Earlier in the year, the FDA renewed warnings about use of balloon angioplasty in neurologic disorders such as multiple sclerosis, a procedure first championed by an Italian vascular specialist and embraced by some in the MS community, although soundly rejected by most neurologists. Click here to see ľֱ's report on the FDA's stance. In this follow-up, we examine what has happened in the field since.
A large randomized controlled trial may have found , but lead investigator Paolo Zamboni, MD, isn't ready to give up on his theory, despite that the rest of the MS research community sees it as the final nail in the coffin.
"I am convinced that the improvement of cerebral venous and lymphatic drainage is a key point to understand inflammation in MS," Zamboni, who birthed the concept of Chronic Cerebrospinal Venous Insufficiency (CCSVI) in MS, told ľֱ in an email. "I plan to work on this."
One of his defenses: the trial was "underpowered due to the lack of co-operation on behalf of the MS centers. The statistical plan calculated the need of 400 patients to be conclusive, but we randomized just 125 patients, including 15 MS secondary progressive cases," he said.
The other? Post-hoc findings on one of two primary endpoints of new MRI lesions "do not completely exclude an effect of angioplasty."
Zamboni -- a vascular specialist, not a neurologist -- came up with his vascular theory of MS in 2009, hypothesizing that restricted venous outflow from the brain and spinal cord was responsible for symptoms of the disease. Opening those blocked veins with angioplasty could diminish symptoms, he posited at the time. He said he was highly motivated by finding a treatment for his wife who has MS.
A Canadian TV documentary, followed by a report in the country's largest newspaper The Globe and Mail, quickly spread among the MS community, leading scores of patients to pursue the treatment. It became commonly known as "liberation therapy."
Academic MS specialists were always skeptical, and several studies published over the years that followed -- though none an RCT -- failed to support Zamboni's theory.
Now, with the publication of Zamboni's randomized controlled trial in , MS experts say they're more than ready to leave the theory and treatment behind.
"Most of the neurologic community thought the existence of CCSVI and the benefit of venoplasty had already been disproven, so this publication just reinforces what most of us already thought," Jeffrey Cohen, MD, of the Cleveland Clinic, told ľֱ.
Jerry Wolinsky, MD, professor emeritus at the University of Texas Health Science Center, who has published several papers suggesting no benefit for venoplasty in MS (albeit none were RCTs), said "as far as I am concerned, we put the nails in the coffin several years ago."
None of the experts contacted by ľֱ have had MS patients approach them about venoplasty recently.
"Although I still hear from some patients that had it done, very few ask me about getting it now," Cohen said.
Edward Fox, MD, of Central Texas Neurology Consultants, said he hasn't had a patient ask about the treatment in a long time since it's "no longer discussed in the lay press."
"The root of this wasted effort may have been Zamboni, but it was the unbridled and unfounded enthusiasm of the public that led to the extended belief in the CCSVI hypothesis," Fox said.
During the procedure's heyday, two Canadian patients and one U.S. patient, who were treated in Costa Rica and California, died following the procedure, Ari Green, MD, of the University of California San Francisco, and colleagues published alongside the RCT.
With more recent negative press, some enterprising practitioners in the U.S. have simply re-named the procedure, and have widened its indications beyond MS to include fuzzy conditions like fibromyalgia and dysautonomia. Last March, the FDA called out Michael Arata, MD, of Synergy Health Concepts in Newport Beach, California, for performing transvascular autonomic modulation (TVAM) -- the same venous angioplasty procedure used by Zamboni -- despite receiving warning letters not to do so outside of a clinical trial setting.
For the CCSVI trial, Zamboni and colleagues enrolled 115 patients at six MS centers in Italy: 76 of them got percutaneous transluminal venous angioplasty, while 39 got a sham procedure. All were said to have confirmed CCSVI on Doppler ultrasound at baseline.
Overall, there was no benefit on one of two primary endpoints of a disability composite of walking, balance, hand function, urinary function, and visual acuity (41.7% in the treatment group versus 48.7% in the sham group; OR 0.75, 95% CI 0.34 to 1.68, P=0.49).
Nor were there any differences in the other primary endpoint of number of new lesions on MRI at 12 months (1.40 with treatment versus 1.95 with sham; mean ratio 0.72, 95% CI 0.32 to 1.27, P=0.45). The proportion of patients free of new lesions didn't differ significantly between groups, either (63% versus 48.6%; OR 1.80, 95% CI 0.81 to 4.00, P=0.30).
A post-hoc analysis suggested that more treated patients remained free of new brain lesions at 6 to 12 months (83% versus 67%; OR 2.64, 95% CI 1.11 to 6.28, P=0.03), but that significance fell off in adjusted models. Still, Zamboni and colleagues wrote in the paper that this data point suggests venoplasty "could affect the dynamic of the blood-brain barrier."
While it seems that Zamboni is poised to continue defiantly defending his theory, the MS community continues to move on.
"He held on to the beliefs far longer than any of us would have preferred," Fox said, "and far too much money and resources were wasted after the initial report."