New evidence on the rates of CCSVI in people with MS

26 June, 2014
Recent months have seen further publication of the findings from ongoing research into chronic cerebrospinal venous insufficiency (CCSVI) in MS, some of which has received coverage in the media.

CCSVI is a condition where drainage of blood from the brain and spinal cord is impeded. It is thought CCSVI may contribute to the development or symptoms of MS and was originally described by Dr Zamboni of Italy in 2009. In his sample, all people with MS had CCSVI whereas healthy individuals showed no evidence of CCSVI. Subsequent studies have been unable to replicate this marked difference in CCSVI prevalence. Some studies have found an increased prevalence of CCSVI in MS, but have also shown that it is present in healthy individuals and in people with other neurological diseases (OND).

Most recently, one of the key research teams in Canada, funded by one of the seven large grants from the USA National MS Society and the MS Society of Canada, have published their findings. The study published in the Canadian Medical Association Journal in early June reports no evidence to support increased prevalence of blood flow abnormalities in people with MS compared to healthy controls. The authors report that, when venous blood flow was measured using ultrasound, a large proportion (>50%) of each group met criteria for at least one of Dr Zamboni’s “criteria”, while a minority of participants (10% controls, 20% patients) met at least 2 criteria. This difference was not statistically significant. When measured using a different imaging technique called magnetic resonance venography, there were no differences between the groups in vein integrity or blood flow.

A key finding of this study is the poor correlation of findings using the two methods, leading the authors to question the validity of the ultrasound criteria used to diagnose CCSVI. They argue that these criteria are tending to over-diagnose CCSVI, and that the measurement cut-offs that are used to define ‘insufficiency’ of blood flow through the veins have not been properly validated. The authors reiterate that apparent vein ‘blockage’ may be a normal occurrence; the width of vein walls is flexible and can change according to factors such as blood pressure, posture and hydration. Veins with narrowings visible by ultrasound may be functionally normal.

In addition to this most recent study, additional results have been published from the seven key studies funded by the National MS Society in the USA and MS Society of Canada. These studies were selected for funding based on their rigorous design and many incorporated alternative methods for assessing the cerebrospinal veins, in addition to the original ultrasound techniques used by Dr Zamboni. These are summarised below.

Please note that very small studies, review articles, conference abstracts and public media or online coverage are not included in this summary.

Prevalence of CCSVI in MS
An important paper published in the highly prestigious medical journal, The Lancet, from Dr Traboulsee and Dr Knox from the University of Saskatchewan in Canada, has reported extremely low rates of CCSVI in people with MS, their unaffected siblings, and in healthy people, measured using catheter venography. Notably, they also report that greater than 50% narrowing of major extracranial veins is an extremely common and normal occurrence, found in over 70% of healthy people and people with MS.

Dr Field and colleagues at the University of Wisconsin published the findings from their study in which they measured the reliability of magnetic resonance imaging (MRI) techniques used to visualise blood flow in veins of the neck and head. They found that measuring blood flow is reliable for veins in the head, but for veins in the neck and chest such as the internal jugular vein – the key vein targeted during CCSVI measurements – the MRI scans had very low agreement between two scans of the same person taken at different time points. This has many implications for making a diagnosis of CCSVI based on a single scan.

Dr Fox and colleagues in Cleveland undertook a study which found that hydration status has a substantial effect on CCSVI criteria, such that people who were dehydrated also had higher rates of CCSVI, but after rehydrating the rates of CCSVI dropped. This finding is important because it demonstrates that the diagnosis of CCSVI is vulnerable to the context in which it is measured. People with MS are known to reduce fluid intake in circumstances where they may wish to avoid the difficulties associated with sphincter dysfunction or incontinence, and this may be a contributing factor to observed differences between people with MS and healthy controls.

Researchers from Ontario, Canada report no population differences in a study of blood flow rate between adolescents with MS compared to age-matched controls. Dr Banwell and her colleagues also previously found no difference in blood flow rate in children with MS compared to healthy children.

A research group from Houston have recently published a study investigating the most reliable method for identifying CCSVI. In this study, 98 individuals were tested with neurosonography or magnetic resonance approaches, and 40 also underwent a transluminal venography procedure. None of these 40 people showed clinically significant abnormalities of vein anatomy. The three imaging approaches provided generally consistent data with discrepancies referable to inherent technique properties.

In addition to these key studies, a number of other studies provide further insight:
A recent meta-analysis has statistically combined the results of 19 studies and over 2100 participants. Overall, they found extremely high variability between the studies, which makes interpretation difficult. When they analysed a smaller subset of studies that had better consistency in the methods used, they found no relationship between frequency of CCSVI and risk of MS.

A second meta-analysis identified a slightly higher frequency of CCSVI in MS, however the authors indicate that these results do not provide evidence for a causative role of CCSVI in MS.

The large COSMO study from Italy has published their findings looking at the association between CCSVI and MS. Involving 35 MS clinical centres across Italy including 1767 participants (1165 with MS), the researchers found no significant differences in rates of CCSVI between groups.

Two separate studies, one from Italy and one from Finland each assessed all participants for the presence of CCSVI by two separate ultrasound technicians, and compared the ratings of each technician. The authors of both studies found extremely low agreement between the diagnostic ratings of each technician, regardless of whether they were CCSVI specialists or non-specialists, neurologists or non-neurologists, with no difference if they were measuring people with MS or controls. These findings raise many questions about the accuracy of comparing results between different technicians and different study sites.

Another Italian study examined blood flow through the internal jugular vein in 57 people with MS, 7 people with clinically isolated syndrome and thirteen healthy individuals. These investigators found reduced flow in people with MS, which correlated with the level of disability. The authors discuss possible reasons for this observation, including a number of possible mechanisms by which brain inflammation and muscle weakness in MS might lead to reduced blood flow.

A research group from the State University of New York, Buffalo, have compared several techniques for diagnosing CCSVI (study details can be found here). They found that non-invasive screening methods alone, such as Doppler sonography (ultrasound), are not sufficient to reliably identify patients with CCSVI, but may be a useful screening tool to identify individuals for more invasive further analysis. However, this study did not compare the accuracy of ultrasound screening compared to more invasive approaches for identifying blood flow abnormalities in people with MS.

Finally, a study from the Netherlands reports inconsistency in CCSVI diagnoses in individuals over time. They found that at an initial assessment, CCSVI was identified in only 5 of 52 MS patients, but none in healthy controls. However, at a subsequent re-assessment 16 weeks later, 3 of the 5 patients no longer showed evidence of CCSVI but another two patients did. These findings suggest vein dynamics can fluctuate over time and question the reliability of CCSVI diagnosis.

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