經過了兩年的研究, 該分析包括在意大利，德國，約旦，和美國數地的比較 CCSVI與非MS患者進行的8項研究。Conclusion;We found a strong association be tween chronic cerebrospinal venous insufficiency and multiple sclerosis. 另外, Dr. Robert J. Fox也提到體內脫水/缺水現象可能會影響血液的流量
ECTRIMS 2011大會上 Dr. Robert J. Fox的專訪
附上原文:
October 19, 2011 — A new meta analysis concludes there is a strong and statistically significant association between chronic cerebrospinal venous insufficiency (CCSVI) and multiple sclerosis (MS), although it raises questions about the blinding of the included studies and the protocol used by technicians evaluating ultrasound results.
However, marked heterogeneity among the studies prevents a definitive conclusion about the role of CCSVI in MS, the researchers add.
"If you're one of those who believes that CCVSI causes MS, I don't think this study tells us that, but conversely, if you're one of the skeptics who says that it's all a bunch of nonsense, this study suggests that maybe that's not the case," lead author Andreas Laupacis, MD, a general internist and executive director, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada, said to Medscape Medical News.
The study was published online October 3 in the Canadian Medical Association Journal.
Ultrasound Parameters
Dr. Andreas Laupacis
The analysis included 8 studies conducted in Italy, Germany, Jordan, and the United States that compared the frequency of CCSVI among patients both with and without MS. One of the studies, by Paolo Zamboni, MD, director of the Vascular Diseases Center at the University of Ferrara, Italy, who first described this potential relationship, found that patients with MS had more abnormalities in the internal jugular and other veins than those without MS, and renewed interest in the vascular theory of MS.
To be included, the studies had to have reported original data in a peer-reviewed publication, used Doppler ultrasonography to detect CCSVI, and included at least 1 control group. The studies enrolled a small number of patients with MS (ranging from 10 to 310), most with relapsing-remitting disease and taking disease-modifying agents, and a small number of control patients (ranging from 7 to 210). All studies included healthy control patients, and 4 also included control patients with a neurological disease other than MS.
All but 1 study described the assessment of the 5 ultrasound parameters for CCVI, one of which is reflux in the internal jugular veins or vertebral veins. The diagnosis of CCSVI requires that a patient have an abnormality in at least 2 of the 5 parameters.
Blinding of the ultrasound technician and the interpreters of images varied among the studies. The method of blinding was well described in only 1 study, poorly described in 2 studies, and "reasonably" well described in 2 others. Three studies were not blinded at all. The success of the blinding was not reported in any study.
"Incredible Variability"
Pooled analysis showed a statistically significant association between CCSVI and MS compared with healthy control patients (odds ratio, 13.5; 95% confidence interval, 2.6 - 71.4), but there was "incredible variability," said Dr. Laupacis. "The Zamboni study found a perfect correlation — everybody with MS had CCSVI, and nobody without MS had it — while 2 other studies found that nobody with MS had CCSVI."
Patients with MS had significantly higher odds than healthy control patients of having reflux in the internal jugular or vertebral veins (odds ratio, 13.7; 95% confidence interval, 2.0 - 93.8) although here, too, there was extensive heterogeneity among study results.
In the comparison with control patients with another neurological disease, CCSVI was more frequent among those patients with MS, but the association was not statistically significant, and heterogeneity among the study results was large. The only ultrasound parameter that was significantly more frequent among patients with MS was reflux in the internal jugular or vertebral veins.
Even when the Zamboni study was removed from the analysis, the odds of CCSVI being more frequent among patients with MS remained statistically significant, although the odds ratio decreased from 13.5 to 4.7.
In an analysis that excluded the Zamboni trial and added one that did not find CCSVI in any patient, the odds ratio was 3.7 and still remained significant.
The analysis highlighted the potential problems with lack of blinding in many of the included studies. "With a borderline test, if you really believed that CCSVI causes MS, you're more likely to call that test positive if you know the person has MS, and you're more likely not to if you know the person doesn't have MS," said Dr. Laupacis. "It's not that you're deliberately trying to cheat, but that's why we blind studies."
Ultrasound Interpretation
The studies varied in terms of the detail they provided about how ultrasounds were interpreted, with the best detail provided in a study published in the July issue of Neurology by Robert Zivadinov, MD, PhD, from the University of Buffalo, New York, and colleagues, said Dr. Laupacis. He added that ultrasound technicians may not use the same standardized technique to assess images.
The results do not mean that CCSVI causes MS; indeed, it could be a consequence of MS. "It could be that MS over a long period of time causes abnormalities in the veins," said Dr. Laupacis.
Ultimately, there just are not enough studies yet to draw firm conclusions, Dr. Laupacis added. "The reason we're convinced that cigarette smoking causes lung cancer is that study after study after study found the same thing; we're clearly not in that situation here with CCSVI and MS."
However, that is changing. Results of other studies being carried out in both Canada and the United States that are investigating the connection between MS and CCSVI are expected within the next year or so, said Dr. Laupacis.
Meanwhile, the meta-analysis will be regularly updated, he said. "Our plan is to update our systematic review about every 3 months, so as new data becomes available, it will be incorporated."
