The central vein sign

A forum to discuss Chronic Cerebrospinal Venous Insufficiency and its relationship to Multiple Sclerosis.

The central vein sign

Postby 1eye » Tue Sep 12, 2017 6:50 am

The CVS (Central Vein Sign) is an unmistakeable indication of MS. I expect it is an unmistakeable sign of CCSVI as well. Prevalence studies in future, as well as particular studies of MS treatments, should all use this sign as a definite verification of the presence of MS. There may be ways to measure changes to this sign to indicate efficacy of MS treatments.



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

Pascal Sati,
Jiwon Oh,
R. Todd Constable,
Nikos Evangelou,
Charles R. G. Guttmann,
Roland G. Henry,
Eric C. Klawiter,
Caterina Mainero,
Luca Massacesi,
Henry McFarland,
Flavia Nelson,
Daniel Ontaneda,
Alexander Rauscher,
William D. Rooney,
Amal P. R. Samaraweera,
Russell T. Shinohara,
Raymond A. Sobel,
Andrew J. Solomon,
Constantina A. Treaba,
Jens Wuerfel,
Robert Zivadinov,
Nancy L. Sicotte,
Daniel Pelletier,
Daniel S. Reich
& on behalf of the NAIMS Cooperative

Affiliations
Contributions
Corresponding author

Nature Reviews Neurology
12,
714–722
(2016)
doi:10.1038/nrneurol.2016.166


Abstract

Abstract•
Introduction•
Methods•
The central vein in MS•
The central vein in other diseases•
Radiological definitions•
Imaging central veins with MRI•
Evaluating the CVS for MS diagnosis•
Conclusions•
References•
Acknowledgements•
Author information

Over the past few years, MRI has become an indispensable tool for diagnosing multiple sclerosis (MS). However, the current MRI criteria for MS diagnosis have imperfect sensitivity and specificity. The central vein sign (CVS) has recently been proposed as a novel MRI biomarker to improve the accuracy and speed of MS diagnosis. Evidence indicates that the presence of the CVS in individual lesions can accurately differentiate MS from other diseases that mimic this condition. However, the predictive value of the CVS for the development of clinical MS in patients with suspected demyelinating disease is still unknown. Moreover, the lack of standardization for the definition and imaging of the CVS currently limits its clinical implementation and validation. On the basis of a thorough review of the existing literature on the CVS and the consensus opinion of the members of the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative, this article provides statements and recommendations aimed at helping radiologists and neurologists to better understand, refine, standardize and evaluate the CVS in the diagnosis of MS.
Subject terms:

Brain imaging
Multiple sclerosis

At a glance
Figures
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left

Perivenous distribution of multiple sclerosis lesions.
Figure 1
Examples of lesions with and without central veins.
Figure 2

right
Introduction

Abstract•
Introduction•
Methods•
The central vein in MS•
The central vein in other diseases•
Radiological definitions•
Imaging central veins with MRI•
Evaluating the CVS for MS diagnosis•
Conclusions•
References•
Acknowledgements•
Author information

At present, the diagnosis of multiple sclerosis (MS) relies heavily on the use of MRI, which can demonstrate disease dissemination in space and time1, 2, 3, 4. The current 2010 McDonald criteria have enabled earlier diagnosis5, 6 and initiation of disease-modifying treatment, with substantial benefits for disease outcome7, 8, but they still have imperfect sensitivity and specificity9, 10. The limited accuracy of the criteria results in challenging cases and misdiagnosis, which are prevalent problems in MS11, 12. Therefore, more-accurate and pathologically specific MRI criteria are still needed to exclude other disorders that can mimic MS13, 14.

The MRI-detectable central vein inside white matter lesions has recently been proposed as a biomarker of inflammatory demyelination and, thus, may aid the diagnosis of MS15. The 'central vein sign' (CVS) has been investigated in various neurological conditions by several groups, and evidence has accumulated that the CVS may have the ability to accurately differentiate MS from its mimics15, 16, 17, 18, 19, 20, 21. As a consequence, recent guidelines from the Magnetic Resonance Imaging in MS (MAGNIMS) group1, 4 and the Consortium of MS Centers (CMSC) task force22 have acknowledged the potential of the CVS and its dedicated MRI acquisitions for the differential diagnosis of MS, while calling for further research before considering a possible modification of the diagnostic criteria. However, the lack of standardization for the definition and imaging of the CVS, as well as a dearth of large-scale prospective studies evaluating the CVS for MS diagnosis, are currently preventing the clinical validation of this potential biomarker1, 23.

This Consensus Statement aims to provide recommendations for the definition, standardization and clinical evaluation of the CVS in the diagnosis of MS. These statements are based on a thorough review of the existing literature on the CVS and the consensus opinion of the members of the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative (Box 1).
Box 1: The NAIMS Cooperative

• Most of the authors of this Consensus Statement are members of the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative, an organization that brings together major North American laboratories working on MRI in multiple sclerosis. The cooperative is run by a steering committee whose members are as follows:

• Rohit Bakshi, Brigham and Women's Hospital, Boston, Massachusetts, USA

• Peter Calabresi, Johns Hopkins University, Baltimore, Maryland, USA

• Ciprian Crainiceanu, Johns Hopkins University, Baltimore, Maryland, USA

• R. Todd Constable, Yale University, New Haven, Connecticut, USA

• Roland Henry, University of California, San Francisco, California, USA

• Jiwon Oh (Co-Chair), University of Toronto, Ontario, Canada and Johns Hopkins University, Baltimore, Maryland, USA

• Daniel Ontaneda, Cleveland Clinic Foundation, Cleveland, Ohio, USA

• Daniel Pelletier, University of Southern California, Los Angeles, California, USA

• William D. Rooney (Co-Chair), Oregon Health and Science University, Portland, Oregon, USA

• Daniel S. Reich (Co-Chair), National Institute of Neurological Disorders and Stroke, Bethesda, USA

• Russell T. Shinohara, University of Pennsylvania, Philadelphia, Pennsylvania, USA

• Nancy Sicotte (Co-Chair), Cedars-Sinai Medical Center, Los Angeles, California, USA

• Jack Simon, Oregon Health and Science University, Portland, Oregon, USA
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Methods

Abstract•
Introduction•
Methods•
The central vein in MS•
The central vein in other diseases•
Radiological definitions•
Imaging central veins with MRI•
Evaluating the CVS for MS diagnosis•
Conclusions•
References•
Acknowledgements•
Author information

In November 2015, a panel of experts on the use of MRI in the management of MS convened at the University of Southern California, Los Angeles, USA. This meeting was organized by the NAIMS Cooperative — an independent network of clinical research groups that utilize MRI to better understand, diagnose and treat MS (Box 1). The panel was composed of neurologists, neuroradiologists, MRI scientists, and statisticians from different NAIMS-affiliated institutions in North America, as well as international experts on the topic of CVS.

