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The Central Vein Sign in Radiologically Isolated Syndrome

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The Central Vein Sign in Radiologically Isolated Syndrome Published April 18, 2019 as 10.3174/ajnr.A6045 ORIGINAL RESEARCH ADULT BRAIN The Central Vein Sign in Radiologically Isolated Syndrome X S. Suthiphosuwan, X P. Sati, X M. Guenette, X X. Montalban, X D.S. Reich, X A. Bharatha, and X J. Oh ABSTRACT BACKGROUND AND PURPOSE: Radiologically isolated syndrome describes asymptomatic individuals with incidental radiologic abnor- malities suggestive of multiple sclerosis. Recent studies have demonstrated that Ͼ40% of white matter lesions in MS (and often substan- tially more) have visible central veins on MR imaging. This “central vein sign” reflects perivenous inflammatory demyelination and can assist in differentiating MS from other white matter disorders. We therefore hypothesized that Ͼ40% of white matter lesions in cases of radiologically isolated syndrome would show the central vein sign. MATERIALS AND METHODS: We recruited 20 participants diagnosed with radiologically isolated syndrome after evaluation by a neu- rologist. We performed 3T MR imaging of the brain and cervical spinal cord. White matter lesions were analyzed for the central vein sign. RESULTS: Of 391 total white matter lesions, 292 (75%) demonstrated the central vein sign (central vein signϩ). The median proportion of central vein signϩ lesions per case was 87% (range, 29%–100%). When the “40% rule” that has been proposed to distinguish MS from other disorders was applied, of 20 participants, 18 cases of radiologically isolated syndrome (90%) had Ն40% central vein signϩ lesions (range, 55%–100%). Two participants (10%) had Ͻ40% central vein signϩ lesions (29% and 31%). When the simpler “rule of 6” was applied, 19 participants (95%) met these criteria. In multivariable models, the number of spinal cord and infratentorial lesions was associated with a higher proportion of central vein signϩ lesions (P ϭ .002; P ϭ .06, respectively). CONCLUSIONS: Most cases of radiologically isolated syndrome had a high proportion of central vein signϩ lesions, suggesting that lesions in these individuals reflect perivenous inflammatory demyelination. Moreover, we found correlations between the proportion of central vein signϩ lesions and spinal cord lesions, a known risk factor for radiologically isolated syndrome progressing to MS. These findings raise the possibility, testable prospectively, that the central vein sign may have prognostic value in distinguishing patients with radiolog- ically isolated syndrome at risk of developing clinical MS from those with white matter lesions of other etiologies. ABBREVIATIONS: CVS ϭ central vein sign; RIS ϭ radiologically isolated syndrome ultiple sclerosis is an inflammatory demyelinating disease they first form, arise from inflammatory infiltrates around small Mof the central nervous system characterized by relapsing or veins, or “perivascular cuffs.”2 On conventional MR imaging, MS progressive neurologic symptoms and focal white matter lesions.1 lesions typically manifest as focal areas of high signal on T2- Histopathologic studies have shown that these WM lesions, when weighted images of the brain and spinal cord. However, focal T2-hyperintense WM lesions can be seen in a variety of settings, including normal aging, migraines, microangiopathy, and CNS Received January 28, 2019; accepted after revision March 25. vasculitis. Misinterpretation of such lesions is the most common From the Division of Neuroradiology (S.S., A.B.), Division of Neurology (S.S., M.G., 3 X.M., J.O.), Department of Medicine, and Division of Neurosurgery (A.B.), Department cause of incorrect MS diagnosis, and partly to address this issue, of Surgery, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada; one can only apply the current MS diagnostic criteria in the setting Translational Neuroradiology Section (P.S., D.S.R.), National Institute of Neurological 4-6 Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; and Depart- of typical clinically isolated syndrome. Diagnosing MS when ment of Neurology (D.S.R., J.O.), Johns Hopkins University, Baltimore, Maryland. such a syndrome is not present is therefore challenging. This work was supported by the MS Society of Canada and the St. Michael’s Hos- Recent studies using high-resolution, susceptibility-based MR pital Foundation Love/Barford Endowment. The funders had no role in the design and conduct of the study; collection, man- imaging sequences have demonstrated an identifiable vein inside agement, analysis, and interpretation of the data; preparation, review, or approval of the manuscripts; and the decision to submit the manuscript for publication. Please address correspondence to Jiwon Oh, MD, FRCPC, PhD, 30 Bond St, Shuter Paper previously presented at: American Society of Neuroradiology Annual Meet- 3–019, Toronto, ON, M4K 1Z1 Canada; e-mail: [email protected] ing and the Foundation of the ASNR Symposium, June 2–7, 2018, Vancouver, British Columbia, Canada (abstract No. O-70). http://dx.doi.org/10.3174/ajnr.A6045 AJNR Am J Neuroradiol ●:●●2019 www.ajnr.org 1 Copyright 2019 by American Society of Neuroradiology. WM lesions, called the “central vein sign” (CVS).3,7-21 On these MATERIALS AND METHODS scans, the CVS is typically visible as a hypointense line that is Standard Protocol Approvals, Registrations, and Patient centered within the lesion; the hypointensity reflects the presence Consent of a paramagnetic substance, either deoxyhemoglobin or, in some This study was approved by the institutional review board of St. circumstances, a gadolinium-based contrast agent.9,11,12 Previous Michael’s Hospital. All participants provided written informed studies assessing the CVS in MS have reported that a high fre- consent. quency of WM lesions in MS demonstrate the CVS compared with WM lesions seen in microangiopathic disease, migraines, Participants CNS inflammatory vasculopathies, and neuromyelitis optica Twenty adults diagnosed with RIS by a neurologist at the St. Mi- spectrum disorders. 3,8,10,13-17,19-23 On the basis of these studies, a chael’s Hospital MS Clinic were recruited for prospective clinical cutoff threshold of 40% (in which Ն40% of WM lesions demon- and MR imaging evaluation between July 2017 and December strate the CVS) has been proposed to distinguish MS from 2017. Because RIS is a rare entity31 and the central vein sign has non-MS disease.8 More recent studies have proposed more sim- not yet been evaluated in RIS, we were not able to perform sample plified criteria, such as the “rule of 6,” whereby if Ͼ6 WM lesions size calculations of power analyses. Inclusion criteria were 18 demonstrate the CVS, MS can be distinguished from other WM years of age and older and meeting previously published clin- disorders.10,21,23 ical and MR imaging criteria for RIS,24 which include the pres- Radiologically isolated syndrome (RIS) describes asymptom- ence of asymptomatic WM abnormalities that are ovoid, well- atic individuals or those with neurologic symptoms that are not circumscribed, Ն3 mm in maximal diameter, and fulfilling 3 of typical of MS, whose MR imaging scans show abnormalities typ- 4 Barkhof criteria28 for dissemination in space (lesions in the ical of those seen in clinical MS.24 Individuals with RIS have an periventricular, juxtacortical, infratentorial, or spinal cord re- increased risk of eventually developing clinical MS, but long-term gions). Brain MRIs were reviewed by experienced neuroradi- prospective studies are lacking. The largest, multicenter, retro- ologists (S.S. and A.B.) and a neurologist (J.O.) to confirm spective study has shown that 34% of patients with RIS eventually inclusion criteria. Individuals who had vascular risk factors manifest clinically definite MS during 4.4 years.25 Factors that and a history of substance abuse or toxic exposure were increase the risk of conversion to MS include the following: male excluded.24 sex, younger age (younger than 37 years of age), and the presence of Ն1 spinal cord lesion on MR imaging.25,26 Another study dem- Clinical Assessment onstrated that among individuals with RIS who develop MS, Within 30 days of MR imaging, study participants underwent an 11.7% develop primary-progressive MS, and these individuals are examination by a neurologist. None of the participants experi- more likely to be older and male and have spinal cord lesions.27 enced a clinical relapse or neurologic symptoms suggestive of MS These data suggest that at least a portion of patients with RIS have between recruitment and the study visit. a subclinical form of MS; of these, many may never develop clin- ical MS. MR Imaging Currently, there is no consensus on the optimal clinical man- MR imaging was performed on a 3T scanner (Magnetom Skyra; agement of RIS because the natural history remains unclear and Siemens, Erlangen, Germany) with a 20-channel head-neck coil there are no evidence-based treatment or management guide- and a 16-channel spine-array coil. lines. Moreover, the current diagnostic criteria for RIS24 likely result in a heterogeneous group of participants being designated Brain MR Imaging as such, including those who are at risk of developing MS and The following parameters were used for brain sequences—3D T1- those who have a minimal risk. This result is likely because the weighted MPRAGE: TR/TE/flip angle ϭ 1900/2.52 ms/9°, num- diagnostic criteria for RIS are based entirely on lesion number and ber of averages ϭ 1, slice thickness ϭ 1 mm, in-plane resolution ϭ distribution (Barkhof28 criteria for dissemination in space), crite- 1 ϫ 1mm2, and number of slices ϭ 176; 3D T2-FLAIR: TR/TE/
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