Association Validation
Approached for comment on these findings, Robert J. Fox, MD, neurologist and medical director, Mellen Center for MS, Cleveland Clinic, Ohio, who contributed a commentary that was also published online October 3 in the Canadian Medical Association Journal, said the study validates the association between CCSVI and MS but does not answer the question of why the association exists.
Dr. Robert J. Fox
"The analysis just tells us about the association; it does not tell us whether the association is specific for MS and the disease itself, or whether a therapeutic intervention will or will not improve the MS patient condition. Those are 2 very important issues," Dr. Fox told Medscape Medical News.
The CCSVI could be related to the disease itself, or it could merely indicate an injured brain that could lead to vascular changes in the blood flowing away from the brain, said Dr. Fox.
Interpreting ultrasound images of venous blood flow and anatomy is not as simple and straightforward as a chest X-ray, for example, he said. "There's a lot more finesse and nuance involved in performing these ultrasounds."
Dr. Fox also pointed out that there is potential for bias among people performing the ultrasound, who may use varying techniques, as well as among those reading the results. For example, how hard a technician presses down on the transducer can change the flow and diameter of the jugular vein, and adjusting the machine can make reflux completely resolve or create it where there was not any, said Dr. Fox.
Even something like hydration can affect ultrasound results, he added. Patients with MS tend to prefer to be a little dehydrated to avoid bladder accidents, which can affect venous blood flow.
Diagnostic Issues
In another recent report published in the September issue of Expert Reviews on Neurotherapeutics, Dr. Zivadinov's group also reviewed the evidence to date on CCSVI in the setting of MS. "The idea behind this paper was to provide what we believe is the current knowledge about this problem, to really contribute to the understanding of what the diagnostic issues are with CCSVI," Dr. Zivadinov told Medscape Medical News. "Also, to identify certain pathogenetic mechanisms that might be related to CCSVI in MS; whether they are true or not, the future is going to show."
Dr. Robert Zivadinov
In general, however, he agreed that the literature to date has been less than reliable, with many small observational studies, varied methodology, and what appears to be a bias for studies showing no relationship between CCSVI and MS being published in neurological journals, and those finding positive relationships being published in radiological journals.
The hope was that their article would summarize the current knowledge and point to ways that studies could be improved, as well as give an overview of "5-year" directions for future research, he said.
One of the issues requiring definition is the various venous abnormalities themselves, not just the blockage of venous outflow but also the precise abnormalities that are causing any blockage, he noted. Multimodal studies that use more than 1 imaging technique to examine these abnormalities appear to be more reliable. Intravenous Doppler, for example, is perhaps the most reliable of these modalities, Dr. Zivadinov noted, allowing direct visualization of the abnormalities in the pulsatile venous setting.
"I really think that one of the key messages of this review paper is that we are making clear the importance of a multimodal approach, of standardized guidelines, and of understanding what you are looking at," Dr. Zivadinov concluded. "While there is a common knowledge among radiologists about how to perform diagnostic imaging and intervention on the extracranial vessels, there are no guidelines for CCSVI, and before people begin to do research studies and say it's something or it's not, they should understand the arguments and understand how to do it, and follow some guidelines."
The authors are critical, however, of the so-called Zamboni criteria that outline 5 abnormalities, the presence of 2 or more of which constitute CCSVI. "I think the binary composite of these criteria is probably the major confusion at the moment in the literature," he said. "Basically, if you don't find that second criteria, you are classifying all of your subjects as negative, although the patient or subject may have important venous abnormalities."
Dr. Laupacis receives honoraria as a member of a data safety monitoring board for studies of 2 drugs for MS funded by Novartis Pharmaceuticals. Coauthor Jodie Burton, MD, has received unrestricted educational support and honoraria for speaking and educational engagements from Teva Neuroscience Canada, EMD Serono, and Biogen Idec Canada. The other authors of the Canadian Medical Association Journal article have disclosed no relevant financial relationships. Dr. Fox has served as a consultant for Avanir, Biogen Idec, Genentech, and Novartis; has served on clinical trial advisory committees for Biogen Idec; has received research support from the National Multiple Sclerosis Society, which includes funding to study CCSVI; and serves on the editorial boards of Neurology and Multiple Sclerosis Journal. The authors of the Expert Reviews on Neurotherapeutics article have declared that their CCSVI studies were supported with internal resources of the Buffalo Neuroimaging Analysis Center, Baird MS Center, and Jacobs Neurological Institute, University of Buffalo. In addition, they received support from the Direct MS Foundation, Kaleida-Health, Volcano, Ev3, Codman, the Jacquemin Foundation, the Bronfman Foundation, and smaller donors. Dr. Zivadinov received personal compensation from Teva Neuroscience, Biogen Idec, EMD Serono, and Questcor Pharmaceuticals for speaking and consultancy fees. He received financial support for research activities from Biogen Idec, Teva Neuroscience, Genzyme, Bracco, Questcor Pharmaceuticals, and EMD Serono. Disclosures for other coauthors appear in the paper.
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