CCSVI Not Linked to MS in Large Study
In CoSMo, the prevalence of CCSVI did not differ in MS, other neurological diseases, or healthy controls
The prevalence of chronic cerebrospinal venous insufficiency (CCSVI) in multiple sclerosis (MS) did not differ from that in other neurological diseases (ONDs) or healthy controls (HCs), according to results from the CoSMo study, an observational case–control study by G. Comi et al., published in the October issue of the Multiple Sclerosis Journal.
"In concordance with other mounting studies performed by highly trained independent groups, the CoSMo study emphatically strengthens the argument that [central nervous system] venous anomalies are neither common nor associated with MS," Andrew D. Barreto, M.D., assistant professor of neurology, University of Texas Health Science Center at Houston, told MSDF when asked to review the study. "I believe that the [question of a] link between these ultrasound findings and MS is indeed definitively answered. In my opinion, future or current pending funding for CCSVI-MS research should be diverted to other areas that still hold promise."
Some researchers have suggested CCSVI may be a possible cause, a diagnostic marker, or even a therapeutic target in MS. In 2009, an Italian group led by P. Zamboni et al. reported 100% sensitivity, specificity, and positive and negative predictive value for CCSVI and MS, using transcranial and extracranial color-Doppler sonography.
"These numbers simply don't exist in clinical trials and immediately signaled alarm that the data should be questioned," Dr. Barreto said. "This issue of 100% concordance transcends the field of MS and should never have gained so much traction until independently studied. Unfortunately, when a researcher names a treatment 'the Liberation Procedure' for an unverified 'disease,' not only will patients suffer from false hope or serious procedure complications but deleterious ripple effects occur in entire fields of medicine to include diverted research support of funding agencies. "
CoSMo showed no association of CCSVI with MS
CoSMo got its name from the Italian title, CCSVI: Studio Osservazionale Sclerosi Multipla e OND, which translates to Observational Study of the Prevalence of CCSVI in Multiple Sclerosis and in Other Neurodegenerative Diseases. The main objective of the multicenter, case–control study was to compare CCSVI prevalence among patients with MS, patients with other neurodegenerative diseases, and healthy control participants. A sonologist performed color-coded duplex sonography and sent the images for a second, blinded reading to 1 of 3 central sonologists. All data collection and analysis were also blinded.
Criteria for diagnosis of CCSVI were that local and central sonologists had to agree on the diagnosis or, in case of disagreement, that it was the predominant judgment among the 3 central readers.
Of 1874 participants aged 18 to 55 years at 35 MS centers across Italy, 1767 (94%) were evaluable. Among 1165 patients with MS, CCSVI prevalence was 3.26% compared with 3.10% among 226 patients with ONDs and 2.13% among 376 HCs.
CCSVI prevalence did not differ significantly among the 3 cohorts. The odds ratio (OR) of CCSVI was 1.55 for MS versus HC (95% confidence interval [CI], 0.72–3.36; P = .30), 1.47 for OND versus HC (95% CI, 0.53–4.11; P = .46), and 1.05 for MS versus OND (95% CI, 0.47–2.39; P = .99). None of these odds ratios was statistically significant.
There was high negative agreement and low positive agreement between the local and centralized readers.
"CCSVI is not a relevant clinical entity with regard to MS," Staley A. Brod, M.D., professor of neurology and director of the Multiple Sclerosis Research Group clinic at the University of Texas, Houston, told MSDF when asked for independent comment. He is also lead author of a case–control study in the same issue of the journal, which also shows no association between CCSVI and MS on neurosonography, magnetic resonance venography, and transluminal venography. Dr. Brod and colleagues conclude that their findings did not support altered venous outflow dynamics as common among patients with MS or as likely to contribute to the disease process.
Michael Rasminsky, M.D., Ph.D., professor emeritus of neurology and neurosurgery at McGill University in Montreal, Quebec, Canada, and Karel terBrugge, M.D., from the Department of Radiology, University of Toronto, Ontario, Canada, wrote an editorial commenting on the main strengths and weaknesses of both studies.
"I have thought for a long time that CCSVI should be a dead letter; in my view, these studies, because of their size and careful blinding, definitively dispose of CCSVI as a viable hypothesis as a cause of MS," Dr. Rasminsky told MSDF. "I see no justification for further research concerning CCSVI—this is throwing money down the drain.... I think that it is now questionably ethical to continue studies of the clinical effectiveness of treatment of postulated CCSVI."
