CCSVI may it rest in peace…

Finally, it’s time for CCSVI to rest in peace! 

JAMA Neurol. 2017 Nov 18. doi: 10.1001/jamaneurol.2017.3825. [Epub ahead of print]

Efficacy and Safety of Extracranial Vein Angioplasty in Multiple Sclerosis: A Randomized Clinical Trial.

Zamboni P1, Tesio L2,3, Galimberti S4, Massacesi L5, Salvi F6, D’Alessandro R6, Cenni P7, Galeotti R8, Papini D9, D’Amico R10, Simi S11, Valsecchi MG4, Filippini G12; Brave Dreams Research Group.



Chronic cerebrospinal venous insufficiency (CCSVI) is characterized by restricted venous outflow from the brain and spinal cord. Whether this condition is associated with multiple sclerosis (MS) and whether venous percutaneous transluminal angioplasty (PTA) is beneficial in persons with MS and CCSVI is controversial.

To determine the efficacy and safety of venous PTA in patients with MS and CCSVI.
Design, Setting, and Participants:

We analyzed 177 patients with relapsing-remitting MS; 62 were ineligible, including 47 (26.6%) who did not have CCSVI on color Doppler ultrasonography screening. A total of 115 patients were recruited in the study timeframe. All patients underwent a randomized, double-blind, sham-controlled, parallel-group trial in 6 MS centers in Italy. The trial began in August 2012 and concluded in March 2016; data were analyzed from April 2016 to September 2016. The analysis was intention to treat.

Patients were randomly allocated (2:1) to either venous PTA or catheter venography without venous angioplasty (sham).

Main Outcomes and Measures:

Two primary end points were assessed at 12 months: (1) a composite functional measure (ie, walking control, balance, manual dexterity, postvoid residual urine volume, and visual acuity) and (2) a measure of new combined brain lesions on magnetic resonance imaging, including the proportion of lesion-free patients. Combined lesions included T1 gadolinium-enhancing lesions plus new or enlarged T2 lesions.

Of the included 115 patients with relapsing-remitting MS, 76 were allocated to the PTA group (45 female [59%]; mean [SD] age, 40.0 [10.3] years) and 39 to the sham group (29 female [74%]; mean [SD] age, 37.5 [10.6] years); 112 (97.4%) completed follow-up. No serious adverse events occurred. Flow restoration was achieved in 38 of 71 patients (54%) in the PTA group. The functional composite measure did not differ between the PTA and sham groups (41.7% vs 48.7%; odds ratio, 0.75; 95% CI, 0.34-1.68; P = .49). The mean (SD) number of combined lesions on magnetic resonance imaging at 6 to 12 months were 0.47 (1.19) in the PTA group vs 1.27 (2.65) in the sham group (mean ratio, 0.37; 95% CI, 0.15-0.91; P = .03: adjusted P = .09) and were 1.40 (4.21) in the PTA group vs 1.95 (3.73) in the sham group at 0 to 12 months (mean ratio, 0.72; 95% CI, 0.32-1.63; P = .45; adjusted P = .45). At follow-up after 6 to 12 months, 58 of 70 patients (83%) in the PTA group and 22 of 33 (67%) in the sham group were free of new lesions on magnetic resonance imaging (odds ratio, 2.64; 95% CI, 1.11-6.28; P = .03; adjusted P = .09). At 0 to 12 months, 46 of 73 patients (63.0%) in the PTA group and 18 of 37 (49%) in the sham group were free of new lesions on magnetic resonance imaging (odds ratio, 1.80; 95% CI, 0.81-4.01; P = .15; adjusted P = .30).
Conclusion and Relevance:

Venous PTA has proven to be a safe but largely ineffective technique; the treatment cannot be recommended in patients with MS.

In the disolute world of academia, careers are made on reputation alone, and nothing comes as close to questioning this as scientific integrity. Dr Paolo Zamboni first shot to fame following claims that 90% of MS subjects in an unblinded study demonstrated narrowing of their veins (internal jugular or azygous veins – see diagram above) leading to insufficient venous drainage of the brain. He was able to quickly link this with at the time known evidence of MS lesions having excess iron deposition and hypothesised that anomalous venous outflow may be a mechanism for this. And, so the phrase chronic cerebrospinal venous insufficiency (CCSVI) was invented and entered into the MS vocabulary (Singh and Zamboni J Cerebral Blood Flow & Metabolism, 2009). 

