CCSVI, Hypoperfusion and MS

A forum to discuss Chronic Cerebrospinal Venous Insufficiency and its relationship to Multiple Sclerosis.

Postby cheerleader » Sun Dec 19, 2010 5:37 pm

From Dr. Haacke's new paper--thanks again, Shayk!
http://www.expert-reviews.com/doi/pdf/1 ... ern.10.174


Recently, it has been demonstrated that there is reduced perfusion and even loss of small medullary vein visibility in MS [8]. Juurlink discusses the role of hypoperfusion in MS [25]. He comments that the reduced perfusion can be detrimental to oligodendrocytes, preferentially affects white matter, causes demyelination and leads to microglial activity. He notes that these can be most marked in the optic nerve and tract. He then states: “There is now ample evidence that ischemic insults of sufficient severity can cause upregulation of cell adhesion molecules onto the endothelial cells, thus allowing infiltration of leukocytes into the brain parenchyma, resulting in an inflammatory lesion.” He goes on to point out that hypertension of genetically susceptible lesions leads to vascular damage, which in turn leads to ischemia. There is actually a body of evidence suggesting reduced perfusion in MS patients. Back in the 1980s, Swank et al. found that past the age of 40 years, MS patients had markedly reduced blood flow compared with normal individuals [26]. Using MRI, there has been a thrust in the last 10 years to study perfusion in MS. The work of Meng Law [27] and others [28–32] demonstrates that there is reduced perfusion as a function of severity of disease. Law et al. reported a significant decrease of cerebral blood flow and a prolongation of mean transit time in the normal-appearing white matter (NAWM) at the level of the lateral ventricles in MS patients [27]. These reductions often appear in the basal ganglia and thalamus and have been related to fatigue [30,31,33]. A study of seven patients with relapsing–remit- ting MS revealed decreased relative cerebral blood volume (CBV) in chronic lesions and further reduced relative CBV in one acute lesion in white matter compared with that in gray matter [27]. Haselhorst et al. examined 25 patients with MS and found that acute lesions had significantly higher relative CBV than NAWM and that chronic plaques had significantly lower relative CBV than NAWM [34]. Inflammatory activity can cause compensative vasodilatation and result in increased cerebral blood flow and CBV, which is found in enhancing lesions. On the other hand, any evidence of increased perfusion in some chronic nonenhanc- ing lesions can be explained by lesion reactivity with new vascular inflammatory changes.
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Postby Billmeik » Mon Dec 20, 2010 8:41 am

Farb RI, Vanek I, Scott JN et al. Idiopathic intracranial hypertension: the prevalence and morphology of sinovenous stenosis. Neurology 60, 1418–1424 (2003).


this is an important paper from 2003. By sino-vnous they mean the big sinus vein high up? Don't even know how this is imaged.
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Postby 1eye » Mon Dec 20, 2010 10:35 am

I'll ask it again... anybody know of any prevalence studies or epidemiology which shows there is or is not an altitude effect or relation between altitude and MS?
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Postby cheerleader » Sun Feb 13, 2011 6:17 pm

Presentations on hypoxia and hypoperfusion in Bologna at the ISNVD conference:

Hypoxia-like aspects of MS--presented by Dr. Bruce Trapp, Chairman, Dept of Neurosicences at The Cleveland Clinic

Hypoperfusion of Brain Parenchyma in CCSVI -presented by Dr. Robert Zivadinov, Neurologist and Director of BNAC

http://www.isnvdannualmeeting.org/scien ... ramme.html

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Postby cheerleader » Mon Mar 07, 2011 3:39 pm

Dr. ZIvadinov and Dr. Zamboni have published their collaborative paper on hypoperfusion in CCSVI/MS and it is available in pdf form:

http://www.biomedcentral.com/content/pd ... 5-9-22.pdf

All 16 MS patients fulfilled the diagnosis of CCSVI (median VH = 4 and median VHISS = 9) and none of the HC (Table 1) (P < 0.001, Fisher’s exact test). This means a CCSVI prevalence in this small group of MS patients of 100%, with prevalence of 0% in HC. The two venous scales, VHISS and number of VH criteria fulfilled, were significantly correlated with CCSVI diagnosis (r = 0.84 for VHISS, r = 0.84 for VH; P < 0.001 for both scales). Therefore, to decrease the number of comparisons, we used
only VHISS for further analyses with PWI outcomes.

