Intra- and Extraluminal Structural and Functional Venous Anomalies in Multiple Sclerosis, as Evidenced by 2 Noninvasive Imaging Techniques

Discussion

This study investigated the intra- and extraluminal structural and functional extracranial venous abnormalities and the potential value of MRV and DS in depicting those abnormalities. Patients with MS showed a significantly higher number of total and intraluminal structural and functional abnormalities on DS compared with HCs. No differences on the morphologic MRV flow scale were found between patients with MS and HCs. Patients with progressive MS presented with significantly more extraluminal DS abnormalities and more flow abnormalities on MRV than those with nonprogressive MS.

From the time it was first mentioned, the CCSVI theory has not ceased to provoke controversy and attention in the scientific community^{20⇓⇓–23} and the media. The originally reported sensitivity and specificity of the CCSVI criteria for MS diagnosis⁵ were not reproduced by recent DS,^{6⇓⇓⇓–10} MRV,^11⇓–13 or CV^14,15 studies. A major point that can explain different findings between the original and subsequent studies is that the CCSVI diagnosis is mainly based on extra- and transcranial echo-color DS criteria, which are operator-dependent and not easy to blind in a clinical setting. Moreover, the value of the CCSVI criteria is controversial because they combine functional and structural intra- and extracranial venous abnormalities in a single binary composite.²⁴ The assessment of the second CCSVI criterion (reflux in deep cerebral veins) is particularly controversial because the direction of the blood flow in veins connecting cortical with deep veins may vary considerably as a consequence of the physiologic interindividual variation of the cerebral venous anatomy.^6,7,9,24 In addition, the value of MRV-based techniques for a diagnosis of CCSVI has not yet been completely elucidated.^13,25 To provide better evidence on the types of venous anomalies, we focused, in this study, on the assessment of extracranial neck veins by 2 different noninvasive imaging techniques. Furthermore, we divided venous abnormalities into structural (intra- and extraluminal) and functional, to better understand their contribution to the CCSVI concept.

The DS examination showed that a substantial number of patients with MS and HCs presented with at least 1 structural venous abnormality in their IJVs. Similar results were found for the number of intraluminal abnormalities in the IJVs. More patients with MS and HCs presented with intraluminal abnormalities compared with the extraluminal ones. Of all the intraluminal abnormalities examined, the septum and flap occurred most frequently in patients with MS as well as in HCs, while no difference between the groups was found for the malformed valve (impaired mobility or thickened fibrotic valve), in line with a recent report.⁹ No membrane abnormalities were found in patients with MS and HCs.

All in all, these results suggest that the most frequent venous abnormalities in the IJVs, indicative of CCSVI, are of intraluminal origin. Although head and neck veins are clearly shown by using MRV, this technique does not have the resolution to visualize intraluminal abnormalities. This is 1 of the main limitations when comparing MRV with DS, as discussed in a recent multimodal diagnostic study.²⁵ The fact that intraluminal abnormalities present the most frequent type of venous abnormality in the CCSVI criteria^5,6,10 can further explain the discrepant results between DS^5,6 and MRV studies.^11⇓–13 Although our intrarater reproducibility results showed modest-to-high agreement for the detection of the type and number of intraluminal abnormalities, the inter-rater agreement for these abnormalities showed low reproducibility for the detection of type and modest reproducibility for the detection of number. In the present study, the presence of intraluminal abnormalities did not imply the presence of functional abnormality or significant IJV stenosis (cross-sectional area, ≤0.3 cm²). Therefore, the results from this study suggest that HCs also present frequently with intraluminal abnormalities, as recently reported.^6,10 The possible origin of these abnormalities could be congenital,²⁶ aging-dependent, or a possible consequence of an inflammatory process.⁶ Therefore, further research is needed to determine whether these anomalies represent a pathologic condition or a physiologic variation.

No significant intraluminal differences were seen in patients with progressive versus nonprogressive MS, which could indicate that intraluminal abnormalities may appear earlier in the disease process. However, we found that age in patients with progressive MS correlated with the presence of DS intraluminal abnormalities. Although we did not find a relationship between age and the number of intraluminal abnormalities either in HCs or in the entire MS group, it cannot be excluded that the prevalence of these abnormalities is aging-dependent. A recent study that investigated IJV changes with aging in HCs found a decreased proportion of venous drainage and increased IJV reflux prevalence in older subjects.²⁷

In the present study, a trend toward a higher prevalence and number of extraluminal abnormalities was found in patients with MS compared with HCs on DS, whereas more patients with progressive-versus-nonprogressive MS presented with those anomalies. The presence of an annulus was not detected, contrary to previously reported results.^5,16 Both intra- and inter-rater reproducibility showed modest-to-high agreement for the presence and number of extraluminal abnormalities. Therefore, our reproducibility data suggest that DS evaluation of extraluminal abnormalities is less operator-dependent and could be more reliable in the evaluation of the venous anomalies in the IJVs.

