The “Central Vein Sign” on T2*-weighted Images as a Diagnostic Tool in Multiple Sclerosis: A Systematic Review and Meta-analysis using Individual Patient Data

AbstractWe aimed to evaluate the pooled incidence of central vein sign on T2*-weighted images from patients with multiple sclerosis (MS), and to determine the diagnostic performance of this central vein sign for differentiating MS from other white matter lesions and provide an optimal cut-off value. A computerized systematic search of the literature in PUBMED and EMBASE was conducted up to December 14, 2018. Original articles investigating central vein sign on T2*-weighted images of patients with MS were selected. The pooled incidence was obtained using random-effects model. The pooled sensitivity and specificity were obtained using a bivariate random-effects model. An optimal cut-off value for the proportion of lesions with a central vein sign was calculated from those studies providing individual patient data. Twenty-one eligible articles covering 501 patients with MS were included. The pooled incidence of central vein sign at the level of individual lesion in patients with MS was 74% (95% CI, 65–82%). The pooled sensitivity and pooled specificity for the diagnostic performance of the central vein sign were 98% (95% CI, 92–100%) and 97% (95% CI, 91–99%), respectively. The area under the HSROC curve was 1.00 (95% CI, 0.99–1.00). The optimal cut-off value for the proportion of lesions with a central vein sign was found to be 45%. Although various T2*-weighted images have been used across studies, the current evidence supports the use of the central vein sign on T2*-weighted images to differentiate MS from other white matter lesions.

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The Use of the Central Vein Sign in the Diagnosis of Multiple Sclerosis: A Systematic Review and Meta-analysis

Diagnostics ◽

10.3390/diagnostics10121025 ◽

2020 ◽

Vol 10 (12) ◽

pp. 1025

Author(s):

Marco Castellaro ◽

Agnese Tamanti ◽

Anna Isabella Pisani ◽

Francesca Benedetta Pizzini ◽

Francesco Crescenzo ◽

...

Keyword(s):

Multiple Sclerosis ◽

Regression Analysis ◽

White Matter ◽

Diagnostic Performance ◽

Individual Patient Data ◽

Meta Analysis ◽

Patient Data ◽

Central Vein ◽

Meta Regression ◽

Meta Regression Analysis

Background: The central vein sign (CVS) is a radiological feature proposed as a multiple sclerosis (MS) imaging biomarker able to accurately differentiate MS from other white matter diseases of the central nervous system. In this work, we evaluated the pooled proportion of the CVS in brain MS lesions and to estimate the diagnostic performance of CVS to perform a diagnosis of MS and propose an optimal cut-off value. Methods: A systematic search was performed on publicly available databases (PUBMED/MEDLINE and Web of Science) up to 24 August 2020. Analysis of the proportion of white matter MS lesions with a central vein was performed using bivariate random-effect models. A meta-regression analysis was performed and the impact of using particular sequences (such as 3D echo-planar imaging) and post-processing techniques (such as FLAIR*) was investigated. Pooled sensibility and specificity were estimated using bivariate models and meta-regression was performed to address heterogeneity. Inclusion and publication bias were assessed using asymmetry tests and a funnel plot. A hierarchical summary receiver operating curve (HSROC) was used to estimate the summary accuracy in diagnostic performance. The Youden index was employed to estimate the optimal cut-off value using individual patient data. Results: The pooled proportion of lesions showing a CVS in the MS population was 73%. The use of the CVS showed a remarkable diagnostic performance in MS cases, providing a pooled specificity of 92% and a sensitivity of 95%. The optimal cut-off value obtained from the individual patient data pooled together was 40% with excellent accuracy calculated by the area under the ROC (0.946). The 3D-EPI sequences showed both a higher pooled proportion compared to other sequences and explained heterogeneity in the meta-regression analysis of diagnostic performances. The 1.5 Tesla (T) scanners showed a lower (58%) proportion of MS lesions with a CVS compared to both 3T (74%) and 7T (82%). Conclusions: The meta-analysis we have performed shows that the use of the CVS in differentiating MS from other mimicking diseases is encouraged; moreover, the use of dedicated sequences such as 3D-EPI and the high MRI field is beneficial.