During the meeting, recently published literature on the CVS in neurological diseases, and associated MRI techniques, was discussed. The following five topics were addressed in detail: the central vein in MS; the central vein in other neurological diseases; radiological definition of the central vein and the CVS; imaging of central veins with MRI; and clinical evaluation of the CVS for MS diagnosis. After open discussion and debate, the group reached a consensus on statements and recommendations on each of these five topics. After the meeting, a draft of the Consensus Statement was written by the first author on the basis of contributions from the panellists. This draft was then circulated to all NAIMS members, who modified the document until a final consensus agreement was reached.
The central vein in MS

Abstract•
Introduction•
Methods•
The central vein in MS•
The central vein in other diseases•
Radiological definitions•
Imaging central veins with MRI•
Evaluating the CVS for MS diagnosis•
Conclusions•
References•
Acknowledgements•
Author information

Discussion

Central vessels (predominantly veins and venules) in MS plaques were reported by pathological studies as early as the 1820s24. The perivascular space surrounding these veins is thought to be a privileged site for immune cells to interact with antigen-presenting cells, which can then trigger an inflammatory cascade leading to the formation of lesions around the veins25, 26. With the development of susceptibility-based magnetic resonance venography in the late 1990s27, it became possible to observe these central veins in MS plaques in vivo, as reported by Tan et al.28. This first in vivo demonstration of the perivenous distribution of MS plaques was further confirmed in 2008 using ultra-high-field MRI29, 30. Follow-up imaging studies confirmed this finding in relapsing–remitting MS (RRMS), secondary progressive MS (SPMS) and primary progressive MS (PPMS)31, 32. This perivenous distribution in different MS subtypes is illustrated in Fig. 1.
Figure 1: Perivenous distribution of multiple sclerosis lesions.
Perivenous distribution of multiple sclerosis lesions.

3 T FLAIR* (combined T2*-weighted MRI and fluid-attenuated inversion recovery) images from four individuals with a variety of neurological conditions, who were scanned at different sites. In the patients with relapsing–remitting or primary progressive multiple sclerosis (MS), a central vessel is visible in most hyperintense lesions (data from the NIH cohort). The dark veins are located centrally in the lesion and can be visualized in at least two perpendicular planes (arrows in magnified boxes). On the other hand, a central vein is absent from most of the lesions (arrowheads in magnified boxes) in the patient with migraine (University of Vermont cohort) and the patient with ischaemic small vessel disease (University of Nottingham cohort).

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In an imaging study, Kilsdonk et al. examined 1,004 brain lesions in 33 patients with MS (19 with RRMS, nine with PPMS and five with SPMS), and found that 78% of the lesions were located around a central vessel31. The proportion of total lesions with a central vein was not related to the clinical phenotype — a finding that was also supported by another study32. However, when lesions were classified according to their location, the authors reported that central veins were most prevalent in periventricular lesions (94%). This finding was consistent across studies28, 30, and might be explained by a higher density of parenchymal veins in periventricular regions. The proportion of CVS-positive lesions decreased with proximity to the neocortex (deep white matter lesions: 84%; juxtacortical lesions: 66%; mixed grey and white matter lesions: 52%; and intracortical lesions: 25%). However, a postmortem study has shown that the sites and characteristics of cortical lesions are strongly influenced by venous topography33 and, therefore, the association between cortical lesions and central veins should be further investigated with dedicated imaging techniques.

Although most studies imaged the supratentorial brain only, central veins have also been demonstrated in lesions located in the thalamus, cerebellum and pons of patients with MS31, 34. To our knowledge, no in vivo reports are available on central veins in MS lesions located in the spinal cord, although pathological evidence of this phenomenon exists35. Another finding from the Kilsdonk et al. study was a significantly lower percentage of perivascular deep white matter lesions (73%) in MS patients aged ≥40 years compared with younger patients (92%). One possible explanation for this discrepancy is the presence of age-related vascular lesions without central veins. This finding, which remains to be confirmed, supports the contribution of comorbidities to the brain lesion load in patients with MS36, 37. To date, no imaging studies have been performed on the venocentric distribution of brain lesions in paediatric MS.
Statements and recommendations

The presence of central veins inside MS lesions is a well-established finding in both ex vivo pathological studies and in vivo imaging studies
The venocentric distribution of lesions exists in all MS clinical phenotypes (RRMS, SPMS and PPMS)
When imaging is used to examine the proportion of MS lesions with a central vein, the location of the lesion should be taken into account. Current evidence suggests that the prevalence of central veins is highest in periventricular and deep white matter lesions
The proportion of MS lesions with a central vein in the cortical, infratentorial and spinal cord regions remains underinvestigated, and additional imaging studies in these areas are recommended
The effects of comorbidities (such as vascular conditions) on the proportion of lesions with a central vein in patients with MS should not be neglected. Additional imaging studies on this issue would be useful
The perivenous distribution of lesions in paediatric MS has yet not been demonstrated, and future imaging studies in this population are recommended

The central vein in other diseases

Abstract•
Introduction•
Methods•
The central vein in MS•
The central vein in other diseases•
Radiological definitions•
Imaging central veins with MRI•
Evaluating the CVS for MS diagnosis•
Conclusions•
References•
Acknowledgements•
Author information

Discussion

Over the past few years, various research groups have used MRI to evaluate the presence of central veins inside white matter lesions associated with various neurological diseases, including neuromyelitis optica spectrum disorder (NMOSD), systemic autoimmune diseases (SAD), cerebral small vessel disease (CSVD), Susac syndrome, and migraine.

Neuromyelitis optica spectrum disorder. NMOSD is a CNS autoimmune disease that predominantly affects the optic nerves and spinal cord. NMOSD shares common radiological and clinical features with MS, and the differentiation between NMOSD and MS at early disease stages remains challenging. Sinnecker et al. reported that in ten patients with NMOSD who tested positive for aquaporin-4 autoantibodies (AQP4-IgG), only 35% of the 140 detected white matter lesions were located in the vicinity of — though rarely centred on — blood vessels19. In a different AQP4-IgG-seropositive NMOSD cohort (n = 10), Kister et al. reported that only eight of 92 lesions (9%) were traversed by a central vessel17, further supporting the idea that vein-sensitive MRI could prove useful for differentiating NMOSD from MS. To date, no equivalent imaging studies have been performed in AQP4-IgG-seronegative negative patients with NMOSD.

Systemic autoimmune diseases. White matter lesions are commonly detected in SAD, especially when patients present with neurological symptoms. A recent pilot study38 recruited 38 patients: 24 with MS, and 14 with SAD, including Behçet syndrome, systemic lupus erythematosus and antiphospholipid syndrome. The SAD group had a significantly lower percentage of lesions with central veins (median 15%, range 0–50%) than did the MS group (median 89%, range 68–100%). Patients with Behçet syndrome presented with the highest percentage of perivenous lesions (median 40%, range 16–50%).

Cerebral small vessel disease. CSVD refers to pathological changes in small brain vessels (small arteries, arterioles, capillaries and small veins) related to various aetiologies. CSVD is commonly associated with ageing, and is observed in populations with significant vascular risk factors. CSVD usually causes white matter lesions in the brain, which can mimic MS lesions. Although an early study by Lummel et al. reported no differences between patients with MS and CSVD in terms of the percentage of white matter lesions containing central veins39, multiple recent studies have consistently reported a significantly lower proportion (45% at most) of venocentric white matter lesions in CSVD15, 16, 18, 40, 41 — a finding that is illustrated by a representative example in Fig. 1.

