the central vein sign on mri - ectrims congress · recent mri studies in ms patient brains have...

Pascal Sati, PhDStaff Scientist, Translational Neuroradiology Section

National Institute of Neurological Disorders and StrokeNational Institutes of Health

Bethesda, Maryland, USA

The central vein sign on MRI

ECTRIMS 2017 NAIMS/MAGNIMS ACTRIMS/ECTRIMS Teaching Course

Imaging the non-MS lesion in MS

Goals of this teaching course

To introduce the concept of central vein sign (CVS) and its potential clinical value

To review the literature on the CVS in MS and its MRI mimics

To present (standard and advanced) MRI techniques for imaging CVS

To discuss proposed guidelines and future directions for the clinical evaluation of CVS

Relationship between veins and MS plaques

First pathological observations Rindfleisch, 1863Charcot, 1869Dawson, 1916

CWM Adams. J Neurol Sci. 1975

Perivenular inflammatory infiltration at the onset of the MS lesionH. Lassmann. Phil. Trans. R. Soc. Lond. B 1999

Okudera et al. Neuropathology 1999 (soft X-ray microscopy of postmortem tissues)

Long, fine vessels of uniform caliber

Lumen caliber: 100 - 250 mm

(Hooshmand et al. Neuroradiology 1974)

V

Deep medullary veins of the brain

Deoxyhemoglobin is paramagnetic (high spin state S = 2 of heme iron)

Venous blood (~70% saturated) has shorter T2* relaxation time and faster dephasing than tissue

Gradient-Echo: long TE (T2* contrast) & high spatial resolution to visualize small veins

Reichenbach et al. Radiology 1997

7T MRI (NIH) (250 mm in-plane resolution) In vivo cerebral venography by MRI

First in vivo observation of central veins in MS

Tan et al., AJNR 2000 (1.5T MRI)

T2-weighted MR venogram

High frequency of central veins in MS lesions

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Percentage of CVS positive lesions

% CVS varies with lesion location in the brainTallantyre et al., Neurology 2008 (96% periventricular, 65% peripheral)Kilsdonk et al., J Neurol 2014 (94% PV, 84% DWM, 66% JC, 52% LC , 25% IC)

Possible age effect % CVSKilsdonk et al., J Neurol 2014 (92% when <40y vs 73% when >40y)

No significant differences between relapsing form vs. progressive from Kuchling et al., MSJ 2014 (80.4% in RRMS vs 76.5% in PPMS)

% CVS is unknown in pediatric MS patients

% CVS is unknown in MS spinal cord

Central vein sign (CVS) is observed in all types of MS lesionsperiventricular, deep white matter, subcortical, juxtacortical, leukocortical, intracortical, infratentorial

Question 1:

Recent MRI studies in MS patient brains have demonstrated the presence of central veins in which type(s) of white matter lesions?

A. Periventricular lesions & deep white matter lesions

B. Subcortical lesions & juxtacortical lesions

C. Infratentorial lesions

D. All of the above

MS non-MS

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Incidental

NMOSD

NMOSD

Headaches

VascularMigraine

Dementia

SVD = small vessel disease

Lower frequency of central veins in non-MS lesions

SVD

SVD

Susac


MS non-MS

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Differentiating MS from its MRI mimics with the central vein sign ?

Incidental

Susac

NMOSD

NMOSD

Headaches

VascularMigraine

Dementia

SVD

SVD

SVD = small vessel disease


Diagnosing MS with the central vein sign ?

Tallantyre et al. Neurology (2011)

Proposed cutoff to establish MS diagnosis

MS WM lesions

incidental WM lesions (healthy or vascular risk factors)

CVS criteria proposed for MS diagnosis

40% cutoff Mistry et al. JAMA Neurol 201313 MS & 9 with microangiopathic lesions. 100% positive and negative predictive of MS diagnosis in 22 patients.

‘VIL45’ (> 45%) and ‘VIL60’ (>60%) cutoff Campion et al. Eur Radiol 2017 25 MS & 10 SVD. VIL45: 100% sensitivity & 80% specificity, VIL60: 96% sensitivity & 90% specificity.

6 morphologically characteristic lesions Mistry et al. MSJ 2014 13 MS & 7 SVD/migraine. Perfect classification of 20 cases.

Select 3 / Select 3* Solomon et al. MSJ 2017 10 MS & 10 migraine. Select 3: 0.52 sensitivity & 0.98 specificity. Select 3*: 0.83 sensitivity & 0.81 specificity.

