This preliminary open study confirms that endovascular treatment for CCSVI in RR-MS patients seems to be safe (16
) and suggests that it might, if used as an adjunct to the usual immunomodulating or immunosuppressive therapy, have sustained beneficial clinical effects, in terms of decreased annual relapse rate and disability.
However, several elements suggest that caution should be exercised in generalizing these results. These include the small sample size, the study design (different from that of a randomized clinical trial), the fact that the study was carried out in two single centers (specializing respectively in neurological assessment and endovascular therapy), the gross clinical measurements used to evaluate the therapeutic effects with the absence of neuroimaging techniques and, especially, the fact that neither the patients nor the clinical assessor were blind to the treatment. However, the self-controlled design is considered a valid tool for preliminary clinical studies (22
), while the annual relapse rate and the EDSS, notwithstanding their limitations, which include different definitions of the former (23
) and relatively low inter-operator agreement for the EDSS, especially for values <4.5 (24
), are accepted clinical outcome measures for new treatments of RR-MS (20
) because they are widely used and effectively photograph the clinical situation. Neurological testing and examination of functional systems are especially important at the “less severe” lower end of the scale, when a patient is still ambulatory, yet experiencing some abnormal signs or disability in other areas.
Finally, the regression of the mean error was a potential shortcoming in the design of our study.
The reasons why five of the 29 patients in our series had no benefit in terms of decreased annual relapse rate (4 patients) or EDSS score (4 patients) following endovascular treatment of CCSVI are not clear. Indeed, review of the endovascular treatment revealed that the vascular result aimed at was achieved. However, occasional cases of patients with a paradoxical increase of lesion activity detected on MR imaging following endovascular treatment of CSSVI have been reported (17
). Also, the high rate of re-stenosis of the extracranial veins in our sample, namely 45% in the two years after the first endovascular treatment session, is in line with a recent observation reporting a 27% re-stenosis rate after one year follow up in another patient sample (17
The lack of a correlation between decrease of annual relapse rate and EDSS in our patients seems to suggest that the endovascular treatment has two distinct beneficial effects. Moreover, it is in line with literature findings indicating a dissociation at biological level between recurrent acute focal inflammation and progressive degeneration of the central nervous system (25
We can only speculate on the mechanisms underlying the beneficial clinical effects of endovascular treatment of CCSVI in our MS patients. A recent perfusion MRI study indicated that hypoperfusion of the brain is associated with the severity of CCSVI in MS patients (26
Hence it is possible that resolution of the obstruction of the venous outflow through endovascular treatment could improve brain perfusion and prevent the tissue damage associated with disability. Interestingly, global brain hypoperfusion is an aspect of MS that cannot be explained by autoimmunity and/or focal disturbed flow linked with inflammation; by contrast, the hypoperfusion could be related to the presence of CCSVI (27
The mechanism accounting for the apparent decrease in the relapse rate following endovascular treatment of CCSVI is obscure. However it has been suggested that abnormal venous reflux in the cerebral and spinal veins associated with CSSVI increases the expression of adhesion molecules, particularly intercellular adhesion molecule-1, by the cerebrovascular endothelium (28
This, in turn, could lead to increased permeability of the blood-brain barrier. Inflamed and activated endothelium could secrete pro-inflammatory cytokines. In these settings, monocytes could transform into antigen-presenting cells and initiate an autoimmune attack against myelin-containing cells. Theoretically, resolution of the venous reflux with endovascular treatment may taper and ultimately extinguish the processes mentioned above and ultimately determine a decrease of the relapse rate.
Although the clinical follow up of our patients was too short to allow inferences about the potentiality of endovascular treatment of CCSVI as a means of preventing secondary progression in patients with RR-MS, this may actually be a consequence of the two beneficial effects mentioned above and constitute a real advance in the therapy of this type of MS. A longer clinical follow up of the present cohort is needed (29
In conclusion, the present preliminary study showing sustained beneficial clinical effects of endovascular treatment of CCSVI in RR-MS fully supports the design and execution of multicenter randomized controlled trials which include the use of neuroimaging techniques. Conversely it does not justify the use of endovascular treatment of CSSVI in RR-MS patients outside the boundaries of clinical studies.