Susac syndrome. Susac syndrome is believed to be an autoimmune vasculopathy that causes occlusion of small vessels in the brain, retina and inner ear. A study of five patients with this very rare disease found that a blood vessel was detectable in 54% of 148 white matter lesions21. Interestingly, the identified blood vessels were most commonly located at the lesion periphery.

Migraine. Radiographic findings in migraine can be mistaken for MS. A recent study found that the percentage of lesions with a central vein was significantly lower in migraine than in MS, with a median percentage of 22 (quartiles: 15, 54) in a cohort of ten patients with migraine20. This finding is illustrated by a representative example in Fig. 1.

Other diseases. The presence of central veins within white matter lesions in disorders with highly overlapping pathological findings to MS, such as acute disseminated encephalomyelitis (ADEM)42, 43, has not yet been investigated.
Statements and recommendations

The available evidence from MRI studies indicates that in comparison to patients with MS, individuals with AQP4-IgG-positive NMOSD, SAD (Behçet syndrome, systemic lupus erythematosus and antiphospholipid syndrome), CSVD, Susac syndrome and migraine have a significantly lower proportion of brain lesions with a central vein. These early results need to be validated by future studies. Other MRI mimics of MS, such as neurosarcoidosis and Sjögren syndrome13, should also be investigated
Pathological mimics of MS, such as ADEM, require further investigation to assess the presence of the central veins on MRI
Because the differential diagnosis of MS is broad, pooling of data from multiple centres would be a realistic strategy to perform a systematic, well-powered evaluation of the central vein in a variety of diseases

Radiological definitions

Abstract•
Introduction•
Methods•
The central vein in MS•
The central vein in other diseases•
Radiological definitions•
Imaging central veins with MRI•
Evaluating the CVS for MS diagnosis•
Conclusions•
References•
Acknowledgements•
Author information

Discussion

An accepted standard radiological definition of the central vein would be useful to enable uniform imaging practices among clinicians. Interestingly, existing studies demonstrate good agreement when defining the radiological characteristics of a central vein15, 16, 17, 20, 28, 30, 31, 32, 38, 44, 45, 46, 47: first, the vein should appear as a thin line or dot; second, when technically possible, the vein should be visualized in at least two perpendicular planes; and third, the vein can run partially or entirely through the lesion, but must be located centrally regardless of the lesion's shape. In Box 2, we suggest a standard radiological definition based on these characteristics. Examples of lesions with and without central veins are provided in Figs 1,2.
Box 2: Radiological definition of a central vein

A central vein exhibits the following properties on T2*-weighted images:

• Appears as a thin hypointense line or small hypointense dot

• Can be visualized in at least two perpendicular MRI planes, and appears as a thin line in at least one plane

• Has a small apparent diameter (<2 mm)

• Runs partially or entirely through the lesion

• Is positioned centrally in the lesion (that is, located approximately equidistant from the lesion's edges and passing through the edge at no more than two places), regardless of the lesion's shape

Exclusion criteria for lesions:

• Lesion is <3 mm in diameter in any plane

• Lesion merges with another lesion (confluent lesions)

• Lesion has multiple distinct veins

• Lesion is poorly visible (owing to motion or other MRI-related artefacts)
Expand
Figure 2: Examples of lesions with and without central veins.
Examples of lesions with and without central veins.

The lesions are classified as harbouring a central vein (parts a–c), not harbouring a central vein (parts d–f), or excluded from analysis (parts g–i). FLAIR* (combined T2*-weighted MRI and fluid-attenuated inversion recovery) images were collected at 3 T from the NIH multiple sclerosis cohort, and were reformatted in all three planes (axial, coronal and sagittal). The relevant lesions are indicated by arrowheads in each case. a | Dawson's finger-shaped lesion with a central vein running perpendicular to the sagittal plane. b | Periventricular lesion with a hypointense rim located next to the atrium of the lateral ventricle. c | Small finger-like lesion with a diameter slightly >3 mm in its short axis. The central vein is not as conspicuous as in previous examples, but it is still visible. d | Small deep white matter lesion with diameter >3 mm and no visible central vein in any plane. e | Small subcortical lesion with diameter >3 mm and no visible central vein in any plane. f | Juxtacortical lesion with no visible central vein in any plane. g | Small hyperintense area with diameter <3 mm located around a parenchymal vein. h | Periventricular lesion with branching veins. i | Confluent lesions with multiple veins.

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A more challenging task is to establish a standard radiological definition of the CVS to improve diagnosis of MS. One proposed definition is the '40% rule', first introduced by Evangelou and colleagues15, which assesses the percentage of lesions with a central vein and uses a cut-off value of 40% to radiologically distinguish MS from non-MS disease states. This simple threshold approach was successfully confirmed (100% positive and negative predictive value for MS) by the same group in a prospective study involving 29 patients who presented with possible MS, that is, typical clinically isolated syndrome (CIS) with insufficient MRI findings, or an atypical CIS presentation with MRI findings suggestive of MS46. The 40% rule was further confirmed by an independent group in a cohort of 17 patients with RRMS44. A recent study, in which patients with MS were compared with healthy volunteers and non-MS patients presenting with neurological syndromes, confirmed that diagnostic certainty could be increased by combining the published MRI criteria with visual assessment of the 40% rule48. However, this rule has some limitations, as counting the number of lesions would be time-consuming in patients with high lesion load and, as highlighted above, >40% of brain lesions can be CVS-positive in some patients without MS.

Another approach, first tested by Kilsdonk et al., combines the number and location of lesions with the percentage of lesions with a central vein16. In a cohort of 16 patients with MS and 16 individuals with risk factors for vascular disease, the authors reported that MS could be diagnosed with a sensitivity of 100% (95% CI 83–100%) and a specificity of 88% (95% CI 62–98%) when all lesions in the brain were considered. When the analysis was restricted to deep white matter lesions, the authors still found a relatively high sensitivity of 81% (95% CI 54–96%), and the specificity increased to 94% (95% CI 70–100%). The capacity of the central vein to discriminate between MS and non-MS white matter lesions was confirmed in another study with five MS and nine non-MS patients, which reported a sensitivity of 84%, a specificity of 89%, a positive predictive value of 94%, a negative predictive value of 73%, and a diagnostic accuracy of 86%45. However, this approach still requires the total number of lesions to be counted in patients' brains.

To overcome this issue, one group recently proposed that assessment of ten lesions per patient might be sufficient. By use of this approach, a diagnosis of MS could be predicted with 90% accuracy in 44 of 45 patients15. More recently, an even simpler set of diagnostic rules for CVS was introduced, consisting of the following three criteria18: if there are six or more morphologically characteristic lesions, the diagnosis is inflammatory demyelination; if there are fewer than six morphologically characteristic lesions, but morphologically characteristic lesions outnumber non-perivenous lesions, the diagnosis is inflammatory demyelination; if neither of these conditions are met, inflammatory demyelination should not be diagnosed. The morphologically characteristic lesions considered here had a 'coffee bean' or 'Dawson's finger' appearance when the MRI slice was along the vein's axis, and a 'ring' or 'doughnut' appearance when the MRI slice was approximately perpendicular to the vein. By applying these rules in a cohort of 13 patients with MS and seven patients diagnosed with small vessel ischaemia, all patients were correctly classified, and the classification process took <2 min per case.