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Individual patient data meta-analysis of time-to-event outcomes: one-stage versus two-stage approaches for estimating the hazard ratio under a random effects model

Research Synthesis Methods ◽

10.1002/jrsm.45 ◽

2011 ◽

Vol 2 (3) ◽

pp. 150-162 ◽

Cited By ~ 25

Author(s):

Jack Bowden ◽

Jayne F Tierney ◽

Mark Simmonds ◽

Andrew J Copas ◽

Julian PT Higgins

Keyword(s):

Random Effects ◽

Individual Patient Data ◽

Meta Analysis ◽

Patient Data ◽

Hazard Ratio ◽

Random Effects Model ◽

Stage Versus ◽

Time To Event ◽

Two Stage ◽

One Stage

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Value of central vein sign in discriminating multiple sclerosis plaques from other white matter lesions

The Egyptian Journal of Radiology and Nuclear Medicine ◽

10.1016/j.ejrnm.2017.12.008 ◽

2018 ◽

Vol 49 (1) ◽

pp. 165-171 ◽

Cited By ~ 4

Author(s):

Eman A.F. Darwish ◽

Yosra Abdelzaher Ibrahim ◽

Dina A. Zamzam

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

White Matter Lesions ◽

Central Vein

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Imaging central veins in brain lesions with 3-T T2*-weighted magnetic resonance imaging differentiates multiple sclerosis from microangiopathic brain lesions

Multiple Sclerosis Journal ◽

10.1177/1352458515616700 ◽

2016 ◽

Vol 22 (10) ◽

pp. 1289-1296 ◽

Cited By ~ 55

Author(s):

Niraj Mistry ◽

Rasha Abdel-Fahim ◽

Amal Samaraweera ◽

Olivier Mougin ◽

Emma Tallantyre ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Multiple Sclerosis ◽

White Matter ◽

Magnetic Resonance ◽

Validation Cohort ◽

Brain Mri ◽

White Matter Lesions ◽

Brain Lesions ◽

Central Vein ◽

Resonance Imaging

Background: White matter lesions are frequently detected using brain magnetic resonance imaging (MRI) performed for various indications. Most are microangiopathic, but demyelination, including multiple sclerosis (MS), is an important cause; conventional MRI cannot always distinguish between these pathologies. The proportion of lesions with a central vein on 7-T T2*-weighted MRI prospectively distinguishes demyelination from microangiopathic lesions. Objective: To test whether 3-T T2*-weighted MRI can differentiate MS from microangiopathic brain lesions. Methods: A total of 40 patients were studied. Initially, a test cohort of 10 patients with MS and 10 patients with microangiopathic white matter lesions underwent 3-T T2*-weighted brain MRI. Anonymised scans were analysed blind to clinical data, and simple diagnostic rules were devised. These rules were applied to a validation cohort of 20 patients (13 with MS and 7 with microangiopathic lesions) by a blinded observer. Results: Within the test cohort, all patients with MS had central veins visible in >45% of brain lesions, while the rest had central veins visible in <45% of lesions. By applying diagnostic rules to the validation cohort, all remaining patients were correctly categorised. Conclusion: 3-T T2*-weighted brain MRI distinguishes perivenous MS lesions from microangiopathic lesions. Clinical application of this technique could supplement existing diagnostic algorithms.

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Multiple sclerosis: High prevalence of the ‘central vein’ sign in white matter lesions on susceptibility-weighted images

The Neuroradiology Journal ◽

10.1177/1971400918763577 ◽

2018 ◽

Vol 31 (4) ◽

pp. 356-361 ◽

Cited By ~ 13

Author(s):

