Radical My ASS

Radical MS Theory Stirs Interest

By Michael Smith, North American Correspondent, MedPage Today Published: November 27, 2009

Can multiple sclerosis be treated with a simple surgical procedure? That question -- raised by the research of an Italian physician -- is causing a stir among those who study the condition, which has long been regarded as an autoimmune disease. Instead, according to Paolo Zamboni, MD, of the University of Ferrara, in Ferrara, Italy, MS may result from poor vascular circulation in the brain. The theory is this: Abnormal flow through the azygous and jugular venous systems results in a build-up of iron in the brain. The excess iron damages blood vessels and allows the metal, as well as other substances, to cross the blood-brain barrier. The hypothesis has immediate clinical implications. First, if narrowed or obstructed veins are the cause of the condition, people might easily be screened for MS long before symptoms appear. And second, a simple surgical procedure -- a percutaneous transluminal angioplasty -- could open the veins and perhaps halt or reverse the course of the disease. The case is not proved, and experts caution that more study is needed to overthrow the reigning paradigm. In particular, they warn patients against seeking vascular surgery before the issue is settled -- one way or another -- by a full-scale, randomized blinded controlled trial. "Most experts regard it as a long shot" that needs to be studied, said John Richert, MD, executive vice president for research and clinical programs at the National Multiple Sclerosis Society. But Zamboni told a Canadian newspaper recently, "I am confident that this could be a revolution for the research and diagnosis of multiple sclerosis." Researchers in Buffalo, led by Robert Zivadinov, MD, PhD, of the Buffalo Neuroimaging Analysis Center, are currently trying to determine whether people with MS are more likely to have what has been dubbed "chronic cerebrospinal venous insufficiency." They are enrolling 1,100 patients diagnosed with possible or definite MS, 300 age-and-sex-matched normal controls, and 300 patients with other autoimmune and neurodegenerative diseases. "If we can prove our hypothesis, that cerebrospinal venous insufficiency is the underlying cause of MS," Zivadinov said in a statement, "it is going to change the face of how we understand MS." The investigators are following up a small pilot study, as well as one conducted by Zamboni and colleagues and reported late last year in the Journal of Neurology, Neurosurgery & Psychiatry. In that study, Zamboni and colleagues looked at venous outflow in 65 patients with clinically defined multiple sclerosis and 235 controls, using transcranial and extracranial Color-Doppler high-resolution examination. The MS patients were 43 times more likely to have abnormalities than the controls, they reported (OR 43.0, 95% CI 29 to 65, P<0.0001). Zivadinov and colleagues found a similar result in their small pilot study of 16 patients with relapsing-remitting MS and eight healthy controls: all the patients, but none of the controls, had chronic insufficient blood flow from the brain. Also, in a report in press at the Journal of Vascular Surgery, Zamboni and colleagues offer results of a study in which they surgically treated 65 MS patients with abnormal cerebral venous outflow. The effect of the surgery on MS symptoms was compared with rates of symptoms during the two years before the procedure. According to published reports -- the final paper is not yet available -- during the 18 months following surgery, half of the patients with the remitting-relapsing form of the disease had no attacks. The corresponding rate before surgery was 27%. As well, the proportion of patients with active gadolinium-enhanced lesions seen on MRI scanning fell from 50% to 12%. While the results seem promising, they fall well short of proof, according to the MS society's Richert. "This is something that requires a well-controlled, blinded prospective study," he said. One danger is that patients may jump the gun, Richert said. "There are a number of patients who may be expecting that they can just go to a vascular surgeon and get this done," he said. "Our feeling is that this is an experimental procedure and that it should be undertaken by people with MS only as part of a formal clinical trial," Richert added. Richert added that the results of Zamboni's surgical trial -- while good science -- aren't enough yet to overturn the existing paradigm. Among other things, Richert said, it's possible that the apparent benefit was a long-lasting placebo effect. In clinical trials with a placebo, he noted "reproducibly and consistently, the group on placebo does better on the trial than they did prior to entering the trial." Zamboni and colleagues measured MS symptoms in patients before and after the procedure, rather than comparing surgical and control groups. The changes that they saw, Richert said, are similar to those "that we tend to see in placebo groups in major drug trials." He added that the MS society is "anticipating" proposals for a randomized trial of the surgery by its February grant deadline. The Canadian MS society said earlier this week that it will support such research if a proposal is made.