Standardized lesion selection, based on existing MRI criteria2, 3, 49, 50, would enable the proposed CVS rules to be compared across different raters and sites. Given the potential confounding factors of small perivascular spaces surrounding veins (Virchow–Robin space), confluent lesions, lesions with multiple distinct veins, and lesions that are poorly visible owing to image artefacts, we introduce a set of exclusion criteria for lesions (Box 2). Examples of excluded lesions are provided in Fig. 2.
Statements and recommendations

A standard radiological definition of a central vein should rely on the characteristics outlined in Box 2
No standard radiological definition of the CVS has yet been established
To define the CVS, we need a set of simple rules that are practical for clinicians to use while providing the highest possible accuracy and confidence
Because patients without MS can display a central vein in >40% of their total lesions, the proposed '40% rule' might not be applicable for all diseases
When defining the CVS, several exclusion criteria should be applied to lesions (Box 2)

Imaging central veins with MRI

Abstract•
Introduction•
Methods•
The central vein in MS•
The central vein in other diseases•
Radiological definitions•
Imaging central veins with MRI•
Evaluating the CVS for MS diagnosis•
Conclusions•
References•
Acknowledgements•
Author information

Discussion

Structural imaging of small cerebral veins is best done using the T2*-based contrast mechanism, which exploits the magnetic properties of blood27. The paramagnetic deoxyhaemoglobin inside venous blood perturbs the local magnetic field and generates reduced signal intensity in voxels containing a vein, causing veins to appear hypointense on T2*-weighted images27, 51. Since the first in vivo observation of central veins in the brains of patients with MS28, a variety of T2*-based acquisitions have been employed at different magnetic field strengths to image veins inside MS plaques30, 34, 45, 46, 52, 53.

Several studies have employed a conventional 2D gradient-echo (GRE) sequence, which allows exquisite submillimetre in-plane resolution, especially at 7 T (Refs 17,19,21,29,32,52). However, 2D GRE acquisitions are typically slow (>10 min), only partially cover the supratentorial brain, and provide poor image resolution in the inferior–superior plane owing to thick slices and/or slice gaps.

Some studies have utilized a 3D T2*-weighted GRE sequence to overcome the slice gap issue, and have applied parallel imaging to shorten scan time while maintaining high image resolution (typically 0.5 × 0.5 × 1–3 mm)39, 45, 54, 55. These T2*-weighted images can be post-processed using the susceptibility-weighted imaging (SWI) technique to further enhance venous conspicuity56. The 3D GRE sequence can also be set up to have a multi-echo read-out57. The multi-echo acquisition can then provide quantitative (and/or multi-contrast) imaging through the use of advanced post-processing techniques58, 59.

Another variation of the 3D GRE sequence uses a segmented echo planar imaging (3D EPI) read-out to speed up the acquisition while providing more-efficient brain coverage and isotropic voxel size60. Isotropic resolution — a feature that is available on many radiology viewing platforms — is particularly useful to reformat images in any desired plane, and enables veins to be well visualized irrespective of their orientation. Moreover, the use of small isotropic voxel dimensions increases the sensitivity to small parenchymal veins within lesions61, while reducing the sensitivity to artefacts due to background field inhomogeneities. A shorter scan is also beneficial for limiting the head motion that can occur during the acquisition. Recently, the 3D EPI approach was demonstrated to image perivenous MS lesions throughout the brain at submillimetre resolution (0.55 mm isotropic) in <4 min using a 3 T MRI scanner53. Moreover, this 3D EPI acquisition was shown to be more sensitive than conventional 3D T2* GRE41, probably owing to its smaller voxel dimensions.

Although T2*-based imaging with a 7 T scanner provides the highest sensitivity for central vein detection47, 1.5 T (Ref. 38) and 3 T (Ref. 61) scanners can still provide high rates (>80%) of vein detection if optimized T2* protocols are used. Another way to increase vein conspicuity on T2*-weighted images is to perform SWI28, 62 and/or inject an intravascular contrast agent (a chelate of gadolinium, which is paramagnetic) during the MRI acquisition28, 53, 63. The latter solution is straightforward to implement, as MRI protocols for MS often involve the injection of contrast agent, which can be accomplished via a power injector while the scan is ongoing. Compared with manual contrast injection by a technician and the recommended 5 min wait before post-contrast imaging4, 22, such a procedure would not prolong the MRI examination.

Unlike T2-weighted fluid-attenuated inversion recovery (FLAIR) images, T2*-weighted and SWI images lack cerebrospinal fluid suppression and are, therefore, less able to demonstrate contrast between lesions and surrounding tissues, making the detection of lesions more difficult. To overcome these issues, two research groups have recently proposed that FLAIR and T2* images should be combined in a single image34, 55. Grabner et al.55 introduced a method that transforms FLAIR images using SWI phase masks from T2*-weighted images, thereby creating a FLAIR–SWI contrast. The other approach, proposed by Sati et al.34 and known as FLAIR*, uses 1 mm isotropic 3D FLAIR (for lesion detection) and 0.55 mm isotropic 3D EPI (for vein detection) sequences — both acquired in <10 min — and provides high-resolution isotropic images of the whole brain. Recent studies reported on the utility of FLAIR* at various field strengths for differentiating MS from other diseases16, 20, 64, and for improving diagnostic accuracy31, 44, 48.

T2*-based imaging of the spinal cord is much more challenging, owing to factors such as the small physical dimensions of the spinal cord, strong magnetic field inhomogeneity caused by surrounding tissues (bones, soft tissues and air), and physiological motion (pulsation of cerebrospinal fluid flow, and cardiac and respiratory movement). Nonetheless, recent studies have demonstrated that high-quality, high-resolution T2*-weighted imaging of the cervical65, 66 and thoracic67 cord is possible in patients with MS. However, no central vein findings have yet been reported.

Standardization of the optimized MRI acquisitions across centres will be important for the widespread dissemination of central vein imaging. Similarly, standardized image reading and interpretation guidelines will be required to train radiologists and neuroradiologists from non-specialist centres. This process could, in principle, be facilitated by future development of automated image analysis tools for the detection of central veins.
Statements and recommendations

Imaging of veins in the brain can be performed using T2*-based MRI sequences at any magnetic field strength (1.5 T, 3 T or 7 T). Although T2* imaging is most sensitive at 7 T, a high detection rate can still be achieved at clinical field strengths (1.5 T and 3 T) with optimized sequences
Owing to the small dimensions of the central veins, images should be acquired at the highest resolution possible. The use of submillimetre voxel dimensions can be particularly helpful
Images should be acquired using isotropic voxels to enable multiplanar visualization of central veins regardless of their orientation in the brain
Specific acquisition protocols (with SWI and/or gadolinium injection) aimed at improving central vein detection require further evaluation, especially at lower field strength (1.5 T)
High-resolution isotropic T2*with 3D EPI is currently the most promising acquisition to adequately detect central veins while preserving a clinically compatible scan time. However, its use will be limited to expert academic centres until the sequence is made routinely available by MRI scanner manufacturers
Combined FLAIR and T2* images have the potential to become a standard clinical protocol, but manufacturer-provided software for direct, automatic image post-processing on the scanner is necessary for widespread dissemination
The intra-rater, inter-rater, scan–rescan and inter-scanner reliability of central vein detection on the optimized MRI sequences should be investigated
High-quality, high-resolution T2*-weighted imaging of the spinal cord to detect central veins in MS lesions needs further development

Evaluating the CVS for MS diagnosis

Abstract•
Introduction•
Methods•
The central vein in MS•
The central vein in other diseases•
Radiological definitions•
Imaging central veins with MRI•
Evaluating the CVS for MS diagnosis•
Conclusions•
References•
Acknowledgements•
Author information

Discussion

Most studies on the use of the CVS for MS diagnosis have included small cohorts of patients in whom the diagnosis (MS or one of its mimics) was already known. As discussed above, the results from these single-centre studies support a beneficial role for the CVS in specifically identifying MS lesions. However, larger-scale studies are still required to confirm these early results.

