CCSVI and MS

Chronic cerebrospinal venous insufficiency (CCSVI)

Professor Paolo Zamboni, a vascular surgeon from the University of Ferrara, Italy, recognized the link between venous pressure, iron deposition and ulceration in venous disease of the legs,¹ and went on to apply this knowledge to MS. It appears this was in response to his wife, Elena Ravalli, being diagnosed with MS in 1995 at the age of 37. Zamboni presented preliminary findings of his research to the Royal Society of Medicine in London on 1st July 2006.² This paper suggested that back pressure in the cerebral veins might induce leakage of blood around the small veins in the brain, and subsequently inflammation.

There were certainly features of the illness that this hypothesis explained, particularly the anatomical location of the inflammatory lesions in MS around small veins, and the well-described deposition of iron in the 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 in the US, led by Dr Robert Zivadinov.

Initially, in comparing 89 people with MS to 60 control people without MS using colour 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 colleagues then went on to devise a new way of measuring venous blood returning to the heart from the brain, a technique that combined high-resolution echo-colour-Doppler (ECD) and transcranial colour coded Doppler sonography (TCCS), in later publications called the TCCS-ECD technique, but basically a form of ultrasound; they felt that this combination was an ideal way to assess venous blood returning to the heart from the brain, and proposed a list of reproducible parameters to evaluate venous return with ultrasound.⁴  Then 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 used five TCCS-ECD criteria they had devised, and showed that none of the control patients had more than one of these five criteria. They reported 180 positive and 145 negative criteria in MS patients, and 33 positive and 1142 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 the different obstruction patterns.

In a later CCSVI and MS study, testing the five TCCS-ECD 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; that is 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 less than two criteria.⁶

It is important to note that to this point, the research had all been undertaken by the research team led by Zamboni in Italy; had tested a diagnostic procedure they themselves had devised; had proposed a new previously unknown condition, CCSVI, for which this new test was 100% diagnostic; and had shown that the new condition occurred only in people with MS and not in other people, with or without neurological disease. Another point of note is that the testing using TCCS-ECD sonography had to this point all been un-blinded, that is the investigators using the ultrasound machine knew whether the patient in front of them being tested had MS or did not have MS, 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 disease like coronary heart disease. In this technique as it is commonly 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 hopefully open the constricted vessel. In heart disease, a device called a stent is sometimes left in the vessel to keep it open. The technique has not been used a lot in veins, as veins are large, floppy vessels that don’t commonly get constricted except in particular clinical situations such as post-transplant surgery and in certain grafts.

Zamboni reported that angioplasty particularly benefited people with relapsing-remitting MS, with 50% relapse-free post-operatively versus 27% before the procedure, but over half of the internal jugular veins re-constricting over the follow up period that averaged 18 months. Importantly, the average relapse rate of the group did not improve after the procedure.

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} These researchers 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 February 2010,¹⁰ but have not been subjected to peer review or published in a journal to date, so it is difficult to know how much weight to place on the findings, or to understand the exact methodology. The results of 500 people, some with MS, some with no illness and others with other neurological diseases, showed that around 55% of people with MS had the criteria for CCSVI, about 22% of people with no illness had the criteria, and around 43% of people with other neurological conditions had the criteria.

It is difficult to be able to interpret these findings given that at the time of writing they have not yet been published. They contradict the complete 100% association found by Zamboni between CCSVI and MS, but suggest that the presence of venous abnormalities of the cerebral circulation may roughly double the risk of having MS or other neurological disease.

More recently, two papers on CCSVI and MS have been accepted for publication in Annals of Neurology, disputing the existence of CCSVI. The first¹¹  is from German authors with a strong track record of research and publication in venous blood drainage from the brain, including publications in Stroke and The Lancet. Because of their experience and expertise in the area, they were able to do additional ultrasound measurements to further highlight venous drainage issues in the brain. In 56 people with MS and 20 controls, they found no evidence of CCSVI in any subjects, with or without MS. The only difference they found was less of a fall in venous blood volume flow in people with MS when they adopted the upright position, suggesting some alteration in the dynamics of brain blood circulation caused by the disease. They concluded that there should be no surgical intervention for CCSVI until more research has been done to clarify the condition. The study was not blinded, so that investigators knew which patients had MS and which ones did not, as was the case with Zamboni's original study.  

The second CCSVI and MS study from Sweden¹² has been reported in the media.¹³ This small study from Umea University in Sweden looked at 21 MS patients and 20 healthy patients and concluded, "We found no differences regarding internal jugular venous outflow." Although the paper was not available for review at the time of writing, an internet review (http://www.tell-us.se/35873004 ) of the paper sheds light on the findings. It appears that Swedish researchers with experience in the area chose to use a technique called phase-contrast magnetic resonance imaging (PC MRI), a non-invasive technique for measuring blood flow. While not adopting Zamboni’s original colour Doppler techniques for assessing cerebral venous flow, they felt that if the entity of CCSVI did in fact exist, it should be detectable by a variety of means assessing the vascular system. In fact, they examined only the internal jugular veins using the technique, and found no changes in blood flow, although three MS patients did have stenoses (narrowings) of these veins. So while not using a technique comparable to Zamboni’s, this study does add some potentially useful information.

It is difficult to summarise these conflicting data. Zamboni developed an ultrasound technique for finding venous abnormalities in the brain, found some abnormalities only apparent with this technique which he termed CCSVI, developed the criteria for its diagnosis, and developed a treatment. Other researchers reproducing his work have either found 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 it was not present in people with MS. This raises the question of the reliability and validity of those early conclusions.

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