MRI Criteria for Diagnosis of MS - History

Citation Criteria Sensitivity (%)

Specificity (%)

Paty et al. Neurology 1988; 38:180-185

≥4 lesions (A), or 3 lesions, one of which is periventricular (B)

94 57

Fazekas et al. Neurology 1988; 38:1822-1825

≥3 lesions with 2 of the following: infratentorial; periventricular; size >6mm

88 100

Gean-Morton et al. radiology 1991; 180:215-221

Lesion at callosal-septal interface 93 98

Tas et al. AJNR 1995; 16:259-264

Gd enhancement, ≥1 enhancing, ≥1 nonenhancing

59 80

Horowitz et al. AJNR 1989; 10:303-305

Ovoid lesions 86 NA

Barkof et al. Brain 1997; 120:2059-2069

MRI in MSMRI in MSMcDonald Criteria 2010

Clinical (Attacks)

Objective Lesions

Additional Requirements to Make Diagnosis

2 or more 2 or more None; clinical evidence will suffice (additional evidence desirable but must be consistent with MS)

2 or more 1 Dissemination in space by MRI or further attack involving different site

1 2 or more Dissemination in time by MRI or second clinical attack

1 (mono-

symptomatic, CIS)

1 Dissemination in space by MRIanddissemination in time by MRIor second clinical attack

0 (progression from onset,

PPMS)

1 One year of disease progression and2 of:Dissemination in space by MRI (brain)Dissemination in space by MRI (spine) >2 cord lesionsPositive CSF (elevated IGG or oligoclonal bands)

ANN NEUROL 2011;69:292–302

MRI in MSMRI in MS

DIS 2001, 2005 (Barkhof, Tintore)

MRI in MSMRI in MS

DIS 2010 Swanton

ANN NEUROL 2011;69:292–302

MRI in MSMRI in MS

MRI – Dissemination in Time

• A T2 lesion that does not enhance likely is of a different age than the clinically active lesion, though possibly within 3 months

• Ring enhancement can also occur with reactivation of an old lesion.

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MRI in MSMRI in MS

DIT 2001, 2005

MRI in MSMRI in MS

DIT 2010

ANN NEUROL 2011;69:292–302

MRI in MSMRI in MS

2010: Why the changes?

• With each revision, the imaging requirements have been simplified.

• Studies have shown that earlier criteria difficult to implement for non-imaging experts.

MRI in MSMRI in MS

Rationale for diagnostic criteria

• Key issue in diagnosis – When can the neurologist say the patient has MS.

• Definitive diagnosis if patient has had at least two separate clinical attacks (DIT) that implicate at least two different CNS areas (DIS) AND other diagnoses excluded.

• If not fully met, paraclinical data needed to make the diagnosis

• McDonald criteria focus what MRI or other paraclinicalevidence is needed to “draw the line” between MS and CIS in patients who have not had >2 clinical attacks with >2 involved areas?

MRI in MSMRI in MS

DIS

A patient can now show DIS with fewer lesions than were required previously.

MRI in MSMRI in MS

DIT

Previously needed to postpone scan until 30 d after onset and show new lesion later.

2010 criteria allow any new T2 and/or Gd-enhancing lesion to establish DIT, irrespective of baseline MRI timing

Simultaneous presence of asymptomatic enhancing and non-enhancing lesions at baseline (or any other time) can now be considered evidence of DIT:

Some CIS patients can now be considered to have DIT – and potentially a diagnosis of MS if they also meet DIS criteria –on the basis of a single scan

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MRI in MSMRI in MS

McDonald 2010 criteria changes may affect sensitivity and specificity of diagnosis

• Changes to sensitivity and specificity of diagnosis has not been fully characterized and will need further study/validation in a wider MS population:

– Validation in selective cohorts in MAGNIMS studies showed Swanton DIS criteria more sensitive and as specific as Barkhof.

– Spanish validation study shows 2010 criteria have higher sensitivity, similar specificity to Barkhof-Tintoré, • low sensitivity but high specificity for DIT determination on a single

scan

Gómez-Moreno M, et al., Mult Scler 2011.

MRI in MSMRI in MS

CIS Presentation

DIS and DIT

CriteriaSensitivity (95% CI) Specificity (95% CI)

McDonald 2001 47% (36‐58) 91% (85‐95)

McDonald 2005 60% (49‐70) 88% (81‐93)

McDonald 2010 72% (61‐81) 87% (80‐92)

McDonald WI, et al., 2001; Polman CH, et al., 2005; 2010.

