By Colby Cosh - Saturday, April 27, 2013 - 0 Comments
“Liberation therapy” for multiple sclerosis is dead; yet long will it live, not only in the hearts of desperate MS patients, but in their bank balances too. In 2009 an Italian physician named Paolo Zamboni issued a study claiming that MS sufferers had poor rates of blood outflow from their brains. He proposed a complex new etiological theory of MS on this basis, proclaiming the existence of a new syndrome: “chronic cerebrospinal venous insufficiency,” or CCSVI.
Zamboni’s study made bold, almost patently insupportable claims about differences between the blood vessels of MS sufferers and healthy persons. His theory of CCSVI seemed to contradict much that is known about MS and failed to account for obvious features like the midlife age of typical onset. The research got little attention outside Canada, a country hit hard by the global north-south gradient of MS rates. Inside Canada, it only took one round of zingy, insufficiently critical news stories by CTV and the Globe and Mail to make Zamboni a hero.
Hundreds of patients, perhaps thousands, have travelled the globe seeking venous angioplasty for MS symptoms, usually against doctors’ advice, and millions of dollars have been invested in CCSVI and “liberation therapy” surveillance after pressure was applied by shouting patients and opportunistic backbench politicians. But after years of empirical setbacks for the whole notion of CCSVI, it is all looking like money down the drain.
The first question to be answered about CCSVI ought to have been, “Is there actually any such thing?” Attempts to reproduce Zamboni’s results have met with mass consternation; researchers cannot even get to the point of determining whether CCSVI is treatable because they cannot detect it as promised. Radiological imaging does not seem to exhibit consistent relevant differences between MS sufferers and healthy patients, and Zamboni’s original criteria for a CCSVI diagnosis are hardly even coherent or well-specified enough for practical use.
The April issue of the Journal of Vascular and Interventional Radiology, for example, contains a report of a Texas study of 276 MS patients and 70 healthy controls: ultrasounds of their necks produced “findings consistent with CCSVI” in four per cent of the MS group—and in seven per cent of the non-MS group. Examples of results like this could be compounded ad nauseam: the Texas paper is not even the only negative CCSVI-Zamboni result in that issue of that journal.
What went wrong? For those seeking an answer, I would recommend a paper open-published in late February by the Journal of Cerebral Blood Flow & Metabolism. Conveniently, its title is: “What went wrong? The flawed concept of cerebrospinal venous insufficiency.” This paper is important because the doctors who wrote it are among the leaders in using ultrasound and other means to study normal venous blood flow. Zamboni depended on their research for background when he was trying to devise diagnostic criteria for CCSVI. If CCSVI were real, they might be expected to be the first to applaud.
They’re not applauding. The authors go point by point through Zamboni’s proposed criteria, showing how he repeatedly misinterpreted earlier literature on vein behaviour and confused abnormal blood flow events with harmless typical ones. They emphasize the basic implausibility of Zamboni’s theory and show that it conflicts with non-Zambonian findings on MS and venous drainage. And they criticize the “open-label” nature of early CCSVI studies and patient registries assembled on the fly for political reasons. The best-designed of these, the authors note, was probably one paid for by the government of Newfoundland; a brusque June 2012 press release announced no evidence of objective benefit, but no peer-reviewed publication of the results has followed.
The “What went wrong?” paper concludes unequivocally that “only a complete halt to [liberation] therapy seems sensible.” The story of CCSVI will not be over until the last frustrated Canadian pays the last Bulgarian or Bengali doctor to be “liberated” for the last time; but from a scientific standpoint, the proverbial fat lady is about halfway between the main performance and the encore. On web forums for MS patients, liberation therapy is already receding into the shadow world of I’ll-try-anything curatives, there to linger with cobra venom and upper-cervical chiropractic.
It would be nice to be able to ladle out guilt for this ignoble episode in medical history, but it is not clear that even Zamboni, whose wife has MS, did anything consciously wrong. On the other hand, the doctor is not likely to miss any meals because he messed up. A Canadian MS patient who forked over for repeated unnecessary angioplasties might.
For more Colby Cosh, visit his blog at macleans.ca/colbycosh
By Julia Belluz - Thursday, November 15, 2012 at 4:35 PM - 0 Comments
This is the third part of a series of articles adapted from the 2012 Hancock Lecture, “Who Live and Who Dies, Will Social Media Decide?” delivered at the University of Toronto by Julia Belluz. This installment looks at the credibility of health information on the Web, and the pitfalls and potential of social media for health. Read parts one, two, and four.
We started the Science-ish blog because it seemed there was a widening gap between science—what is known in health research—and how it’s presented in the media by key opinion leaders, and then implemented in health policy. The question was: If we believe what’s reported about health, what politicians say about health, could we really make well-informed choices about health? This is a public health problem.
Sometimes even sources that seem credible mislead us. This year, I had an opportunity to interview Dr. Oz. when he was in Toronto and ask about his use of scientific evidence to back the claims on his show. I was prompted to do this after hearing from doctors who had patients coming into their offices on myriad supplements because Dr. Oz told them to do so.
By Colby Cosh - Thursday, August 25, 2011 at 12:20 PM - 101 Comments
A group of Calgary neurologists has published a report on foreseeable complications faced by locals who have returned from going abroad and receiving trendy “liberation therapy” for multiple sclerosis. It is not clear whether the casefiles include the woman who was inadvertently liberated from the world by the treatment, but their contents sound troubling enough. “These five cases,” the authors note in their abstract, “represent the beginning of a wave of complications for which standardized care guidelines do not exist.”
They sound somewhat nervous, don’t they? It is almost as if they had not heeded the repeated reassurances of journalists and “liberation” enthusiasts that venous angioplasty and stent installation in major neck veins are routine procedures, of about as much clinical concern as having one’s shoe size measured. That tricky little distinction between veins and arteries turns out to be fairly important to the discussion: as an April letter in Clinical Neuroradiology pointed out, “Balloon dilatation and stent implantation have not primarily been developed for the venous system and are associated with a substantial risk for complications…with possible fatal outcomes.” [Emphasis mine]
Since the butcher’s bill is beginning to be drawn up, and not just in Calgary, it may be worth examining how well the “chronic cerebrospinal venous insufficiency” theory has fared over a full year of research. In April, SUNY Buffalo researcher Robert Zivadinov, a close colleague of CCSVI theorist Paolo Zamboni, delivered a controlled study of 500 patients that offered, at best, feeble confirmation of Zamboni’s original results. Zivadinov’s findings, as Colleague Anne Kingston pointed out at the time, could conceivably provide some comfort to both sides of the debate. But the one thing one could not possibly do with Zivadinov’s figures was to reconcile them with Zamboni’s original study, which claimed a perfectly sensitive, perfectly specific link between indicia of CCSVI and the presence of MS.
In the meantime, other results from preliminary studies of CCSVI and MS have been trickling out, to less fanfare. There is a cruel unrelentingness to them—a lamentable finality even to the titles of the articles. From Italy alone we have “No evidence of chronic cerebrospinal venous insufficiency at multiple sclerosis onset” (January); “Proposed chronic cerebrospinal venous insufficiency criteria do not predict multiple sclerosis risk or severity” (July); “Progressive multiple sclerosis is not associated with chronic cerebrospinal venous insufficiency” (last week).
A German team attracted some attention in January with a finding that “Intracranial venous pressure is normal in patients with multiple sclerosis”. A similar study from a VA hospital in Texas, using Zamboni’s own detection criteria to define the presence of CCSVI, was published earlier this month. The title: “No Cerebral or Cervical Venous Insufficiency in US Veterans With Multiple Sclerosis”. Meanwhile, the journal Neurology has a preprint from Greece which confirms the objectivity of the proposed CCSVI criteria—but also confirms the absence of any apparent link with MS. And for what it’s worth, a June study of animal models provides a smidgen of evidence against Zamboni’s speculation that vascular problems create autoimmune difficulties by causing localized deposits of iron to be left in the brain.
There is also the new study you might have read about which establishes that most of the gene markers statistically linked with MS are known to influence the immune system. For my money, that is actually an overhyped blow to the Zamboni hypothesis, in comparison with the lengthening train of papers finding no simple empirical connection between veins and MS at all. Most researchers agree that the CCSVI hypothesis is still worth following up with randomized controlled trials of larger size and longer duration. But they advocate this, not because there is any doubt that MS is fundamentally immunological, but because some far less radical variant of Zamboni’s idea might conceivably be, well, sort of true-ish. (See, for example, this note from neurologists in Erlangen: “…it certainly seems awkward to think of the complex disease MS solely as result of a simple venous outflow obstruction. Yet, the investigation of new vascular concepts as one variable in the pathophysiology of the autoimmune attack seems very worthwhile…”.)
Other researchers are frankly not so open to keeping up a chase that was, after all, set off by a study (Zamboni’s 100%-specific 100%-sensitive investigation) that almost certainly has to have been junk. The frustrations of a few scientists are discernible in the literature: one German group basically thumbed their noses at CCSVI by calling it the “perfect crime”—a supposed primary cause of MS that seems to leave no trace when sought in MS patients, using any means, by anyone but Zamboni or his very early supporters. Another comment in a senior journal asks whether CCSVI is “science fiction”. Either way, unfortunately, the premature enthusiasm for “liberation therapy” is cold inescapable fact.
By Colby Cosh - Thursday, September 16, 2010 at 1:11 PM - 0 Comments
I see that Colleague Kingston is unsure why the federal Minister of Health is frustrated at media coverage of her ministry’s approach to the vein-centered Zamboni hypothesis about multiple sclerosis. One possible reason, I think, is that statements like those of Liberal health critic Kirsty Duncan are being repeated rather uncritically. Duncan told Kingston “They say we need evidence-based medicine but they are doing nothing to gather evidence.” Nothing? I wonder how else, but as “evidence-gathering”, one could possibly characterize the seven MS Society-funded preliminary studies Aglukkaq mentioned in her burst of finger-wagging at the media. These studies are designed to establish precisely what needs to be confirmed before the dream of a pan-Canadian trial of vein therapy for MS can appropriately be fulfilled: namely, whether there is any such thing at all as “chronic cerebrospinal venous insufficiency”, and whether it is really correlated with MS.
The religious conviction of some MS patients that they have a venous disorder is hard to account for, given the state of the evidence. It seems to be a by-product of natural frustration with slow progress on MS treatment, and, often, of conspiracy theories about sadistic drug companies and greedy, arrogant “neuros”. Some of these patients now reject the idea that they have multiple sclerosis at all—and, indeed, one must admit that there is something refreshingly categorical about such views. MS is not diagnosed by direct observation of demyelination, after all, but largely by means of functional criteria. The idea that CCSVI is not MS at all sidesteps the multiple logical problems with attributing MS to CCSVI. (One obvious example: why doesn’t anybody develop MS beyond middle age, even as the vascular system in most humans continues to fall into ever-worse disrepair?) I suspect it is almost easier to believe that there are some non-MS patients whose real problem might be a chronic vein blockage than it is to believe that MS, which is known to be a demyelinating disease, is caused or worsened by such blockages.
The problem with making grandiose statements about this wholly novel ontological entity, CCSVI, seems similar to the one that plagued the field of back surgery until fairly recently: patients presenting with chronic lower-back pain would be given MRIs, and a surgeon would go “Ahhh, here’s your problem”, point to some apparent lesion—a “slipped disc” or the like—and recommend an expensive, disabling operation. We now know, because people got around to checking by means of controlled investigations, that many of these lesions are indistinguishable from ones commonly found in asymptomatic individuals. Put in plain English, everybody’s back kind of looks like hell in an MRI, because we are imperfectly evolved to walk upright. Stronger criteria have thus been established for surgical interventions into chronic lower back pain, and even for mere medical imaging of bad backs. Something similar is likely to happen with tonsillectomies for children, which are increasingly thought to have been performed much too commonly in the past (although the rates at which they are done seem to be about as high as ever).
Like it or not, medicine no longer cuts first and asks questions later. We can’t presume CCSVI into existence; we have to ascertain the natural background rate of vein blockages, even ones that look dramatic in a venogram. You can see for yourself that this is the basic aim of the studies Aglukkaq points to; all seven involve vascular comparisons of MS patients with healthy controls.
For the record, I would like to politely distance myself from any suggestion that the strongly evidence-based treatments developed for vein-obstruction problems in the legs should be used, on the premise of a “right to blood flow”, to justify vaguely analogous and non-evidence-based treatments in the region of the head and neck. I would also like to observe that surgery for varicose veins does not normally involve surgical widening of the affected vessels with balloons or stents: instead, the veins are simply removed, perforated, or destroyed, precisely because a sufficient volume of blood can be counted on to return to the heart from the leg through other tissues.
By Colby Cosh - Thursday, September 2, 2010 at 11:05 AM - 0 Comments
You all know I’m sceptical of Paolo Zamboni’s vascular hypothesis about multiple sclerosis, so allow me to express support for Saskatchewan health minister Don McMorris, who is defending his province’s right to fund research into the idea. I didn’t like Saskatchewan’s politically-driven funding decision, but I don’t think there is any reason to believe that the funding cannot be useful even if the hypothesis is true. That seems to be what the MS Society is suggesting when it argues that Saskatchewan can’t possibly muster up a large enough sample to conduct a useful test of the hypothesis. From today’s Globe:
Yves Savoie, president of the MS Society of Canada, said a true clinical trial must be conducted at more than one institution and in more than one province. Because MS is so variable, “it will require well over 1,000 participants that will be recruited through a number of centres,” he said. “A single province or a single site would simply not be a way to get to the definitive answers that we all want.”
Logic and experience suggest an obvious rejoinder: a single trial, however large, won’t be the way to get an answer either. Pure statistical power is a good thing, but so is experimenter diversity. If there is any merit in the Zamboni hypothesis, the scientific community is likely to arrive at a consensus about it on the basis of many different kinds of tests, some of them modest in scale, most of them performed independently. There is danger in Savoie’s apparent insistence on a One True Trial and in his gratuitous, pre-emptive criticism of what Saskatchewan is doing: he is inadvertently encouraging the Zamboni believers’ cherished conviction that they are being ganged up on by a conspiratorial clique that desires a monopoly on truth.
And if the MS Society thinks a single, giant experimentum crucis is advisable, it would be fair to ask why it isn’t advocating one, instead of funding CCSVI research in dribs and drabs. The fact is that piecemeal accumulation is the usual means of accumulating scientific knowledge. There’s no unitary global Science Court where hypotheses can be hauled in for exoneration or hanging.
We don’t really need a trial with a sample size of thousands to confidently confirm or disconfirm the most basic claim of Dr. Zamboni: that an MS diagnosis can conceivably be verified, or falsified, from nothing more than medical images of a patient’s head and neck veins. As I’ve suggested before, we could arrive at a good initial answer to that question quickly and inexpensively. There is no sense in going ahead with inquiries into causality, or into the effectiveness of any particular therapeutic regime, until we have first established that yes, there is such a thing as “chronic cerebrospinal venous insufficiency”. Trap your unicorn first, then study its anatomy.
By Colby Cosh - Wednesday, August 11, 2010 at 5:38 AM - 0 Comments
Alberta Health Services, the centralized corporate behemoth that runs the province’s healthcare system, disappointed advocates of “liberation therapy” for multiple sclerosis last week by putting out an amazing discussion paper [PDF] surveying the relationship between MS and “chronic cerebrospinal venous insufficiency”. It summarizes clinical knowledge in an accessible way and raises points that even CCSVI skeptics have overlooked. One simple example: “If proven, the association between MS and CCSVI may actually be explained by MS causing CCSVI.”
Given the logical and empirical problems with Dr. Paolo Zamboni’s theory and the special risks of venous angioplasty and stent insertion, Alberta politicians can feel comfortable in taking a hands-off attitude toward Saskatchewan Premier Brad Wall’s aggressive push for more trials of liberation therapy. If members of the Stelmach cabinet still want to pay for some risk-free research, though, I have a completely serious suggestion: why don’t we test Zamboni himself? We could do it live on cable TV. Actually, since CTV’s flagship W5 program (with synergistic assistance from the Globe & Mail) played such a large role in creating the furore over Dr. Zamboni’s theories, it’s possible the network would like first crack at the broadcast rights.
Zamboni claims to be able to tell MS sufferers apart from healthy individuals with virtually perfect accuracy just by looking at suitable medical images of the neck veins. There is no reason why the world should settle for his mere assurance that he can do so, since this ability ought to be simple to prove. And if he can do it he has no reason to be afraid to demonstrate it. It does not make much sense for the world to perform countless multi-million-dollar trials of his treatment before we check out the most basic, inexpensively verifiable element of his claims. (It certainly does not make sense to let people buy MRIs and other scans for “venous insufficiency” until we know whether that phrase has any practical meaning.)
So why not let Dr. Zamboni declare what images he requires, take 50 sets of snapshots of MS patients and 50 sets from healthy controls, and let him have at the pile of 100 file folders? Invite him to Alberta. Pay his expenses. Give him as much time as he needs. Have clinicians (and, preferably, some conjurors) present to establish proper, bulletproof double-blinding. The cost would probably come in at well under $100,000 and we would have our result instantly. Either he identifies the MS patients at a rate much better than chance or he doesn’t. If he scores close to 100%, as he has implied he can, then we would have strong reason to believe that vein structures are associated with MS. And we could justifiably move on toward establishing the proper direction of the causal arrow that those crotchety killjoys at AHS are so concerned with.
By Colby Cosh - Thursday, July 29, 2010 at 5:36 AM - 103 Comments
On Tuesday, the Globe‘s Patrick White discussed Saskatchewan premier Brad Wall’s announcement that he wants to set aside cash for trials of Paolo Zamboni’s “liberation therapy” for multiple sclerosis. White says that Wall’s audible “serve[s] up an uncomfortable nudge to political leaders elsewhere who have largely avoided the emotionally charged debate” over the Zamboni technique.
This is factually true. But the wording seems hard on our “political leaders”—most of whom have, and I’m just guessing here, avoided the “emotionally charged debate” because the debate is not really their business, but that of deputy ministers, health bureaucrats, foundations, and research establishments. To be sure, there is a place for improvisational, rapid-response policymaking at the top of the pyramid of state where justifiable public demand for it exists. But “the squeaky wheel gets the grease” is a dangerous maxim, full of moral hazard, and hardly a fit foundation for a system of funding scientific research. (Surely no level of hell can possibly be hot enough for opposition politicians who abuse a scientific controversy in order to establish their emotional bona fides.)
Wall’s moment of inspiration will have the effect, intended or not, of encouraging sufferers of painful, intractable illnesses like MS to besiege the Saskatchewan legislature directly with appeals for the latest internet nostrum-of-the-week. Nobody’s good intentions will stem that tide: let thy voyage unto Regina begin now, O ye with lupus, ye sore afflicted with fibromyalgia! Having conjured a research project into existence in the interests of anecdote-armed Victim A, on what grounds will Wall and his successors be able to turn away B, and C, and D?
It bothers me that Wall talks of the “hope” offered to MS patients by the Zamboni theory as if it were a virtue in itself; it seems to me that this is precisely what remains to be decided—whether the hope consciously cultivated by a handful of instant medical celebrities is fully justified, or whether it is an irresponsible, tragic delusion propagated for personal gain. It could well be either: the story of Barry Marshall reminds us that weird, unanimously heckled theories sometimes turn out to be true. The patients themselves can hardly help experiencing hope, though I rather admire the stoicism, evidently informed by experience, of one CBC.ca commenter (indeed, this may be the first cogent utterance ever made by any CBC.ca commenter):
This is the third “cure” I have seen for MS in my lifetime and it wont be long before it too is relegated to the scrap heap to lay beside the hyperbaric oxygen chamber and the snake farm. I still hope to see the one that works but this isn’t it.
How could anyone be so pessimistic? Well, even leaving aside the history of MS quackery and hype, there is no shortage of circumstantial reasons. The “liberation therapy” tag is an obvious mark of heavy con-artist and/or halfwit involvement in the publicity effort. Why not go all the way and just call the Zamboni technique “super amazing unicorn magic”? In newspaper accounts (and even in our own exemplary coverage), recipients of the therapy often report renewed energy without necessarily enjoying total relief from symptoms; this may not be a sign of the placebo effect at work, but it is certainly consistent with it. And it is hard to understand how the instantaneous improvements so often described by the “liberated” can possibly be consistent with Zamboni’s actual theory of MS etiology—i.e., that poor drainage of blood from the brain encourages, over a long term, the formation of cerebral iron deposits that then lead to immunological issues and demyelination of the nerves.
These things make you go “hmm”, and when you throw in the additions to the “hmm” list provided by a March review of the Zamboni theory published in Annals of Neurology, you start sounding a little like a downed power line. Zamboni’s study claimed to be able to distinguish the intracranial veins of MS patients from those of normal people perfectly. This is not a figure of speech: they claimed literal perfection. “They reported that only MS patients and not controls met the criteria for abnormal extracranial cerebral venous outflow. This observation perfectly overlapped with the diagnosis of MS, with a reported 100% sensitivity, 100% specificity, 100% positive predictive value, and 100% negative predictive value.” Major “hmm” points there.
The authors of the review also point out that Zamboni’s proposed etiology offers no obvious explanation for why women contract MS twice as often as men, or why incidence rates around the globe get larger with greater distance from the equator. They wonder why, if MS is a vascular disorder, it almost never appears after the age of 50. They ask why retinopathy and other known consequences of poor vein drainage aren’t statistically associated with MS. Perhaps most interestingly, they point out that sufferers of head and neck cancer have, for more than a century, been receiving a (horrifying-sounding but surprisingly inconsequential) treatment known as “radical neck dissection”, which involves, among other things, the total removal of the jugular veins. If Zamboni were right, one would have expected demyelination and MS symptoms to have been noticed in these patients immediately, or at least at some point since 1906.
There might be good answers to these questions, and, indeed, Zamboni’s angioplasty/stent approach might relieve MS symptoms for reasons having nothing to do with his theoretical ideas. But his treatment will have to do significantly better than placebo in proper trials, because angioplasties and stents come with known mortality risks. And if Zamboni and his advocates are to receive the benefit of all the hypothetical “ifs”—it might work for some reason we don’t yet understand!—then common sense demands that the “ifs” whose spear-points run in the other direction be considered: everybody who’s had “liberation therapy” might drop dead at midnight on New Year’s Eve for reasons we don’t yet understand!