Dworkin et al. (P575) Poster Session 1, Thurs 26th

Solomon et al. (P842) Poster Session 2, Friday 27th

Single-center studies indicate that CVS may help with differential diagnosis (discrimination between MS lesions and ischemic lesions)

Lummel et al., Neuroradiology 2011 (80% in MS lesions vs 78% in ischemic lesions)Lamot et al., Mult Scler Relat Disord 2017 (62% in MS lesions vs 71% in ischemic lesions)

Conflicting results on %CV in small vessel diseases

Need for more data on inflammatory MRI mimics of MSBehçet's disease, Sjögren’s syndrome, systemic lupus erythematosus, neurosarcoidosis,…

Massacesi et al., European Academy of Neurology 201689% in MS vs 15% in SAD (Behçet, SLE, APS)

Need for large-scale comparative studies using standardized methodsFilippi et al. Lancet Neurol 2016 (MAGNIMS)Sati et al. Nature Review Neurology 2016 (NAIMS)

Kilsdonk et., Eur Radiol 2014

Lummel et al., Neuroradiology 2011

Different criteria for the central vein sign

Tallantyre et al., Neurology 2011

Solomon et al., ACTN 2015

Reference MRI technique B0 (T) Gad

Tan et al., AJNR 2000 SWI 1.5 Yes

Ge et al., Arch Neurol 2008 T2*w Gradient-Echo 7 No

Tallantyre et al., Neurology 2008 T2*w Gradient-Echo 7 No

Tallantyre et al., Invest Radiol 2009 T2*w Gradient-Echo 7 No

Lummel et al., Neuroradiology 2011 SWAN 3 No

Tallantyre et al., Neurology 2011 T2*w Gradient-Echo 7 No

Wuerfel et al., Mult Scler 2012 T2*w Gradient-Echo 7 No

Sinnecker et al., Neurology 2012 T2*w Gradient-Echo 7 No

Dixon et al., Eur J Radiol 2013 T2*w Gradient-Echo 7 No

Kister et al., Mult. Scler. Int. 2013 T2*w Gradient-Echo 7 No

Kau et al., Eur Radiol 2013 T2*w Gradient-Echo 3 No

Kilsdonk et., J Neurol 2014 FLAIR* 7 No

Kilsdonk et., Eur Radiol 2014 FLAIR* 7 No

Sati et al., Mult Scler 2014 T2*w seg EPI 3 Yes

Kuchling et al, Mult Scler 2014 T2*w Gradient-Echo 7 No

Dal-Bianco et al, Eur Radiol 2015 FLAIR-SWI 7 No

Solomon et al., Ann. Clin. Transl. Neurol. 2015

FLAIR* / T2*w seg EPI 3 Yes

Lane et al., J. Comput. Assist. Tomogr. 2015 SWI 1.5 No

Lamot et al., Mult Scler Relat Disord 2017 SWI 3 No

Mistry et al., Mutl Scler 2016 T2*w Gradient-Echo 7 No

Campion et al., Eur Radiol 2017 FLAIR* / T2*w seg EPI 3 Yes

Different MRI protocols for the central vein sign

T2*-weighted Gradient-Echo

Signal

Echo Time

T2* decayWhite matter

T2* decayVeins

TE

SWM

SVein

Scan time > 8 min

Partial brain coverage

Anisotropic voxel ( ~ 0.5 x 0.5 x 2 mm)

Ge et al., Arch Neurol 2008 (7T)

Siemens: FLASHPhilips: T1 FFEGeneral Electric: SPGR

General Electric: SWAN

Lummel et al., Arch Neurol 2008 (3T)

Scan time ~ 6 min

Partial/Whole brain coverage

Anisotropic voxel (~ 0.5 x 0.5 x 2 mm)

Signal

Echo Time

T2* decay

STE2

STE1

STE3

STE4

TE1 TE2 TE3 TE4

T2* Multi-Echo Gradient-Echo

Magnitude Phase SWI

Siemens: SWI

Philips: SWIp

Haacke et al. AJNR 2009

Scan time = [4 min - 6 min]

Partial/Whole brain coverage

Anisotropic voxel (~ 0.5 x 0.5 x 2 mm)

Susceptibility Weighted Imaging

FLAIR

SWI (minIP)

T2-weighted

Kau et al., Eur Radiol 2013 (3T)

minIP = minimum intensity projection

Susceptibility Weighted Imaging

FLAIR-SWI: a fusion of FLAIR and SWI

Grabner et al. JMRI 2011

FLAIR FLAIR-SWI

T2* segmented 3D echo-planar-imaging (3D EPI)

Scan time = [3 ½ min - 6 min]

Whole brain coverage

Isotropic voxel = [0.5 mm - 0.75 mm]

Prototype sequence (Siemens, Philips)

Sati et al., MSJ (2014)Sati et al., Magnetom FLASH (2017)

3D EPI, 3T Siemens, 0.65 mm iso, ~ 5 ½ min

T2*w

Phase

Absinta et al. (oral #243, Parallel Session 15, Friday 27th)

Optional step: intensity correction (N4)

FLAIR*: a combined MR contrast

3T

Sati et al., Radiology (2012)

