LYON, FRANCE—Chronic cerebrospinal venous insufficiency (CCSVI) appears to occur at a similarly low rate among patients with multiple sclerosis (MS), patients with other neurologic disorders, and healthy controls, researchers reported at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). CCSVI also appears to occur at similar rates among patients with various types of MS.
The study results cast doubt on the hypothesis, first proposed by Paolo Zamboni, MD, Associate Professor of Morphology, Surgery, and Experimental Medicine at the University of Ferrara, Italy, that CCSVI is an important factor in MS. The findings also call into question Dr. Zamboni’s proposal that a type of angioplasty known as “liberation therapy” could be an effective treatment for patients with CCSVI and MS.
Testing the Zamboni Hypothesis
To determine whether there was a relationship between CCSVI and MS, under the sponsorship of the Italian Multiple Sclerosis Society, Giancarlo Comi, MD, Head of the Neurorehabilitation Unit at Fondazione San Raffaele del Monte Tabor in Milan, and colleagues enrolled subjects in a case–control observational study conducted at 35 Italian clinical centers. Of the study population, 1,165 patients had MS, 226 patients had other neurologic disorders, and 376 subjects were healthy controls. Subjects between ages 18 and 55 were eligible to participate.
All patients were evaluated by a neurologist. Local neurosonologists, who previously had been certified as having learned standardized criteria for diagnosing CCSVI, then performed blinded Echo Color Doppler (ECD) evaluations according to a predefined protocol to determine whether the subjects had CCSVI. Each exam was recorded and sent in a random manner to one of three expert central neurosonologists, who also had blind access to the ECDs.
The study’s primary end point, the presence of CCSVI, was determined by the agreement of the local and central neurosonologists. When the local and central neurosonologists disagreed, the exam was sent to the other two central neurosonologists, and the final diagnosis was made by a consensus of two of the three central neurosonologists.
The researchers excluded patients for technical reasons and 55 other subjects because of protocol violations. A total of 1,767 patients were included in the final analysis.
Most Subjects Did Not Have CCSVI
CCSVI was diagnosed in 3.26% of patients with MS, 3.10% of patients with other neurologic disorders, and 2.13% of healthy controls. The investigators found no statistical difference in CCSVI prevalence among the three groups. After comparing patients with various types of MS, the researchers found no statistical difference in CCSVI prevalence.
The central neurosonologists diagnosed CCSVI in 3.3% of patients with MS, 2.7% of patients with other neurologic disorders, and 3.2% of healthy controls. The investigators found no statistical difference between the three groups. The local neurosonologists diagnosed CCSVI in 15.9% of patients with MS, 15% of patients with other neurologic disorders, and 12% of controls. The investigators found no statistical difference between these groups.
Local clinical centers varied widely in their diagnoses of CCSVI. Some centers found CCSVI in 60% of all evaluated cases, and others found no cases, said Gianluigi Mancardi, MD, Head of the Department of Neuroscience at the University of Genoa and a coauthor of the study.
Local and central neurosonologists agreed on the absence of CCSVI 92% of the time, but disagreement on positive diagnoses was common. Central neurosonologists evaluated as positive 28 cases that had been evaluated as negative by local neurosonologists. Of 236 cases that had been evaluated as positive by local neurosonologists, 28 were evaluated as positive by central neurosonologists.
The three central neurosonologists agreed 99% of the time on negative diagnoses, but they had an “extremely low” rate of agreement for positive diagnoses, reported Dr. Comi and his coinvestigators. This result suggests that CCSVI diagnoses are highly subjective. “Even for experts, it was extremely difficult to say, ‘Oh yes, this is CCSVI,’” Dr. Comi noted.
Liberation Therapy May Have No Medical Basis
“This is the first multicenter study done in a blinded manner with a tremendous amount of patients,” said Dr. Mancardi. “The conclusion is that CCSVI is not associated with MS or with other neurologic disorders. There is no statistical difference [in CCSVI prevalence] between [patients with] MS, healthy controls, and [patients with] other neurologic disorders. Therefore, there is no evident role for CCSVI in MS.”
More than 1,000 patients worldwide have undergone angioplasty to treat CCSVI, according to Dr. Comi. Although it is understandable that patients with MS would seek alternative therapies, angioplasty “is an interventional type of treatment,” he said. “Interventional means that you expose the patient to potential risks. And this is one of the main reasons why we need to use a very objective approach, because we are taking care of our patients.”
To perform a clinical trial of angioplasty for CCSVI in patients with MS, researchers must first demonstrate that patients with MS have an increased risk of CCSVI, compared with normal controls or patients with other neurologic diseases. Dr. Comi’s study, however, found no difference among the three patient groups. “If we … decide to operate for this condition, then we should theoretically operate also on the normal controls,” said Dr. Comi.
“There is no rationale for a trial exploring the efficacy of the liberation therapy,” and a randomized trial of an endovascular procedure in patients with MS would be unethical, Dr. Comi commented. “The risk to treat patients is that the adverse effect of the intervention would overcome all the potential advantages,” he concluded.
Zamboni P, Galeotti R, Menegatti E, et al. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 2009;80(4):392-399.
Zamboni P, Galeotti R, Menegatti E, et al. A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency. J Vasc Surg. 2009;50(6):1348- 1358.e1-3.