Gianvincenzo Sparacia ◽

Francesco Agnello ◽

Angelo Gambino ◽

Martina Sciortino ◽

Massimo Midiri

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Magnetic Resonance ◽

Small Vessel Disease ◽

White Matter Lesions ◽

Magnetic Resonance Images ◽

Inversion Recovery ◽

Central Vein ◽

Fluid Attenuated Inversion Recovery ◽

The Difference

Purpose The aim of this study was to determine the occurrence and distribution of the ‘central vein’ sign in white matter lesions on susceptibility-weighted magnetic resonance images in patients with multiple sclerosis (MS) and cerebral small vessel disease (CSVD). Materials and methods T2-weighted and fluid-attenuated inversion recovery magnetic resonance images of 19 MS patients and 19 patients affected by CSVD were analysed for the presence and localisation of focal hyperintense white matter lesions. Lesions were subdivided into periventricular or non-periventricular (juxtacortical, subcortical, deep white matter and cerebellar) distributed. The number and localisation of lesions presenting with the central vein sign were recorded and compared between MS and CSVD lesions. Results A total of 313 MS patients and 75 CSVD lesions were identified on T2-weighted and fluid-attenuated inversion recovery magnetic resonance images. The central vein sign was found in 128 MS lesions (40.9%), and the majority of them (71/128, 55.5%) had a periventricular distribution. The central vein sign was found in 22 out of 75 (29.3%) CSVD lesions, and periventricular distribution was seen in six out of 22 (27.2%) CSVD lesions. The difference in the proportion of white matter hyperintense lesions that presented with the central vein sign on susceptibility-weighted images in patients with MS and CSVD was statistically different, and a significantly higher number of MS patients presented with lesions with the central vein sign compared to CSVD patients. Conclusion The presence of the central vein sign on susceptibility-weighted images for MS lesions improves the understanding of the periventricular distribution of MS lesions and could contribute as adjunctive diagnostic criteria for MS disease.

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Diagnostic performance of central vein sign for multiple sclerosis with a simplified three-lesion algorithm

Multiple Sclerosis Journal ◽

10.1177/1352458517726383 ◽

2017 ◽

Vol 24 (6) ◽

pp. 750-757 ◽

Cited By ~ 24

Author(s):

Andrew J Solomon ◽

Richard Watts ◽

Daniel Ontaneda ◽

Martina Absinta ◽

Pascal Sati ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

White Matter Lesions ◽

Correct Prediction ◽

Central Vein ◽

White Matter Abnormalities ◽

Specificity And Sensitivity ◽

Magnetic Resonance Imaging Mri ◽

Weighted Sequences

Background: Detection of a “central vein sign” (CVS) on FLAIR* magnetic resonance imaging (MRI) is highly specific and sensitive for multiple sclerosis (MS). We evaluated the specificity and sensitivity of simplified CVS algorithms for MS diagnosis. Methods: MRIs from 10 participants with MS without additional comorbidities for MRI white matter abnormalities; 10 with MS and additional comorbidities for white matter abnormalities; 10 with migraine, white matter abnormalities, and no additional comorbidities; and 10 who had previously been erroneously diagnosed with MS were evaluated. 3T MRI T2-FLAIR and T2*-weighted sequences were acquired to create FLAIR* images. Three MS physician reviewers, blinded to diagnosis, evaluated two different algorithms: (1) three lesions pre-selected on FLAIR were subsequently evaluated for CVS on FLAIR*( select3). (2) FLAIR* was evaluated for up to three lesions with CVS ( select3*). Results: For select3, average specificity across reviewers for MS was 0.98 and sensitivity 0.52 and a correct prediction of diagnosis demonstrated kappa = 0.29. For select3*, specificity was 0.81, sensitivity was 0.83, and kappa was 0.31. Conclusion: A simplified determination of CVS in three white matter lesions on 3T FLAIR* MRI demonstrated good specificity and sensitivity and fair inter-rater reliability for a diagnosis of MS and with further study, may be a candidate for clinical application.

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Multiple sclerosis: prevalence of the ‘central vein’ sign in white matter lesions on gadolinium-enhanced susceptibility-weighted images

The Neuroradiology Journal ◽

10.1177/19714009211008750 ◽

2021 ◽

pp. 197140092110087

Author(s):

Gianvincenzo Sparacia ◽

Francesco Agnello ◽

Alberto Iaia ◽

Aurelia Banco ◽

Massimo Galia ◽

...

