Multicenter Study

. 2024 Jan;30(1):25-34.

doi: 10.1177/13524585231214360. Epub 2023 Dec 13.

A multicenter pilot study evaluating simplified central vein assessment for the diagnosis of multiple sclerosis

Lynn Daboul^{1

2}, Carly M O'Donnell³, Moein Amin⁴, Paulo Rodrigues⁵, John Derbyshire⁶, Christina Azevedo⁷, Amit Bar-Or⁸, Eduardo Caverzasi^{9

10}, Peter A Calabresi¹¹, Bruce Ac Cree¹⁰, Leorah Freeman¹², Roland G Henry¹⁰, Erin E Longbrake¹³, Jiwon Oh¹⁴, Nico Papinutto¹⁰, Daniel Pelletier⁷, Vesna Prchkovska⁵, Praneeta Raza², Marc Ramos⁵, Rohini D Samudralwar¹⁵, Matthew K Schindler⁸, Elias S Sotirchos¹¹, Nancy L Sicotte¹⁶, Andrew J Solomon¹⁷, Russell T Shinohara³, Daniel S Reich¹, Pascal Sati^{1

16}, Daniel Ontaneda¹⁸

Affiliations

¹ Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
² Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA.
³ Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁴ Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.
⁵ QMENTA Cloud Platform, QMENTA Inc., Boston, MA, USA.
⁶ Functional MRI Facility, NIMH, National Institutes of Health, Bethesda, MD, USA.
⁷ Department of Neurology, University of Southern California, Los Angeles, CA, USA.
⁸ Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁹ Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
¹⁰ Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
¹¹ Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
¹² Department of Neurology, Dell Medical School, The University of Texas, Austin, TX, USA.
¹³ Department of Neurology, Yale University, New Haven, CT, USA.
¹⁴ Division of Neurology, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.
¹⁵ Department of Neurology, University of Texas Health Science Center, Houston, TX, USA.
¹⁶ Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁷ Department of Neurological Sciences, Larner College of Medicine, The University of Vermont, Burlington, VT, USA.
¹⁸ Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, OH, USA.

PMID: 38088067
PMCID: PMC11037932
DOI: 10.1177/13524585231214360

Multicenter Study

A multicenter pilot study evaluating simplified central vein assessment for the diagnosis of multiple sclerosis

Lynn Daboul et al. Mult Scler. 2024 Jan.

. 2024 Jan;30(1):25-34.

doi: 10.1177/13524585231214360. Epub 2023 Dec 13.

Authors

Affiliations

¹ Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
² Cleveland Clinic Lerner College of Medicine, Cleveland, OH, USA.
³ Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁴ Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.
⁵ QMENTA Cloud Platform, QMENTA Inc., Boston, MA, USA.
⁶ Functional MRI Facility, NIMH, National Institutes of Health, Bethesda, MD, USA.
⁷ Department of Neurology, University of Southern California, Los Angeles, CA, USA.
⁸ Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁹ Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
¹⁰ Department of Neurology, University of California at San Francisco, San Francisco, CA, USA.
¹¹ Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
¹² Department of Neurology, Dell Medical School, The University of Texas, Austin, TX, USA.
¹³ Department of Neurology, Yale University, New Haven, CT, USA.
¹⁴ Division of Neurology, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada.
¹⁵ Department of Neurology, University of Texas Health Science Center, Houston, TX, USA.
¹⁶ Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹⁷ Department of Neurological Sciences, Larner College of Medicine, The University of Vermont, Burlington, VT, USA.
¹⁸ Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, OH, USA.

PMID: 38088067
PMCID: PMC11037932
DOI: 10.1177/13524585231214360

Abstract

Background: The central vein sign (CVS) is a proposed magnetic resonance imaging (MRI) biomarker for multiple sclerosis (MS); the optimal method for abbreviated CVS scoring is not yet established.

Objective: The aim of this study was to evaluate the performance of a simplified approach to CVS assessment in a multicenter study of patients being evaluated for suspected MS.

Methods: Adults referred for possible MS to 10 sites were recruited. A post-Gd 3D T2*-weighted MRI sequence (FLAIR*) was obtained in each subject. Trained raters at each site identified up to six CVS-positive lesions per FLAIR* scan. Diagnostic performance of CVS was evaluated for a diagnosis of MS which had been confirmed using the 2017 McDonald criteria at thresholds including three positive lesions (Select-3*) and six positive lesions (Select-6*). Inter-rater reliability assessments were performed.

Results: Overall, 78 participants were analyzed; 37 (47%) were diagnosed with MS, and 41 (53%) were not. The mean age of participants was 45 (range: 19-64) years, and most were female (n = 55, 71%). The area under the receiver operating characteristic curve (AUROC) for the simplified counting method was 0.83 (95% CI: 0.73-0.93). Select-3* and Select-6* had sensitivity of 81% and 65% and specificity of 68% and 98%, respectively. Inter-rater agreement was 78% for Select-3* and 83% for Select-6*.

Conclusion: A simplified method for CVS assessment in patients referred for suspected MS demonstrated good diagnostic performance and inter-rater agreement.

Keywords: Central vein sign; FLAIR*; MRI; biomarkers; multiple sclerosis.

