The Great Debate: CCSVI and MS
Written by Al Ossorio

Related Documents:

CCSVI Treatment and Efficacy

CCSVI Treatment Risk


The Great Debate: Quick Facts
  • Research linking CCSVI and MS is very controversial: some research shows a clear link, other research suggests that CCSVI does not exist at all.
  • The best way to make sense of the conflicting data is to perform a "meta-analysis." A meta-analysis "rolls-up" results from many studies and examines the trends that emerge.
  • CCSVI Alliance' meta-analysis addressed this question: DOES CCSVI EXIST, and if so, IS IT RELATED TO MS?
  • The meta-analysis considered a wide range of research. Data was "rolled up" and presented in Graph 1 (see main text). The results suggest three key points: 
    1. The overall weight of existing research suggests that CCSVI likely does exist.

      However, the relationship between CCSVI and MS, while statistically significant, is not as high as initially proposed.
    2. The debate is not settled: more research is needed.
    3. Current research does not adequately address the question of whether CCSVI is a cause or a consequence of MS
  • Future CCSVI research must avoid the mistakes of past efforts. Specifically, CCSVI research must
    1. Use a consistent definition of CCSVI
    2. Use reliable technologies for measuring CCSVI
    3. Ensure that investigators get hands-on training from experienced CCSVI researchers (poorly trained researchers have contributed to unreliable data about CCSVI)
    4. Develop new methods for defining and measuring


A great debate has emerged: does CCSVI exist? Is it linked with MS?

Summarizing the current research on CCSVI is not simple – the results are wildly contradictory. Consider the following:

As researchers, patients, and physicians, what do we make of these conflicting conclusions?

Clearly, given the contradictory research, no truly definitive statements about CCSVI can currently be made. However, a careful review of the studies does reveal important trends, and hints at where and how research should proceed.

Before moving on, we must clarify one issue:  This article does NOT address CCSVI treatment effectiveness.  Some may be disappointed by this, but the fact is that only two studies have explored CCSVI Treatment.16, 17 Both were “open label” (not scientifically conclusive), and both found similar results (that treatment may help, but that more research is needed before any conclusions can be drawn). Thus, no contradictions in treatment data currently exist.  Obviously, there is widespread dispute about CCSVI Treatment, but this dispute is not grounded in research, because science has not yet addressed the issue.

Hopefully, results from the several CCSVI clinical trials currently underway will emerge over the next twelve months, and then we will have some good treatment data to consider. Until then, we are left to consider research that does exist, and what it has to say about the presence of CCSVI and its relationship (or lack of relationship) to MS. To this end, however, we will consider how the two existing treatment studies factor into the debate over the existence of CCSVI and its connection to MS.

Lastly, CCSVI Alliance considers this a “living document” that will be updated and refined as additional research data becomes available, and as additional researchers and informed patients and physicians review and respond to the material.


Making Sense of the Research

To date, over 40 studies or articles investigating CCSVI have been published.  However, only a subset of these focuses on the heart of this debate:  does CCSVI exist, and if it does, is it associated with MS?

Given this subset of studies, a possible starting point is simply to count them up. Hence, Table 1 below summarizes relevant findings:

(Please note that for brevity’s sake we will refer to studies by the principal researcher’s last name and the year in which the study was conducted. Further, when a team/center has conducted multiple studies and all studies have found similar results (e.g. Zamboni and colleagues; Zivadinov and colleagues), we will only list that team’s work once.)

Table 1: Studies Measuring the Presence of CCSVI in MS Patients

Studies supporting CCSVI in MS

Studies not supporting CCSVI in MS

Zamboni, 2009

Mayer, 2011

Simka, 2010

Barachinni, 2011 (see note below)

Al Omari, 2010

Doepp, 2010 (see note below)

Yamout, 2011

Krogias, 2010

Zivadinov, 2011

Sundstrom, 2010

Wattjes, 2011

Centonze, 2011

Note: Negative results from Barachinni 2011 and from Doepp 2010 have been professionally disputed in the literature.

Unfortunately, simply counting the studies doesn’t tell us much: what does five studies supporting CCSVI in MS versus seven studies refuting CCSVI in MS actually mean?

