LYON, France -- The largest study to date testing the venous-obstruction theory of multiple sclerosis failed to support it, leading the Italian Multiple Sclerosis Society to declare the theory dead.
Reported here by leaders of the group, known by its Italian abbreviation AISM, the study of nearly 2,000 individuals with blinded central imaging analysis found the condition in only about 3% of MS patients and in only slightly fewer healthy controls or patients with other neurological conditions.
Key data were released at a press briefing by principal investigator Giancarlo Comi, MD, of the University of Milan, and other study leaders in advance of Comi's formal presentation, scheduled for Saturday at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis.
They characterized the study as the largest yet conducted on the so-called chronic cerebrospinal venous insufficiency theory (CCSVI), advanced in 2009 by Paolo Zamboni, MD, of the University of Ferrara in Italy.
The CCSVI theory quickly took the MS community by storm, leading many patients to seek venous angioplasty and stenting procedures in hope of obtaining relief or even a cure, as Zamboni and some other vascular surgeons claimed was possible.
But the theory also drew substantial criticism, especially after numerous other researchers were unable to reproduce Zamboni's original findings of 100% presence of CCSVI in MS patients and 0% in non-MS controls. Some groups were unable to detect CCSVI in more than a small fraction of patients, while others found that it was relatively common but without specificity for MS.
In the new study, sponsored by AISM and called CoSMo, ultrasound analyses were performed on 1,874 individuals at 35 clinics throughout Italy. A total of 107 were subsequently excluded because of technical problems with the images or because participants were found not to meet the specified inclusion criteria (such as age or disease duration).
The analysis included 1,165 patients with MS (including 104 with clinically isolated syndrome), 376 healthy controls, and 226 patients with other neurological diseases.
All participants were evaluated for MS under standard diagnostic criteria.
Initial diagnoses of CCSVI or its absence were made by the sonographers at each clinic, who had received special training in cerebral venous imaging. Some of them had previously trained in Zamboni's clinic. The local sonographers were blinded to participants' diagnoses.
The local clinic diagnoses were then reviewed by one of three blinded central imaging experts: Erwin Stolz, MD, of Justus-Liebig University in Giessen, Germany; Massimo Del Sette, MD, chairman of the Italian Society of Neurosonology and Cerebral Hemodynamics; and Giovanni Malferrari, MD, chairman of the Italian Interdisciplinary Neurovascular Society.
When there was disagreement between the local and central readers, all three of the central readers reviewed the images, with the opinion shared by two counted as the final diagnosis. Analyses in the two-year study were completed last month.
The prevalence of CCSVI as determined under this process was as follows in the three groups of participants:
MS patients: 3.26% (95% CI 2.38% to 4.45%)
Healthy controls: 2.13% (95% CI 1.10% to 4.14%)
Other neurological disorders: 3.10% (95% CI 1.58% to 6.44%)
On the basis of these small values, and the lack of significant (P<0.05) differences between them, the AISM issued a statement declaring that "CCSVI is not a disease connected to multiple sclerosis."
Moreover, it continued, "for people affected by MS, there is no need to carry out additional tests to diagnose CCSVI, nor is vein surgery required."
The AISM is the first national MS society to make such a conclusive determination. In the U.S. and Canada, research on CCSVI commissioned by the major organizations in those countries is still under way, and no similar declaration is likely until those studies are completed.
Comi said that Zamboni had been invited to participate in CoSMo, and did for a time. But he quit before all the sonographers had been trained, objecting to multiple aspects of the study design that he believed would bias the results against finding a relationship between CCSVI and MS.
Stolz said that the sonographers were not trained specifically in Zamboni's method, but that he and others who had conducted the training had extensive experience in cerebrovascular ultrasound imaging.
He noted that this had also been the case with other groups that failed to replicate Zamboni's findings, despite having been trained in his clinic. Stolz added that a diagnostic procedure is only meaningful if it can be taught and used reliably by other experienced practitioners.
"If it is not repeatable, it has no value," he said.
Comi said that other researchers would be permitted to conduct their own evaluations of sonograms collected during the study, as long as the blinding to clinical diagnosis was maintained.
Initial diagnosis of CCSVI in the individual clinics in fact varied widely, Comi said. At one clinic, the condition was found in 60% of participants; in two others, the prevalence was 0%.
Overall, the detection rate at the initial step was considerably higher than after central review: 15.9% among MS patients, 12% in healthy controls, and 15% in patients with non-MS neurological disorders. Comi noted that even at these higher prevalences, there was still no meaningful difference between MS patients and other participants.
He also indicated that central reviewers rarely overruled the local clinic sonographers on negative diagnoses. In only 3% of cases in which the local sonographer found no CCSVI did the central reviewers say it was present.
Agreement was poorer for positive diagnoses. Central reviewers overturned 89% of the CCSVI diagnoses made by local sonographers.
Stolz attributed the lack of concordance on positive findings to the fact that "local sonographers are not on the moon." He suggested that seeing participants, and noting any physical or mental impairments, could have biased them toward diagnosing CCSVI.
Gianluigi Mancardi, MD, head of the AISM's scientific committee and co-principal investigator on the study with Comi, said he hoped the study would put the CCSVI theory permanently to rest.
"In our opinion, this is the final answer," he said.
Noting that the AISM had spent some $2 million to conduct the CoSMo study, he said the group now hoped to direct its attention to more fruitful areas of research in MS and its treatments.
The study was funded by the Italian Multiple Sclerosis Society.
Comi reported consulting fees for participating on advisory boards from Novartis, Teva, sanofi-aventis, Merck Serono, and Bayer Schering; lecture fees from Novartis, Teva, sanofi-aventis, Merck Serono, Biogen Dompè, Bayer Schering, and Serono Symposia International Foundation. Mancardi reported honoraria for lecturing, travel expenses for attending meetings, and financial support for research from Bayer Schering, Biogen Idec, sanofi-aventis, Novartis, and Merck Serono.
Stolz declared that he had no relevant financial interests.
http://www.medpagetoday.com/MeetingCove ... RIMS/35292
Πηγη ccsvi lokator
Και κανεις δεν ειναι τελειος λεμε.