To formally establish the clinical value of the CVS for the differential diagnosis at disease onset, a large, prospective, multicentre study including patients at first presentation of possible MS is necessary. In any study design, important factors such as disease duration, disease severity and lesion load would need to be taken into account, as they might affect the frequency of the central vein in MS mimics. For example, larger lesions are more likely to incidentally harbour a blood vessel, although the vessel location in lesions caused by MS mimics is more likely to be eccentric than central.

Although differential diagnosis is the most obvious diagnostic application of the CVS, one study has prospectively investigated the predictive diagnostic value of the CVS in patients in whom the question of inflammatory demyelination had been raised at first presentation, that is, patients showing typical CIS or with atypical neurological presentations46. In this longitudinal study, 29 undiagnosed individuals were recruited and underwent a T2*-weighted scan. On the basis of the CVS only, a provisional diagnosis of MS was predicted using the 40% rule. Of the 22 patients who eventually received a clinical diagnosis within a median follow-up period of 26 months, 13 patients diagnosed as having MS had central veins in >40% of brain lesions at baseline. All nine patients whose condition was not diagnosed as MS had central veins in <40% of lesions. According to these data, the CVS had 100% positive and negative predictive value for the diagnosis of MS, although the conclusions were limited by the small number of participants.

To further validate these early results, the same group is currently conducting a prospective longitudinal clinical trial68 aiming to recruit 60 patients suspected — but not proven — to have MS. Recruited patients will undergo a single research MRI brain scan at 3 T, which will be evaluated by blinded investigators to make a diagnosis of MS or non-MS on the basis of the CVS criterion only. No other research tests will be performed, and the patients will be followed up over time until a final diagnosis is made. Although this prospective study should provide strong evidence to support or refute the predictive value of the CVS for MS diagnosis, it remains a single-centre trial and is, therefore, limited in terms of cohort size and external validity. The clinical validation would benefit from a multicentre trial using a similar design but including a larger number of participants and centres, as well as standardized MRI protocols and methodology for CVS identification.

An alternative study design could be used to investigate whether the CVS improves the accuracy of the 2010 McDonald criteria. Modifications of existing MRI criteria to incorporate the CVS could be tested initially in a single-centre prospective study recruiting patients with CIS (or even with radiologically isolated syndrome), followed by a larger-scale multicentre study if the preliminary results are positive.
Statements and recommendations

The clinical value of the CVS should be evaluated in the context of the differential diagnosis of suspected MS, the diagnostic predictive value in patients with possible or early MS, and the potentially improved accuracy of the 2010 McDonald criteria
Currently available evidence from a small prospective study supports the high predictive value of the CVS in the diagnosis of MS in patients with typical CIS or atypical neurological presentations
Large, prospective multicentre trials including patients at first presentation of neurological signs are needed to evaluate the clinical value of the CVS for MS diagnosis
Care should be taken when using the CVS in routine clinical practice until its diagnostic value has been formally established

Conclusions

Abstract•
Introduction•
Methods•
The central vein in MS•
The central vein in other diseases•
Radiological definitions•
Imaging central veins with MRI•
Evaluating the CVS for MS diagnosis•
Conclusions•
References•
Acknowledgements•
Author information

The NAIMS Cooperative has developed this Consensus Statement to better define and evaluate the CVS, as detected by MRI, for the diagnosis of MS. More precisely, our recommendations underscore the need for further investigation of the central vein in MS and its mimics. We have proposed a standard radiological definition of the central vein (Box 2), but we strongly recommend additional investigation to define the optimal CVS criteria. Our recommendations also promote standardization of MRI protocols and lesion selection criteria to assess central veins. Finally, we recommend investigation of the clinical value of the CVS through large multicentre studies involving patients with established diagnoses of MS and its mimics, as well as undiagnosed patients suspected of having MS.

Taken together, our recommendations provide a roadmap to help establish a high-impact role for the CVS in improving the diagnosis of MS. This Consensus Statement is in line with recent guidelines from the MAGNIMS group1, 4 and CMSC task force22, which both highlighted the potential of the CVS and its associated MRI acquisitions while calling for further research before considering an update of the diagnostic criteria. Overall, the NAIMS Cooperative is optimistic that the CVS will eventually find substantial clinical utility in daily practice, thus adding another layer of success to a technology that has changed the field of neurology over the past few decades.
References

Abstract•
Introduction•
Methods•
The central vein in MS•
The central vein in other diseases•
Radiological definitions•
Imaging central veins with MRI•
Evaluating the CVS for MS diagnosis•
Conclusions•
References•
Acknowledgements•
Author information

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Acknowledgements

The authors would like to thank Christina J. Azevedo, Michael G. Dwyer, Léorah Freeman, Christoph Juchem, Shannon Kolind, Naila Makhani, Govind Nair, Nico Papinutto, Haochang Shou, Daniel Schwartz, Ferdinand Schweser, Elizabeth Sweeney, Ian Tagge, Shahamat Tauhid and Subhash Tummala for their participation in, and contribution to, the group workshop at the NAIMS meeting in Los Angeles. Matthew Schindler is acknowledged for helpful suggestions. The authors also acknowledge Rohit Bakshi, Peter Calabresi, Ciprian Crainiceanu and Jack Simon for their contribution as NAIMS members. The authors, on behalf of the NAIMS Cooperative, would also like to thank the Race to Erase Multiple Sclerosis for financial support, and Joel Arnold, Aracely Delgadillo, and Liz Seares for helping with organization of the NAIMS meeting. This research was supported in part by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke.
Affiliations