More importantly, when looking carefully at each of these studies, we see vast differences not just in results, but in the methods and technologies used to measure CCSVI, the type of study conducted (open label, Blinded/controlled), the very definition of the phenomenon being measured (CCSVI), and even in conclusions drawn from the same results.  In fact, the closer we look at the research, the more clouded the picture becomes.

Nonetheless, despite this complexity, we can make some sense of this research.   Here’s how: we will conduct a meta-analysis. A meta-analysis is a scientific process where results from multiple studies are selected, vetted, combined, and analyzed.  A meta-analysis can help reveal the “big picture" (or trends) that emerge from a group of studies that may, individually, report conflicting results.

The objective of our meta-analysis will be to determine whether CCSVI exists, and if so, whether it is associated with MS . To this end, the meta-analysis will give us a formal process to review current research and discern any meaningful patterns. More specifically, we our meta-analysis process will:

  1. Define “inclusion criteria” to help determine what types of research can and can’t answer our question. (Does CCSVI exist and, if so, is it associated with MS?)
  2. Seek out and identify relevant research that can answer our question.
  3. Review and analyze eligible research, noting and accounting for any biases that may impact the reliability of the study’s results.
  4. Analyze and “roll up” results from all eligible studies to discern any “big picture” trends.
  5. Review and discuss the trends. Describe what research is needed to clarify issues that remain uncertain, and note problems or shortcomings in research which have contributed to the current confusion.

Please see our note in the Appendix for more information on biases our methodology.


CCSVI Meta Analysis - Getting Reliable Information from the Studies We Have

Finding Studies for Review

Table 1 above lists all studies listed in PubMed (as of June 1, 2011), that self-describe as answering the question of whether CCSVI exists, and whether it is or is not related to MS. Because PubMed is by no means exhaustive, we have cross-checked our list with informal lists maintained by various on-line CCSVI research tracking sites, and have confirmed that PubMed currently lists most studies that are available in English. (This is likely because CCSVI research is comparatively new and most research has been conducted by either U.S. or E.U. research sites.)

Note: A very large group of studies that either describe specific aspects of CCSVI, or attempt to measure ancillary/downstream effects of CCSVI, are not included in our analysis because they are not directly investigating our research question: does CCSVI exist, and, if so, is it associated with MS.  Please see our note on Inclusion Criteria in the Appendix for more information.

Inclusion  Criteria

Clearly, a study’s self-described assessment of its merit is not sufficient to determine whether it actually does address our objective (Does CCSVI exist, and if so, is it associated with MS?).  Studies that use incompatible approaches, conflicting or inadequate definitions of what is being studied, or unreliable diagnostic means, cannot in fact answer our question.

Thus, we have defined a very specific set of criteria for evaluating each study and determining whether each study does in fact address our question. In short, we begin by evaluating whether the “methods and means” used by each study are sufficient for addressing whether CCSVI exists and if it is related to MS. (“Methods” refers to the soundness of the study’s scientific methodology. “Means” refers to the suitability of the diagnostic technologies and processes used to acquire the study’s results.)

Specifically, our inclusion criteria are outlined as follows:

The only published formal definition of CCSVI is Dr. Zamboni’s 5-part technical definition of CCSVI.  Studies reporting results that do not define CCSVI using Dr. Zamboni's five part technical definition simply cannot be compared against studies that do. Thus, studies not using the  5-part definition of CCSVI cannot meet the inclusion criteria and will not be included in the analysis.

Please note: We recognize that Dr. Zamboni’s definition of CCSVI has been questioned. However, no other researchers have proposed an alternative definition, and no research has cast doubt specifically on Dr. Zamboni’s definition. Thus, the only way to systematically measure CCSVI must adhere to the only existing definition of CCSVI. In other words, research not employing Dr. Zamboni’s criteria is not measuring CCSVI; it is measuring something else instead. This will remain true until the current definition is changed, or until other measures/definitions of CCSVI are proposed and corroborated. (For more discussion of these issues, please see Definitions in the Appendix.)

