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Àlex Rovira Secció de Neurorradiologia. Servei de Radiologia

Hospital Universitari Vall d’Hebron Barcelona

alex.rovira@idi.gencat.cat

‘‘MRI in the diagnosis of MS ”

• Highly sensitive for detecting MS plaques (white matter)

• Provide quantitative assessment of disease activity and severity

• Characterize disease course over time

• Monitor and predict treatment response

• Early detection of treatment-related adverse effects

Most important paraclinical tool for diagnosing and monitoring MS

T2-weighted (FLAIR)

Post-contrast T1-weighted

MR imaging in MS

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Incidental finding aging (80-100%) normal young adult population (5-10%) migraine (x4) Virchow-Robin spaces Hipoxic-ischemic vasculopathies

Lipohyalinotic small-vessel disease Cerebral amyloid angiopathy Genetic vascular disorders: CADASIL…

Primary demyelinating diseases multiple sclerosis and variants ADEM neuromyelitis optica

Vasculitis primary systemic: lupus, Behçet, APLAS

Multifocal WM signal abnormalities: “white spots”

Sánchez Aliaga E, Barkhof F. Handb Clin Neurol 2014;122:291-316; Charil et al. Lancet Neurol 2006;5:841-52

Miscellaneous neurosarcoidosis Lyme disease PML metabolic: Leber, xantomatosis, adult forms of leukodystrophy effects of radiation therapy or drugs lymphoma metastasic disease

Comprehensive checklist for evaluation of focal lesions

Brief and precise diagnostic impression that must consider:

Demographics Family history Vascular risk factors Clinical information and question Lab findings

Diagnosis of MS Identify typical lesions

Systematic reading

•Lesion distribution / involvement subcortical/periventricular U-fibers cortical grey matter deep grey matter corpus callosum brainstem spinal cord

•Lesion shape •Central vein sign, hypointense rims (SWI) •Enhancement pattern

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Rovira et al. Nat Rev Neurol 2015; Wattjes et al. Nat Rev Neurol 2015; Traboulsee et al. Am J Neuroradiol 2016

0.1 mmol/kg Minimum delay 5 minutes

Gadolinium injection

3D T1 2D proton density-T2 3D T1-Gadolinium

3 mm. slice thickness (no gap) for 2D sequences Isotropic 1x1x1 mm for 3D sequences

3D FLAIR

Standardised MRI acquisition protocol

0.1 mmol/kg Minimum delay 5 minutes

Gadolinium injection (low risk GBCA)

T2 sequences: spinal cord

Single echo heavily T2 weighted1-2 : – limited sensitivity in depicting signal abnormalities1-2.

Combination of at least two T2w sequences: T2 and STIR, T2 and PD

1. Philpott et al. Eur J Radiol 2011; 80:780-5; 2. Bot et al. Eur Radiol 2000; 10:753-8; 3.Rovira et al. Nat Rev Neurol 2015;11:471-82.

T2 STIR

Do not use a single echo T2w sequence as a stand-alone sequence3 !!!!

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•MRI focal white matter lesions (incidental, vascular?): Prevalence 5-10% (20-40 years)

Focal WMLs involving the subcortical frontal white matter Small and non confluent Stable over time Weak association with vascular risk factors More prevalent in migraine headaches

•Multiple sclerosis: Prevalence <0.1% (20-40 years)

Charil et al. Lancet Neurol 2006

Multifocal White matter lesions in young adults

Solomon et al. Neurology 2012;78:1986-91

•Survey: 122 Neurologist (90% from Academic Hospitals) •95% reported having evaluated 1 or more patients who had been diagnosed with MS, but who they strongly felt did not have MS (within the last year) •Mainly due to overuse and improper interpretation of MRI (non specific findings) •>25% under treatment (difficult to take away)

Increase specificity of MRI findings is highly required

Misdiagnosis of Multiple Sclerosis

2013

2015

55 year old female with a diagnosis of multiple sclerosis. Treated with DMDs since 2009

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Fazekas et al. Eur Neurol. 1989; Solomon et al. Neurology 2016; Solomon et al. Curr Neurol Neurosci Rep 2013; Charil et al. Lancet Neurol 2006; Solomon et al. Neurology 2012; Rudick et al. Neurology 2013; Kim et al. Mult Scler. 2013