A decade on, after innumerable procedures to dilate supposed narrowed veins, the theory is disproved by MS researchers across the globe, leading to overarching statements from the EFNS, ENS Multiple Sclerosis Scientist Panel, and ECTRIMS Executive Committee: we “…emphasize the high risk and absence of a scientific basis for “liberation procedures” in MS patients“. So can Dr Zamboni find his way back from the footprints of obscurity? According to quaint and whimsical humorists in JAMA Neurology anything is possible.

This publication is openly available to all and is work from the ‘Brave Dreams’ (Brain Venous Drainage Exploited Against Multiple Sclerosis) team, which is a multi-centre, placebo-controlled (i.e. sham procedures were undertaken ?ethical) trial to investigate the safety and efficacy of CCSVI procedures in Italy. The trial comprised of both RRMS and SPMS, with disability scores (EDSS) 2-5.5 and a disease duration of 15y or less, also not receiving MS treatments (immunosuppressive or immunomodulatory) for at least 6 months. MS participants were assigned to either real dilatation or sham procedure at a 2:1 ratio. To maintain the blinding, during the sham procedures the surgeon had to pass the catheter into the venous system. In those assigned to the real dilatation, but there was no evidence of a narrowing, they still received the catheter venography but without the dilatation procedure. The endpoints were assessed at one year and included functional (not MSFC or EDSS but a composite of walking control, balance, manual dexterity, postvoid residual urine volume and visual acuity) as well as an MRI endpoints (T2 lesion loads, gadolinium enhancement, proportion of subjects free of new lesions).

The findings were that 41% in the real dilatation group and 49% in the sham group improved on the functional end point, and functional stability was maintained in 23% in the real dilation group and 22% in the sham group. A mixed outcome (improvement and worsening in some aspects) was found in 22% in the real dilatation group and 11% in the sham group. As for MRI, the number of new lesions on MRI at 12 months were not significantly different between the two groups, and the proportion of those free of new lesions did not differ between the two groups. Whilst, at 12 months 68% in real dilatation and 57% in the sham group (not statistically significant) were free of new or enlarging T2 lesions, and 73% in real dilatation and 49% in the sham group (P=0.08) were free of gadolinium enhancing lesions. Safety wise, there were no serious adverse events related to either the dilation procedure or the sham procedure.

The bottom line is that venous dilatation procedures did not result in clinical improvement or a statistically significant improvement in MRI activity.  The findings of this larger randomised, properly blinded study, therefore did not confirm the earlier positive findings from open-label pilot studies. 

Hopefully, this lays to rest CCSVI theorists and activists once and for all. Especially, since it comes from the man himself.

About the author

Neuro Doc Gnanapavan


  • Went to webpage of ProfGs number one fan….it says

    "snarky editorial that says that we should not pursue this treatment any further, and that CCSVI research is over".

    To recap—this published paper from the neurologists of the Brave Dreams trial just proved, conclusively-
    1. CCSVI is a real condition in people with MS.
    2. There are a variety of venous malformations. There were patients with closed jugular valves, refluxing blood flow, and hypoperfusion.
    3. Venoplasty was able to restore normal flow in 54% of the patients. Not all malformations can be treated with PTA alone.
    4. 63% of treated patients had no new MS lesions on MRI at 12 months.

    Doesn't this count for something? At least additional study?"

    Sorry to say no I'm afraid…its over.

    However, the HSCT social media storm will hits us again this week with the miracle cure. For neurologists reading are you ready

  • "HSCT social media storm". Yes but this no chemo plus stem cells. This is actually repairing the damage in CNS. A similar treatment in New York was given FDA not to peruse late phase 2 trials. The same technique is being used in stroke partients and ALS which is in phase 3. I think this maybe be the real thing!

  • "HSCT social media storm I've already decided without watching the programme this is the treatment for me. When can barts provide the equivalence of this treatment?. If not why not!!!!

  • "Flow restoration was achieved in 38 of 71 patients (54%) in the PTA group."

    So, there were really problems in the flow. But half were of the kind that PTA could not fix. I wonder if such problems are found in 93% of healthy individuals too. If not, then CCSVI is more real than ever.

  • The Jama paper acknowledges that CCSVI aka vein issues in MS patients exists.
    Why is that so hard to swallow?
    If the Neuro's doing the research study can acknowledge that the issue is real, and that PTA in some cases, and I say LOUDLY, some cases because this group was screened and the reasons for PTA not achieving an improvement were not listed. EVEN more important is that the % of improvement or otherwise was not published which is reason to be concerned that the methods and skills were sub-optimal.
    This can also be called changes between tests with or without PTA which has to be acknowledged and the Australian study (Alfred Study) did state that Doppler analysis tests taken that were months apart (without PTA simply observation of Dopple test over time in CCSVI) showed varying results has to be a factor of interest.
    So why does outright lying by saying that CCSVI doesn't exist improve this web sites credibility?