Study strengths and limitations
Dr. Barreto noted that the CoSMo study is the largest study to date in a series of studies attempting to replicate the original Zamboni findings. The number of participants with MS was more than 3.5 times larger than any prior CCSVI study.
"Since only ultrasounds were performed, the study cannot comment on the accuracy of their ultrasound results compared to other modalities (MRI, transluminal venography, etc.) that study venous flow in the brain and neck," Dr. Barreto said. "However, other studies have investigated this (including our own study that performed both [magnetic resonance venography] and transluminal venography) and have shown no evidence that venous anomalies are common or associated with MS patients."
Study strengths identified by Dr. Barreto include reduced bias, as the study was not funded by a pharmaceutical company or device manufacturer; large sample size, allowing not just a more precise estimate of the prevalence of CCSVI but also more power to investigate subgroups; and an ultrasound training regimen.
"Physician-sonologists were already experts in head and neck color-coded Duplex ultrasound," Dr. Barreto explained. "Each of them underwent a 2-month training course designed by 2 Italian neurosonology societies. Sonologists had to pass a final exam before they could qualify to perform the ultrasound procedures."
In addition, the study used many different ultrasound machines, whereas other studies have used only a single make or model. There were 2 levels of blinding, in that the local sonologists were blinded to subject type.
"However, it can be difficult to completely blind this interaction, as certain disabilities might become apparent during the examination, such as the tremor of a Parkinson's patient," Dr. Barreto said. "All images were uploaded to central sonologists, who were blinded to all subject characteristics."
Clinical intervention for CCSVI unethical
One of the major limitations of using ultrasound to look for CCSVI in patients with MS is the considerable subjectivity in interpretation, as reflected in the large difference in CCSVI prevalence among local (14.9%) and central (3.2%) readers in the CoSMo study. Whether the "diagnosis" of CCSVI was made locally or centrally, there were no differences among participants with MS, those with other neurological disorders, and healthy control participants.
"Having performed and interpreted thousands of transcranial and neck Duplex ultrasound studies (including blind interpretation of all 276 studies in our study here in Texas), I have concluded that many of the 5 ultrasound criteria described by Zamboni and colleagues are the result of tremendous subjectivity and/or misinterpretation of ultrasound artifacts," Dr. Barreto said. "[Because] CCSVI is not a disease or syndrome that necessitates diagnosis or treatment,... there is no identifiable reason for any MS patient to undergo diagnostic testing (or risky treatment for 'blocked veins'). In fact, unless performed in the setting of an ongoing, properly designed, randomized clinical trial, I would consider it unethical for physicians to propagate the theory of venous blockage underlying the pathophysiology or to offer treatment for CCSVI."
Dr. Rasminsky agreed that there is now no justification for ongoing treatment trials. There have been only anecdotal reports of improvement by some patients who paid considerable amounts of money and traveled considerable distances for intervention, with reported improvements being highly subjective and nonspecific.
"The medical/scientific community must become much more proactive in developing relationships with the media that will encourage them to exercise more caution in presenting possibly sensational stories that have not yet garnered significant scientific support but that have the potential to inflame the public," Dr. Rasminsky and Dr. terBrugge wrote in their editorial.
"A reality of the Internet age of medicine is that there will undoubtedly continue to be many passionately vocal devotees of the view that treating CCSVI is a useful approach to MS. Nonetheless, it is now difficult to see how the CCSVI hypothesis should continue to animate interventional clinical trials that are expensive, possibly dangerous, [and] almost impossible to adequately control and that divert scarce funds from the several promising lines of investigation that have begun in the last few years finally to offer some real hope to those suffering the scourge of MS."
Key open questions
- Can criteria be developed to improve the objectivity and interreader consistency of venous ultrasonography?
- What education and information dissemination to physicians and persons with MS would help put to rest misplaced belief in any relationship between CCSVI and MS?
The Italian Multiple Sclerosis Foundation funded this study. Some of the study authors reported various financial disclosures involving Novartis, TEVA, sanofi-aventis, Merck-Serono, Bayer-Schering, Biogen-Dompè, Serono Symposia International Foundation, Italian MS Foundation, Biogen-Idec, Roche, the European Union Sixth Framework Program, Allergan, Actelion, and/or Synthon. Dr. Barreto and Dr. Rasminsky reported no financial disclosures. Dr. terBrugge is a current member of the Canadian MS Society’s Medical Advisory Committee. Dr. Brod has received funding from the National Multiple Sclerosis Society as well as from the pharmaceutical industry for clinical trials of investigational drugs for MS treatment.