On DS, patients with MS showed a significantly higher prevalence and number of functional abnormalities in the IJVs than HCs. No differences were seen between patients with progressive and nonprogressive MS. The most prevalent abnormality was reflux in patients with MS and in HCs, followed by no flow. A recent study found a strong correlation between jugular venous reflux and age-related white matter changes in elderly healthy subjects.²⁸ Although a significant relationship was found between the number of functional and the number of intra- and extraluminal abnormalities, this relationship could explain, at best, only 20% of the variance. In addition, modest-to-high intrarater agreement for the detection of type and number of functional abnormalities was not observed for inter-rater agreement. More quantitative measures for the definition of functional abnormalities such as blood flow velocity and blood volume flow could be potentially more reliable in assessing the degree of venous outflow obstruction in the IJVs.⁷

An attempt was made to distinguish intra- versus extraluminal structural and functional abnormalities in the IJVs with both MRV techniques used in this study, but ultimately, this distinction was not possible.^13,25 Consequently, all MRV abnormalities were classified as flow abnormalities due to possible intra- or extraluminal origin. No significant differences on the morphologic flow MRV scale were found between patients with MS and HCs, in line with 3 recently published smaller scale MRV venous flow studies.^11⇓–13 In a recent study,¹³ modest-to-low scan-rescan reproducibility agreement between baseline and follow-up MRV was detected. Nevertheless, we found significantly more flow abnormalities in patients with progressive versus nonprogressive MS both on TOF and TRICKS, confirming the DS extraluminal results. One of the limitations in the present study is the use of conventional MRV techniques, which are more prone to artifacts compared with other more advanced approaches.^12,29 Although we did not perform contrast MRV sequences in HCs as recommended by our institutional review board, we showed high correlation between TOF and TRICKS in the present and previous studies.^25,30

In the present study, there was a trend toward a higher number of collateral veins in patients with MS compared with HCs, contrary to our previous study.¹³ Patients with MS with a higher number of DS intraluminal IJV flow abnormalities showed a significantly higher number of collateral veins on both MRV sequences. No significant difference in the number of collaterals between patients with nonprogressive versus progressive MS was found. These results indeed provide an important finding, because they support the existence of collateral circulation as a possible compensatory mechanism for the higher number of functional and intraluminal abnormalities in the IJVs, as previously proposed.^5,16 It could be hypothesized that collaterals develop as a compensatory mechanism for the presence of intraluminal structural flow abnormalities; and when their compensatory ability is overcome, extraluminal abnormalities begin to develop. This theory is supported by recent work of Yamout at al,¹⁴ who performed CV on 42 patients with MS in various phases of the disease (at onset and after 5 and 10 years) and found that extracranial venous stenosis was very rare at onset but became more frequent in subjects with longer MS duration. We considered the use of DS for visualizing collaterals; however, due to Doppler inability to follow the complete course of the collateral vein, we were unable to identify the vein with 100% accuracy. Therefore, MRV is more accurate than DS for following and labeling collaterals of the extracranial venous system. In a majority of cases, there was also a correlation between the size of the ipsilateral IJV and collateral veins, meaning that prominent collaterals followed stenotic IJVs with no visible flow. However, there were cases with normal patent IJV lumens and prominent collaterals. If the IJVs are developmentally smaller, then the other veins would likely be more prominent. Longitudinal studies should investigate the evolution of collaterals in stenotic or developmentally smaller IJVs.

We did not find VV flow differences on MRV and DS between patients with MS and HCs or between MS subgroups, which is in line with recent studies.^13,25

The value of DS and MRV for screening of CCSVI was tested against CV with promising results in 2 recent pilot studies that included patients with MS and HCs.^25,30 In 1 of these studies, DS showed 82% sensitivity, 100% specificity, and 99% positive and 95% negative predictive values compared with CV in 10 patients with MS.²⁵ However, another recent study found no overlap between CV and DS in 7 of the 8 patients who presented with a sonographic finding of CCSVI.⁹ A multimodal approach by using noninvasive and invasive diagnostic techniques is recommended to determine the degree of extracranial venous structural and functional impairment in patients with MS and HCs.

One of the limits of this study is that we did not use invasive CV to confirm the DS and MRV findings. Although CV is considered the criterion standard for assessing and grading endovascular stenoses, CV is merely lumenography, providing little or no data on the wall of the vessel or its intraluminal structures. Malformed and/or reversed valve cusps can be crossed by the catheter and kept open artificially, thereby preventing documentation of stenosis.²⁴ No established criteria or guidelines currently exist on CV for the detection of venous anomalies indicative of CCSVI.²⁴ Any venous lumen reduction >50% on CV is considered a sign of significant stenosis, which is somewhat arbitrary.^5,16 More sophisticated CV categoric criteria (ranging from grade 1 to grade 4) were recently proposed.¹⁵ Our preliminary experience with CV^25,30 indicates that proper training is needed for recognition of pathologic intraluminal anomalies indicative of CCSVI and that more sophisticated criteria for detection of these anomalies, such as time to empty contrast from veins or waisting of the balloon, need to be tested and validated.²⁴ In addition, CV is an invasive method that requires radiation exposure, and there are ethical concerns in applying this technique to a large group of HCs.

Another limitation of our study is that we did not measure directly the venous pressures and flow patterns in the dural venous sinuses (the common pathway out of the brain before the cervical veins) to demonstrate any evidence of increased pressure or abnormal flow patterns, such as reflux or bidirectional flow. Additionally, because there are no indications that patients with sinus thrombosis and elevated intracranial pressures or those with jugular occlusions or resections (eg, with radical neck dissections) ever develop demyelinating lesions,²⁰ our DS and MRV findings need further evaluation.