CCSVI and Multiple Sclerosis - a white paper
Mark Lillywhite
Introduction
This paper is intended to introduce chronic cerebrospinal venous insufficiency (CCSVI) and explain it’s possible relationship to multiple sclerosis.
Recent research in Italy, Poland and the USA suggests that CCSVI may be a common underlying cause of the neurodegeneration found in MS. MS is widely considered an autoimmune disease with an unknown precipitating event; CCSVI is theorised to be the precipitating event, and an ongoing aggravator. Although still in the research phase, testing for CCSVI is inexpensive, non-invasive and painless.
The Autoimmune Theory of MS
That MS is an autoimmune disease has, until recently, been uncontroversial. However, an article recently published in the Annals of Neurology [15] show little or no immune system activity in early stages of MS. The report concludes that “macrophage activity is largely an innate scavenging response to the presence of degenerate and dead myelin […] The findings suggest that plaque formation has some basis other than destructive cell-mediated immunity directed against a myelin or oligodendrocyte antigen.”
De Keyser, Steen, Mostert and Koch [16] write that “The classic teaching is that MS is a T-cell-mediated autoimmune disorder of the central nervous system. However, a number of pathophysiological observations cannot be simply explained on the basis of autoimmune mechanisms. First, the progressive (neurodegenerative) component of the disease continues despite intense immunosuppressive interventions that effectively stop inflammatory disease activity. Second, pathologic studies have shown that some demyelinating lesions develop without a preceding inflammatory reaction. Third, another intriguing finding difficult to explain by autoimmune phenomena is the finding of a diffuse cerebral white matter hypoperfusion…” (citations removed; please see original paper)
Despite these recent findings, MS is still considered by some to be an autoimmune disease. This theory persists despite the failure of immunosuppressants and anti-inflammatory drugs to control MS [16], or to substantially reduce the effect of the disease over the long term [10], and despite the fact that no treatment has ever been found to effectively help those with the primary progressive form of the disease [8, 10].
CCSVI
The autoimmune theory also spurns a large body of peer-reviewed research, published over the last 30 years, which predicts a relationship between the vascular system and MS. In particular, MS lesions are known to be venocentric [3], and share significant similarities with lesions caused by vascular stenoses elsewhere in the body [2]. Diseases in tissue upstream from a venous stenosis are well studied, and are caused by a change in vascular haemodynamics [11]. Despite the similarities, cranial vascular haemodynamics has, until recently, been poorly studied [2] - in part because the technology required to study blood flow in the deep cranial veins has not been available until recently.
Researchers in Italy, Poland and the USA are now studying vascular haemodynamics in relation to stenosis of the azygos and jugular veins draining the brain. This research has demonstrated that major stenoses exist in the veins draining the brain in 100% of the 300+ MS patients tested [12]. Remarkably, not a single one of the over 600 age-and-gender matched control subjects were found to have a significant stenosis. This research suggests that stenoses of the veins draining the brain may be pathognomonic for MS.
Stenoses of the veins is an operable vascular issue which can be treated with balloon angioplasty and/or stent placement. Patients who have undergone one of these procedures as part of the research have reported a cessation of relapses and an improvement in quality of life metrics. In particular, patients with secondary and primary progressive MS have seen a reduction of progression of the disease, though it is too early to see if progression of the disease has stopped. However, in the case of RR MS, not one patient from the original cohort whose procedure was successful
had relapsed within 12 months of the surgery. Although preliminary, these results would only be expected if stenosis were a causative factor in MS.
Research History
In the mid 1980s, Dr F. Alfons Schelling published a book [7] in which he explored historical images of MS and wrote that “The first prerequisite for plaque veins’ injurious activities appears to be a disproportionately severe valvular incompetence of that internal jugular vein by which these plaque veins are specifically drained”.
In a lecture given to the Royal Society of Medicine in 2006 and later published as an article in the JRSM, Italian MS researcher Paolo Zamboni provided the first comprehensive theory of a possible vascular cause for MS [1]. Comparing MS to chronic venous disease (CVD), Zamboni documented 13 similarities [2]. An additional, important factor - venous haemodynamics - was not correlated because venous haemodynamics was a poorly studied aspect of MS.
