Many have sent me this write up from Dr. James D. Bowen at the MS Center at the Swedish Neuroscience Institute.
http://swedish.org/About/Blog/May-2011/Questionable-Hope-for-CCSVI-in-Multiple-Sclerosis
I've gone thru it for all, point by point, with references. For those of you who work with this neurologist or live in Seattle, perhaps you can print him out the research papers I've linked, bring him a copy of Marie's book, and help him understand the points I've clarified. I know that Dr. Torrance Andrews, an advocate for CCSVI treatment studies, works at Swedish. Maybe we can help them collaborate on a treatment study?
http://www.swedish.org/Services/Neuroscience-Institute/Neuroscience-Services/General-Neurology
Here is Dr. Andrews contact info:
http://www.swedish.org/Physicians/R--Torrance-(Torre)-Andrews
Dr. Bowen's writing is in italics, mine in plain type. Here you go......
Questionable Hope for CCSVI
James D. Bowen, M.D., Medical Director, Multiple Sclerosis Center, Swedish Neuroscience Institute
Spring 2011
Once again, multiple sclerosis patients are abuzz over a new theory and treatment for the disease. The theory is called chronic cerebrospinal venous insufficiency (CCSVI); and, this time, social media is driving the patient excitement.
-Actually, the research is driving the excitement. We just report it and share it online.
CCSVI is based on a controversial idea that impaired venous drainage of the brain due to blockage in venous structures causes MS. Increase in venous pressure promotes leakage of blood across capillaries, with inflammation resulting from the iron deposition into the brain. In 2009 Paolo Zamboni, M.D., reported that virtually all MS patients in a study had abnormalities in the jugular or azygous veins, whereas no control patients had such findings. The Zamboni, or Liberation, procedure involves either angioplasty or stenting of the abnormal vein. Many MS patients are understandably enthusiastic about this theory and treatment.
There are, however, a number of problems with the CCSVI theory that patients and MS neurologists should consider.
• Diagnostic criteria for CCSVI are not standardized or accepted
--Dr. Zamboni designed the very specific criteria for diagnosing CCSVI, utilizing doppler, transcranial doppler, and venography. This protocol is being replicated and fine-tuned. The Esaote MyLab TCD machine was just accepted for transcranial diagnosis by the FDA. BNAC is utilizing this protocol and SIR is in the process of creating their own diagnostic criteria for venography.
Here is Dr. Zamboni's 5 part criteria-
http://jnnp.bmj.com/content/80/4/392.full
Those who follow this criteria are finding a very high associaton of CCSVI in pwMS. Here is a recent abstract to be published in a vascular journal. (Note, these researcher used the complete doppler protocol, including TCD. Sadly, BNAC did not use the TCD protocol on 42 pwMS, and placed them in the no CCSVI column. That affected their results.)
Discussion and Conclusions: We have studied 258 patients ( 161 females and 97 males) affected by Multiple Sclerosis with extracranial and transcranial venous ecocolor-doppler made in conformity with Zamboni’s protocol. 220 of the 258 patients studied (85,3%) turned out to be affected by CCSVI demonstrating that there is a high association between these two pathologic entities. To the best of our knowledge the result of our study goes with the result of other recently published studies.
http://ccsvism.xoom.it/ISNVD/Other/Abstract-Guerra.pdf
• CCSVI does not seem to explain the distribution of white matter lesions or the relapsing and remitting course that most patients experience
-If we hold CCSVI to this measure, perhaps we should hold the autoimmune theory to this as well?
CCSVI does explain the lesion distribution, since white matter lesions are perivenous (along the veins in the brain), which would certainly be in line with venous reflux and slowed venous drainage. In fact, Rindfleisch noted the tiny, engorged veins inside each white matter lesion while looking thru a microscope at an MS brain in 1863. Dr. Alfons Schelling writes of venous back pressure and the location of MS lesions in his book. http://www.ms-info.net/evo/msmanu/839.htm
Here is research from 2011 showing MS white matter lesions are perivenous in over 80% of those with MS:
http://www.ncbi.nlm.nih.gov/pubmed/21300968
-The relapsing-remitting nature of MS has NEVER been explained by MS specialists. As a matter of fact, the animal model of MS, EAE, is NOT relapsing and remitting, but constant, and more like ADEM in humans. That said, venous stenosis and reflux can be worsened in CCSVI by increases in hypoxic environments caused by viruses, colds, stress, high altitude, smoking--all situations which are known to exacerbate MS and possibly lead to relapses. How does the EAE model of MS explain relapses???