At present, the only scientifically validated method for measuring CCSVI via the 5-part definition is a very specific use of Doppler sonography (DS). Importantly, the reliability and reproducibility of measuring CCSVI via Doppler sonography has been demonstrated in three distinct studies across two continents.18,19,20 Hence, we will exclude research that does not measure CCSVI via Doppler Sonography.

We appreciate that requiring DS to measure CCSVI is limiting; however, until alternative definitions of CCSVI are proposed, and methods for measuring CCSVI via alternative means are identified, we have no choice but to move forward with the only existing validated processes and definitions.

Note: Excluding Magnetic Resonance and venographic research does NOT mean that MRI/MRV and venography are invalid tools for investigating CCSVI. To the contrary – MRV (especially via the Haacke-Hubbard protocol) and venography are essential and irreplaceable tools for investigating CCSVI.  However, MRV and venography simply cannot measure CCSVI via Dr. Zamboni’s 5-part technical definition. To learn more, please see our notes on MRV/Venography in the Appendix.

Simply put, the question of CCSVI's relationship to MS cannot be clearly addressed without using a healthy control group for comparison.

Note: For those concerned about the exclusion of studies not using healthy controls, please see our note on Healthy Controls in the Appendix.

Next, we can apply our inclusion standards to the research listed in Table 1, and determine which research is NOT eligible for inclusion (that is, which research cannot reasonably address our central question: Does CCSVI exist, and is it related to MS?). Research not meeting our inclusion requirements includes:

Finally, we note that one study (Barachinni, 2011) proved difficult to assess: it used both DS and venography for diagnosis, but came to different results based on the respective technologies. Lacking an ideal solution, we will allow both the positive and negative results from Barachinni, 2011 (for more information, please see the Barachinni discussion in the Appendix).

Moving forward, we can now update Table 1 to include only research that passes eligibility requirements for legitimately answering the question “Does CCSVI Exist, and if so, is it related to MS?”:


Table 2: Validated (Eligible) Studies Measuring the Presence of CCSVI in MS Patients

Studies supporting CCSVI in MS

Studies not supporting CCSVI in MS

Zamboni, 2009

Doepp, 2010

Al Omari, 2010

Mayer, 2011

Zivadinov, 2011

Centonze, 2011

Barachinni, 2011

Barachinni, 2011

Next, using the studies in Table 2, we proceed to the next phase of the meta-analysis: determining which of the eligible studies offer more convincing results and which offer less convincing results. In other words, while all studies in Table 2 have met the inclusion requirements, they are not all “equal.” Important factors separate them and strongly suggest that results from some studies should be given greater weight than others (here, “weight” reflects the probable predictability/accuracy of the study’s results).

To weigh the studies in Table 2, we consider each study with respect to three factors known to impact the accuracy and/or reliability of research results: 

  1. The size of the study.
  2. Whether the researchers were trained in CCSVI diagnosis (to minimize bias effects).
  3. Whether the study used a blind (more reliable) or open label (less reliable) protocol to minimize bias effects.

Study Size

The larger the sample size of a study, the more suggestive the results (assuming all other variables and biases are equal). Given the studies in Table 2 above, we can rank the size of each study based on the number of subjects involved:

Largest Study:

Intermediate-sized Studies

Smaller Studies:

Next, given that CCSVI diagnostic accuracy has been very clearly tied to training18, we can prioritize all studies in Table 2 based on the diagnostic experience of the investigators:

More Reliable (investigators had hands-on training in CCSVI diagnosis via Doppler ultrasound. Training information was obtained from study’s methodological and/or discussion section):

Less Reliable (higher probability of errors in the results):

Lastly, we can quickly separate out the studies that used a blinded/controlled protocol (more reliable) from those that did not (less reliable).

Blinded/controlled studies

Unblinded (less reliable)


Putting the Picture Together

Finally, we can compile all this information into a single comprehensive snapshot, as seen in Graph 1 below, which provides a comprehensive view of all eligible studies, weighted for accuracy/predictability, and plotted on two dimensions:

1) Does CCSVI exist?
2) Does CCSVI contribute to MS?




Given Graph 1 above, several key points become apparent.