Translational Neuroradiology Section, National Institute of Neurological Disorders and Stroke, NIH, 10 Center Drive MSC 1400, Building 10 Room 5C103, Bethesda, Maryland, USA.
Pascal Sati,
Henry McFarland &
Daniel S. Reich
St. Michael's Hospital, University of Toronto, Ontario, Canada.
Jiwon Oh
Department of Neurology, Johns Hopkins University, Baltimore, Maryland, USA.
Jiwon Oh
Department of Diagnostic Radiology, Yale University, New Haven, Connecticut, USA.
R. Todd Constable
Division of Clinical Neuroscience, University of Nottingham, UK.
Nikos Evangelou &
Amal P. R. Samaraweera
Center for Neurological Imaging, Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Charles R. G. Guttmann
Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA.
Roland G. Henry
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Eric C. Klawiter
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Caterina Mainero &
Constantina A. Treaba
Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Italy.
Luca Massacesi
Multiple Sclerosis Research Group, Department of Neurology, University of Texas Health Science Center at Houston, Texas, USA.
Flavia Nelson
Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, Cleveland, Ohio, USA.
Daniel Ontaneda
Department of Pediatrics, Division of Neurology, UBC MRI Research Centre, University of British Columbia, Vancouver, Canada.
Alexander Rauscher
Advanced Imaging Research Center, Oregon Health & Science University, Portland, Oregon, USA.
William D. Rooney
Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Russell T. Shinohara
Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
Raymond A. Sobel
Department of Neurological Sciences, University of Vermont College of Medicine, Burlington, Vermont, USA.
Andrew J. Solomon
Medical Image Analysis Center, University Hospital Basel, Switzerland.
Jens Wuerfel
Buffalo Neuroimaging Analysis Center, Department of Neurology, State University of New York at Buffalo, New York, USA.
Robert Zivadinov
Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Nancy L. Sicotte
Multiple Sclerosis Center, Department of Neurology, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
Daniel Pelletier

Consortia

on behalf of the NAIMS Cooperative

Contributions

P.S. researched the data for the article. P.S., D.P. and D.S.R. wrote the text. All authors made substantial contributions to discussions of the content, and reviewed and/or edited the manuscript before submission. D.P. and D.S.R. contributed equally to the work.
Competing interests statement

The authors declare no competing interests.
Corresponding author

Correspondence to:

Pascal Sati

Author details

Pascal Sati earned his PhD in physics in France. After postdoctoral experience at the Mallinckrodt Institute of Radiology Washington University in St. Louis, Missouri, USA, he joined the National Institute of Neurological Disorders and Stroke (Bethesda, Maryland) where he specialized in ultra-high-field MRI in multiple sclerosis (MS). He is currently a staff scientist at the Translational Neuroradiology Section directed by Daniel Reich. Dr Sati's research focuses on developing novel MRI techniques for better understanding, diagnosing and monitoring MS. He is also working on preclinical imaging of animal models of MS to test novel biomarkers and therapeutics targeting inflammation and tissue repair.

Jiwon Oh is an Assistant Professor of Medicine in the Division of Neurology at the University of Toronto and a staff neurologist at St. Michael's Hospital, Toronto, Ontario, Canada. She is also a scientist at the Keenan Research Centre of the Li Ka Shing Knowledge Institute and holds an adjunct faculty appointment at the Johns Hopkins School of Medicine, Baltimore, Maryland, USA. She specializes in the care of patients living with multiple sclerosis (MS), and her research focuses on the development of advanced MRI techniques in the spinal cord in MS.

R. Todd Constable is a Professor of Radiology and Biomedical Imaging and of Neurosurgery at Yale University School of Medicine, New Haven, Connecticut, USA. He is also the Director of MRI Research at the Anlyan Center in New Haven. His research interests are related to diagnostic imaging, MRI, neurosurgery and neuroimaging.

Nikos Evangelou is a Clinical Associate Professor in Neurology at the University of Nottingham, UK. He is also the Head of Service for Neurology at the Nottingham University Hospital. Dr Evangelou has published over 60 peer-reviewed journal articles and five book chapters in basic science, neuroimaging and clinical aspects of multiple sclerosis.

Charles R. G. Guttmann is the Director of the Center for Neurological Imaging at Brigham and Women's Hospital and an Associate Professor of Radiology at Harvard Medical School, Boston, Massachusetts, USA. His main interest is the quantitative evaluation of normal and pathological states of the brain using MRI. His specific goals include shedding light on physiological and pathological mechanisms in multiple sclerosis and age-related neurological diseases. Dr Guttmann is currently directing the development of SPINE (Structured Planning and Implementation of New Explorations), a web-based platform for collaborative science, with added special emphasis on citizen science and education.

Roland G. Henry is the Rachleff Distinguished Professor with expertise in biomedical imaging in the University of California, San Francisco Departments of Neurology, Radiology, and Graduate Group in Bioengineering (University of California, Berkeley and UCSF, California, USA). Dr Henry directs the imaging programme for the Multiple Sclerosis Research Group in the Department of Neurology at UCSF. Dr Henry's laboratory focuses on technical developments in MRI, and translation and application of these methods to enable discovery in multiple sclerosis (MS) and other neurological disorders. Recent work includes spinal cord grey matter imaging and genotype–MRI studies in MS.

Eric C. Klawiter is an Assistant Professor of Neurology at Massachusetts General Hospital, Boston, Massachusetts, USA. He received his medical degree from Sanford School of Medicine of the University of South Dakota. Dr Klawiter's research interests include multiple sclerosis (MS) clinical research, and the development of new imaging techniques to better understand, diagnose and treat MS.

Caterina Mainero is an Assistant Professor of Radiology at Harvard Medical School and Director of Multiple Sclerosis Research at the A. A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital, Boston, Massachusetts, USA. Dr Mainero is interested in using innovative neuroimaging approaches that combine different imaging modalities, including ultra-high-field MRI and MRI–PET, and multiple imaging contrasts to study brain tissue pathology in multiple sclerosis (MS), with a particular emphasis on neuroinflammation, neurodegeneration and tissue repair. Her goal is to combine these methods with clinical and/or biological markers to investigate the impact of different aspects of MS pathology on disease activity and evolution.

Luca Massacesi is a Professor of Neurology in the Department of Neurosciences, University of Florence, Italy. He is the Director of Division of Neurology 2 and Regional Reference Center for Multiple Sclerosis at the Careggi University Hospital. He is also Co-Chairman of the Scientific Panel Neuroimmunology at the European Academy of Neurology and the Scientific Advisory Group (SAG)–Neurology at the European Medicines Agency. His research interests are related to mechanisms of inflammation in the nervous system, multiple sclerosis, autoimmune diseases of the nervous system, biomarkers of diseases, and clinical trials.

Henry McFarland is a neurologist, researcher and former Chief of the Neuroimmunology Branch at the NIH. Over the past 35 years, he has dedicated his career to multiple sclerosis (MS) research and is internationally known for his groundbreaking research into genetic components, immune mechanisms, and use of MRI to monitor disease course in MS. He has published 250 papers, and in 1998 he received the Dystel Prize. Dr McFarland has been an active member and chair of numerous society committees and task forces involving research, clinical trials, and paediatric MS.

Flavia Nelson is the Interim Chief of the Multiple Sclerosis Division, the Associate Director of the Magnetic Resonance Imaging Analysis Center and an Associate Professor of Neurology at the University of Texas Medical School at Houston, Texas, USA. She received her MD degree from Autonomous University of Chihuahua in Mexico. She is board certified in internal medicine and neurology, and she completed a research/clinical fellowship in multiple sclerosis under Professor Jerry S. Wolinsky at her current institution. She actively participates in trials of new treatments in multiple sclerosis (MS). Her main research focus is functional MRI changes in MS-related cognitive impairment, and she is also a pioneer in the imaging of cortical brain lesions in MS.