• CCSVI does not explain the presence of inflammation in MS lesions
-Yes, it does. Please read Dr. Zamboni's paper on how venous ulcers in the leg (CVD) are representative of the venous lesions in the MS brain.
"Fibrin cuffs are not an exclusive finding of chronic venous disease, but are commonly visible around cerebral veins in the course of MS and today they are interpreted as ongoing reparative processes20,21 (Figure 1B). MRI venography confirms in vivo the close relationship between the main cerebral veins and the inflammatory plaques. In 94/95 MS lesions, a central vein was visible.22 When cortical lesions occur, they arise within the territory of the principal cortical veins.23,24 In another study, contrast MRI allowed documentation of the break-down of the blood-brain barrier (BBB). Such an injury preceded other MRI abnormalities and the clinical evidence of a new lesion. This supports the view that a defect in the BBB, and therefore inflammation, is an early and possibly crucial event in thepathogenesis of a new lesion in MS.25
Inflammation in MS is characterized by expression of adhesion molecules,26 followed by a migration of macrophages and T-cells across the BBB. Infiltration of the matrix by macrophages, as in CVD, is considered a crucial step27 (Figure 3A and B). In both situations, macrophages appear with considerable intracellular iron stores due to phagocytosis of senescent erythrocyte. Iron overload in MS plaques has been demonstrated in vivo by MRI.28 In addition, we observed haemosiderin in the urine of patients with active inflammation of MS (personal unpublished data).
Here is the full paper: http://jrsm.rsmjournals.com/cgi/content/full/99/11/589
• Iron in MS lesions is contained within macrophages, not erythrocytes or free, as predicted by the CCSVI theory
Again, I refer you to Dr. Zamboni's study on chronic venous disease, and the similarities to MS:
"Macrophages take up iron accumulated in the tissue and store it in intracellular ferritin-like structures (Figure 3B). Intra- and extra-cellular overload of iron in the tissue could potentially be dangerous for generation of free radicals due to possible release of free iron from deposits.4-9,13,14 Wenk et al.7 and Yeoh-Ellerton13 found increased iron levels in exudates from chronic leg ulcers as compared to acute wounds. They also observed significant concentrations of metabolites from oxidative stress.7,13"
• Other diseases with increased venous pressure do not resemble MS
Actually, from the paper above, chronic venous disease of the legs shares many similarities. In the brain, idiopathic intracranial hypertension can also create tinnitus, headache, dizziness, visual disturbances and fatigue, similar to MS. It is diagnosed more quickly than MS, since it develops more rapidly, but low-level, chronic venous hypertension created by CCSVI shares many similar features, included the change of the third ventricle.
• Venous drainage is highly redundant, so stricture of a vein usually does not increase venous pressure in the brain.
How can you say that with such confidence??? Idiopathic intracranial hypertension is called "idiopathic" because it is seemingly not changing pressure...yet it is! Again, idiopathic intracranial venous hypertension often presents with dural venous stenosis, something observed in some with CCSVI (like my husband)
Cerebral spinal fluid reabsorption is affected by CCSVI--and can potentially create an idiopathic increase in venous pressure:
http://www.roneurosurgery.eu/atdoc/4StMIenceanIntracranial.pdf
Here is Dr. Zamboni/Zivadinov's research
CSF dynamics and brain volume in multiple sclerosis are associated with extracranial venous flow anomalies: a pilot study
http://www.fondazionehilarescere.org/pdf/08-2503-ANGY.pdf
• Changes in muscle tone or posture from neurological disease may explain some venous blockages; and neurological disease can lead to lower venous blood flow due to circulatory autoregulation
How to explain the many with CCSVI who still have low EDSS and absolutely no loss of muscle tone? My husband could walk and bike at diagnosis, was a 1.5 on EDSS, but he could not keep his eyes open for longer than an hour. He had fine physical abilities....but his jugular veins and dural sinus were stenosed.
Studies that have been performed to date have not supported the CCSVI theory. Preliminary results from the Buffalo Neuroimaging Analysis Center at the University at Buffalo, The State University of New York, found 56 percent of patients with MS, 42 percent of those with neurological diseases other than MS, and 20 percent of controls met criteria for CCSVI. This group found a decrease in cerebral venous volume in MS patients compared to normal, whereas blockage in venous flow would be expected to induce vascular dilation and increased venous volume. At the recent ECTRIMS (European Committee for the Treatment and Research of Multiple Sclerosis) meeting in Sweden, groups from Gotteborg, Berlin, Padua, Amsterdam and London found no evidence for venous obstruction in MS patients compared to controls. A study from London, Ontario, found that venous blockage increased with age in both MS and controls. A study from Beirut, Lebanon, found venous changes in only 9 percent of patients after their first MS attack, increasing to 92 percent with advanced MS, possibly suggesting a late finding that is unrelated to the cause of the disease. Nevertheless, as anecdotal reports continue to circulate of individual patients with dramatic responses to treatment of CCSVI, the theory has been of great interest
among MS patients and has become the subject of a significant number of studies.
