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Lancet Neurol. 2010 May;9(5):464-5.
Venous abnormalities and multiple sclerosis: another breakthrough claim? Qiu J.
Recent reports of a possible link between venous abnormalities and multiple sclerosis have been associated with high levels of media hype. Many experts caution against premature promotion of the hypothesis and call for objectivity and scepticism in follow-up studies. Jane Qiu reports.
Poor judgment in medicine can lead to interventions with fatal consequences. Lives should not be lost before these interventions are halted, but they often are. In August, 2009, a patient with multiple sclerosis (MS) had two stents inserted into her right jugular vein; she died shortly afterwards of a brain haemorrhage while on the anticoagulant warfarin as a result of the procedure. 3 months later, another patient with MS had to have open-heart surgery to remove a jugular-vein stent that had come loose and moved into the right ventricle.
In December, 2009, Michael Dake, chief of interventional radiology at Stanford Medical Centre (CA, USA), who inserted stents in both patients as a way to treat MS, told his colleagues and patients that no further endovascular procedures would be done for the assessment or management of extracranial venous obstruction in any patients, with or without a diagnosis of MS, until clinical protocols were approved. The decision was made after “deep soul-searching”, said Dake in an email to his colleagues.
Dake is among the investigators who believe that venous stricture is a cause of MS and that endovascular procedures, such as balloon angioplasty or stent placement to widen the vein, could alleviate some of the symptoms. But the hypothesis is yet to be proven, let alone the safety and efficacy of the intervention. Many experts, such as Alasdair Coles, a neurologist at the University of Cambridge, UK, are openly critical that Dake subjected his patients to a grave risk without any evidence that the procedure would help to treat MS.
For a long time, neurologists have noted that some patients with MS have venous abnormalities in the brain. But it took many experts by surprise when Paulo Zamboni, a vascular surgeon at the University of Ferrara, Italy, and his colleagues reported that almost every one of the 65 patients with MS who they had examined with doppler ultrasound and venograms showed venous stricture in the jugular or azygous veins.
They also noted that different forms of MS were associated with different patterns of venous abnormality and, on the basis of ultrasound results, named the condition chronic cerebrospinal venous insufficiency (CCSVI). Such abnormalities were absent in the 235 control individuals, including healthy controls and patients with other neurological diseases.
The researchers suggested that venous stricture could lead to hypoxia and a breakdown of the blood—brain barrier, causing red-blood cell and fluid leakage into brain and spine tissues; as a result, iron and plasma from the blood that accumulate in the CNS over time might break the immune tolerance and set off a cascade of immune responses.
The team then reported an open-label prospective study of 65 patients with MS—35 relapsing-remitting, ten primary progressive, and 20 secondary progressive—who had undergone angioplasty to widen the veins. The researchers found that the procedure had “a minor and negligible complication rate” and, despite the fact that the study was neither blinded nor controlled, concluded that the treatment “significantly improved MS clinical outcome measures, especially in the [relapsing-remitting] group”.
Some neurologists think that the CCSVI hypothesis has weight. “The autoimmune hypothesis doesn't explain everything about MS, especially the neurodegeneration aspect of the disease, which has been increasingly noted in the past few years”, says Bianca Weinstock-Guttman, a neurologist at the University at Buffalo (NY, USA). For years, Weinstock-Guttman and other research groups have noted iron deposits around injury sites in the brain; the amount of iron deposits as measured by MRI seems to be associated with MS disease progression.
Others, however, are unconvinced. “The sensitivity and specificity of Zamboni's ultrasound tests are so high that they are hardly believable”, says Richard Rudick, director of the Mellen Centre for MS at the Cleveland Clinic Foundation (OH, USA). Similarly, Coles finds it “extremely surprising that Zamboni could distinguish different types of MS based on different patterns of venous abnormality”.
Experts are adamant that the observation needs to be confirmed by independent research groups and the underlying physiology and CCSVI better defined using modalities other than ultrasound. However, a recent study (as yet unpublished) by Robert Zivadinov, also at Buffalo, seems to have led to more confusion than assurance.
The team examined the venous system of 500 people, including 161 healthy controls, 280 patients with MS, mostly the relapsing-remitting form, as well as patients with other neurological disorders, and found that 56% of patients with MS and 22% of healthy controls showed narrowing of the extracranial veins. Furthermore, the more serious the disease was, the more venous abnormalities there were.