There was a significant association between increased VHISS and decreased CBF in the majority of examined regions of the brain parenchyma in MS patients (Figures 3 to 5 and Table 2). The most robust correlations were observed for GM (Figure 3) and WM (Figure 4) (r = -0.70 to -0.71, P < 0.002, Q = 0.022) and for the putamen, thalamus, pulvinar nucleus of thalamus, globus pallidus and hippocampus (r =-0.59 to -0.71, P < 0.01, Q < 0.05). No results for correlation between VHISS and CBV
or MTT survived multiple comparison correction (Figures 3 and 4 and Table 2). No significant relationship was observed between VHISS and PWI outcomes in HC.

To the best of our knowledge, this pilot study is the first to report a significant relationship between the presence and severity of CCSVI and hypoperfusion in the brain parenchyma. These preliminary findings should be confirmed in a larger cohort of MS patients to ensure that they generalize to the MS population as a whole. Reduced perfusion could contribute to the known mechanisms of virtual hypoxia in degenerated axons.


All pwMS had CCSVI, none of the healthy controls had CCSVI. All pwMS had hypoperfusion, and the area that suffered the most slowed blood flow was gray matter.

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Postby Cece » Mon Mar 07, 2011 6:04 pm

1eye wrote:I'll ask it again... anybody know of any prevalence studies or epidemiology which shows there is or is not an altitude effect or relation between altitude and MS?

I don't know of one off hand, 1eye, although I have heard that Colorado has a very bad rate of MS (and is at a high altitude).

Glad to see the Zivadinov/Zamboni paper at last.
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Postby ikulo » Mon Mar 07, 2011 7:59 pm

Cece wrote:
1eye wrote:I'll ask it again... anybody know of any prevalence studies or epidemiology which shows there is or is not an altitude effect or relation between altitude and MS?

I don't know of one off hand, 1eye, although I have heard that Colorado has a very bad rate of MS (and is at a high altitude).

Glad to see the Zivadinov/Zamboni paper at last.


Then again, lower altitude areas of Switzerland have higher rates of MS than higher altitude parts.

http://www.ncbi.nlm.nih.gov/pubmed/9316607

As for Colorado, many people claim that it has a very high incidence. However, I've only seen figures that place Colorado at about the top 10. http://neurology.ucsf.edu/msc/images/te ... graphy.jpg
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Postby 1eye » Tue Mar 08, 2011 8:24 am

Thanks Cece and Ikulo. I don't really know if it has any significance, because over the eons, high-altitude populations have been successful at adaption. What causes the venous anomalies is just as likely to be 'sloppy genes' which, because nothing's survival until reproduction age depends on them, have just been random.
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Postby MegansMom » Sat Mar 12, 2011 11:08 am

Just wanting to bump one of the best threads for those that are new or just want a good review of the dynamics involved in CCSVI.

The better folks understand CCSVI the more comfortable they will be with making diagnosis/ treatment decisions.

My daughter had CIS (early MS) for merely a month when she had her CCSVI diagnosed and treated back in Sept 2010. She is coming up on her 6 month milestone. I would encourage the newly diagnosed to strongly consider getting diagnosed and having angioplasty. My Megan remains completely MS symptom free and her MRI shows no new lesions, no signs of inflammation and resolution of the old lesions. what more could a person with MS want?

She follows a endothelial healthy diet and exercise program. Takes a few supplements and a baby aspirin daily. No DMDs.

She looks great and feels great.
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My 35 yo daughter is newly dx 8/19/10 (had 12 symptoms)
Dx with Type A CCSVI- 1 IJV & double "candy wrapper" appearance of her Azygos
Venoplasty done Sept 21, 2010
Doing extremely well-
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Postby Rokkit » Sat Mar 12, 2011 11:38 am

MegansMom, can you clarify a little bit on your daughter's case? Are you saying that she did have symptoms that led her to be diagnosed with CIS and that those symptoms resolved post angioplasty? If so, what were those symptoms? Also, are you saying she had lesions on her MRI that have gone away? Thanks!
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Postby Leonard » Mon Mar 14, 2011 4:11 am

thank you Sharon for this very interesting thread!

From dr. Haacke's paper:
Back in the 1980s, Swank et al. found that past the age of 40 years, MS patients had markedly reduced blood flow compared with normal individuals [26].
http://www.expert-reviews.com/doi/pdf/1 ... ern.10.174
The same text is now proliferating through other channels e.g. http://www.medscape.com/viewarticle/734517_3

But the actual publication suggests something more than what is mentioned in dr. Haacke's paper, namely that it is not just the blood flow, but also the RBC delivery: Swank RL, Roth JG, Woody DC Jr. Cerebral blood flow and red cell delivery in normal subjects and in multiple sclerosis. Neurol. Res. 5(1), 37–59 (1983).
In the patients with multiple sclerosis there occurred a progressive generalized decrease in CBF and in RCD with age which was significantly greater than observed in normal subjects. The rate of decrease in CBF and RCD correlated directly with the rate of progress of the disease. (RCD = Red Cell Delivery)
http://www.ncbi.nlm.nih.gov/pubmed/6140655

This ties in with an earlier posting on TIMS on the increased ATP level in MS patients (300%). The high level is probably best explained by signallers in the body calling out loudly for help (Endothelin1?) and the fact that the RBC (Red Blood Cells) do not release the ATP, at least not enough.

This may well be related to the hardening/calcification starting at mid age (but not necessarily exclusively). Traditionally, this hardening was understood as a hardening of the arteries, we know now that also the veins are subject to hardening. But I found several references that, besides the hardening of the vessel walls, also the release of the nutrition (= the release of ATP from the RBC) is now understood to be an issue. Just this morning, I got that confirmed by a medical professional.

I read the material on ATP on Wikipedia. The ATP is the main supplier of energy to the body. It is a phosphor something that contains the mixture of the glucose with the oxygen. In fact, it is not just the glucose or oxygen that passes through the veins to the cells; that is done through a more sophisticated mechanism involving the ATP and is called the "aerobic glycolysis". My attention that that was drawn on this thread (which shows the value of these fora) http://www.thisisms.com/ftopic-15188-da ... sc-45.html

Just to demonstrate the scale of the issue which gives a feeling for the size of the problem: the total volume of ATP that is recycled every day (that is ATP taking on glucose and oxygen and releasing that in the destined cells) is as big as the total mass of the body. You can see that if there is a problem with the RBC release of ATP, the body will have a problem. If in addition to the locking of the ATP in the RBC, you already have a low flow because of the stenoses, you have a serious problem. The concept that is described here is no different from my hypothesis on the above thread.

Last month, I have done a lot of searching on ATP, glucose and insulin. And I believe that I can tell from the search engine (if you understand how Google works), that people - probably including many professionals- are massively searching on this topic. And there are some names, mainly in the US, who are in fact on top of this.

In this same context of ATP, this hypothesis is interesting
http://www.pnas.org/content/96/2/329.long
It concludes quote … greatly expanding the list of tangible hypotheses for the etiology and treatment of non-insulin-dependent diabetes mellitus unquote to which I would add … and for the etiology and treatment of MS.
(but then I am back again riding my own hobby horse – that is that late onset MS is strongly related to Diabetes2. Sorry for that :roll: )
Last edited by Leonard on Tue Mar 15, 2011 3:01 am, edited 1 time in total.
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Postby cheerleader » Mon Mar 14, 2011 7:27 am

Here is video from CTV on Dr. David Hubbard's current perfusion study. He has found that angioplasty corrects the slowed perfusion seen in MS/CCSVI-when measured on fMRI.

http://www.ctv.ca/CTVNews/TopStories/20 ... dy-110313/

A preliminary study, due to be presented at a meeting in Italy on Monday, adds weight to Zamboni's hypothesis.

Researchers in the U.S. studied 20 patients with MS and found that, compared to 20 healthy people, the MS patients suffered from impaired blood flow to the brain.

The study, which hasn't been independently reviewed, was led by a San Diego-based group called the Hubbard Foundation, which is using functional magnetic resonance imaging to examine CCSVI.

The study's results link problems with blood flow in the brain to delays in blood circulation in the jugular veins, as Dr. Zamboni theorized.

"The blood is lingering longer and taking longer to get out again," said Dr. David Hubbard, a neurosurgeon who founded the group.

But after MS patients received angioplasty treatment to open blockages in jugular veins, the study found that blood flow in the brain improved.

"Their venous flow in their brain looks normal again," said Dr. Hubbard, who began studying the CCSVI theory after his son was diagnosed with MS at age 19.
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Postby Leonard » Tue Mar 15, 2011 4:17 am

The flow is very important, but we should not entirely forget the capacity of the RBCs to carry the suppy of energy, that is for making/recycling the ATP and releasing the ATP.