Yes, there are many negative studies coming out from neurologists. But if we refer to these, or cherry-pick our research, we must also refer to the studies that are finding a correlation of Dr. Zamboni's research.
Again, the BNAC study did not utilize the complete Zamboni protocol, with TCD. The interest is being pushed by people who have seen significant changes in the course of their MS. My husband, now 2 years past angioplasty, has seen reversal of gray matter atrophy. He has no new lesions, no MS progression. Only healing. No CRAB could claim that. I make no money for this work, but continue to push for research because I have seen the anecdotal and published proof.
Before CCSVI can be considered as contributing to MS, three criteria should be required.
1. Venous blockage must be shown to be increased in MS patients relative to healthy controls and other neurological diseases. This would demonstrate an association between CCSVI and MS, but not prove causation.
I find it strange that CCSVI is being held to much stricter standards than the flawed EAE model of MS, but will answer these points. When researchers utilize the correct protocol, which includes transcranial doppler and venography, high association with CCSVI and MS is being shown around the world.
2. Treatment of CCSVI should stop the progression of MS symptoms in placebo- controlled, blinded, multi-center studies. This would prove that CCSVI contributes to MS, but not prove causation.
We would love to have placebo-controlled, blinded multicenter studies!! Please! Will you work with Dr. Andrews so he can get his IRB approved? He's in the same hospital with you. Contact him ASAP. I'll link his information once again:
http://www.swedish.org/Physicians/R--Torrance-(Torre)-Andrews
3. MS should develop in humans or animals with venous blockage.
The mouse model from Stanford, presented at the ISNVD in Bologna in March, showed venous blockage created paralysis. A marmoset model is coming.
http://ccsvism.xoom.it/ISNVD/Abstract-Thanaporn.pdf
The scientific community is taking CCSVI very seriously. Most of the studies currently under way are testing whether MS patients have venous blockage. The National MS Society and the MS Society
of Canada funded seven 24-month studies in June 2010, totaling $2,400,000 of ultra- sound, MRI and angiographic techniques to determine whether venous blockage is specific to MS patients in both adult and pediatric populations. The MS Society of Italy is contributing £900,000 (nearly $1.3 million) to study the question. The Buffalo Neuroimaging Analysis Center is conducting a study of venous imaging, as well as a small treatment trial. Saskatchewan and MS Research Australia have also initiated large studies.
The risks of the Liberation procedure in MS are not entirely understood, though stent migration and fatal intracerebral bleeding have already been described. Only controlled studies will teach us the true complication rate. In the meantime, most MS neurologists are recommending that patients await the results of current studies before proceeding with this controversial treatment.
I'm not sure that all scientists are taking CCSVI "very seriously." The money allocated to CCSVI research is a drop in the bucket compared to pharmaceutical funded research. The reason activists and patients and the IRs that have actually studied people w/CCSVI are very serious, is because they see how venous flow impacts the MS brain....and "time equals brain" in MS. There is a large difference between talk and action. If you are truly serious about learning more regarding CCSVI, I suggest you work with the IRs in your town, and begin to study this in pwMS.
I would also refer you to the best publication on CCSVI, which explains many of the points answered, and cites research and the history of MS--
CCSVI as the Cause of Multiple Sclerosis: The Science Behind the Controversial Theory
by Marie Rhodes.
http://www.amazon.com/CCSVI-Cause-Multiple-Sclerosis-Controversial/dp/0786460385/ref=sr_1_1?ie=UTF8&s=books&qid=1307723598&sr=1-1
thank you for your concern, Dr. Bowen--
all best,
Joan
By means of full disclosure---Dr. Bowen is currently involved in several clinical trials for MS drugs.
James D. Bowen, MD has received honoraria from Berlex, Inc., Biogen Idec, EMD Serono Inc., and Teva Neurosciences; has received financial support for research from Biogen Idec, BioMS Medical, EMD Serono, Genzyme Corporation, Novartis Pharmaceuticals Corporation, and UCB S.A. and has ownership interest in Amgen Inc.
http://www.projectsinknowledge.com/neurology/multiple-sclerosis_III_cpfaculty.cfm?jn=1946
I receive no money for my work, but Jeff just brought me another cup of coffee with a kiss :-)