Controversial Intravascular Therapy for Multiple Sclerosis Moves from Cath Lab to the OR

New York, NY—An Italian doctor who stunned the world 6 years ago by reporting remarkable success treating multiple sclerosis (MS) patients with balloon angioplasty of neck veins told an audience at the VEITH symposium last week that open surgery may be an option for patients who cannot undergo the minimally invasive procedure. Whether or not so-called “liberation therapy”—endovascular or otherwise—actually helps MS patients remains an open question. 

Paolo Zamboni, MD, of Azienda Ospedaliero-Universitaria di Ferrara (Ferrara, Italy), is the so-called father of the chronic cerebrospinal venous insufficiency (CCSVI) theory of MS. Zamboni contends that obstructed or impaired venous flow is a contributor or causative agent in MS, based largely on studies he himself conducted showing that patients with MS have evidence of CCSVI while control subjects do not.

Various researchers have tried and failed over the years to replicate Zamboni’s imaging studies using identical methods and criteria, with some suggesting that inability to reproduce his data signaled “a death knell” for the CCSVI hypothesis. Despite this, interest in treating MS has nonetheless continued, with countless patients all over the world undergoing balloon angioplasty and/or stenting of the internal jugular or azygous veins—often repeatedly—in the hopes their symptoms will abate or disappear altogether.

According to symposium chair Frank J. Veith, MD, of the Cleveland Clinic (Cleveland, OH), the lack of randomized trial evidence supporting CCSVI does not mean it doesn’t have a future.  “Randomized controlled trials are not the be-all and end-all. They can be very misleading and they can be misinterpreted,” he told TCTMD. “The bottom line is that MS is cyclical, it has exacerbations and remissions,” so determining the best end point to use or demonstrating a benefit of a therapy “is extremely hard to do with a randomized controlled trial.”

Improved Flow Seen

In his presentation in New York last week, Zamboni showed results of 41 patients—27 who underwent surgery and 14 who served as controls. All had “CCSVI associated with neurological disease,” Zamboni said, although he stopped short of identifying them outright as MS patients. In an interview with TCTMD, he said the patients “were not ideal candidates [for angioplasty] because they were very complex cases.” Many of them had external compression coupled with valvular malformation, he added.

Among the surgical procedures performed were: endophlebectomy, muscle section (when appropriate), and autologous vein patch angioplasty. Procedures were bilateral in 15 patients.

On laser Doppler flowmetry, venous outflow and collateral flow index were substantially improved from baseline following the procedure. 

Additionally, 3D assessment showed improved brain ventricular volumes after the procedure in the intervention group and no difference from baseline in controls.

“Creating Better Venous Drainage”

Commenting on Zamboni’s presentation, Veith called the data “quite interesting, but inconclusive.”

“The first question is, does correcting a venous narrowing or venous obstruction help MS? And we don’t know the answer to that yet. What he’s showing is that you can have patients in whom stenting is not feasible, so he is opening [these obstructions] surgically. That’s an interesting point, but it doesn’t address the key question, so the controversy continues. And there are many, many people who believe this theory is a hoax and there are others who believe that there’s something real there, that it is of therapeutic value for some patients. But Zamboni’s talk didn’t address the key questions that will settle that controversy.”

The theory, in principle, makes sense to Michael D. Dake, MD, of Stanford University Medical School (Stanford, CA), who also commented on the data in a telephone interview with TCTMD.  “Outflow insufficiency, whether you call it CCSVI or not, creates a venous obstruction that has upstream effects on the villi that reabsorbs cerebrospinal fluid and causes it to be less effective … such that there is a backup of fluid that makes the ventricles enlarge and when they enlarge there is a corresponding potential for brain atrophy and degeneration,” he noted.

Dake, an early proponent of stenting for CCSVI, said he believes Zamboni is correct that many venous abnormalities may not be sufficiently addressed by balloon intervention alone.

“What [Zamboni] is doing is somehow surgically creating better venous drainage,” Dake said. “But honestly it is unclear from this presentation exactly how he is achieving that and so that definitely requires more explanation as to what his process is for determining which patients and which abnormalities are surgical candidates.”

Who Needs Surgery?

According to Zamboni, the complication rate was low in the study and included hematoma in 4 patients, a single incidence of thoracic duct injury, 1 case of bleeding, and 1 cranial nerve injury. Although he did not publicly report follow up during his presentation, he told TCTMD that the patency rate in the surgical intervention group was 85% at 1 year.

While acknowledging that the surgical procedure is more invasive than angioplasty, he added “the more we have in the arsenal … the better it is for the patient.”

Dake observed that not everyone will be convinced that open surgery is necessary. In fact, he said he believes it is possible that some of the venous abnormalities for which Zamboni is proposing surgery may be amenable to stenting.

For those cases that are not amenable, however, Dake said the study does not suggest how to select patients or predict which ones have a high probability of failing angioplasty. If that were possible, he added, “we would probably offer [surgery] earlier.” However, he acknowledged that for many clinicians, the study is “way out of the margin in terms of being persuasive.”

For now, the various studies that have been done in this arena are each a tiny piece of a mosaic, Dake maintained.

“Eventually someone, somewhere is going to take all of this disparate data and pull the seams together to give a more comprehensive perspective that ties together veins, lymphatics and CSF,” he concluded. “In my heart of hearts, there is something here. It may not be this generation that figures it out, but you can’t [assume] that the head and neck are somehow impervious or immune to the same venous problems we find elsewhere in the body. Whether it results in the same pathology or not, I don’t know, but I have to assume on some level it does. We just have to prove it.”

Veith, for his part, says he’ll definitely be inviting Zamboni back to the VEITH Symposium next year. He predicts interest in CCSVI is likely to be cyclical. Last year an entire session was devoted to the topic; this year, Zamboni’s data was a stand-alone presentation. “I would say, right now, that interest in CCSVI is in decline as a concept, but it’s still an interesting concept. It may not come back [into vogue] with the level of enthusiasm that it [enjoyed] a year or two ago, but there will still be a place for it and I will continue to put it on the program.”