  1. The overall weight of the research trends toward suggesting that CCSVI exists and is associated with MS.
    1. Two of the three largest studies (particularly BNAC 2011, which included by far the largest number of patients, together with data validating their diagnostic technique) support CCSVI in MS.
  2. The debate over the presence of CCSVI in MS remains unsettled.
    1. Results from Centonze, 2011, produce an intriguing counterweight to Zivadinov, 2011 and Zamboni, 2009. Centonze, 2011, raise legitimate questions about the presence of CCSVI in MS.
  3. As a whole, the results do not address the question of whether CCSVI may play a contributing role in MS or may be a consequence of MS.
    1. Results from Zamboni 2009 and Al Omari 2010 hint that CCSVI may play a causative role in MS.
    2. All results suggesting that CCSVI doesn't exist (Mayer 2011, Doepp 2010, Barachinni 2011, Centonze 2011) portray CCSVI as having no causative role in MS.
    3. BNAC 2011 suggests that CCSVI does not have a "primary" causative role in CCSVI. However, BNAC does note that "the role of CCSVI in contributing to or being a consequence of MS progression cannot be excluded and should be further investigated."7



New theories often enter the scientific discourse amid a flurry of conflicting data. In fact, inconsistencies or gaps in the data often spur the development of new theories to begin with.

Further, during early stages of research, results may be particularly confusing. Consider, for example, the decades-long debate and starkly differing research results on the link between smoking and lung cancer. Thus, we should not be surprised that research on CCSVI has produced conflicting results.

Studying CCSVI is complicated. Diagnosis requires expertise in a particular application of Doppler sonography and, in the best cases, catheter venography, vascular science and neurology, together with a deep understanding of CCSVI theory.  It is, however, precisely this complexity that has allowed us to make some sense of the data:  by excluding studies whose methods or means were technically insufficient to determine whether CCSVI exists, we have simplified the research landscape and made clear at least three important trends:

  1. The preponderance of evidence trends toward suggesting that CCSVI does exist and is correlated with MS.
  2. Due to conflicting data from well-designed studies, the debate over the existence of CCSVI is not settled.
  3. At present, research focusing on the presence of CCSVI does not clearly address whether CCSVI is a contributor to, a consequence of, or perhaps even unrelated to, MS.

Most apparent in Graph 1 is the weight of evidence provided by Zivadnov, 2011, which remains by far the largest, most well documented, and arguably most accurate study to date. With results falling very much in the middle of the debate, Zivadinov 2011 casts doubt on the degree of association between CCSVI and MS reported in Zamboni, 2009, as well as on the failure to find any association between MS and CCSVI as reported by Doepp 2010, Mayer 2011, and Barrachini, 2011. (It should be noted that results from Doepp, 2010 and Barrachini, 2011 have also been professionally disputed in the literature.)

Given these results, CCSVI begins to appear similar to many other factors associated with MS. Like genetic markers, geographic region, sunlight/vitamin D levels, exposure to certain viruses, or smoking, we see a higher prevalence in MS patients, but of course not in all MS patients. Further, as with all these factors, we see varying degrees of the same in healthy controls.

While these results suggest that CCSVI is not the sole cause of MS, the research has in no way excluded that CCSVI may (or may not) play a contributing role in both disease emergence and/or progression.

Moreover, while both published CCSVI treatment studies have been open label, both have nonetheless documented a plausible association between CCSVI treatment and alleviation of symptoms for at least some MS patients. This data, while suggestive only, adds an additional dimension to the notion that CCSVI and MS may indeed be related.

Given these findings, it becomes clear that the urgent need for well-designed studies continues.

HOWEVER, new research must avoid the missteps of past efforts. Specifically, we urge the scientific community to use the methods and means proven to produce accurate results (or, better still, to propose and validate more reliable alternative approaches to measuring CCSVI). Specifically:

  1. Until a new definition of CCSVI is proposed, future studies not relying on the current 5-part definition of CCSVI simply cannot make credible research claims about the existence (or lack thereof) of CCSVI.  

    We appreciate the limitations of the current 5-part definition, but, at present, it is the only definition available.
  2. Until non-ultrasound methods for documenting CCSVI are validated and available, studies not employing Doppler ultrasound (DS) cannot make credible claims about the existence (or lack thereof) of CCSVI. Research "proving" that CCSVI does or doesn't exist via techniques not shown to reliably measure CCSVI is a waste of everyone's time.  

