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.
從今年5月以來, 國外病友紛紛討論靜脈窄化的情形擴展到 iliac and renal veins 這些靜脈can play a part in lower body mobility. 而紛紛也針對這些靜脈也做進一步的檢查, 我大致整理了其中3位病友的檢查狀況和恢復情形, 有2位有特別針對這兩個靜脈再做一檢查. 其中一位特別發現有窄化, 而她更進一步發現可能靜脈辦膜無法閉合的困難。
A clear understanding of Multiple sclerosis has proved elusive for generations of doctors and scientists.
The first suggestion that there could be a vascular component to the disease dates back 180 years to Sir Robert Carswell from Glasgow. He was drawing an image of a post mortem sample of brain tissue from an MS patient and commented that "there appears to be vascular lesions here".
Dr Franz Schelling from Austria has been a lone voice for many years in promoting this theory and I spent an intriguing half hour with Franz as he drew the various venous sinuses on napkins at the CCSVI conference in Poland this year. It was Franz who convinced Paulo Zamboni to explore this field and the results of that collaboration has changed the world of medicine. The recent discovery of the importance of CCSVI has filled in many of the gaps in our understanding of the disease.
At the International Society of Neurovascular Disease meeting in Bologna in March this year, Dr David Hubbard, a consultant neurologist from San Diego, gave the clearest description of MS that I have ever heard. He described how leakage of blood products across the blood brain barrier caused the initial damage in the brain tissue. The immune system became aware of this damage and was triggered to respond as a secondary event. I sought him out later to congratulate him on his presentation and particularly the clarity of his description of how the vascular and immune parts of the disease interact. This made sense on many levels and explained why most current treatments are only partially effective as they are aimed at the secondary and not the primary driver of the disease. This new paradigm does not exclude the immune system and immune modulating drugs as part of a treatment regime but this new understanding gives new possibilities for treatment with the possibility of improved outcomes.
Treating venous pressure by means of angioplasty could be a relatively safe and easy way of improving outcomes in MS if this theory is proven to be correct. A recent study by Ivo Petrov from Bulgaria, presented a series of over 461 CCSVI procedures carried out in Sofia, showed no major complications which confirmed the safety of angioplasty in MS (1).
A new paper published in the Journal 'Brain' in June 2011 appears to support this new paradigm (2). A research team from Vienna examined post mortem samples of 30 MS patients and 25 controls who died of other causes. For the first time, they have shown that the most recent MS lesions were associated with oxidative stress damage consistent with leakage across the blood brain barrier. Older lesions showed the T lymphocyte infiltration typical of an immune response.
A good demonstration of the damage that blood products can produce is in cellulitis in legs associated with varicose veins. As the veins enlarge, the increased pressure in the vessel causes the junction between endothelial cells lining the vein to widen allowing blood products to leak into the leg tissues. This causes inflammation in the tissues with the classic inflammatory signs of redness, heat, swelling and pain as seen in this image.
The brain has the relative protection of the blood brain barrier but this is simply a tighter connection between endothelial cells, thirty proteins joining the cells as opposed to the usual ten. Increased venous pressure in the deep veins of the brain will eventually loosen even these tight junctions and when the blood products leak into brain tissue the damage will be similar to that seen in leg cellulitis. The secondary immune response is triggered to try in an attempt to limit this damage but in itself, this response can increase inflammation.
After seven years of successfully using LDN in the management of MS, I knew that the immune system was an important factor in all types of the disease. Paulo Zamboni, Franz Schnelling, David Hubbard and others are helping us to understand the complex interplay between the immune system and the venous system in MS. A combined approach to the management of the disease is a logical way forward.
Like any new paradigm, this will take some time to be accepted by all of those involved in treating and raising the awareness of this condition but as the research stacks up, it will become clear that a major step towards understanding and successfully treating MS has taken place.
There is still much to learn and many unanswered questions but CCSVI has taken us a long way towards better understanding and treatment of this complex condition.