Daniel Ontaneda is a staff member of the Cleveland Clinic Mellen Center for Multiple Sclerosis and an Assistant Professor of Neurology/Medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University (CWRU), Cleveland, Ohio, USA. He received his MD from the Universidad Católica del Ecuador and an MSc in clinical research from CWRU. He completed a postdoctoral fellowship at Baylor College of Medicine, followed by neurology and neuroimmunology training at the Cleveland Clinic. He has been awarded a Sylvia Lawry Award and a KL2 Award. His main research interests include imaging outcomes for progressive multiple sclerosis, diffusion tensor imaging, and magnetic resonance fingerprinting.

Alexander Rauscher obtained his PhD in physics at the Vienna University of Technology, Austria in 2005. In 2010, he became Assistant Professor in the Department of Radiology at the University of British Columbia (UBC) in Vancouver, British Columbia, Canada. In 2015, he became Canada Research Chair in Developmental Neuroimaging and joined the Department of Pediatrics (Division of Neurology) at UBC. His research focuses on the development of quantitative MRI scans for the mapping of damage and repair in CNS tissue.

William D. Rooney earned his PhD in chemistry from Stony Brook University, New York, USA in 1990, and completed a postdoctoral fellowship in neuroimaging at the University of California, San Francisco (UCSF) in 1993. Dr Rooney was an Assistant Professor in the Department of Radiology at UCSF until 1997. From 1997–2005, he was a faculty member in the Chemistry Department of Brookhaven National Laboratory (BNL), and he directed the BNL High-Field MRI Laboratory from 2003–2005. He joined Oregon Health & Science University in Portland, Oregon in 2005, where he is a Senior Scientist and Director of the Advanced Imaging Research Center, and holds academic appointments in behavioural neuroscience, biomedical engineering, and neurology.

Amal P. R. Samaraweera is a neurologist and research fellow in the Division of Clinical Neuroscience, University of Nottingham School of Medicine, UK.

Russell T. Shinohara is an Assistant Professor of Biostatistics at the University of Pennsylvania, Philadelphia, USA. He completed a master's degree in probability and statistics at McGill University (Montreal, Quebec, Canada) in 2007, and a doctoral degree in biostatistics at the Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. Dr Shinohara is an expert in methods for the analysis of multimodality neuroimaging, specializing in the use of MRI in multiple sclerosis.

Raymond A. Sobel is a Professor of Pathology (Neuropathology) at Stanford University School of Medicine, Stanford, California, USA. His main research interests are the mechanisms of immune-mediated injury in the CNS, and clinicopathological correlations of CNS inflammatory diseases. He has published more than 200 papers and is on the editorial boards of several neuroscience journals. He has been the Editor-in-Chief of the Journal of Neuropathology and Experimental Neurology since 2007.

Andrew J. Solomon is Division Chief of Multiple Sclerosis and Assistant Professor in Neurology at the University of Vermont Multiple Sclerosis Center, Burlington, Vermont, USA. Dr Solomon received his MD from the Mount Sinai School of Medicine, New York and completed his neurology training and a postdoctoral research fellowship in multiple sclerosis (MS) at Oregon Health & Science University, Portland, Oregon, USA. His research interests include the investigation of methods to improve diagnosis and recognize misdiagnosis of MS.

Constantina A. Treaba is a Romanian board-certified radiologist with over 10 years' experience in neuroradiology. Dr Treaba received her degrees from the University of Medicine and Pharmacy at Târgu Mureş, Romania. She is Assistant Professor of Radiology at the same university, and since 2015 has been working as a research fellow at the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. She has a broad list of medical publications, has written book chapters, and has taught medical students and residents. Her special research interests are in multiple sclerosis and brain tumours.

Jens Wuerfel underwent medical training in neurology at the Charité University Medicine Berlin from 2001–2007, and in radiology/neuroradiology at the Universities of Lübeck and Göttingen, Germany from 2008–2015. Since 2015, he has been the CEO of the Medical Image Analysis Center AG, Basel, Switzerland. He holds research positions in the Department of Biomedical Engineering, University of Basel, and at NeuroCure, Charité University Medicine Berlin. His research focuses on advanced quantitative MRI in ultra-high and ultra-low fields, including magnetic resonance perfusion, MRI in animal models, and magnetic resonance elastography.

Robert Zivadinov is a Professor of Neurology with tenure in the Department of Neurology, School of Medicine and Biomedical Sciences, University of Buffalo, State University of New York, Clinical Professor of Neurology at the Florida International University College of Medicine, Miami, Florida, USA, and Honorary Professor of Neurology at the University of Sydney, Australia. He is Director of the Buffalo Neuroimaging Analysis Center and of the MR Imaging Clinical Translational Research Center. He has performed extensive research in multiple sclerosis and other neurodegenerative disorders, having published more than 300 articles and 550 abstracts in leading peer-reviewed journals, with an h-index of 60.

Nancy L. Sicotte is Professor and Vice Chair for Education, and Director of the Multiple Sclerosis and Neurology Residency Programs in the Department of Neurology at Cedars-Sinai Medical Center, Los Angeles, California, USA. She is a past recipient of the Harry Weaver Junior Faculty Award of the National Multiple Sclerosis Society. Her research has focused on developing informative imaging outcome measures of novel therapeutics as well as measures of disease progression, depression and cognitive dysfunction in multiple sclerosis (MS). She is the Director of the clinical and research programme for MS and neuromyelitis optica at Cedars-Sinai Medical Center.

Daniel Pelletier received his MD degree in 1994 and completed his neurology training at Laval University (Quebec City) and McGill University (Montreal), Quebec, Canada. He subsequently received research training in multiple sclerosis and advanced MRI techniques at the Montreal Neurological Institute. He joined the University of California, San Francisco Multiple Sclerosis Center in 1999 as a recipient of a National Multiple Sclerosis Physician Fellowship Award Grant for his work in molecular imaging. He was appointed at Yale University, New Haven, Connecticut, USA in January 2011 to lead the Multiple Sclerosis Program as Chief of the Neuro-Immunology Division and Yale Multiple Sclerosis Center. In April 2015, he joined the University of Southern California to become Vice-Chair of Research and Chief of the Neuro-Immunology and Multiple Sclerosis Division.

Daniel S. Reich — a neurologist and neuroradiologist — directs the Translational Neuroradiology Section at the National Institute of Neurological Disorders and Stroke, part of the NIH (Bethesda, Maryland, USA). In his clinical practice, he cares for patients with multiple sclerosis (MS) and other neurological diseases, and he also leads several clinical studies focusing on MS. Research in his laboratory focuses on the use of advanced MRI techniques to understand the sources of disability in MS, and on ways of adapting these approaches for research trials and patient care. He is particularly interested in harnessing noninvasive imaging modalities to dissect biological mechanisms of tissue damage.
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Re: The central vein sign

Postby vesta » Thu Sep 14, 2017 9:55 am

It's good to see that the Vascular Connection (that is to say CCSVI) is long last getting official recognition as an MS issue. Joan Beal on her "Vascular Connection" blog posted the following on Sept 20, 2013.

ccsviinms.blogspot.com/.../the-central-vein-sign-and-new-research...

The Central Vein Sign and New Research

September 20, 2013

"It was 150 years ago, in 1863, when Eduard von Rindfleisch first peered through his microscope at an MS lesion and noted a vein inside the cerebral MS lesion.