Many note that the prevalence of venous abnormalities in Zivadinov's study is much lower than that reported by Zamboni, and wonder what the real association is. Zivadinov says that his study might have been “better blinded”, which might have removed some levels of subjectivity during ultrasound scanning. “All patients walked in [to the ultrasound test room] with a walking stick, so the technician wouldn't know which subjects had MS or other neurological disease”, says Zivadinov.
Zamboni's team also used a more sensitive ultrasound machine, which might explain the much higher prevalence of CCSVI among patients with MS in their study, says Zivadinov. This, however, does not explain why Zamboni's more sensitive machine did not pick up any venous abnormalities in the control individuals, whereas the Buffalo team found that 22% of healthy control individuals had CCSVI.
“What all these are telling us is that we really don't know where we are at the moment in terms CCSVI and MS”, says Rudick. Even if there is an association, many suspect that venous abnormalities are likely to be part of the overall pathology of MS, rather than a cause of it. “The brain of patients with MS is a diseased organ: you get all sorts of abnormalities there and it would be almost impossible to imagine that the venous physiology would be normal”, says Rudick. “There are well known syndromes of venous occlusion where you don't get the kind of self-perpetuating autoimmune responses you see in MS.”
Many experts think that Zamboni's open-label study falls short of the standards and quality that are acceptable in clinical research. “The study is not blinded and is uncontrolled”, says Coles. Indeed, the study didn't include patients with MS with CCSVI who didn't undergo angioplasty, and those who had the surgery were also on other treatments for MS. Therefore, their findings “are totally uninterpretable in terms of efficacy”, he says.
There is also widespread criticism of the media hype associated with the CCSVI hypothesis, which has been partly promoted by some of the investigators and has caused a whirlwind of exaggerated claims and expectations. For example, there is a CCSVI page on Facebook; a newsletter dedicated to the syndrome is sent to thousands of patients with MS by Zivadinov's team; and, according to a press release about a meeting in Bologna, Italy, in which Zamboni presented his studies, “endovascular therapy showed a decrease in the number of disease relapses, a marked reduction in the number of active brain and spinal lesions, and also a clear-cut improvement in the patients' quality of life”.
The premature promotion of the CCSVI hypothesis has led to a situation in which many patients with MS seek venous testing and, if the result turns out to be abnormal, endovascular interventions. “Patients are desperate for help, and the media and some of the investigators have played into that desperation in pushing forward this hypothesis”, says Rudick.
MS societies on both sides of the Atlantic are cautious of the CCSVI hypothesis. While acknowledging that it is “an interesting avenue of research”, Doug Brown, biomedical research manager at the MS Society in the UK, stresses that “the evidence isn't there at the moment to back up some of the bold claims that CCSVI is a cause of MS or that the treatment of CCSVI will cure MS”. He adds: “We would absolutely recommend against seeking so-called treatment of CCSVI because there is no evidence that this would benefit people with MS.”
Patricia O'Looney, vice president of biomedical research at the National MS Society in the USA agrees: “It's important that this possible association [between CCSVI and MS] is fully evaluated by others.” The society has made a special call for research proposals around the world to look into this issue. Rudick, who chairs the advisory committee of its research programme, says that the priority at the moment is to establish an association, rather than to fund a clinical trial.
Meanwhile, venous testing and surgical procedures for CCSVI “should be undertaken only as part of formal clinical trials that include all of the standard safeguards”, says O'Looney. Critics are adamant that clinical trials have to be undertaken with considerable objectivity and scepticism. “For clinical research to be valid, there needs to be equipoise on the part of the investigators who have no personal interest in what the outcome is”, says Rudick. “There should be real uncertainty in terms of research findings.”
“We have to guard against therapeutic misconception”, says Judy Illes, an ethicist at the University of British Columbia (BC, Canada). “Patients mustn't get into a trial thinking that they would benefit from it. That's the fundamental nature of clinical research and informed consent, especially when it comes to early trials.”
As for the CCSVI hypothesis, experts like Rudick would rather take it with a pinch of salt. “Over the years, we have seen all sorts of claimed breakthroughs that have come and gone in the field of MS”, he says. “We are yet to see whether this is one of them.”
Mark Walker - Oxfordshire, England. Registered Pharmacist (UK). 10 years of study around MS.
Mark's CCSVI Report 7-Mar-11: