The central vein sign in MS

T
Multiple Sclerosis (From Reich et al NEJM 2018)

Last week, I blogged on smoldering lesions visualized on MRI as a marker of progressive MS. Today, I will discuss the central vein sign. This publication in JAMA by the MAGNIMS group (a group of MRI bods from the world over) is therefore, timely.

If you haven’t heard of the central vein sign, it is the presence of a vein within an MS lesion (see Figure 1 below). This is less frequently seen in other MS mimics, such as small mini strokes, neuromyelitis optica, or Susac’s syndrome.

Figure 1: veins within MS lesions (Campion et al European Radiology 2017)

The visualization of veins within white matter MS lesions implies a perivenous development of MS lesions at these sites. Pathologically, this is in fact one of the hallmarks of MS (see Figure 2 below).

Figure 2: Perivascular lymphocytes (purple blobs, the red blobs are red cells in the vessel) in an MS lesion (figure from neuropathology-web.org)

So, can the central vein sign be used to diagnose MS?

In this work, the MAGNIMS group reviewed the MRI brain scans 648 participants in this study (but, 606 were included in the study after excluding scans that were of poor quality). Of this 19.3% were CIS, 38.9% RRMS, 5% Aquaporin positive NMO, 4% SLE, 5% migraine, 1% cluster headaches, 3% diabetes, 23% small strokes.

A positive central vein sign was found in 47% of RRMS lesions and 54% of CIS lesions. By person, 91% of those analysed had at least 1 lesion with a central vein. Two or more lesions with a central vein was found in 76%.

In those without MS, a positive central vein sign was found in 148 of 942 lesions (15.7%, see Table 1 according to diagnosis). By person, 55% did not have a single lesion with the central vein sign.

Table 1: Central vein sign in MS and non-MS cases

So, I return to my original question, how good is the central vein sign in diagnosing MS? Using the 35% of lesions threshold with a positive central vein sign, the specificity (true negative rate) was 83%, whilst the sensitivity was 68% (true positive rate). Using the 3 or more positive central vein sign had a specificity of 89% and a sensitivity of 62%. Upon combining the two, specificity dropped to 68%, but the sensitivity improved to 83%.

To put this into perspective, oligoclonal bands when done by certified laboratories has a sensitivity 93% and specificity of 94%. In other published reports the specificity is reported to be more than 86%.

Abstract

JAMA Neurol. 2019 Aug 19. doi: 10.1001/jamaneurol.2019.2478. [Epub ahead of print]

Evaluation of the Central Vein Sign as a Diagnostic Imaging Biomarker in Multiple Sclerosis.

Sinnecker T, Clarke MA, Meier D, Enzinger C, Calabrese M, De Stefano N, Pitiot A, Giorgio A, Schoonheim MM, Paul F, Pawlak MA, Schmidt R, Kappos L, Montalban X, Rovira À, Evangelou N, Wuerfel J; MAGNIMS Study Group.

Importance:

The central vein sign has been proposed as a specific imaging biomarker for distinguishing between multiple sclerosis (MS) and not MS, mainly based on findings from ultrahigh-field magnetic resonance imaging (MRI) studies. The diagnostic value of the central vein sign in a multicenter setting with a variety of clinical 3 tesla (T) MRI protocols, however, remains unknown.

Objective:

To evaluate the sensitivity and specificity of various central vein sign lesion criteria for differentiating MS from non-MS conditions using 3T brain MRI with various commonly used pulse sequences.

Design, Setting, and Participants:

This large multicenter, cross-sectional study enrolled participants (n = 648) of ongoing observational studies and patients included in neuroimaging research databases of 8 neuroimaging centers in Europe. Patient enrollment and MRI data collection were performed between January 1, 2010, and November 30, 2016. Data analysis was conducted between January 1, 2016, and April 30, 2018. Investigators were blinded to participant diagnosis by a novel blinding procedure.

Main Outcomes and Measures:

Occurrence of central vein sign was detected on 3T T2*-weighted or susceptibility-weighted imaging. Sensitivity and specificity were assessed for these MRI sequences and for different central vein sign lesion criteria, which were defined by the proportion of lesions with central vein sign or by absolute numbers of lesions with central vein sign.

Results:

A total of 606 participants were included in the study after exclusion of 42 participants. Among the 606 participants, 413 (68.2%) were women. Patients with clinically isolated syndrome and relapsing-remitting MS (RRMS) included 235 women (66.6%) and had a median (range) age of 37 (14.7-61.4) years, a median (range) disease duration of 2 (0-33) years, and a median (range) Expanded Disability Status Scale score of 1.5 (0-6.5). Patients without MS included 178 women (70.4%) and had a median (range) age of 54 (18-83) years. A total of 4447 lesions were analyzed in a total of 487 patients: 690 lesions in 98 participants with clinically isolated syndrome, 2815 lesions in 225 participants with RRMS, 54 lesions in 13 participants with neuromyelitis optica spectrum disorder, 54 lesions in 14 participants with systemic lupus erythematosus, 121 lesions in 29 participants with migraine or cluster headache, 240 lesions in 20 participants with diabetes, and 473 lesions in 88 participants with other types of small-vessel disease. The sensitivity was 68.1% and specificity was 82.9% for distinguishing MS from not MS using a 35% central vein sign proportion threshold. The 3 central vein sign lesion criteria had a sensitivity of 61.9% and specificity of 89.0%. Sensitivity was higher when an optimized T2*-weighted sequence was used.

Conclusions and Relevance:

In this study, use of the central vein sign at 3T MRI yielded a high specificity and a moderate sensitivity in differentiating MS from not MS; international, multicenter studies may be needed to ascertain whether the central vein sign-based criteria can accurately detect MS.

About the author

Neuro Doc Gnanapavan

4 comments

  • How easily could this become integrated into clinical practice? Looks like the scans were done prospectively, so probably under a specialist MRI protocol…. It seems like a useful tool for the poor folk in eternal diagnostic hiatus, but this (similar to your NFL work for monitoring) sounds like something super specialist and unlikely to be available to on the shop floor anytime soon?

    • The vein scan is very simple and any scanner can do it. Already is being used in a number of centres. The question if it is better than the oligoclonal bands can only be answered in a clinical trial. Imagine if we can avoid the dreaded lumbar puncture!! This study is starting soon and Bart’s, oxford, cardiff and nottingham in the uk take part ! The only way to find out!!

        • Thanks both – for me the logistical delays of LP was worse than the procedure itself. I suppose that’s the point though. One of those centres is close to home, so I’ll try to remember it down the line!

          BW

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