Sati et al., Magnetom FLASH (2017)

Effect of static magnetic field strength (B0)

Tallantyre et al., Invest Radiol 2009

7T (0.5 mm) 3T (0.8 mm)

% CVS = 87% % CVS = 45%

Fechner et al. (ePoster) 3DEPI sequence optimized for different field strengths (NIH)


Effect of gadolinium-based contrast agent

Pre-injection

Sati et al., Mult Scler. 2014

3T venogram (minIP) with 3DEPI sequence

During injection

single dose gadobutrol (0.1 mmol/kg)

Post-injection (15 min)

Maggi et al., Acta Radiol Open. 2015

1.5T SWI(w/o gd)

1.5T SWI(w/ gd)


Which of the following MRI techniques cannot be used to image central veins in brain lesions?

A. T2*-weighted gradient-echoB. T2-weighted spin-echoC. Susceptibility-weighted-imagingD. T2*-weighted segmented 3DEPIE. FLAIR*

Question 2:

Proposed radiological definition of the central vein sign

A central vein exhibits the following properties on T2*‐weighted images:

Appears as a thin hypointense line or small hypointense dot

Can be visualized in at least two perpendicular MRI planes, and appears as a thin line in at least one plane

Has a small apparent diameter (<2 mm)

Runs partially or entirely through the lesion

Is positioned centrally in the lesion regardless of the lesion’s shape

Exclusion criteria for lesions:

Lesion is <3 mm in diameter

Lesion merges with another lesion (confluent lesions)

Lesion has multiple distinct veins

Lesion is poorly visible

Susceptibility-based (T2*) contrast

High-resolution (~ 0.5 mm)

High-field strength (3T and above)

With gadolinium contrast agent injection at 1.5T

SWI, SWAN, SWIp (clinical scanners)

Segmented 3D EPI (research scanners)

Isotropic voxels (multi-planar reconstruction)

Combined FLAIR* for improved lesion detection

Technical recommendations for imaging the central vein sign by MRI

Future directions for the clinical evaluation of CVS

Differential diagnosis for all MRI mimics of MS (both adult and pediatric)Hypoxic-ischemic vasculopathy, inflammatory/inflammatory autoimmune, infectious, toxic and metabolic, traumatic, tumoral, hereditary/unknown. Aliaga and Barkhof, Handb Clin Neurol 2014

Prediction of MS conversion in clinically isolated syndrome (CIS) Miller et al. Lancet Neurol 2012

Prediction of MS conversion in radiologically isolated syndrome (RIS) Okuda, Neuroimaging Clin N Am. 2017Makhani et al., Neurol Neuroimmunol Neuroinflamm 2017

Undiagnosing the misdiagnosedSolomon et al., Neurology 2012Solomon & Corboy, Nat Rev Neurol 2017

The central vein sign in multiple sclerosis: a real-life multi-centre MAGNIMS study

Background: first large-scale multi-centre 3T MRI study to test the usefulness of the central vein sign (CVS)

as an MS specific biomarker in a “real world” setting

479 patients with a variety of conditions (e.g. CIS/RRMS,NMOSD, (cerebral) vasculitis, migraine, small vessel ischaemia,diabetes) from nine MAGNIMS centres were included yet.3784 lesions were analysed. The initial findings areencouraging. A final batch with additional patients is currentlybeing analysed.

Blinding to global lesion loadand distribution: image is splitinto 8 equal-size blocks

Operator views overlay of SWI/FLAIR to decide on thepresence of central vein in accordance to NAIMS CVScriteria

Courtesy of Drs. Tim Sinnecker and Jens Wuerfel (MIAC, University Hospital Basel)

CentrAl Vein Sign in the early diagnosis of Multiple Sclerosis (CAVS-MS)

A pilot study to demonstrate the feasibility of utilizing 3T FLAIR* for central vein imaging in a multi-center setup

Which of the following statements is not part of the radiological definition for the central vein proposed by the NAIMS guidelines?

A. Appears as a thin hypointense line or small hypointense dot on T2* contrastB. Can be visualized in at least two perpendicular MRI planesC. Has a large apparent diameter (>2mm) D. Runs partially or entirely through the lesion E. Is positioned centrally in the lesion

Question 3:

Does this lesion meet the NAIMS definition for the central vein sign?

A. YesB. NoC. I don’t know…

Axial

Question 4:



Axial

Question 4:

SagittalCoronal

Axial

Question 5:



Axial

Question 5:


A. YesB. No (no visible vein)C. I don’t know…

SagittalCoronal

Axial

Question 6:



Axial

Question 6:


A. YesB. No (excluded, confluent & multiple vessels)C. I don’t know…

SagittalCoronal

Central Vein Sign should only be used in a research setting

Thank you for your attention

the central vein sign on mri - ectrims congress · recent mri studies in ms patient brains have...

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