Keyword(s):

Multiple Sclerosis ◽

White Matter ◽

Magnetic Resonance ◽

Detection Rate ◽

White Matter Lesions ◽

Clinical Information ◽

Susceptibility Weighted Imaging ◽

Central Vein ◽

Magnetic Resonance Scanner ◽

Clinical Subtype

Aims To evaluate prospectively whether an intravenous gadolinium injection could improve the detection of the central vein sign on susceptibility-weighted imaging sequences obtained with a 1.5 T magnetic resonance scanner in patients with multiple sclerosis compared to unenhanced susceptibility-weighted images. Materials and methods This prospective, institution review board-approved study included 19 patients affected by multiple sclerosis (six men; 13 women; mean age 40.8 years, range 20–74 years). Patients had the relapsing–remitting clinical subtype in 95% of cases, and only one (5%) patient had the primary progressive clinical subtype of multiple sclerosis. T2-weighted images, fluid-attenuated inversion recovery images, unenhanced and contrast-enhanced susceptibility-weighted images were evaluated in consensus by two neuroradiologists for the presence of the central vein sign. The readers were blinded to magnetic resonance imaging reports, clinical information, the presence and the localisation of focal hyperintense white matter lesions. Any discordance between readers was resolved through a joint review of the recorded images with an additional neuroradiologist. Results A total of 317 multiple sclerosis lesions were analysed. The central vein sign had a higher prevalence detection rate on gadolinium-enhanced susceptibility-weighted images (272 of 317 lesions, 86%) compared to unenhanced susceptibility-weighted images (172 of 317 lesions, 54%). Conclusion Gadolinium-enhanced susceptibility-weighted imaging improves the detection rate of the central vein sign in multiple sclerosis lesions.

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Are exercise referral schemes associated with an increase in physical activity? Observational findings using individual patient data meta-analysis from The National Referral database

10.31236/osf.io/ckdwn ◽

2019 ◽

Author(s):

Nikita Rowley ◽

James Steele ◽

Matthew Wade ◽

Robert J. Copeland ◽

Steven Mann ◽

...

Keyword(s):

Physical Activity ◽

Random Effects ◽

Individual Patient Data ◽

Meta Analysis ◽

Patient Data ◽

Activity Levels ◽

Random Effects Model ◽

Physical Activity Levels ◽

The Impact ◽

Exercise Referral

Background: Exercise referral schemes (ERSs) within clinical populations offer inactive individuals the opportunity to increase physical activity levels over the length of scheme. Schemes are also intended to support the treatment of specific health conditions of medically referred individuals through increased physical activity behaviours. The extant literature concerning the impact of exercise referral on physical activity levels is inconsistent. It is of interest researchers, policy makers, commissioners and practitioners to to consider broadly whether meaningful change in physical activity levels are observed in people who undergo exercise referral, to identify potential effective policy actions in supporting active living. Purpose: To examine if ERSs increase physical activity levels in a large cohort of individuals throughout England, Scotland and Wales from The National Referral Database. Method: Data were obtained from 5246 participants from 12 different referral schemes. Average age was 53±15 years and, 68% of participants were female. Participants self-reported International Physical Activity Questionnaire (IPAQ) scores pre- and post- scheme, to determine if exercise referral had any impact on change in physical activity levels. Two stage individual patient data meta-analysis was performed on the both pre-ERS, and change scores, (i.e. post- minus pre-ERS scores) for MET-minutes/week calculated from IPAQ. Analyses were conducted on the continuous data collected using the IPAQ. Results: For pre-ERS MET-minutes/week the estimate and 95%CI from random effects model was 676 MET-minutes/week [539 to 812 minutes]. For change in MET-minutes/week the estimate and 95%CI from random effects model for was an increase of 540 MET-minutes/week [396 to 684 minutes]. Significant heterogeneity was evident among the schemes (I2 > 80%). Changes in total PA levels occurred as a result of increases in vigorous activity of 17 minutes [95%CI 9 to 24 minutes], increases in moderate activity of 29 minutes [95%CI 22 to 36 minutes], and reductions in sitting of -61 minutes [95%CI -78 to -43 minutes], though little change in walking (-5 minutes [95%CI -14 to 5 minutes]). Conclusion: Observation of participants undergoing ERSs suggests that most are already ‘moderately active’ upon entering an ERS. Changes in physical activity behaviour associated with ERS participation were varied and primarily facilitated by increased moderate-to-vigorous physical activity and reduced sitting. However, this was not sufficient to result in IPAQ categorical change and participants where thus on average still classed as ‘moderately active’. Further work is required to ensure ERSs are implemented to targeting the appropriate populations where they may result in the greatest benefit.

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