In this study we described the association between MS and the altered modality of venous return determined by extracranial multiple venous strictures. In our controls, venography resembled the normal imaging of extracranial cerebrospinal veins.25
The hampered cerebrospinal venous drainage in patients with MS determines a complex haemodynamic picture defined as CCSVI. It is characterised by multiple substitute circles, with a very high incidence of reflux in both intracranial and extracranial venous segments, and loss of the postural regulation of cerebral venous outflow.
The mechanism underlying this reflux differs from the reflux caused by incompetence of the jugular valve. In the latter case, valvular insufficiency tested with Valsalva can be related to a picture of transient global amnesia.14
In our study, the reflux occurred in any body position without the need to elicit it by a forced movement, suggesting that it is not an expression of valvular incompetence but rather of a stenosing lesion that cannot be crossed with postural or respiratory mechanisms, thereby becoming a long-lasting reverse flow.
Substitute circles are alternative pathways or vicarious venous shunts29
() that allow for the piping of blood toward available venous segments outside the CNS. In accordance with the pattern of obstruction, both the intracranial and the intrarachidian veins can also become substitute circles; they permit redirection of the deviated flow, preventing intracranial hypertension. However, over time, they become overloaded because they carry two different flows, their own draining flow and the shunted flow ().
The ECD-TCCS protocol was performed once by a single team of investigators (EM and PZ: vascular technician and interpreting physician, respectively), thus not permitting the assessment of the intraobserver and interobserver variability coefficient. This is a limitation of our study because the assessment of the reproducibility of the proposed protocol, although beyond the aim of the present study, certainly deserves further investigation. However, it should be noted that our ultrasonic assessment can be easily performed in the clinical setting, and, despite the operator-dependency of ultrasounds, there is general agreement on the proposed technique.9–19
Our results need to address two main questions:
- Does CCSVI influence the clinical course of MS?
- Are venous stenoses the cause or products of MS?
First, we identified four main patterns of CCSVI, according to the location, number and association of venous stenosis, and the modality of collateral circulation.
We also observed that the PP course was related to a CCSVI pattern significantly different as compared with RR and SP, suggesting that the location of venous obstruction plays a key role in determining the clinical course.
For instance, PP course, characterised by a slowly progressive syndrome with spastic paraparesis and MRI demonstration of MS plaques in the spinal cord,20 30–32
was significantly associated with obstruction at several levels of the azygous vein and of the lumbar plexuses (type D pattern, , ). In this situation, venous blood of the spinal cord can be drained only in an upward direction and is shunted toward the venous plexuses inside the spine (), thus helping to explain the correlation between type D and spinal cord involvement in PP patients.
Figure 4 Selective venography and MRI in a clinically defined multiple sclerosis case with chronic cerebrospinal venous insufficiency pattern D. Left: selective venography showing membranous obstruction of the outlet of the azygous vein (AZY) combined with atresia (more ...)
In contrast, the RR course was significantly associated with type A and B patterns (83% of cases), and particularly to type A, a group in which three-quarters of patients were RR (). The more favourable clinical course could be explained in the latter by the presence of a patent IJV (), with a compensatory outflow function proved by increased CSA (data not shown). Finally, the conversion to SP course was consistently observed in type A, B, C patterns (95%), but proportionally higher in patients with both the IJVs blocked (56% of type C). However, longitudinal studies are needed, with clinical and advanced MRI analyses3
of MS diffusion over time and space in relation to the CCSVI patterns discovered and described in this study.
Second, regarding the causative role of CCSVI in MS, our review of the literature revealed descriptions of associations between the extracranial venous obstructive malformations described herein and disabling neurological pictures however, the latter were defined by these authors generically as myelopathies, without a precise diagnosis and any mention of MS.27 28
Venous hypertension has been hypothesised as a cause of MS,33 34
but in our study blood pressure was not found to be significantly different from that measured in controls. However, it has been recently demonstrated that a pressure gradient across a central vein stenosis of 2.2 cm/H2
O corresponds to a CSA reduction greater than 50%.35
In our study the pressure gradient across the stenosies between the cava and the azygous arch was significantly different and measured 3.9 cm/H2
O (). The gradient between the stenotic IJVs and the superior vena cava was lower, 1.8 cm/H2
O, but again significantly different.
Moreover, the absence of Doppler and venographic features of CCSVI in controls suggests that venous obstructions may be causative of MS rather than a coincidental finding.
Interestingly, similar venous stenoses considered to be congenital malformations have been described in other human diseases, that is, membranous obstruction of the inferior vena cava and a minor group of chronic venous diseases of the lower limbs.27 28
Such venous obstruction brings about an insufficient venous drainage, respectively, at the level of the liver and of the cutaneous tissue, subsequently causing inflammation, sclerosis, and degenerative lesions.24 25 36
In contrast with the malformation hypothesis, cases have been reported of white cell infiltration and endophlebohypertrophy in venous valves where endocarditis is present.37
Even though this correlation has never been studied in MS, reports of valvulitis in the course of significant inflammatory disease should certainly be taken into consideration, since they support the hypothesis that these malformations are a result of CDMS rather than a cause. However, if vessel abnormalities were due to an inflammatory-autoimmune disease, they would be less frequent in patients treated with immunomodulating/immunosuppressant agents. On the contrary, our analysis in the RR-SP group did not demonstrate an increased number of extracranial venous stenosing lesions in untreated as compared with treated patients.
Finally, an additional possibility could be related to the side effects of MS drugs on the venous wall, although these have never been reported.38
The hypothesis of venous malformations of congenital/developmental origin associated with CDMS seems to be plausible. Nevertheless, additional longitudinal studies are necessary to confirm this hypothesis, as well as to understand the contribution of chronic insufficient venous drainage of the CNS to the process of inflammation and neurodegeneration. Finally, on the basis of our study, we propose the introduction of the ECD-TCCS protocol when a patient presents the first acute episode of demyelinating origin, mostly involving the optic nerve, the so-called clinically isolated syndrome (CIS). Currently, only longitudinal clinical and MRI observation in time and space is capable of establishing the possible conversion of a CIS into a CDMS.20