MRI in MSMRI in MS

Issues

– Validation in small, selective cohorts with typical CIS.• Overrepresentation of patients presenting with

optic neuritis

– ? not representative of general imaging referral population

– Even if the patient meets DIT and DIS definitions, clinical judgment is still key

MRI in MSMRI in MS

McDonald criteria fit in at the end of the clinical algorithm

Symptoms consistent with inflammatory demyelinating

disease (monofocal or

multifocal)

Exclude non-demyelinating

syndrome(based on demographics, signs & symptoms, clinical

course, radiology, labs)

Determine diagnosis of non-inflammatory

demyelinating disease(red flags for specific diagnosis or

comprehensive evaluation if diagnosis not apparent)

Classify idiopathic inflammatory

demyelinating disease(based on demographics, signs &

symptoms, clinical course, radiology, labs)

Not MS (e.g., NMO, ADEM,

unclassified)

DIS and DIT?

Inflamm-ation?

Yes

No

Consistent with prototypic MS?

No

Yes

McDonald criteria

No

YesMS

CIS

Courtesy of Dr. Dan Selchen Adapted from Miller DH, et al., 2008.

MRI in MSMRI in MS

• MRI criteria taken on their own can be fulfilled in other disorders

– acute disseminated encephalomyelitis,– neuromyelitis optica,– neurosarcoidosis, – Lyme– CNS vasculitis, – systemic lupus erythematosus, – CNS lymphoma,– small vessel disease.

MRI in MSMRI in MS

MS RR

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MRI in MSMRI in MS

MS Tumefactive

T2 FLAIR T1 T1+Gd

• 25 female; 3 months post-partum• 3 weeks L sided numbness partial L

hemisensory deficit

? Diagnosis

MRI in MSMRI in MS

MS Tumefactive

Characteristics aiding in choosing MS• Enhancement (50%), well defined and rounded,

presence of other lesions, relative lack of mass effect and/or vasogenic edema given the size of lesion (Dagher and Smirniotopoulos 1996; 38:560565)

MRI in MSMRI in MS

MS Variants

• Schilder’s – pediatric, rapid progression, diffuse sclerosis

• Balo’s – concentric sclerosis• Marburg (fulminating leukoencephalopathy)

MRI in MSMRI in MS

• http://www.ajnr.org/site/imgquiz/04162012qz.xhtml http://neuropathology-web.org/chapter6/images6/6-balo.jpg

MRI in MSMRI in MS

Optic Neuritis• DDX

– MS– Ischemia– Vasculitis– Other: SLE, sarcoid, syphilis, Lyme,

infection, chemoradiation

• High T2 signal in the nerve

• Caliber may be normal or slightly increased acutely; atrophy in chronic setting

• >50% enhance, – Often short segment, intracannicular

MRI in MSMRI in MS

MS Spine

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MRI in MSMRI in MS

• Clinical disability not always correlated to severity of MRI abnormalities

• MRI can detect abnormalities that are not clinically evident

• Difficult to predict long term results or response to therapy from a single scan

• Serial imaging will need standardized paradigms

MRI in MSMRI in MS

Advanced MR Imaging

MRI in MSMRI in MS

Double IR

• Cortical involvement well described in pathological studies but often not well seen on conventional MR

• Small, low contrast lesions obscured by partial volume effects from CSF

• Double IR sequences use two inversion times to suppress CSF and WM

MRI in MSMRI in MS

Double IR

Filippi Radiology: 2011:259(3) 659-81

MRI in MSMRI in MS

Magnetization Transfer• Magnetic transfer is an exchange of magnetization from immobile

macromolecules to mobile protons water (T1 relaxation coupling)• In MTI, an off resonance RF pulse suppresses signal from the

macromolecular protons, which is then transferred to the mobile protons which form the bulk of the MR signal.

• Ratio is the difference in signal with and without MT

• Abnormally low MTR’s associated with breakdown in the macromolecular structure of cell membranes

MTNo MT Calculated MTI

MRI in MSMRI in MS

Magnetic Transfer Ratio

Decrease in the transfer of magnetization is greater for MS plaques when compared to similar lesions of ischemic white matter

Lesion type Mean SEM

Range

Normal white matter

38.4±0.2 36-40

Ischemic white matter

34.2±0.3 31-38

Perivascular edema

30.2±0.4 29-37Mehta et al. AJNR 1996; 17:1051-1055

Percentage of MT Between Different White Matter Lesions

normal

MS

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MRI in MSMRI in MS

Extracellular

Intracellular

• Protons moving (diffusing) in an inhomogenous magnetic field dephase more rapidly than static protons

• normal diffusion “dark”; restricted diffusion “bright”

• In MS lesions tend to have a higher ADC than NAWM

• Acute lesions can restrict (cellular infiltrate)

• Reliably differentiates vasogenic and cytotoxic edema

Diffusion Weighted Imaging

MS Infarct

MRI in MSMRI in MS

Diffusion Tensor Imaging

Wiegell et al. Radiology 2000;217:897-903

Diffusion can have preferential directionality, i.e. along axons.

