We assessed the presence of CCSVI in MS patients and HCs, with a high interrater concordance (85.4% and 92.7%, respectively). Our study showed a higher prevalence of CCSVI in MS patients and a relatively higher specificity of CCSVI for MS, with a high OR for the diagnosis of MS vs HCs. The presence of CCSVI was strongly related to age in the whole sample and in MS patients, without any other clinical correlation. Single venous criteria were also related to age, and the absence of detectable flow in the IJV and/or VV (criterion 4) was more prevalent in PPMS patients compared with the other forms of MS, and was also related to age.
Our results are consistent with other studies that reported an increased prevalence of CCSVI in MS, despite our finding that sensitivity and specificity were lower than previously reported values
[4, 9, 10]. Our finding of a higher prevalence of criterion 4 in PPMS (58%) is also consistent with other studies that showed significantly more MR venography abnormalities in PP patients
, as well as a longer cerebral circulation time in patients with progressive MS compared with nonprogressive MS
[25, 26], suggesting a role of hypoperfusion in neurodegeneration.
We did not find any relation of CCSVI with any clinical or demographic parameters, apart from age. These results do not indicate that CCSVI has a primary causative role in MS, as recently suggested in a recent review
. Moreover, a strong correlation between CCSVI and age, especially in MS patients, does not favour the hypothesis of the congenital nature of neck vascular alterations. The absence of such a correlation in HCs in our study might be because of the small number of subjects in this group (power=30%). Haemodynamic alterations in neck veins, such as jugular reflux in elderly people, have been described, and interestingly, they are associated with infratentorial white matter hyperintensity
With regard to our finding of the correlation of criterion 4 with progressive forms of disease, the absence of flow in the IJV and/or VV could be related to factors that determine extrinsic compression of neck veins. The IJV passes below the sternocleidomastoid muscle to join the subclavian vein. Therefore, contraction of neck muscles or rotation of the head may result in a compression of these veins with a significant reduction in blood flow, even approaching complete occlusion
. The relation between vein biomechanics, surrounding muscle tone and trophism, and the fascial envelope has been demonstrated in the leg
[30, 31], but not in the IJVs. Moreover, in our study, the examiner paid attention to the inclination of the patient’s head and used an appropriate neck support to avoid hyperextension or rotation of the head. However, it is not possible to exclude with certainty the influence of neck muscles on venous haemodynamics, especially in patients with higher neurological disability. In the current study, progressive patients were older than nonprogressive patients, and criterion 4, similar to criteria 1 and 3, was related to age, confirming that this appears to strongly influence venous hemodynamic alterations in MS. Indeed, PP and SP patients who showed a similar mean age had a comparable prevalence of criterion 4 (p=0.053).
However, it remains unknown if CCSVI is a causal factor or a consequence of MS. Our findings suggest that CCSVI may be a secondary effect rather than a cause of MS, and they indicate that in MS patients, venous valves become less continent with ageing, in association with morphological and functional changes. Many reports have shown the presence of ageing-related increased fibrosis and thickening of the valve leaflets and vein wall
[32–36], and decreased compliance of the vein wall
[37–39]. Changes in compliance in the vein wall affect venous blood flow, and thickened, stiff leaflets disrupt normal blood flow during the valvular cycle. Several studies have reported hypoperfusion of brain parenchyma in patients with MS, advancing with disease progression
[40–43], and it is possible that neck venous anomalies develop secondarily to reduced perfusion. The combination of chronic hypoxia or intermittent hypoxia and haemodynamic factors creates conditions that convert the endothelium of veins to a proinflammatory and procoagulant phenotype
, which is characterized by the production of plasminogen activator inhibitor-1, release of von Willebrand factor, exposure of P-selectin, secretion of the vasoconstrictor endothelin-1, and production and release of reactive oxygen species. Moreover, hemodynamic forces are important modulators of vascular structure. In rabbits, progressive intimal thickening occurs when shear stress is reduced to subnormal levels with preserved endothelium
. There is no evidence of inflammatory infiltrates in neck vein walls in MS
. In MS patients, vein walls appear to undergo remodelling of collagen fibres, altering the collagen I/III proportion
. The presence of collagen alterations might be due to age-related changes in the vein wall and valves, which have been described in renal veins
. In our study, changes corresponding to those found in normal ageing of veins were found in MS patients, and interestingly, this phenomenon was more evident in progressive MS forms where changes in the vein wall and valves caused the most serious hemodynamic consequences. An interesting hypothesis was recently raised in an article suggesting that a neurological process could play a role in CCSVI progression through vasoactive substances (e.g., endothelin-1) or proinflammatory agents, which could act on previously susceptible segments of blood vessels (i.e., malformed vein valves)
. This hypothesis would explain the higher prevalence of CCSVI in MS patients and its relation to patients’ age. The same article also suggested a parallel between venous and aortic valves stenosis, which are different entities, but probably share common features. MS patient live in a state of venous stasis that can be attributed to excessive ageing of veins and venules secondary to three elements: 1) chronic inflammation that induces changes in structure and function of the vein wall (in particular, the endothelium); 2) MS-associated alteration in blood flow; and 3) a shift to a hypercoagulable state
[46, 47]. These changes are located in the trunk wall and the lesions are non-homogeneous and dispersed. The development of new and modern biomedical imaging techniques would be useful for investigating venous valvular pathophysiology in animal models and human subjects.