•Frequent contemporary reason for misdiagnosis •MRI features not considered in the context of appropiate clinical findings •Overdiagnosis of RIS

Misdiagnosis of MS: overreliance on MRI interpretation, wrong application of DX criteria

•Incidental multifocal WM brain lesions on MRI

normal population aged 18-50 (5-10%) migraine (x4)

Misdiagnosis has significant consequences: • Clinical, psychosocial and scientific • Health care system cost (overtreatment with DMTs)

Solomon et al. Neurology 2016

Misdiagnosis of Multiple Sclerosis

•Neurologists at 4 academic MS centers submitted data on patients determined to have been misdiagnosed with MS. •110 misdiagnosed patients:

51 (46%) “definite” misdiagnoses 59 (54%) “probable ” misdiagnoses

70% received ≥ 1 DMD

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Solomon et al. Neurology 2016

Misdiagnosis of Multiple Sclerosis

Diagnosis and syndromes mistaken for MS

Contributors to MS misdiagnosis

Typical imaging findings in MS

Periventricular /ovoid Juxtacortical Cortical Pons (periphery) Middle cerebellar peduncles Inferior margin CC

Spinal cord Short segment <50% cord transverse area Lateral/posterior

Open-ring enhancement Central vein sign Hipointense rims (iron)

Susceptibility-weighted imaging

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MS diagnosis: McDonald 2017 criteria

Clinical Attacksa Clinical Evidence of Lesions Additional Requirements for MS Diagnosis

≥2 Objective clinical evidence of ≥2 lesions or objective clinical evidence of 1 lesion with reasonable historical evidence of a prior attack

None

≥2

Objective clinical evidence of 1 lesion

Dissemination in space, defined as:

● ≥1 T2 lesion in ≥2 MS-typical CNS regions; or

● Await further clinical attack implicating a different CNS site

1 Objective clinical evidence of ≥2 lesions

Dissemination in time, defined as:

● Simultaneous Gd-enhancing and non-enhancing lesions at any time; or

● New T2 and/or Gd-enhancing lesion(s) on follow-up MRI, irrespective of its timing; or

● Await a second clinical attack

1 Objective clinical evidence of 1 lesion (clinically isolated syndrome)

Dissemination in space AND time (as defined above)

● Requirements can be met by a single MRI scan

Thompson AJ et al. Lancet Neurol 2017

Only apply them if clinical and MRI findings are suggestive of MS!!!!! Exclude alternative diagnosis

Kutzelnigg et al. Brain 2005

RRMS SPMS PPMS

focal demyelinated plaques in the white matter

cortical demyelination

demyelinated lesions in the deep grey matter

Cortical gray matter involvement in MS

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• Characterised by: – demyelination1

– microglial activation1

– often meningeal inflammation2,3

• Less often associated with4

– immune cell influx

– complement activation

– BBB leakage

• Difficult to detect by MRI5

• Three types of cortical lesion*6

*Based on post-mortem tissue samples taken from 22 patients with MS. Leukocortical Type I lesions involve neocortex and subcortical white matter; intracortical Type II lesions are confined to the neocortex and often located around a vessel; subpial Type III lesions extend from the pial surface into the neocortex. 1. Peterson JW et al. Ann Neurol 2001; 2. Lucchinetti CF et

al. N Engl J Med 2011; 3. Magliozzi R et al. Ann Neurol 2010; 4. Klaver R et al. Prion 2013; 5. Filippi M et al. Neurology 2010; 6. Wegner C et al. Neurology 2006

38% are Type I (leukocortical)

18% are Type II (intracortical)

44% are Type III (subpial)

Focal lesions in grey matter 90% of MS autopsy cases show cortical demyelination

Type I Type II Type III

Courtesy of Dr. García-Merino

T2-FLAIR

leukocortical lesion Lucchinetti et al. NEJM 2011;365:2188-97

Juxtacortical lesions (type I)

9T MRI (T2) Schmierer et al. Brain 2010

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MRI sensitivity depends on lesion type and sequence