Zamboni then embarked on a study of intercranial venous haemodynamics. In his 2007 paper [3], he studied 89 MS patients and 60 healthy controls using color-coded duplex sonography. Using this non-invasive ultrasound technique, Zamboni showed that a large fraction of the MS patients exhibited venous reflux compared to almost none of the age-and-gender matched controls.
This study demonstrated in vivo, for the first time ever, altered haemodynamics in veins anatomically related to MS lesions. Other research has shown how a disturbance of flow in the veins promotes an inflammatory reaction [11], and the reversed flow is known to promote the expression of surface adhesion molecules, which allows macrophages and T-cells to infiltrate the BBB. Together, this research indicates that Zamboni may have found a simple underlying cause for MS.
In 2008, Zamboni undertook a larger trial in which 65 MS patients and 235 controls (controlling for age-gender, onset age of MS, other neurological diseases, and patients unaffected by neurological disease but scheduled for venography) were tested using transcranial colour-coded Doppler sonography and echocolour Doppler sonography [4]. All MS patients, and those controls who were already scheduled for venography, were then subject to venography.
Remarkably, 91% of MS patients were found to have unilateral or bilateral stenoses of the jugular veins, and 86% of MS patients were found to have stenoses of the azygous vein, with some patients having both. In total, 100% of MS patients had a significant stenosis of the jugular or azygous vein, compared to none of the controls. In addition, Zamboni was able to demonstrate a correlation between certain patterns of stenosis and the type of MS (RR, SP or PP).
Zamboni subsequently coined the term Chronic Cerebrospinal Venous Insufficiency, or CCSVI, to describe these patterns (formally, CCSVI will be known as congenital truncular malformation [13]), and discusses the likelihood that CCSVI is causative of MS. A later study by Zamboni [5] using different controls demonstrates that CCSVI is very likely to be causative of MS, and demonstrates that even patients with other neurological diseases are no more likely to have CCSVI than the controls, and that CCSVI may be pathognomonic for MS.
Given the extremely high correlation between venous stenosis and MS, Zamboni undertook a study of treatment of MS patients using venous angioplasty using balloons and stents [6,7]. Patients so treated had significant reductions in relapses and reported substantial improvements in fatigue and other quality-of-life measures.
Remarkably, 100% those patients who subsequently suffered relapses were found to have had restenosis.
These results have been replicated in Poland [14].
Anecdotally, patients who have undergone a venous stent or angioplasty report significant, immediate improvement in cognition and fatigue. Although these results have been dismissed by some as a placebo effect, the effect appears to be long term and measurable.
Conclusion
It goes without saying that additional research is necessary to demonstrate any relationship between CCSVI and Multiple Sclerosis. Nobody is asking for more research to be undertaken than Zamboni himself. It is clear that more time is required before treatment can be considered successful.
Nevertheless, Multiple Sclerosis is a progressive disease and it is unlikely that the neurological damage caused by it will be reversed by any current therapy. Therefore, it is imperative that the disease course is stopped as soon as possible. The sooner an effective treatment is found, the less disability patients will suffer.
Because testing is straightforward, non-invasive and inexpensive, MS patients have nothing to lose from being tested for CCSVI. An MS patient who is found to have a significant jugular or azygos stenosis will have a medical condition regardless of the relationship between MS and CCSVI, and appropriate treatment options should then be considered.
An MS patient who is found not to have a stenosis will falsify the CCSVI theory of Multiple Sclerosis and help move the research agenda forward.
From the point of view of an MS patient, there is very little to lose from testing, but a great deal to lose from waiting.
Recommended Reading and Viewing
The “This Is MS” internet forum is central to the collection and dissemination of information about CCSVI and I have shamelessly plagiarised information from that web site.
Current state of research (large number of links to online research articles):
http://www.thisisms.com/ftopict-7098.html
Patient diaries and testimonials from various treatments (balloon angioplasty and stents):
http://www.thisisms.com/ftopic-7191-days0-orderasc-0.html
http://www.thisisms.com/ftopic-7318-150.html
http://www.thisisms.com/ftopict-8346.html (many patients)
Lay documentary on CCSVI:
http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20091120/W5_liberation_091121/20091121?s_name=W5
References
