A year and a half ago, Sharon Richardson underwent a procedure to treat chronic cerebro- spinal venous insufficiency (CCSVI), compromised blood flow in the veins that drain the central nervous system and appear to have caused her multiple sclerosis. The controversial treatment—as yet unapproved in the United States--has gained much attention since that time and has proponents and skeptics debating its merit. ISET yesterday took a comprehensive look at the issue by inviting speakers with unique perspectives to the panel table, among them physicians with direct knowledge of the work and Mrs. Richardson, now the president of a patient advocacy group.
The theory of CCSVI became popular after the 2009 publication of a study by Paolo Zamboni, M.D. Working on the premise that MS is an immune-mediated unknown, meaning a variety of treatments may be needed, Dr. Zamboni theorized that the venous system may play a role in MS therapies.
It’s not a new theory, he told a ballroom full of attendees. J.M. Charcot, who discovered MS, wrote in the 1890s that “frequently, in the center of the plaque, there is a dilated vein,” Dr.Zamboni said.
Dr. Zamboni began his research by comparing the histology of cardiovascular disease with the histology of MS around the central vein, noting that MS is the only neurodegenerative disorder with iron stores in the white matter encircling the vein wall.
Dr. Zamboni’s approach was three-pronged: to consider the possibility that venous insufficiency might
be related to pathology in the extra-cranial main trunk, to develop a noninvasive Doppler methodology investigation of what is considered physiological venous return and to demonstrate extracranial venous pathology by the means of gold-standard catheter venography.
The resulting data produced a CCSVI-MS neurological outcome with seven components: safety, significant reduction of venous pressure, good rate of relapse-free patients, improved performance in early stages of MS, reduction of Gad+ lesions, improved quality of life and improved chronic fatigue, Dr. Zamboni said. Study limitations were lack of a control group and a blinded clinical assessment.
Michael Dake, M.D., who performed Ms. Richardson’s procedure, said follow-up research is underway at Stanford. Basic studies include evaluation of human tissue, preclinical animal studies with a murine model of experimental autoimmune encephalomyelitis, MR physiological assessments of flow and MR myelin mapping.
Clinical assessments include duplex ultrasound studies using the Zamboni criteria, magnetic resonance venography beyond anatomic renderings, catheter venog- raphy, intravascular ultrasound examination of valvular apparatus, and validated clinical testing tools to evaluate cognitive performance, upper and lower extremity function, fatigue and quality of life.
The result is that global symptoms attributed to MS, such as fatigue, headache, heat sensitivity, brain fog and urinary urgency, show short- term improvement and in some cases completely resolve, Dr. Dake said. “This suggests that these particular ‘MS’ symptoms may be more accurately categorized as related to venous obstruction,” he added.
“So where does that leave us?” he concluded. “For now, it’s a step-by- step focus. Personally, for starters I want to know if a patient with MS has CCSVI, and if the narrowing is successfully treated, is it possible to objectively demonstrate physi- ological improvement in relevant parameters and an associated relief of symptoms?”
In Canada, there are seven different venography CCSVI and MS trials currently underway, said Lindsay Machan, M.D. As incidence of MS increases as distance from the equator increases, MS is the leading cause of disability in young Canadians, Dr. Machan said. The trials were spurred by an explosion of popular demand following a TV documentary on the Zamboni study.
“Outside the U.S., there is a general skepticism [about CCSVI] from the neurological community, but a willingness to participate in trials,” Machan said.
Jack Burks, M.D., gave a neurologist’s perspective on CCSVI treatment for MS. “My goals are first of all to reduce the turf wars between vascular interventionalist experts and MS experts and patients,” he said. “We need to work together to encourage a united message for the MS world.”
Currently, neurologists are being overwhelmed by patient requests for CCSVI treatment, but are saying “not so fast,” he said. “Very naïve interventionalists, who we refer to as cowboys, are overstating the pos- sible value of CCSVI. Neurologists think we need to shut down these interventionalists.”
Patients see interventionists as the “liberators” and neurologists as the “nihilists,” he said, and think neurologists resist CCSVI because they’re afraid of losing their patient- care income and are controlled by the drug companies. But neurologists are justifiably wary, Dr. Burks said, considering that past MS “cures” include malaria, laminectomy, snake venom, bee stings, cow’s milk and vertebral artery surgery.
Dr. Burks said practitioners who treat MS need a document that defines “superior” CCSVI diagnostic test outcomes, treatment standards for interventionalist procedures, criteria for diagnosis of MS, established standards for “quali- fied” CCSVI specialists, uniform IRB requirements, standards for follow- up care, and criteria for retreatment and procedural standards. They then need to disseminate the document widely to all interested groups and third-party payers, he said.
James Benenati, M.D., president of the Society of Interventional Radiology, detailed SIR’s position statement on CCSVI, which was published in the September 2010 Journal of Vascular and Interventional Radiology.
Dr. Benenati said SIR recognizes the urgent need for more effective treatments for MS patients, that MS patients are particularly vulnerable and that interventional radiologists need to ensure their safety, and that the published literature is incon- clusive. At the same time, he said, interventional radiologists possess the ideal skill set to provide inter- ventional MS therapy.
SIR strongly supports urgent performance of high-quality clinical research on CCSVI, Dr. Benenati said. There are currently two SIR groups working on MS marketing, research and diagnosis issues, he said, and SIR representatives have met with the FDA about future investigations. The society is also educating members and compiling lists of physicians involved in solid research trials or who have designed their own CCSVI protocols and are monitoring patients thoroughly, he said.
In the panel discussion that followed the Town Hall presentations, Martin Leon, M.D., noted that “it’s striking to see how far this has gone, but I have to say we’ve encountered many of these things before, most recently with transcatheter valve therapy. I agree we need an immediate multidisciplinary commitment to overcome some of the limitations.”
Practitioners need good multi- center clinical trial evidence, Dr. Leon said, but he doesn’t know if they’re ready for a double-blind, controlled, randomized trial. Dr. Zamboni said he thinks the neurological commu- nity is likely to accept a double-blind trial, and Italian researchers hope to begin such a trial in the next few months.
Dr. Burks said any clinical trials on CCSVI and MS should have accurate MS diagnostic criteria or best treat -ment outcome. But Dr. Dake cautioned: “It’s not easy to make a diagnosis. We have to realize there’s not going to be a perfect trial.”
Dr. Machan closed the panel discussion with a warning. “I would really stress there’s a real danger zone here.” With the high level of interest in a procedure to treat CCSVI, any mistakes made along the way are going to have an effect, he said. “Regulators look for negatives, and they apply them across the board.”
As for Sharon Richardson, she credits the procedure with restoring her quality of life. “Do I feel fortunate? Heavens yes,” she said. “I would do it again.” As for the doctors that heard her speak, she hopes they will keep an open mind.