CCSVI – Part 3
By early 2010, the stage was set for an epic battle that some called the Plumbers vs. the Electricians. Many vascular surgeons (the “plumbers”) were keen on the idea of venous angioplasty (widening the veins) as an MS treatment. Neurologists (the “electricians”) were more cautious, and with good reason. They had recently witnessed the hype over a study (also from Italy as it happens) suggesting that lithium could delay the progression of Lou Gehrig’s disease (amyotrophic lateral sclerosis). A few years and several million dollars later, this claim was shown to have no merit. Lithium provided no benefit for people suffering from ALS (Aggarwal et al. Lancet Neurol 2010; 9: 481-488). A second lithium study had to be stopped early because of the high rate of deaths and severe side effects (Chio et al. AAN, S16.001). So perhaps it wasn’t surprising that CCSVI reminded some of how the lithium story had unfolded.
But the greater problem with CCSVI was that it didn’t fit the paradigm of MS. While the actual cause of MS was unknown, a great deal was known about the dysregulated immune response seen in MS. To neurologists, there was no direct connection between MS as an autoimmune disorder, and MS as something to do with blood flow in the brain. There were other aspects of the theory that also strained credulity (Awad and colleagues. Ther Adv Neurol Disord 2011; 4:231-235):
– MS occurs more commonly as you move away from the equator (Alonso & Hernan. Neurology 2008;71:129-135), a pattern of distribution that CCSVI isn’t able to explain.
– MS is a highly individual disease. The symptoms occur differently in different people, the disease course can be mild or severe, and it causes varying degrees of tissue damage. This degree of variability is unlikely to be caused by a single defect.
– If MS is a vascular problem, it should occur more frequently as you get older. But this isn’t the case.
– There are characteristic types of tissue damage seen in people with insufficient blood flow in the brain (Schaller & Graf. Cerebrovasc Dis 2004;8:179-188). This damage hasn’t been seen in autopsy studies of people with MS.
In other words, to many doctors experienced in treating MS, CCSVI as a theory didn’t make sense.
To CCSVI advocates, the problem was the medical paradigm. Doctors view things through their own unique lens – and what if they were wrong? Of course there were paradigms aplenty from which to choose. Some people with MS viewed CCSVI as a reboot of the AIDS/HIV story, in which patient activists stormed the Bastille of Burroughs-Wellcome to gain access to antiretroviral drugs. Some pointed to the famous case of Barry Marshall, who was pilloried for his belief that ulcers were caused by bacteria rather than stress and diet (for which he was later awarded the Nobel Prize). Paradigms are a mold for our experience, or a procrustean bed. They help us see meaningful patterns, or they can blinker us.
Ultimately, opinions about CCSVI – pro and con – must be informed by the facts. Researchers had been blindsided by CCSVI, so they were a little slow off the mark in investigating the idea. But numerous studies over the past few years have now investigated different aspects of the CCSVI story.
The first published studies by CCSVI skeptics were conducted in Germany. One found that only 1 in 5 people met the criteria for CCSVI (Krogias and colleagues. Nervenarzt 2010;81:740-746). A second study couldn’t find evidence of CCSVI in any of the 56 people it examined (Doepp and colleagues. Ann Neurol 2010;68:173-183). A third study looked at blood flow in 57 people with and without MS (Meyer-Schwickerath and colleagues. Mult Scler 2011;17:637-638). It found that blood pressure in the brains of people with MS wasn’t higher, suggesting that there was no obstruction of the veins.
Subsequent investigations showed similar results. A report from Italy found that 16% of people with possible MS met CCSVI criteria when examined by ultrasound, but there were no vein abnormalities when investigated further with venography (Baracchini and colleagues. Ann Neurol 2011;69:90-99). A study in Frankfurt found that none of the 16 people with MS had evidence of blood in the veins flowing back into the brain (Mayer and colleagues. J Neurol Neurosurg Psychiatry 2011;82:436-440). This was followed by a series of studies reporting that CCSVI was actually more common in healthy controls compared to people with MS (Auriel and colleagues. J Neurol Sci 2011;309:102-104; Tsivgoulis and colleagues. Neurology 2011;77:1241-1245; Blinkenberg and colleagues. Acta Neurol Scand 2012; epublished April 25, 2012).
Other researchers investigated other aspects of the CCSVI story. The underlying problem caused by CCSVI was believed to be iron deposits in the brain, so a European study looked at iron levels (by measuring ferritin, a protein that stores and transports iron in the body) in the cerebrospinal fluid (CSF) of different groups (Worthington and colleagues. Neurology 2010;75:1617-1622). Iron levels were high in 10% of people with relapsing-remitting MS, 11% with primary-progressive MS, and 23% with secondary-progressive MS. However, iron levels didn’t change over a three-year period in any of the MS groups. And high levels of iron were much more common in some other groups, such as people who had suffered a stroke.
A more radical approach was taken by researchers at Harvard. They cut off blood flow in the jugular veins of mice (Atkinson and colleagues. PLoS One 2012;7:e33671). This was “superCCSVI” – complete blockage of the main vessel draining blood from the brain. Over the course of the next six months, the animals showed no signs of breakdown in the blood-brain barrier, no inflammation in the central nervous system, and no demyelination. So blood flow appeared to have no connection to the pathological changes seen in MS.
Throughout this period, advocates of CCSVI were performing their own studies. An early proponent of the Zamboni theory, Dr. Robert Zivadinov of Buffalo, New York, conducted a large study of 499 people (Zivadinov and colleagues. Neurology 2011;77:138-144). He diagnosed CCSVI in 62.5% of people with MS, 45.8% of people with other neurological disorders, and 25.5% of healthy controls. So CCSVI in this study continued to be more common in people with MS – but it was only modestly specific to MS. Indeed, the researchers’ somewhat surprising conclusion was that CCSVI didn’t appear to be a primary cause for the development of MS. A second study by the Buffalo group found that CCSVI had little association with the key genetic risk factor for MS (called HLA DRB1*1501) (Weinstock-Guttman and colleagues. PLoS One 2011;6:e16802).
These studies – by researchers on both sides of the divide – made a considerable dent in the CCSVI theory. Abnormal blood flow was so common that it fell within the range of normal. And there was little evidence that blood flow anomalies in one or more veins led to a build-up of iron in the brain, or contributed to MS symptoms.
But what about the people who got their veins “done”? How did they fare? Was the angioplasty procedure safe? We’ll look at those issues in the final installment in this series.
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