On Wikipedia, the 'Ischemic cascade' is defined as a series of biochemical reactions that are initiated in the brain short time after inadequate blood supply, typically due to stroke. The series of events that happens then shows some similarities with MS. This makes make wonder whether MS is perhaps something like an Ischemic cascade but then on the long-term, that is not due to immediate inadequacy of blood supply, but a real slow process of under-nourished cells that eventually start to die? This would suggest a nutrition concept of the issue.

On this nutrition side, these articles are of interest.

The first article was published in May 2007 and was republished on 29 December 2010 reads: A glucosamine-like dietary supplement has been found to suppress the damaging autoimmune response seen in multiple sclerosis....
Now carefully watch the working used: the use of the word 'suppress' is an indication of how people in the research field think about the concept of issue, it is starting from the presumption that MS is an immune disease that needs to be suppressed.
But perhaps they should have looked at it from the other side: that is to say ... the supplement has been found to calm down the immune system..
where the nutrition or better lack thereof causes a cascade of effects that eventually leads to MS.
http://www.health-caree.com/glucosamine ... betes.html

The second article is a bit more of the same: again reasoning from the side of anti-inflammatory effects. But the same article talks ... of the drugs' effect on the body's response to insulin. Here I ask myself: is the way to look at the problem from the side of the anti-inflammatory effects the right way? Just like with diabetes2, shouldn't we look from the other side, that is to say: to calm down the immune system and inflammation by better feeding of the cells..
Then you get exactly the debate that was held in the 80's when endocrinologists proved that diabetes was not an auto-immune disease. And as a result the entire field was carried over from the neurology to the endocrinology.
http://www.sciencedaily.com/releases/20 ... 171809.htm

I compare the picture that emerges here a bit with a cookie factory producing nice cakes with a chocolate topping. The production belt fails somewhere in the cascade of steps. At the end of the belt, the alarm bell starts ringing. And what does the operator do? He throws his jacket over the alarm bell and rests back in his chair. And the chain just rumbles on ..
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Postby ikulo » Thu Mar 31, 2011 1:33 pm

bump with a new article.


The Relationship between Normal Cerebral Perfusion Patterns and White Matter Lesion Distribution in 1,249 Patients with Multiple Sclerosis.
Holland CM, Charil A, Csapo I, Liptak Z, Ichise M, Khoury SJ, Bakshi R, Weiner HL, Guttmann CR.

Center for Neurological Imaging and Partners MS Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (CMH, IC, ZL, SJK, RB, HLW, CRGG); Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA (CMH); Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Quebec, Canada (AC); Brain Molecular Imaging Program, Division of Nuclear Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (MI).
Abstract
BACKGROUND AND PURPOSE: The pathological differences underlying the clinical disease phases in multiple sclerosis (MS) are poorly characterized. We sought to explore the relationship between the distribution of white matter (WM) lesions in relapsing-remitting (RR) and secondary progressive (SP) MS and the normal regional variability of cerebral perfusion.

METHODS: WM lesions were identified and quantified on a single magnetic resonance imaging scan from 1,249 patients with MS. The spatial distribution of lesions was compared between early RR, late RR, and SP MS in the context of normal cerebral perfusion patterns provided by a single-photon emission-computed tomography atlas of healthy individuals.

RESULTS: Patients with SP MS had more distinct and larger lesions than patients with RR MS. Across all subjects, lesions were present in regions of relatively lower normal perfusion than normal appearing WM. Further, lesions in SP MS were more common in areas of lower perfusion as compared to the lesion distribution in early and late RR MS.

CONCLUSION: Chronic plaques were more prevalent in WM regions with lower relative perfusion. Lesions in more highly perfused regions were more commonly observed in early RR MS and therefore, may be more likely to successfully remyelinate and resolve.
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Postby cheerleader » Thu Mar 31, 2011 2:14 pm

Thanks, Ikulo--I'd been following that one on Dr. Bakshi's website--

Here is the link to the abstract, the paper is published in the Journal of Neuroimaging

link

Chronic plaques were more prevalent in WM regions with lower relative perfusion. Lesions in more highly perfused regions were more commonly observed in early RR MS and therefore, may be more likely to successfully remyelinate and resolve.

Perhaps this might explain the remyelination we are seeing in some after angioplasty and an increase in perfusion and mean transit time.
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