Effect of GBCA Use on Detection and Diagnostic Performance of the Central Vein Sign: Evaluation Using a 3-T FLAIR* Sequence in Patients With Suspected Multiple Sclerosis

Lynn Daboul^{1

2

3}, Carly M O'Donnell⁴, Quy Cao⁴, Moein Amin⁵, Paulo Rodrigues⁶, John Derbyshire⁷, Christina Azevedo⁸, Amit Bar-Or⁹, Eduardo Caverzasi¹⁰, Peter Calabresi¹¹, Bruce A C Cree¹⁰, Leorah Freeman¹², Roland G Henry¹⁰, Erin E Longbrake¹³, Kunio Nakamura¹⁴, Jiwon Oh¹⁵, Nico Papinutto¹⁰, Daniel Pelletier⁸, Rohini D Samudralwar¹⁶, Suradech Suthiphosuwan¹⁷, Matthew K Schindler⁹, Elias S Sotirchos¹¹, Nancy L Sicotte¹⁸, Andrew J Solomon¹⁹, Russell T Shinohara⁴, Daniel S Reich², Daniel Ontaneda²⁰, Pascal Sati^{2

18}

Affiliations

¹ Department of Neurology, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.
² Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD.
³ Cleveland Clinic Lerner College of Medicine, Cleveland, OH.
⁴ Department of Biostatistics, Epidemiology, and Informatics, Penn Statistics in Imaging and Visualization Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
⁵ Neurological Institute, Cleveland Clinic, Cleveland, OH.
⁶ QMENTA, Inc., Boston, MA.
⁷ Functional MRI Facility, NIMH, NIH, Bethesda, MD.
⁸ Department of Neurology, University of Southern California, Los Angeles, CA.
⁹ Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
¹⁰ Department of Neurology, University of California at San Francisco, San Francisco, CA.
¹¹ Department of Neurology, Johns Hopkins University, Baltimore, MD.
¹² Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, TX.
¹³ Department of Neurology, Yale University, New Haven, CT.
¹⁴ Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
¹⁵ Division of Neurology, St. Michael's Hospital, University of Toronto, ON, Canada.
¹⁶ Department of Neurology, The University of Texas Health Science Center at Houston, Houston, TX.
¹⁷ Department of Medical Imaging, St. Michael's Hospital, University of Toronto, ON, Canada.
¹⁸ Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA.
¹⁹ Department of Neurological Sciences, Larner College of Medicine, The University of Vermont, Burlington, VT.
²⁰ Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, OH.

PMID: 35975888
PMCID: PMC10016223
DOI: 10.2214/AJR.22.27731

Multicenter Study

Effect of GBCA Use on Detection and Diagnostic Performance of the Central Vein Sign: Evaluation Using a 3-T FLAIR* Sequence in Patients With Suspected Multiple Sclerosis

Lynn Daboul et al. AJR Am J Roentgenol. 2023 Jan.

. 2023 Jan;220(1):115-125.

doi: 10.2214/AJR.22.27731. Epub 2022 Aug 17.

Authors

Affiliations

¹ Department of Neurology, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.
² Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD.
³ Cleveland Clinic Lerner College of Medicine, Cleveland, OH.
⁴ Department of Biostatistics, Epidemiology, and Informatics, Penn Statistics in Imaging and Visualization Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
⁵ Neurological Institute, Cleveland Clinic, Cleveland, OH.
⁶ QMENTA, Inc., Boston, MA.
⁷ Functional MRI Facility, NIMH, NIH, Bethesda, MD.
⁸ Department of Neurology, University of Southern California, Los Angeles, CA.
⁹ Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.
¹⁰ Department of Neurology, University of California at San Francisco, San Francisco, CA.
¹¹ Department of Neurology, Johns Hopkins University, Baltimore, MD.
¹² Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, TX.
¹³ Department of Neurology, Yale University, New Haven, CT.
¹⁴ Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
¹⁵ Division of Neurology, St. Michael's Hospital, University of Toronto, ON, Canada.
¹⁶ Department of Neurology, The University of Texas Health Science Center at Houston, Houston, TX.
¹⁷ Department of Medical Imaging, St. Michael's Hospital, University of Toronto, ON, Canada.
¹⁸ Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA.
¹⁹ Department of Neurological Sciences, Larner College of Medicine, The University of Vermont, Burlington, VT.
²⁰ Mellen Center for Multiple Sclerosis, Cleveland Clinic, Cleveland, OH.

