Venous Abnormalities and MS

Discovering and naming the condition

CCSVI (chronic cerebrospinal venous insufficiency) was first observed and named in 2008 by Professor Paolo Zamboni, a vascular surgeon from the University of Ferrara, Italy. In 1995, his wife, Elena Ravalli, had been diagnosed with MS at the age of 37.

He recognized the link between venous pressure, iron deposition and ulceration in venous disease of the legs1 and applied that knowledge to MS. His paper suggested that reflux pressure in the cerebral veins might induce leakage of blood around the small veins in the brain, subsequently leading to inflammation that causes MS and other diseases.

Zamboni presented his preliminary findings to the Royal Society of Medicine in London in July 2006.2 His hypothesis explained features of the illness, particularly the anatomical location of the inflammatory lesions in MS around small veins, and the well-described deposition of iron in those lesions.

Zamboni went on to study venous drainage from the brain in people with and without MS using ultrasound, both in Italy and with colleagues from Buffalo, New York, led by Dr. Robert Zivadinov.

Initially, in comparing 89 people with MS to a 60-person control group without MS using color Doppler ultrasound, Zamboni found reflux of venous blood back into the brains of people with MS and markedly higher venous resistance to blood flow.3 Zamboni and his colleagues devised a new form of ultrasound to measure venous blood returning to the heart from the brain, a technique that combined high-resolution echo-color-Doppler (ECD) and transcranial color-coded Doppler sonography (TCCS).4

In April 2009, they published a series of 65 people with MS and compared them using this combined technique to 235 control patients, of whom 45 had other neurological diseases.5 They devised five TCCS-ECD criteria and showed that none of the control patients had more than one of these five.

They reported 180 positive and 145 negative criteria in MS patients, and 33 positive and 1,142 negative criteria in controls, giving a 43-fold higher risk of MS for those patients with positive criteria. They coined the term chronic cerebro-spinal venous insufficiency (CCSVI) for the apparent venous obstruction they reported, and noted four distinct patterns of obstruction, with different clinical patterns of disease correlating with each one.

Testing the criteria

In a later CCSVI and MS study, testing the criteria they had devised in 109 people with MS and 177 control patients who were well or had other neurological diseases, they found that, if they used a cut-off of two or more of these five criteria, there was an exact fit with MS – every single patient with MS had two or more of the five criteria, and every single control patient, either well or with a different neurological disease, had fewer than two criteria.6

Note that until this point, the research had:

  • All been undertaken by Zamboni’s research team in Italy
  • Tested a diagnostic procedure they themselves had devised
  • Proposed a new previously unknown condition, CCSVI, for which this new test was 100% diagnostic
  • Shown that the new condition occurred only in people with MS and not in other people, with or without neurological disease

The testing using TCCS-ECD sonography had to this point all been un-blinded; i.e., the investigators using the ultrasound machine knew whether each patient being tested had MS or not, raising the issue of observer bias in interpretation of the scan.

Soon after, in December 2009, Zamboni and colleagues published their preliminary work in treating CCSVI with surgery.7 In an un-blinded study of 65 people with MS, they used percutaneous transluminal angioplasty (PTA) to “open” these proposed venous constrictions in a technique similar to what had been used in arterial conditions like coronary heart disease.

When this technique is used in heart disease, a catheter is threaded up through the big arteries in the groin and into blockages in the coronary arteries, before a balloon on its tip is inflated to stretch the vessel at points of stricture and, ideally, open the constricted vessel. In heart disease, a device called a stent is sometimes left in the vessel to keep it open. The technique is not often used in veins, which are large, floppy vessels that rarely become constricted.

US researchers from Buffalo soon joined Zamboni’s group in further investigating CCSVI. Neurologists Robert Zivadinov and Bianca Weinstock-Guttman published papers with Zamboni further evaluating diagnostic techniques for this new condition.8, 9 They then tried to validate Zamboni’s original findings in a group of people with MS in the US. Their CCSVI and MS results were reported in 2011.10 The results, comprising nearly 500 people, some with MS, some with no illness and others with other neurological diseases, showed:

  • Around 56% of people with MS had the criteria for CCSVI
  • About 23% of people with no illness had the criteria
  • Around 42% of people with other neurological conditions had the criteria

In the Methods section of the paper, the authors stated that “blinding was a challenge,” as in any study where some people are disabled due to the disease being studied. This is a key issue in CCSVI research.