Reduction of anisotropy suggests disruption of structural integrity

MRI in MSMRI in MS

Diffusion Tensor Imaging

Wiegell et al. Radiology 2000;217:897-903

MRI in MSMRI in MS

Diffusion Tensor Imaging - MS

Guo et al. Radiology2002;222:729-736

T2 PD Anisotropy Maparrows mark region of reduced anisotropy

MRI in MSMRI in MS

MR Spectroscopy

• Decreased NAA peak• Increased Choline/Creatine

ratio • Lactate and lipid peak

MRI in MSMRI in MS

fMRI

• EPI BOLD sequences during task and rest states.

• Allows study of cortical reorganization in MS.

• Early: Increased motor and SMA activation during simple motor task.

• Late: Bilateral and widespread recruitment during simple motor task.

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MRI in MSMRI in MS

Filippi Radiology: 2011:259(3) 659-81

MRI in MSMRI in MS

Perfusion Imaging

• Multiple methods (DSC, DCE, ASL)

• Provide estimates of various parameters depending on technique (rCBV, rCBF, MTT, ktrans)

• Acute enhancing lesions show increased perfusion while chronic lesions show decreased CBV/CBF

• May be helpful in distinguishing from tumor.

MRI in MSMRI in MS

Iron Sensitive Imaging (SWI)• Velocity compensated, high-resolution, 3-dimensional gradient

echo sequence eqquisitely sensitive to magnetic susceptibility

• GM areas, including thalamus, dentate nucleus, BG, and rolandic cortex, commonly show hypointensity on T2-weighted images, suggesting iron deposition.

• unclear whether iron deposition contributes to neurotoxic effects or epiphenomenonclosely

• associated with cognitive impairment

MRI in MSMRI in MS

SWI

• Iron deposition within MS lesions now recognized (?ring of iron rich macrophages)

• Perivenular distribution of lesions sometimes demonstrated.

MRI in MSMRI in MS

High Field Imaging

• Imaging at 3T and higher allows higher SNR/spatial resolution

• 3T is now routinely available for clinical use. Better delineation of lesions but most studies comparing 3T to 1.5T has not shown significant change in diagnostic yield.

• At >3T, specialized coils and sequences are required, still a work in progress

MRI in MSMRI in MS

7T

ARCH NEUROL/VOL 68 (NO. 12), DEC 2011

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MRI in MSMRI in MS

Mimicks

MRI in MSMRI in MS

Patient with history of migraine

MRI in MSMRI in MSNon-Specific White Matter

• Aging brain• Diabetes• Hypertension• Prominent perivascular

spaces

MRI in MSMRI in MSRecent Vaccination

Acute Disseminated Encephalomyelits

MRI in MSMRI in MSIs it MS? or Mimic?

Diagnosis: Lymphoma

MRI in MSMRI in MS

Acute Disseminated Encephalomyelits - ADEM

• Hypersentivity reaction mediated by T-lymphocytes

• Triggered by viral infection or vaccination 1-2 weeks previously

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MRI in MSMRI in MSIs it MS? or Mimic?

Diagnosis: Watershed Infarcts

MRI in MSMRI in MS

48 maleConfusion, seizureDysphasia, limb weakness

MS or Mimic?

Cerebral Vasculitis

MRI in MSMRI in MSProgressive Multifocal Leukoencephalopathy

(PML)

MRI in MSMRI in MS

PML

• Most often in the immunosuppressed patient i.e. lymphoma or AIDS

• Infection of oligodendrocytes by a papovavirus known as JC virus

• Myelin breakdown products in macrophages and astrocytes with reactive changes including bizarre pleomorphic nuclei which can be misinterpreted as tumor

• Tysabri– >200 cases of PML in HIV(-) MS pts on Tysabri

(natalizumab) = 1/1000

MRI in MSMRI in MSMS-Devic’s

98 99 00 03

MRI in MSMRI in MS

NMO (Devic’s)• Clinically defined severe demyelinating syndrome now thought to

be distinct from MS with monophasic or relapsing– Optic neuritis– Acute myelitis (can be separated temporally)

• CNS symptoms outside the ON and cord no longer excludes the dx

• More common in Latin and asian population

• Anti- AQP-4 IgG implicated

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MRI in MSMRI in MS

JBR–BTR, 2007, 90 (4)

NEUROLOGY 2006;66:1485–1489

MRI in MSMRI in MSIs it MS? or Mimic?

Systemic Lupus (SLE)

MRI in MSMRI in MS

Summary

• Reviewed MR imaging of MS• 2010 McDonald Criteria• Advanced MR Imaging• Imaging “Mimics” of MS

MRI in MSMRI in MS

THANK YOU!

• Acknowledgements

– Bruce Grey MD– Walt Montanera MD– Lyne Noel de Tilly MD– Dan Selchen MD