    , we are in no way denying the value of MR and Venographic technologies. Indeed, both are potentially superb at documenting the characteristics of the venous anatomy. Moreover, both are invaluable tools for treating physicians. However, at present, MR and venography simply cannot measure CCSVI via the 5-part definition of CCSVI.
  3. Studies not using technicians specifically trained in CCSVI diagnosis cannot be relied on to provide accurate results. Peer reviewed published data supporting this conclusion has been widely available since early 2010.18,19,20  

    Research "proving" that CCSVI does or does not exist that is published by researchers who have not been specifically trained in CCSVI diagnosis should be given little weight (and, potentially, are a waste of everyone's time and money).
  4. The methods and means for diagnosing CCSVI must be improved.  

    The current Doppler Ultrasounds process is prone to error and difficult to reproduce. This places considerable time and resource burdens on researchers looking to conduct legitimate investigations of CCSVI.

    Those seeking to advance CCSVI research must focus on creating a diagnostic approach that is more clearly defined, easier to reproduce, and less reliant on diagnostician training. Moreover, the relationship between Doppler diagnosis of CCSVI, MR investigations of CCSVI, and catheter venographic investigations of CCSVI must be better understood.




--------------------------------        End of Main Text       ---------------------------------------


(Additional and Supporting Information (linked from the text above)

Additionally, most meta-analyses rely heavily on statistical analysis, yet you will find that the present analysis does not. The bias present in many of the studies is extensive, and there is no rational (statistical) method for weighting that bias (e.g. all studies not using researchers trained in CCSVI diagnosis are suspect, as research has shown that diagnosis requires extensive training). Thus, the amount of data from fully qualified studies is relatively narrow, and we found that a graphical representation of the data (as found in Graph 1 above) was more effective and informative than a statistical analysis.

However, it is currently impossible to use MRV or venography to measure CCSVI per the 5-part definition of CCSVI. This is because the definition requires venous blood flow measurements in various patient postures (from upright to supine), but MRV and venography cannot measure a patient in the upright position). Moreover, while many treating physicians are using the Haacke-Hubbard MRV protocol, most published research has not.







1. Zamboni P, Galeotti R, Menegatti E, Malagoni AM, Tacconi G, Dall'Ara S, Bartolomei I, Salvi F. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2009 Apr;80(4):358.

2. Zamboni P, Consorti G, Galeotti R, Gianesini S, Menegatti E, Tacconi G, Carinci F. Venous collateral circulation of the extracranial cerebrospinal outflow routes. Curr Neurovasc Res. 2009 Aug;6(3):204-12.

3. Al-Omari MH, Rousan LA. Internal jugular vein morphology and hemodynamics in patients with multiple sclerosis. Int Angiol. 2010 Apr;29(2):115-20.

4. Simka M, Kostecki J, Zaniewski M, Majewski E, Hartel M, et al. Endovascular treatment for chronic cerebrospinal venous insufficiency: is the procedure safe? Phlebology. 2010 Dec;25(6):286-95.

5. Zivadinov R, Schirda C, Dwyer MG, et al. Chronic cerebrospinal venous insufficiency and iron deposition on susceptibility-weighted imaging in patients with multiple sclerosis: a pilot case-control study. Int Angiol. 2010 Apr;29(2):158-75.

6. Menegatti E, Genova V, Tessari M, Malagoni AM, Bartolomei I, Zuolo M, Galeotti R, Salvi F, Zamboni P. The reproducibility of colour Doppler in chronic cerebrospinal venous insufficiency associated with multiple sclerosis. Int Angiol. 2010 Apr;29(2):121-6.

7. Zivadinov R, Marr K, Cutter G, Ramanathan M, Benedict RH, Kennedy C, Elfadil M, Yeh AE, Reuther J, Brooks C, Hunt K, Andrews M, Carl E, Dwyer MG, Hojnacki D, Weinstock-Guttman B. Prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in MS. Neurology. 2011 Jul 12;77(2):138-44.