    • Conclusion and Relevance:

      Venous PTA has proven to be a safe but largely ineffective technique; the treatment cannot be recommended in patients with MS.

    • Dear NZer1, none of the docs here has ever accepted that valve malformations, vein entrappments or hypoplasias are real. They still talk about narrow veins as a plain description of their SHAPE and point to ultrasound studies that dealed with that SHAPE only.

      It is a luxury to ask for anything more. The only countermeasure is constructive critisism of their current views , namely all the flavours of alleged autoimmune or viral causes of MS.

  • From the commentary on the study "The study was smaller than initially intended, but the results suggested absolutely no benefit to treatment, with the primary end point actually favoring the sham procedure."
    You can read the (full (free to view) commentary here;

    "It is difficult to refute one’s own prior findings, but the authors have used the right methods to test the CCSVI theory and have yielded an unequivocal result."

    • Let's say it again: it was not the CCSVI theory that was tested, but PTA angioplasty as a way to treat CCSVI.

    • This might be a shock to you MD so take a seat and a pill.
      The study wasn't out to prove or deny CCSVI.
      The study conclusion was a mathematical assessment of the data regarding the PTA that was performed within the trial.
      Each individual px in the trial had a different occlusion or group of occlusions and therefore the % improvement or not of CCSVI by PTA cannot be a mathematical conclusion and statement.
      Take another pill if you need to.
      The issues that occur due to CCSVI can be MS or other neuro-degeneration diseases.
      The study results interpreted in the Jama article are not providing enough information to conclude whether PTA is effective in some but not all cases. That screams that the article is incomplete information and warrants further unbiased assessment of all the data and the outcomes, which Dr Zamboni is planning to do to give understanding to the scant report published by Jama.

    • Dear NZer1

      Happy to post if…I have not read the post or the paper so I can't comment….Sorry I have not had the time.

    • Randomised clinical controlled trials are the gold standard in science as long as the randomisation is maintained. The 2:1 randomization allows you to favour the treatment, which is now a favourite of every drug trial out there. The fact that this is not a drug trial and participants actually underwent their assigned treatments (i.e. compliance or adherence to treatment was not an issue), makes the findings of this study doubly irrefutable. By hanging onto personal ideologies, you are advertising the fact that people should just have whatever they believe that works for them, regardless of what science has found.

      If I take this discussion point out of the MS field into cancer; are you implying that despite no evidence in favour of the treatment from say RCT 'x', cancer patients the world-over should still under go that treatment simply based on belief? This is a slippery slope, and we left this behind decades ago.

      The fact that Dr Zamboni was first author in this paper means that these were his conclusions, or do you think JAMA Neurol had control over the final published article? If the latter, then that appeals to the character of Dr Zamboni, which is that despite disagreeing with the final conclusions, he still wanted his moment of fame!!! I don't think this is true in any sense of the word…

    • There is too much emphasis on the truly negative results of the treatment, but no reference to the fact that almost all participants had blood flow issues identified by both ultasonography and venography. That fact alone sheds new light to the pathology of MS, but is completely ignored.

      Doc, do comment on that, please.

  • I have no venous problem in the jugular, I even did Doppler to see this.
    What I have is vines (varicose veins) on my legs.
    But this my whole family has, and I'm the only case of MS after a relapse of IM.

    Now I saw a pwMS that had a lot of sequels and she did the HSCT and I was amazed how some sequels improved and some even disappeared.
    This much more caught my attention as treatment.

    • A dogmatic answer would be that a clear MS diagnosis is a verification of venous problems, but since we play in the field of arguments, to really exclude the possiblity of any venous problem, a mere neck ultrasound is not enough.

      You need catheter venography with IVUS to examine:
      – Both jugulars from the jugular foramen down to the junction with the brachiocephalic vein, with emphasis on the valve leaflets.
      – The azygos and hemiazygos veins
      – The left renal vein for possible nutcracker syndrome

  • It should never have been a therapeutic modality in the first place !!! Wasted dollars and tax-dollars, at that !!! The NMSS in the US of A spent about 6 million dollars or thereabouts. Scientists got to pad up their resumes; a couple of patients, meanwhile, died, unfortunately, because of this procedure in Stanford U, I believe. The beat goes on… MMPs. What else is new ?

    Avasarala J



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