Ultrasound is highly operator-dependent; that is, scan interpretation is very subjective. This was precisely the concern with Zamboni’s original paper. The authors of a recent properly blinded study, which found that CCSVI was equally common in people with and without MS,11 argued that any future CCSVI research must include blinding those who are reading the scans to the patients’ conditions.

The Buffalo Surprise

The Buffalo authors concluded that these findings argued against a primary causative role for CCSVI in MS. This was a great surprise, given that the lead author, Zivadinov, had trained with Zamboni in Italy, and was funded by patient groups keen to verify this link.

The findings contradicted the complete 100% association found by Zamboni between CCSVI and MS but do suggest that the presence of venous abnormalities of cerebral circulation may roughly double the risk of having MS or other neurological diseases.

More recently, multiple publications on CCSVI have appeared, and it is fair to say that the findings have been extremely confusing for the scientific community. Some groups have found no evidence of CCSVI in people with MS, while others have concluded that CCSVI is real and bears a causal link to MS in some way.

Further, studies are now being completed on the ‘Liberation Procedure’ or angioplasty (dilation) of the obstructed veins in people with MS, though the findings from properly randomized and controlled trials have still not been released. We will update this page as these findings arrive. At present, evidence that CCSVI plays a major causative role in MS is not strong,12 and no reliable research shows that angioplasty is of benefit,13 despite the many convincing video testimonials about the procedure one can find on the Internet.

Conflicting data

It is difficult to summarize these conflicting data. Zamboni developed an ultrasound technique for finding venous abnormalities in the brain, but he found abnormalities that were only apparent with this technique. He termed them CCSVI, developed the criteria for a diagnosis, and developed a treatment.

Other researchers reproducing his work have found either a significantly different incidence of the condition in MS, not found it at all with a comparable technique, or used a different technique that suggested the condition was not present in people with MS. This raises questions about the reliability and validity of those early conclusions.

Much more research is needed before the association between CCSVI and MS can be verified.

1. Zamboni P, Izzo M, Tognazzo S, et al. The overlapping of local iron overload and HFE mutation in venous leg ulcer pathogenesis. Free Radic Biol Med 2006;40(10):1869-73
Zamboni P. The big idea: iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis. J R Soc Med 2006;99(11):589-93
Zamboni P, Menegatti E, Bartolomei I, et al. Intracranial venous haemodynamics in multiple sclerosis. Curr Neurovasc Res 2007;4(4):252-8
Menegatti E, Zamboni P. Doppler haemodynamics of cerebral venous return. Curr Neurovasc Res 2008;5(4):260-5
Zamboni P, Galeotti R, Menegatti E, et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2009;80(4):392-9
Zamboni P, Menegatti E, Galeotti R, et al. The value of cerebral Doppler venous haemodynamics in the assessment of multiple sclerosis. J Neurol Sci 2009;282(1-2):21-7
Zamboni P, Galeotti R, Menegatti E, et al. A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. J Vasc Surg 2009;50(6):1348-58 e1-3
Hojnacki D, Zamboni P, Lopez-Soriano A, et al. 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;29(2):127-39
Zamboni P, Menegatti E, Weinstock-Guttman B, et al. The severity of chronic cerebrospinal venous insufficiency in patients with multiple sclerosis is related to altered cerebrospinal fluid dynamics. Funct Neurol 2009;24(3):133-8
Zivadinov R, Marr K, Cutter G, et al. Prevalence, sensitivity, and specificity of chronic cerebrospinal venous insufficiency in MS. Neurology 2011;77:138-44
Leone MA, Raymkulova O, Naldi P, et al. Chronic cerebrospinal venous insufficiency is not associated with multiple sclerosis and its severity: a blind-verified study. PLoS One 2013; 8:e56031
12. Zwischenberger BA, Beasley MM, Davenport DL, et al. Meta-Analysis of the Correlation Between Chronic Cerebrospinal Venous Insufficiency and Multiple Sclerosis. Vasc Endovascular Surg 2013
13. van Zuuren EJ, Fedorowicz Z, Pucci E, et al. Percutaneous transluminal angioplasty for treatment of chronic cerebrospinal venous insufficiency in people with multiple sclerosis: a summary of a Cochrane systematic review. J Neurol Neurosurg Psychiatry 2013