8. Doepp F, Paul F, Valdueza JM, Schmierer K, Schreiber SJ. No cerebrocervical venous congestion in patients with multiple sclerosis. Ann Neurol. 2010 Aug;68(2):173-83.

9. Krogias C, Schröder A, Wiendl H, Hohlfeld R, Gold R. "Chronic cerebrospinal venous insufficiency" and multiple sclerosis: critical analysis and first observation in an unselected cohort of MS patients. Nervenarzt. 2010 Jun;81(6):740-6.

10. Worthington V, Killestein J, Eikelenboom MJ, Teunissen CE, Barkhof F, Polman CH, Uitdehaag BM, Petzold A. Normal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency. Neurology. 2010 Nov 2;75(18):1617-22.

11. Baracchini C, Perini P, Calabrese M, Causin F, Rinaldi F, Gallo P. No evidence of chronic cerebrospinal venous insufficiency at multiple sclerosis onset. Ann Neurol. 2011 Jan;69(1):90-9. doi: 10.1002/ana.22228.

12. Mayer CA, Pfeilschifter W, Lorenz MW, Nedelmann M, Bechmann I, Steinmetz H, Ziemann U. The perfect crime? CCSVI not leaving a trace in MS. J Neurol Neurosurg Psychiatry. 2011 Apr;82(4):436-40.

13. Worthington V, Killestein J, Eikelenboom MJ, Teunissen CE, Barkhof F, Polman CH, Uitdehaag BM, Petzold A. Normal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency. Neurology. 2010 Nov 2;75(18):1617-22.

14. Centonze D, Floris R, Stefanini M, Rossi S, Fabiano S, Castelli M, Marziali S, Spinelli A, Motta C, Garaci FG, Bernardi G, Simonetti G. Proposed chronic cerebrospinal venous insufficiency criteria do not predict multiple sclerosis risk or severity. Ann Neurol. 2011 Jul;70(1):52-9. doi: 10.1002/ana.22436.

15. Yamout B, Herlopian A, Issa Z, Habib RH, Fawaz A, Salame J, Wadih A, Awdeh H, Muallem N, Raad R, Al-Kutoubi A. Extracranial venous stenosis is an unlikely cause of multiple sclerosis. Mult Scler. 2010 Nov;16(11):1341-8.

16. Zamboni P, Galeotti R, Menegatti E, Malagoni AM, Gianesini S, Bartolomei I, Mascoli F, Salvi F. A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. J Vasc Surg. 2009 Dec;50(6):1348-58.e1-3.

17. Malagoni AM, Galeotti R, Menegatti E, Manfredini F, Basaglia N, Salvi F, Zamboni P. Is chronic fatigue the symptom of venous insufficiency associated with multiple sclerosis? A longitudinal pilot study. Int Angiol. 2010 Apr;29(2):176-82.

18. Menegatti E, Genova V, Tessari M, Malagoni AM, Bartolomei I, Zuolo M, Galeotti R, Salvi F, Zamboni P. The reproducibility of colour Doppler in chronic cerebrospinal venous insufficiency associated with multiple sclerosis. Int Angiol. 2010 Apr;29(2):121-6.

19. Hojnacki D, Zamboni P, Lopez-Soriano A, Galleotti R, Menegatti E, Weinstock-Guttman B, Schirda C, Magnano C, Malagoni AM, Kennedy C, Bartolomei I, Salvi F, Zivadinov R. Use of neck magnetic resonance venography, Doppler sonography and selective venography for diagnosis of chronic cerebrospinal venous insufficiency: a pilot study in multiple sclerosis patients and healthy controls. Int Angiol. 2010 Apr;29(2):127-39.

20. Zivadinov R, Galeotti R, Hojnacki D, Menegatti E, Dwyer MG, Schirda C, Malagoni AM, Marr K, Kennedy C, Bartolomei I, Magnano C, Salvi F, Weinstock-Guttman B, Zamboni P. Value of MR venography for detection of internal jugular vein anomalies in multiple sclerosis: a pilot longitudinal study. AJNR Am J Neuroradiol. 2011 May;32(5):938-46. Epub 2011 Apr 7.