參考文獻:
Petrov I, Grozdinski L, Kaninski G, Iliev N, Iloska M, Radev A. J Endovasc Ther. 2011 Jun;18(3):314-23. Safety profile of endovascular treatment for chronic cerebrospinal venous insufficiency in patients with multiple sclerosis.
Haider et al. Oxidative damage in Multiple Sclerosis Lesions. Brain 7th june 2011
In a statement, Lamb said his wife "was looking forward to the procedure as it was to improve her quality of life…. She was even planning to go back to work."
Clarke had been discharged from the clinic and returned to her hotel where, according to her husband, Frank Lamb, she complained of "one hell of a headache." 手術後出院，感到劇烈的頭痛
Frank Lamb says his wife, 56 year old Maralyn Clarke, went to a California clinic to have the surgery to widen veins in her neck on April 13th.
But just hours after the surgery, Lamb says she suffered massive bleeding in her head.
Lamb suspects that his wife's blood pressure issues may have contributed to her death. Clarke had been diagnosed with white coat syndrome, where patients experience high blood pressure in clinical settings. She had also been on blood thinners.
white coat syndrome: 白袍高血壓綜合症
blood thinners: 血液稀釋劑(抗凝血劑)
病友的先生Lamb推測他的太太血壓的問題可能是原因之一。他太太也服用血液稀釋劑(抗凝血劑)
"My advice to other hopeful patients is that if your blood pressure is high, do not have the procedure done," Lamb said.
病友的先生建議 : 若你的血壓太高, 不建議施行這個手術。
Despite her death, Lamb says he's not discouraging anyone from trying liberation therapy.
He says only a few people have died after having the treatment.
New York - People who get shingles are more likely to also develop multiple sclerosis, with researchers in Taiwan finding that people who developed shingles had four times the risk of being diagnosed with MS within the next year.
But the team led by Jiunn-Horng Kang at Taipei Medical University Hospital warned that their study did not show that shingles itself could cause MS, although there were "several potential mechanisms" that could explain why the two diseases are linked.
"Our findings support the notion that occurrence of MS could be associated with herpes zoster attack," Kang and colleagues wrote in the Journal of Infectious Diseases.
"We found a significantly higher risk for MS within one year of [a] herpes zoster attack compared with the control population."
Shingles is a painful condition caused by reactivation of the virus that causes chicken pox, known as varicella-zoster virus. Once a person has had chicken pox, the virus goes into a dormant state, dwelling in the body's nerve fibres. Symptoms
However, in some people the virus can reactivate and cause shingles, which usually begins with a burning pain or itch in one location on one side of the body, followed by a rash of fluid-filled blisters.
MS occurs when the protective coating around nerve fibres begins to break down, slowing the brain's communication to the rest of the body. Symptoms include fatigue and problems with balance and muscle co-ordination, as well as memory loss and trouble with logical thinking in some people.
About 2.5 million people have MS worldwide, according to the Multiple Sclerosis Association of America. Most experience their first symptoms between the ages of 15 and 50.
Reviewing a database from the insurer that covers 98% of Taiwan's population, the researchers found more than 300 000 people with shingles. They compared them to nearly 950 000 others with similar characteristics, who didn't have the disease.
Over the course of a year, fewer than one in 10 000 in the group with shingles developed MS - but that was still nearly four times as many as in the group without shingles.
"After adjusting for monthly income and geographic region, the hazard of MS was 3.96 times greater for the study group than controls," the researchers wrote.
Kang said that shingles is associated with disruptions to the immune system, which in turn might trigger MS. Also, a reactivation of the shingles virus may "provoke a series of immune responses in the host which may be linked to MS", Kang said.
The authors cautioned that most people included in the study were Han Chinese, among whom MS occurs relatively infrequently, so the findings might not apply to Western populations.
In addition, the authors did not have information about whether people smoked or drank alcohol, another potential influence on the findings.
"These factors may be confounding to our results and need to be further explored," Kang added.
謝建台教授表示： Your concern about the presence of plasticizers in人體內是否也會對於中樞神經系統或者是免疫系統造成一定的改變或損害may be true. I think many medical issues related to plasticizers (including yours) will be incurred by this plasticizer scandal. Let's wait and see.
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