The Central Vein Sign and Paramagnetic Rim Sign in White Matter - PowerPoint PPT Presentation

The Central Vein Sign and Paramagnetic Rim Sign in White Matter Lesions of Radiologically Isolated Syndrome Suradech Suthiphosuwan 1,2 , Pascal Sati 3 , Melanie Guenette 2 , Martina Absinta 3 , Daniel Reich 3 , Aditya Bharatha 1,4 , Jiwon Oh 2,5 1 .Division of Neuroradiology, Department of Medical Imaging, St . Michael ’ s Hospital, University of Toronto 2 .Division of Neurology, Department of Medicine, St . Michael ’ s Hospital, University of Toronto 3 . Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, NIH 4. Division of Neurosurgery, Department of Surgery, St . Michael ’ s Hospital, University of Toronto 5. Department of Neurology, Johns Hopkins University

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Background: Multiple Sclerosis (MS) Popescu et al, Multiple sclerosis, Elsevier 2016 Mistry et al, MSJ 2015 Tallantyre et al, Neurology 2011 MS lesions: perivenular MS: A high proportion of WML with CVS+ MRI: Central vein inside inflammatory infiltrates A cut-off threshold of 40% has been white matter lesion (WML) propose to distinguish MS vs. non-MS = “Central Vein Sign” (CVS)

Background: Multiple Sclerosis (MS) MRI: “Paramagnetic rim sign (PRS)” = Chronic active inflammation attributed to paramagnetic effects from iron-laden microglia macrophages at the lesions edge. Absinta M, JCI 2016

Background: Radiologically Isolated Syndrome (RIS) • RIS cases are at increased risk of developing MS . • One-third of RIS cases developed clinical definite MS within 5 years. • Risk factors of developing MS • Young age (<37 years) • Being Male Asymptomatic cases with • Presence of Spinal cord lesion incidental MRI findings suggestive of MS

Objective To assess for the presence of the CVS and PRS in WMLs of RIS.

Methods: Subjects • IRB Approved • RIS cases were prospectively Barkhof’s criteria (at least 3 out of 4) recruited from the St Michael’s Number of T2 lesions ≥ 9 T2 hyperintense or ≥ 1 Gd enhancing Hospital MS clinic from July 2017 ≥ 1 Infratentorial or cord to December 2017. lesions ≥ 1 Juxtacortical lesions • Inclusion criteria: adult subjects ≥ 3 Periventricular lesions meeting previously published clinical and MRI criteria for RIS (Okuda et al, Neurology 2009)

Methods: MRI Protocol • 3.0T MRI scanner: Siemens Skyra, Erlangen, Germany. • 20 - channel head - neck coil • 3D FLAIR: lesion detections, lesion count, and location • 3D T2* EPI: • Magnitude: CVS 3D T2* EPI 3D T2* EPI 3D FLAIR assessment Magnitude Phase • Phase: PRS assessment

Methods: CVS assessment Central Vein Sign on 3D T2* EPI (Sati et al, Nrneurol, 2016) • Thin hypointense line or small dot • Visualized in at least two perpendicular planes, and appears Ax as a thin line in at least one plane • Small apparent vein diameter Cor • Runs through the lesion • Positioned centrally in the lesion Sg

Methods: CVS assessment Exclusion criteria for lesions (Sati et al, Nrneurol, 2016) • Lesion is <3 mm in diameter • Confluent lesions • Lesion has multiple veins • Lesion is poorly visible T2* EPI FLAIR

Methods: PRS assessment PRS positive lesion • WML >3 mm in size • Presence complete/incomplete hypointense rim on Phase image Exclusion • WML <3 mm in size • Poorly visible lesion due to artifact 3D T2* EPI 3D T2* EPI Magnitude Phase

