A controversial new theory on the etiopathology of multiple sclerosis (MS), which suggests that reduced blood flow in the azygotic and internal jugular vein — chronic cerebrospinal venous insufficiency (CCSVI) — may be at the root of the disease, has been called into question by two new papers published in the August Annals of Neurology.
The MS-CCSVI hypothesis, first suggested in a 2007 paper in Current Neurovascular Research by Paulo Zamboni, MD, professor of vascular surgery at the University of Ferrara in Italy, has generated both excitement and skepticism among MS specialists, advocacy organizations, and patients. The MS Societies of the US and Canada announced in June that they had committed over $2.4 million to support seven operating grants to explore the relationship of CCSVI to MS.
But many MS experts have regarded the theory, and its attendant approach to treatment— endovascular surgery to open the lesions causing the insufficiency, which some patients have called a “miracle cure”— with a high degree of suspicion. “There is a relatively large body of evidence suggesting that this is a primarily immunological disorder,” said John Corboy, MD, professor of neurology at the University of Colorado-Denver and co-director of the Rocky Mountain MS Center at Anschutz Medical Campus. “In addition, these types of venous abnormalities are commonly seen in a whole host of patients as normal variants, found sporadically by chance when various studies are done for other indications.”
The two new papers both failed to confirm the CCSVI hypothesis, which also speculates that the reverse flow of blood back into the brain might set off the inflammation and immune-mediated damage associated with MS.
REFLUX IN VEINS
The first study, published by Florian Doepp, MD, and colleagues at the University Hospital Charite in Berlin, sought to replicate Zamboni's findings of reflux in the deep cerebral veins and/or the internal jugular (IJVs) and vertebral veins (VVs), stenosis of the IJVs, missing flow in IJVs and VVs, and inverse postural response of the cerebral venous drainage.
The authors performed an extended extra- and transcranial color-coded sonography study, involving 56 patients with MS and 20 controls. Their findings differed markedly from Dr. Zamboni's published results: except for one patient, blood flow direction in the IJVs and VVs was normal, and IJV stenosis was not detected in any patients. There was no difference between IJV and VV blood volume flow in the MS patients as opposed to the normal controls, and no differences were seen between the groups in intracranial veins and during the Valsalva maneuver.
Indeed, MS patients differed from healthy controls in only two venous indices. The first was blood volume flow (BVF) in an upright position, in which patients with MS had a higher BVF. This finding, the authors theorized, might represent vascular dysregulation, possibly due to the effects of MS on the autonomic nervous system. But they noted that it contradicts the theory of CCSVI: “If anything, however, higher BVF in patients should suggest a better than normal cerebral venous drainage (at least in an upright position) in MS,” they wrote.
In the second index, global cerebral arterial blood flow (CBF), controls had higher values compared to patients with MS, but this finding was only a trend difference and not statistically significant. “Provided this trend would, in a larger cohort, reach statistical significance, it could reflect lower energy demand in patients with MS due to brain atrophy,” the authors wrote.
They concluded: “Our results therefore call into question the existence of CCSVI — certainly in a large proportion of patients with MS — and do not underpin a role of cerebral venous congestion leading to reflux of blood into the CNS in the pathophysiology of MS.”
CASE-CONTROL STUDY:RELAPSING-REMITTING MS
The authors of the second paper, a case-control study from Umea University in Sweden, used phase-contrast MRI and contrast-enhanced magnetic resonance angiography (the second in MS patients only) to study 21 relapsing-remitting MS (RRMS) patients and 20 healthy controls. They found no differences regarding internal jugular venous outflow, aqueductal CSF flow, or the presence of internal jugular blood reflux.
“As MS-CCSVI has been described, with IJV insufficiency in 94 percent of RRMS cases, and almost never present in controls, this case-control study should have had sufficient power to detect a difference,” the authors wrote. “If MS-CCSVI is an entity associated with MS, the association is likely to be weaker than previously reported, and most importantly, we found no support for a treatment rationale of endovascular procedures like angioplasty or stenting.”
“These two new papers add independent voices using different techniques that both fail to identify similar types of abnormalities as described by Dr. Zamboni,” noted Dr. Corboy.
FINDINGS TOO GOOD TO BE TRUE?
Dr. Zamboni's original findings have not been replicated and were almost too good to be true, in the view of many researchers, with CCSVI demonstrating 100 percent sensitivity and positive and negative predictive values for MS. ”
“I've never heard of that in any disease with any test,” said Robert Lisak, MD, the Parker Webber Chair of Neurology and Professor of Immunology and Microbiology at Wayne State University School of Medicine, who was one of 11 co-authors of an extended critique of the MS-CCSVI theory first published in the Feb. 12 online edition of Annals of Neurology.
“These technical issues of what measures are being used, and how they're used, to identify the phenomenology itself must be resolved,” said Bruce A. Cohen, MD, professor of neurology at the Feinberg School of Medicine of Northwestern University and the director of the Northwestern Comprehensive MS Program. “But accepting for the sake of argument that the methodology question is resolved, and this phenomenon does exist in some disproportionate way in MS patients, what does it mean? Is it a phenomenon related to the cause of MS, or is it a consequence of some of the pathologic changes in MS? We don't know that at this point.”
The “therapeutic” studies are the weakest part of the CCSVI theory, said Dr. Cohen. “They're all based on a certain amount of anecdote, and it's evident that there was no standardized MRI protocol.”
“They were unblinded and had no controls,” agreed Dr. Lisak. “If someone says they haven't had a relapse in 18 months, I can show you patients who aren't even on immune-modulatory agents who haven't had a relapse in 18 months. This represents a real danger for the people pursuing the so-called ‘therapy’.”
Experts say that the new Annals papers further support their caution with regard to MS-CCSVI. “Although they are smaller than Zamboni's, they seem well done and appropriately controlled,” said Dr. Corboy. “They will not necessarily by themselves answer all those who are pursuing this concept, of course. It's going to require larger studies with different control groups, looking at pathology, looking at pediatric patients — who should also show evidence of CCSVI if this is a real cause of MS — to answer this question. Those kinds of studies are now going forward. If there are data that supports this, then of course it should go forward. And if there are data that refute it, it should die its natural death like other ideas that are found to be incorrect.”
In the meantime, most neurologists agree that no matter how exciting CCSVI may seem, patients should be strongly discouraged from pursuing related approaches to treatment outside of a well-controlled clinical trial approved by an institutional review board at a major research institution.
ARTICLE IN BRIEF
Two new papers both failed to confirm the CCSVI hypothesis, which also speculates that the reverse flow of blood back into the brain might set off the inflammation and immune-mediated damage associated with MS.