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Conflict of interest statement

Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: L.D., C.M.O.D, M.A., J.D., E.C., P.Ra., and M.K.S. have declared no conflicts of interest. P.Ro. employed by and holds stocks in QMENTA. C.A. received consulting fees for scientific advisory boards for Genentech, EMD Serono, Alexion Pharmaceuticals, and Sanofi Genzyme. A.B.O. has received personal fees for advisory board participation and consulting from Abata, Accure, Atara Biotherapeutics, Biogen, BMS/Celgene/Receptos, GlaxoSmithKline, Gossamer, Horizon Therapeutics, Immunic, Janssen/Actelion, Medimmune, Merck/EMD Serono, Novartis, Roche/Genentech, Sangamo, Sanofi Genzyme, Viracta; and grant support to the University of Pennsylvania from Biogen Idec, Roche/Genentech, Merck/EMD Serono, and Novartis. P.A.C. is a PI on grants to JHU from Biogen and Annexon and served on scientific advisory boards for Disarm Therapeutics and Biogen. B.A.C.C. received compensation for consulting from Alexion, Atara, Biogen, EMD Serono, Novartis, Sanofi, and TG Therapeutics. L.F. received fees for consultancy and advisory board participation from Genentech, Novartis, Celgene/Bristol Myers Squibb, EMD Serono, and TG Therapeutics; received fees for educational activities from Medscape, LLC, and the MS Association of America; program sponsorship to UT from EMD Serono; and grant support to UT from NIH/NINDS, PCORI, Genentech, and EMD Serono. R.G.H. received research support from Roche, Genentech, Atara, and MedDay and consulting for Novartis, Sanofi/Genzyme, Roche/Genentech, QIA, and Neurona. E.E.L. received research support from Genentech, Biogen and consulting for Genentech, Janssen, TG Therapeutics, NGM Bio, Bristol Myers Squibb, and EMD Serono. J.O. received research support from Biogen Idec, Roche, and EMD Serono; consulting compensation from EMD Serono, Sanofi/Genzyme, Biogen Idec, Roche, Celgene, and Novartis. N.P. received research support from the Race to Erase MS Foundation. D.P. received consulting compensation from EMD Serono, Sanofi Genzyme, Roche, and Novartis. V.P. employed by and holds stocks in QMENTA. M.R. employed by and holds stock options in QMENTA. R.D.S. received fees for advisory board participation (Biogen, EMD Serono, Sanofi Genzyme) and consulting (EMD Serono, Biogen). E.S. received fees for scientific advisory boards and consulting for Alexion, Viela Bio, Horizon Therapeutics, Genentech, and Ad Scientiam; speaking honoraria from Alexion, Viela Bio, and Biogen. N.L.S. received research support from the National Institutes of Health, National Multiple Sclerosis Society, Patient-Centered Outcomes Research Institute, Race to Erase MS Foundation, and Biogen Idec. A.J.S. received fees for consulting: Greenwich Biosciences, Horizon Therapeutics, Kiniksa Pharmaceuticals, Octave Bioscience, TG Therapeutics; non-promotional speaking: EMD Serono; research funding: Bristol Myers Squibb; contracted research: Sanofi, Novartis, Actelion, Genentech/Roche. R.T.S. supported NIH R01NS112274, R01MH112847, and R01MH123550 and received consulting income from Octave Bioscience. D.S.R. supported by the Intramural Research Program of NINDS; received additional research support from Vertex Pharmaceuticals, Sanofi Genzyme, and Abata Therapeutics. P.S. received research support from the National Institutes of Health and the National Multiple Sclerosis Society. D.O. received research support from the National Institutes of Health, National Multiple Sclerosis Society, Patient-Centered Outcomes Research Institute, Race to Erase MS Foundation, Genentech, Genzyme, and Novartis; consulting fees from Biogen Idec, Genentech/Roche, Genzyme, Novartis, and Merck.

Figures

**Figure 1:**
Flow diagram for study participants

**Figure 2:. Example of central vein sign positive lesions on FLAIR* contrast obtained on different scanners.**
Examples of Central Vein Sign (CVS) Positive lesions as visualized with FLAIR* imaging. A) Axial slice demonstrating multiple CVS+ lesions in a participant with MS; magnified view of representative CVS+ lesions in different participants obtained on a: B) Siemens Prisma Fit scanner, C) Philips Ingenia scanner, and a D) Siemens Skyra scanner.

**Figure 3:. Diagnostic Performance of Select-n* Method.**
Receiver Operating Curve (ROC) for diagnosing MS using different select-n* thresholds based on the ratings of ten institutional raters (red line) and a central rater (black line) using post-Gd FLAIR* imaging of 78 scans. For the ratings of a single rater, the AUROC is 0.80 (95% CI: 0.71-0.90). For the ratings of the aggregate of ten raters, the AUROC is 0.83 (95% CI: 0.73-0.93). For both sets of ratings, Youden’s J Index was maximized with Select-6*.

**Figure 4:. Central Vein Sign Percentage by Site and Diagnosis.**
Central vein sign detection using post-Gd FLAIR* imaging of the 78 participants. Participants who met 2017 McDonald Criteria for MS had significantly higher percentage of CVS positive lesions (median [IQR] 79% [39%]) compared to non-MS participants (12% [39%]), (p<0.0001, Mann-Whitney U Test). The different sites that participants were recruited from are denoted by the color key.

**Figure 5:. Diagnostic Performance of Percentage Threshold-based Method.**
Receiver Operating Curve (ROC) for predicting MS through use of the central vein sign using the percentage-based method and post-Gd FLAIR* scans. The AUROC is 0.90 (95% CI: 0.83-0.97, p <0.0001). Using Youden’s J Index, the diagnostic performance was optimized at a threshold of 43% (highlighted in red on the graph).

See this image and copyright information in PMC

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A multicenter pilot study evaluating simplified central vein assessment for the diagnosis of multiple sclerosis

Affiliations

A multicenter pilot study evaluating simplified central vein assessment for the diagnosis of multiple sclerosis

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical