In his latest column, my colleague Colby Cosh put on his coroner’s cap, declared CCSVI “dead,” and did exactly what columnists do: stir up controversy. As evidence, he cited two recent negative CCSVI studies—here and here–and noted a study funded by the government of Newfoundland and Labrador that concluded MS patients who received venoplasty to treat chronic cerebrospinal venous insufficiency, a vascular condition identified in 2006 by Paolo Zamboni, experienced “no measurable benefits” and in some cases saw a worsening of symptoms.
This research is damning, no doubt. But a mortal blow it’s not. It also demands greater context within the polarized—and politicized—sea of CCSVI research. PubMed lists 136 CCSVI-related studies: the positive ones, which outnumber the negative, tend to be reported by vascular specialists in vascular journals; negative reports tend to be found in neurology journals.
Colby’s column arrives amid a rising crescendo of negative CCSVI buzz. As an indicator of how over-heated and irrational the subject has become, last week the supermarket trash tabloid Globe magazine blamed Annette Funicello’s recent death on CCSVI treatment she had two years ago, though they failed to summon any evidence. Recently, the University of Buffalo researchers who staged the first randomized, controlled clinical treatment trial (on nine patients) took the usual step of reporting its negative results on YouTube before they’d been accepted for publication. Even so, they didn’t see their results driving a stake in CCSVI’s heart: “This is not the last word on this endovascular treatment for MS,” Dr. Adnan Siddiqui said: “This is the first word.” Their work also showed benefit of venoplasty in improving cerebrospinal fluid (CSF) flow in MS patients.
The 2013 study Colby referenced from the Journal of Cerebral Blood Flow & Metabolism was produced by the same team that delivered one of the first negative CCSVI studies in the Annals of Neurology. That 2010 study elicited this letter to the editor from Zamboni who claimed the findings supported his theory that MS patients have venous flow irregularities. This new study also identifies venous flow abnormalities in people with MS: “findings on cerebral veins are also reflected by low magnetic resonance perfusion measures (cerebral venous blood flow and cerebral venous blood volume) and other measures suggesting an underutilization of oxygen in MS brain tissue.”
Detroit-based physicist Mark Haacke, an internationally respected MRI imaging pioneer who invented the imaging techniques referred to by the researchers in this new paper, waves off doomsday talk: “CCSVI is far from dead,” he says. Haacke, also affiliated with Hamilton’s McMaster University, has screened more than 2,000 MS patients with MRI (he says the operator-dependent ultrasound used in many CCSVI studies is inconsistent). “We see significant abnormalities in the 650 cases we have processed so far,” he says.
Other much-needed research is ongoing. Canadian clinical trials, announced in 2011, are finally screening potential candidates, says neurologist Anthony Traboulsee, the lead researcher. After months of bureaucratic delay, MS patients from Saskatchewan are again being sent to Albany, NY, to participate in a trial. Zamboni’s own delayed clinical trial is underway in Italy, after the sort of intrigues usually reserved for opera.
Zamboni appears unperturbed to hear his hypothesis has been declared “dead.” He’s used to media seizing on negative studies. “Every scientific paper with negative CCSVI results is invariably written by authors weighed down by conflicts of interest,” he said in an email. He noted that the Berlin editorial office of Journal of Cerebral Blood Flow & Metabolism is in the same department the study’s authors work. (I also noticed that in disclosures in the 2010 study, one of the authors revealed a conflict–“K.S. has received speaking honoraria from Sanofi-Aventis, Novartis, and Merck-Serono”; this time, there are no conflicts declared.) But CCSVI pathology is an accepted medical entity, he says, with the “vast majority” of PubMed research “confirmatory.”
Colby writes that CCSVI is some kind of made-in-Canada mania unleashed by CTV and Globe and Mail coverage in 2009. In fact, Zamboni presented two papers on the topic to the Royal Society of Medicine in London, the first in 2006; researchers, including those at the University of Buffalo and Stanford, saw enough merit in his theory to commence their own research; a clinic in Poland began offering CCSVI treatment. He also took Zamboni to task for being out of sync with medical orthodoxy concerning MS: “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,” he writes. But what is actually “known” about MS, an incurable, degenerative condition of uncertain cause, is inconclusive–though we do know that typical MS onset is not “midlife”: it’s typically diagnosed between ages 15 and 40.
We also know the condition is wildly heterogeneous in terms of symptoms and progression; it is also often misdiagnosed, confused with conditions with known vascular, infectious or auto-immune etiologies—lupus, Lyme disease, myasthenia gravis, central nervous system angitis, the list goes on, which could help explain why some people diagnosed with MS benefit from CCSVI treatment and others don’t.
In fact, vascular links to MS predate the French neurologist’s Jean-Martin Charcot’s naming of it in 1868; the notion that they could be a co-morbidity factor exists in medical research, unproven, throughout the 20th century, as compiled here. Yet the still unproven auto-immune theory has prevailed, fuelling neurologist-lead MS research and education since the 1930s; it’s based on an EAE mouse model that some neurologists say offers a “misleading” proxy for the condition. Even so, it’s become the foundation of a billion-dollar MS infrastructure buttressed by symptom-modifying drugs that can run upward of $50,000 per patient a year and are subsidized by governments: it’s a market forecast to reach $20 billion in 2017—up from $8.2 billion in 2009.
The economics—and politics–of MS treatment is a subject ripe for investigation, especially given concerns about drug safety and efficacy. Colby reserves his concern for the wallets of CCSVI patients: “But after years of empirical setbacks for the whole notion of CCSVI, it is all looking like money down the drain,” he writes. To put this in context, we’re talking three years–and upwards of an estimated 20,000 treatments. But he’s right that CCSVI treatment outside of a clinical setting can be an opportunistic Wild West; standards and quality vary. Zamboni himself has cautioned people to await clinical trial results. It’s also true that some people have spent tens of thousands of dollars on treatment that didn’t help and contains risks. There have been three known deaths. Post-procedure complications can occur, with Canadians facing the additional worry of being denied after-care for CCSVI treatment at home, which—shamefully–is happening.
But CCSVI treatment has also benefited many, according to anecdotal accounts and research. Some improvements have been dramatic, as seen with Barrie, Ont. resident Steve Garvie who was treated in a limited trial in Canada in 2010. For more it has provided vital symptom modifying relief, as seen with Funicello, who was diagnosed with MS in 1989 and was extremely disabled when she underwent venoplasty in 2011. According to this CTV documentary, her husband reported small improvements that contributed to her quality of life.
CCSVI remains a puzzle. But increasingly it’s clear it’s a puzzle piece–and building block in terms of sparking investigation into the woefully understudied and little-understood venous system. We’re now seeing research into venous abnormalities in other neurodegenerative disease, including Parkinson’s and Alzheimer’s, as outlined here. Haacke is now scanning Parkinson’s patients. Zamboni’s theory has also mobilized the formation of the interdisciplinary International Society of Neurovascular Disease which has planned its fourth annual meeting next year. Venoplasty studies have begun to identify grey matter (rather than white matter lesions) as an important marker of brain health in MS patients. So, as Zamboni jokingly puts it: “Who is really dead?” The question is rhetorical.