Geurts et al. J Neurol 2008; Wattjes et al. Am J Neuroradiol 2006; Geurts et al. Radiology 2005; Roosendaal et al. Mult Scler 2009

• cMRI detects <10% of pure intracortical lesions • Higher detection of mixed lesions • Improved sensitivity by using DIR or heavily 3D T1-weighted sequences

mixed lesion intracortical lesion

Cortical lesions (type II-III)

T2-FLAIR DIR

Double inversion recovery

T GM GM/WM Subpial

FLAIR 4% 65% 0%

DIR 9% 83% 7%

Seewan et al. Neurology 2012

GM GM/WM Subpial

FLAIR 9% 91% 6%

DIR 29% 96% 33%

Prospective

Retrospective

3D FLAIR and 3D DIR 1.1 x 1.1 x 1.3 mm

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Phase sensitive inversion recovery (PSIR)

DIR PSIR

Courtesy Juan Linera (Madrid)

Phase sensitive inversion recovery (PSIR)

Lesion type Mean lesion counts

DIR PSIR GM 6 18 GM/WM 7 13

(60 MS; 30 controls)

DIR 83% MS ≥l purely GML All controls 0 GML PSIR 100% MS ≥l purely GML 3% controls ≥l purely GML

Sethi et al. JNNP 2012

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Leukocortical lesions

Present in 44% of CIS and in 70% of MS patients

Absent in NMO, migraine…

Calabrese et al. Neurology 2012; 79:1671-6; Absinta et al. J Neurol 2012; 259:2695-8; Pareto et al. Am J Neuroradiol 2016

Perivenular topography of MS plaques “Dawson‘s fingers“

Post-mortem pathology studies show central vein in > 90% white matter lesions

Dawson J. Trans Roy Soc Edinb 1916; 50:517-740 Horowitz et al. Am J Neuroradiol 1989;10:303-5

venule plaque

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Perivenular topography of MS plaques “Dawson‘s fingers“

Multiple sclerosis Kuijf et al. Eur Radiol 2017

Susceptibility-weighted MRI (7T)

FLAIR=fluid-attenuated inversion recovery. Kilsdonk ID et al. Eur Radiol. 2014;24:841–849

Axial 7-T FLAIR images of an MS patient and a patient with non-MS brain lesions

Dawson J. Trans Roy Soc Edinb 1916; 50:517-740 Horowitz et al. Am J Neuroradiol 1989;10:303-5

venule plaque

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Central vein sign

Absinta et al. Nat Rev Neurol 2016

Courtesy Pascal Sati. NIH (ECTRIMS teaching course 2017)

SWI + FLAIR

Central vein sign

Magi et al. Ann Neurol 2018

The “central vein sign” differentiates inflammatory CNS vasculopathies from MS at standard clinical magnetic field strengths.

31 patients with inflammatory CNS vasculopathies and 52 with RRMS 3D T2*-w EPI acquired during or after iv injection of a single dose (0.1 mmol/kg)

of GBCA

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Central vein sign (3 T) MS vs NMO

Cortese et al. Neurology 2018

•The clinical value of the CVS in the context of the differential diagnosis between MS and NMOSD is now extended to clinical 3T scanners •Step towards the use of CVS in clinical practice. •Class III evidence that the CVS on 3T MRI accurately distinguishes patients with MS from those with seropositive NMOSD.

•Cutoff value of 54% of lesions with CVS was optimal in differentiating MS from NMOSD in the groups with high lesion numbers (sensitivity 94%; specificity 100%; accuracy 94%). •In patients with low lesion numbers, the cutoff point rose to 80% of lesions with CVS and produced less convincing results (sensitivity 50%; specificity 93%; accuracy 88%).

Intralesional susceptibility signal (ISS) in MS (3T)

SWI FLAIR

Intralesional susceptibility signal (ISS) 48% of non-enhancing MS lesions 58% of enhancing MS lesions

Susceptibility-weighted MR imaging

Likely represents iron-rich macrophages / microglia Myelin loss also contributes

Rovira et al. Multiple Sclerosis Journal 2015; 21 (S11):209

Hagemeier et al. J Magn Reson Imaging 2012;36:73-83; Bian et al. Mult Scler 2013;19:69-75

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Susceptibility-weighted MR imaging Determinants in image contrast

Myelin, iron, deoxyhemoglobin, and free radicals—all relevant in MS pathogenesis—influence susceptibility signal

• T2*/phase contrast in acute MS lesions appear to be influenced by the presence of free radicals

• T2*/phase contrast in chronic MS lesions appear to be influenced by the topography of iron-laden macrophages / activated microglia within lesions

Absinta et al. Ann Neurol 2013

T2-FLAIR

Migraine-related WMLs vs Multiple Sclerosis (3T)

Rovira et al. Multiple Sclerosis Journal 2015; 21 (S11):209

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SWI

Migraine-related WMLs vs Multiple Sclerosis (3T)

Areas of intralesional signal loss on SWI increases

diagnostic specificity and accuracy

MS

Migraine

Rovira et al. Multiple Sclerosis Journal 2015; 21 (S11):209

T2-FLAIR

Phase imaging in the diagnosis of MS

6 RR, 6 PP and 4 SP MS patients

Ten MS lesions (2.3 %) were surrounded by a hypointense rim on FLAIR*, and 24 MS lesions (5.5 %) were hypointense on T2*. No lesions in vascular patients showed any rim or hypointensity.

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1. Early active

2. Center, chronic-active

Large, myelin-laden macrophages without iron

Small myelin-laden macrophages and occasional iron-containing macrophages

Macrophages with large amounts of iron, but without myelin

Perls’ staining

3. Rim, chronic-active

Myelin debris within macrophages detected with oil red-O

Mehta et al. PLOS one 2013;e57573

MS: Lesion categories and iron deposition

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2

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No or only small amounts of iron

4. Chronic silent white matter lesions

Iron within activated microglia is demonstrated to enhance the release of pro-inflammatory cytokines and free radicals

Rathnasamy et al. CNS & Neurological Disorders - Drug Targets, 2013

Iron deposition in developping plaques

Absinta et al. Nat Rev Neurol 2016

baseline 3 months 9 months

3T

T2-FLAIR

T1-Gad

SWI

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Serial analysis with QS mapping at 3T

•Magnetic susceptibility increases rapidly as it changes from enhanced to non-enhanced •High susceptibility values during the first 2-4 years •Then gradually decreases (susceptibility similar to NAWM)

Chen et al. Radiology 2014; 271:183-92

Susceptibility-weighted MR imaging in focal MS lesions

• Iron in microglia/macrophages with a pro-inflammatory status

• Indicate chronic lesion activity • Future marker of disease activity? • No correlations USPIO/phase imaging

Expanding MS lesions

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Chronic active lesions Associated with • microglia activation • ongoing axonal injury

Partially explain disability progression (pre-existing symptoms)

MRI: Lesion evolution Slowly expanding plaques (smoldering)

2002 2003 2005

MRI: Lesion evolution (SPMS) Slowly expanding plaques (smoldering)

Baseline Two years

Mixed active / inactive and post-demyelinating

Kuhlmann et al. Acta Neuropathol 2017

Mixed active / inactive and post-demyelinating

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Frontal subcortical lesions

No subclinical spinal cord lesions

No juxtacortical, corpus callosum lesions

No ISS

SWI

Incidental findings

FLAIR

Clinical case: young female with migraine

SWI

FLAIR

Ovoid lesions

Juxtacortical lesions

Corpus callosum lesion Juxtacortical lesion

ISS within lesions

Preclinical multiple sclerosis or Radiologically isolated

síndrome (RIS)

Clinical case: young female with migraine

Spinal cord lesion

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Summary

Wide variety of causes may present with multifocal WM lesions

MRI is the preferred imaging technique for diagnostic workup Radiological interpretation with demographic, clinical history,

and lab findings Standardized brain (spinal cord) MRI protocol Comprehensive checklist for evaluation of WM spots is crucial Spinal cord MRI and SWI improve diagnostic specificity

Sánchez Aliaga E, Barkhof F. Handb Clin Neurol 2014;122:291-316; Charil et al. Lancet Neurol 2006;5:841-52; Rovira et al. Nat Rev Neurol 2015;11:471-82