Results: Clinical and MRI Characteristics of RIS subjects Demographics Radiological Characteristics Participants, n 15 Total brain lesion count, n 680 Age, mean (SD) 45 (11.5) No. brain lesion per subject, meadian (range) 31 (9-165) Female, n (%) 11 (73%) No. Brain lesion per location Reasons for Performing Initial Brain MRI Cortical/Juxtacortical 147 (22%) Headaches 7 (46%) Subcortical/Deep white matter 342 (50%) Transient paraphasic symptoms atypical for demyelinating disease 2 (13%) Periventricular white matter 160 (23%) Intermittent subjective cognitive symptoms 1 (7%) Infratentorial 31 (5%) Intermittent nocturnal tremor 1 (7%) Cervical spinal cord lesion Pars planitis 1 (7%) No. of Participants with cervical spinal cord lesions 10 Back pain 1 (7%) Dental pain 1 (7%) Total cervical spinal cord lesions 22 Tinnitus 1 (7%) No. of Cervical spinal cord lesions per subjects, median (range) 1 (0-4)

Results: Proportion of WML with CVS + per Subject Total WML 680 Exclusion Inclusion 424 (62%) 256 (38%) %CVS+ >40% 14 cases (93%) CVS+ 217 (85%) CVS- %CVS+ < 40% 39 (15%) 1 cases (7%) Median %CVS+ per RIS case 83% (range 31% – 100%)

Results: • The PRS was present in 11 cases (73%) Total WML • The mean proportion of PRS 680 + WMLs per case was 19% (range:8-44%). Exclusion Inclusion • PRS were absent in 4 cases 231 (34%) 449 (66%) (27%): • 3 had low total lesion loads PRS + (9-25 WMLs per case) 81 (18%) • 1 had the lowest proportion of CVS+ WML (31%) PRS - 368 (82%)

Figures: High %CVS = 92% PRS+ = 30%

Figures: Low %CVS = 31% No PRS

Results: Regression Analyses Evaluating the Association of Baseline Characteristics with the Proportion of CVS+ WMLs Univariable model Multivariable model Variable p - value p - value Age 0.584 0.830 Sex 0.907 0.920 Total No. Brain lesion 0.970 0.049 0.096 0.027 No. Cervical spinal cord lesion Proportion of PRS+WML 0.015 0.015

Discussion: • A large number of WMLs in RIS demonstrates CVS. • The majority of RIS cases had > 40% CVS+ per case. • Meets 40% threshold that has been proposed to distinguish MS from Non- MS. • A large (though smaller) proportion of WMLs in RIS also had PRS+ • RIS without PRS had low WML load and/or low proportion of CVS+WML • %CVS+WML had significant correlation with %PRS+WML • Number of total brain lesions and cervical spinal cord lesions are also associated with %CVS+.

Conclusions • Most RIS cases had a large proportion of CVS+ WMLs and also had PRS+WMLs • RIS subjects harbor both perivenular inflammation and subclinical chronic active demyelination similar to MS • RIS with high %CVS+ and PRS+ may be at risk of eventually developing progressive clinical symptoms • Both CVS and PRS could potentially be useful to differentiate true RIS (i.e. subclinical inflammatory demyelination) from mimickers. • Prospective follow-up of this cohort is planned • Better understanding of the differential diagnostic and predictive value of the CVS in RIS.

References • Okuda DT, Mowry EM, Beheshtian A, et al. Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. Neurology 2009;72:800-805 • Maggi P, Absinta M, Grammatico M, et al. Central vein sign differentiates Multiple Sclerosis from central nervous system inflammatory vasculopathies. Ann Neurol. 2018;83(2):283-294. • Absinta M et al., Persistent 7-tesla phase rim predicts poor outcome in new multiple sclerosis patient lesions. JCI 2016;126(7):2597-609 • Absinta M, Sati P, Fechner A, et al. Identification of Chronic Active Multiple Sclerosis Lesions on 3T MRI. Am J Neuroradiol. 2018; Advance online publication. • Sati P, Oh J, Constable RT, et al. The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative. Nat Rev Neurol. 2016;12(12):714-722. • Tallantyre EC, Dixon JE, Donaldson I, et al . Ultra - high - field imaging distinguishes MS lesions from asymptomatic white matter lesions . Neurology 2011;76 : 534 - 539

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