If one looks carefully at freshly altered parts of the white matter ...one perceives already with the naked eye a red point or line in the middle of each individual focus,.. the lumen of a small vessel engorged with blood...All this leads us to search for the primary cause of the disease in an alteration of individual vessels and their ramifications; All vessels running inside the foci, but also those which traverse the immediately surrounding but still intact parenchyma are in a state characteristic of chronic inflammation. 

Rindfleisch E. - "Histologisches detail zu der grauen degeneration von gehirn und ruckenmark". Archives of Pathological Anatomy and Physiology. 1863;26:474–483.

We've known for over a century that MS lesions are perivenous, meaning lesions form around a vein.  There is a vein in the center of almost every cerebral MS lesion, and this makes the MS lesion unique.

So, it was interesting to see THREE brand new papers on this topic in 2013, coming from neurological research. 

Here's one from July 2013, published in "Frontiers of Neurology"--suggesting that these central veins and perivenous lesions, which are now very clear on 7Tesla MRI, might be helpful in making an MS diagnosis.

Venocentric Lesions: an MRI marker in MS?
In the past decade, numerous studies have explored a promising biomarker for MS: MRI-detectable veins within lesions.This biomarker is well established as detectable at 3 and 7T and efforts should be made to identify/optimize clinically practical methods for its evaluation. Prospective studies have shown that the presence of venocentric lesions at an early but ambiguous clinical presentation is highly predictive of future MS diagnosis. Work remains to be done to confirm or exclude lesions of common MS mimics as venocentric. Common imaging practice and lesion-rating paradigms should be adopted by scientists working in this field.
http://www.frontiersin.org/Multiple_Scl ... 00098/full

Here's another paper entitled "The Central Vein Sign: is there a place for susceptibility weighted imaging in possible multiple sclerosis." (Readers of this page know that CCSVI investigator, Dr. Mark Haacke, is the inventor of SWI.  He has noted these central veins and iron deposition in the MS brain for almost a decade now, and linked their presence to CCSVI.)

Susceptibility weighted imaging (SWI) may have the potential to depict the perivenous extent of white matter lesions (WMLs) in multiple sclerosis (MS). We aimed to assess the discriminatory value of the "central vein sign" (CVS).

The "central vein sign" was predominantly seen in MS lesions. The "central vein sign" helps discriminate between MS and non-MS lesions.
http://www.ncbi.nlm.nih.gov/pubmed/23436147

Here's yet another study published in the Journal of Neuroimmunology in May 2013 which notes the central veins visible in MS lesion.

Of the 29 patients enrolled and scanned using 7-T MRI, so far 22 have received a clinical diagnosis. All 13 patients whose condition was eventually diagnosed as MS had central veins visible in the majority of brain lesions at baseline. All 9 patients whose condition was eventually not diagnosed as MS had central veins visible in a minority of lesions.
In our study, T2*-weighted 7-T MRI had 100% positive and negative predictive value for the diagnosis of MS. Clinical application of this technique could improve existing diagnostic algorithms
.
http://www.ncbi.nlm.nih.gov/pubmed/23529352

+++++++++++++++++++++++++++++

These papers are no surprise--researchers have been noting these veins inside MS lesions for over a century.  But what continues to shock me is that researchers aren't asking WHY?



Rindfleisch, with his microscope in 1863, was wondering why there was a change in the blood vessels in the MS brain.

Here is Dr. C.W. Adams in 1987, looking at autopsied brain tissue in the hopes of understanding the mechanism of lesion formation in MS.

The periventricular region was studied in the brains of 129 cases of multiple sclerosis, with the purpose of establishing the mechanism and order of events in the development of the periventricular plaque, and deciding whether there is any relationship between granular ependymitis and such plaques. Periventricular plaques were found in 82.2% of cases. Observation and computerized morphology showed that the early stage of the periventricular plaque is the formation of a lesion around a subependymal vein and that adjacent lesions later coalesce. 
(Subependymal means below the ependymal zone, in the lateral ventricles of the brain.)

http://www.ncbi.nlm.nih.gov/pubmed/3614542


++++++++++++++++++++++++++++++

One cardiovascular doctor has asked why, and utilized Dr. Zamboni's research to explain the central vein found in MS lesions.

Here's Dr. Michael Dake's illuminating powerpoint presentation, explaining how CCSVI would create vessel wall breakdown, due to disturbed venous blood flow, microbleeds and perivenous fibrin cuffs, activating the inflammatory process. This would lead to adhesion molecule and cytokine expression, oxidative stress and reduced NOS activity--endothelial dysfunction and a breech in the blood brain barrier.  We know how this happens in chronic venous disease in other parts of the body.  Laminar, or smooth blood flow, maintains the endothelium.  Disturbed blood flow leads to a break down.
This would explain the central vein inside the lesion.

http://www.ucsfcme.com/2011/slides/MSU1 ... cyInMS.pdf


Perhaps neurologists do not want to ask why there is a central vein; because they know the answer points to a vascular connection to multiple sclerosis.  Their studies are looking at this central vein in MS lesions as purely a means to aid MS diagnosis, so they might begin disease modifying medications in their patients.  

But the looming question remains....why the central vein?
The answer will provide healing for those with MS.

Joan

PS--for those who wish to learn more about this history, Dr. Schelling has written the most comprehensive and thorough evaluation of the history of MS lesion studies.
http://www.ms-info.net/ms_040504.pdf

Posted by Joan at 11:27 AM"


Thanks to Joan and 1eye
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Re: The central vein sign

Postby 1eye » Thu Sep 14, 2017 9:24 pm

I was given an MRI one year before I was finally diagnosed. I was not told what the result was. It was a definitive diagnosis. I missed the follow-up appointment. The doctor did not do anything further, to this day I have not been told.

One year later my neurologist sent me for another MRI. I think the second one was given because of the "time and space" criteria. At any rate I asked to speak to the radiologist after the MRI. He said there must have been some kind of disconnect. I had already been diagnosed a year before! I asked him how he could tell. He said by the pattern of the lesions. Radiologists were already familiar with the pattern of lesions (the central vein sign). So this time I was officially diagnosed. It was already common knowledge. It just had to wait for the paper in Nature twenty years later to show how he had done it (besides the time and space nonsense).
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Re: The central vein sign

Postby 1eye » Fri Sep 15, 2017 3:06 pm

However, the lack of standardization for the definition and imaging of the CVS, as well as a dearth of large-scale prospective studies evaluating the CVS for MS diagnosis, are currently preventing the clinical validation of this potential biomarker


"Lack of standardization" and "dearth of large-scale prospective studies" can both be blamed firmly on those neurologists who love media coverage more than science, and have gone out of their way to suppress the suggestion that there might be venous problems associated with MS, and that CCSVI is a real, problematic condition with implications for both brain and heart health.
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Re: The central vein sign

Postby Cece » Sun Sep 17, 2017 6:54 pm

1eye wrote:"Lack of standardization" and "dearth of large-scale prospective studies" can both be blamed firmly on those neurologists who love media coverage more than science, and have gone out of their way to suppress the suggestion that there might be venous problems associated with MS, and that CCSVI is a real, problematic condition with implications for both brain and heart health.

Agreed!
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