PMID: 35975888
PMCID: PMC10016223
DOI: 10.2214/AJR.22.27731

Abstract

BACKGROUND. The central vein sign (CVS) is a proposed MRI biomarker of multiple sclerosis (MS). The impact of gadolinium-based contrast agent (GBCA) administration on CVS evaluation remains poorly investigated. OBJECTIVE. The purpose of this study was to assess the effect of GBCA use on CVS detection and on the diagnostic performance of the CVS for MS using a 3-T FLAIR* sequence. METHODS. This study was a secondary analysis of data from the pilot study for the prospective multicenter Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS), which recruited adults with suspected MS from April 2018 to February 2020. Participants underwent 3-T brain MRI including FLAIR and precontrast and post-contrast echo-planar imaging T2*-weighted acquisitions. Postprocessing was used to generate combined FLAIR and T2*-weighted images (hereafter, FLAIR*). MS diagnoses were established using the 2017 McDonald criteria. Thirty participants (23 women, seven men; mean age, 45 years) were randomly selected from the CAVS-MS pilot study cohort. White matter lesions (WMLs) were marked using FLAIR* images. A single observer, blinded to clinical data and GBCA use, reviewed marked WMLs on FLAIR* images for the presence of the CVS. RESULTS. Thirteen of 30 participants had MS. Across participants, on precontrast FLAIR* imaging, 218 CVS-positive and 517 CVS-negative WMLs were identified; on post-contrast FLAIR* imaging, 269 CVS-positive and 459 CVS-negative WMLs were identified. The fraction of WMLs that were CVS-positive on precontrast and postcontrast images was 48% and 58% in participants with MS and 7% and 10% in participants without MS, respectively. The median patient-level CVS-positivity rate on precontrast and postcontrast images was 43% and 67% for participants with MS and 4% and 8% for participants without MS, respectively. In a binomial model adjusting for MS diagnoses, GBCA use was associated with an increased likelihood of at least one CVS-positive WML (odds ratio, 1.6; p < .001). At a 40% CVS-positivity threshold, the sensitivity of the CVS for MS increased from 62% on precontrast images to 92% on postcontrast images (p = .046). Specificity was not significantly different between precontrast (88%) and postcontrast (82%) images (p = .32). CONCLUSION. GBCA use increased CVS detection on FLAIR* images, thereby increasing the sensitivity of the CVS for MS diagnoses. CLINICAL IMPACT. The postcontrast FLAIR* sequence should be considered for CVS evaluation in future investigational trials and clinical practice.

Keywords: FLAIR*; central vein sign; gadolinium; multiple sclerosis.

PubMed Disclaimer

Figures

**Fig. 1—**
Flowchart shows patient selection. CAVS-MS = Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis, CVS = central vein sign, WML = white matter lesion.

**Fig. 2—**
Representative FLAIR* MR images of study participants. MS = multiple sclerosis, CVS = central vein sign, WML = white matter lesion. A, Sagittal image in 32-year-old participant with MS shows periventricular CVS-positive WML (*arrows*). B, Axial image in 41-year-old participant without MS shows subcortical and deep white matter CVS-negative WMLs (*arrows*). Representative FLAIR* MR images of study participants. MS = multiple sclerosis, CVS = central vein sign, WML = white matter lesion. C, Coronal image in 38-year-old participant with MS shows juxtacortical CVS-positive WML (*arrow*). D, Axial image in 36-year-old participant with MS shows subcortical CVS-positive WML (*arrow*). E, Sagittal image in 38-year-old participant with MS shows infratentorial CVS-positive WML (*arrow*). F, Axial image in 42-year-old participant without MS shows subcortical CVS-negative WML (*arrow*). G, Axial image in 37-year-old participant with MS shows subcortical CVS-indeterminate WML (*arrow*). H, Coronal image in 57-year-old participant without MS shows subcortical WML (*arrow*) that was excluded owing to size of 2.2 mm.

**Fig. 3—**
Graph shows patient-by-patient comparison of central vein sign (CVS)-positivity rate between precontrast (*black boxes*) and postcontrast (*gray circles*) FLAIR* images. Participants with multiple sclerosis (MS) diagnosis and participants with no MS diagnosis based on 2017 McDonald criteria during study are shown. Thin diagonal lines connect precontrast and postcontrast values for individual participants, and thick horizontal lines denote median percentage across participants for precontrast and postcontrast images. Asterisk indicates statistically significant difference (p < .001).

**Fig. 4—**
Comparison of precontrast and postcontrast FLAIR* images in terms of central vein sign (CVS) visualization in white matter lesions (WMLs). In this example, patient is 43-year-old participant with multiple sclerosis. A and B, WML (*arrow*) was classified as CVS-negative on precontrast image (A) but as CVS-positive on postcontrast image (B). C and D, WML (*arrow*) was classified as CVS-negative on precontrast image (C) but as CVS-positive on postcontrast image (D).

See this image and copyright information in PMC

Comment in

Editorial Comment: Gadolinium-Based Contrast Agent and the Central Vein Sign.
Rubinstein D. Rubinstein D. AJR Am J Roentgenol. 2023 Jan;220(1):125. doi: 10.2214/AJR.22.28454. Epub 2022 Sep 7. AJR Am J Roentgenol. 2023. PMID: 36069490 No abstract available.

References

1. Kavaliunas A, Manouchehrinia A, Stawiarz L, et al. Importance of early treatment initiation in the clinical course of multiple sclerosis. Mult Scler 2017; 23:1233–1240 - PubMed
1. Schwenkenbecher P, Wurster U, Konen FF, et al. Impact of the McDonald criteria 2017 on early diagnosis of relapsing-remitting multiple sclerosis. Front Neurol 2019; 10:188. - PMC - PubMed
1. Kaisey M, Solomon AJ, Luu M, Giesser BS, Sicotte NL. Incidence of multiple sclerosis misdiagnosis in referrals to two academic centers. Mult Scler Relat Disord 2019; 30:51–56 - PubMed
1. Solomon AJ, Bourdette DN, Cross AH, et al. The contemporary spectrum of multiple sclerosis misdiagnosis: a multicenter study. Neurology 2016; 87:1393–1399 - PMC - PubMed
1. Sati P, Oh J, Constable RT, et al.; NAIMS Cooperative. 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; 12:714–722 - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Effect of GBCA Use on Detection and Diagnostic Performance of the Central Vein Sign: Evaluation Using a 3-T FLAIR* Sequence in Patients With Suspected Multiple Sclerosis

Affiliations

Effect of GBCA Use on Detection and Diagnostic Performance of the Central Vein Sign: Evaluation Using a 3-T FLAIR* Sequence in Patients With Suspected Multiple Sclerosis

Authors

Affiliations

Abstract

Figures

Comment in

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous