CCSVI, Hypoperfusion and MS

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

CCSVI, Hypoperfusion and MS

Postby Shayk » Sun Jul 19, 2009 7:19 pm

Hi all

I've been lurking through the CCSVI discussion and it seems to me a facet of CCSVI that doesn't seem to have received a lot of attention yet is the whole concept of slowed or "hypoperfusion" and its relationship to MS. I've found it's a pretty fascinating topic.

Per Cheer in the "Just the Facts" thread,
Blood that stays in the brain too long creates “slowed perfusion”...a delay in deoxyginated blood leaving the head. This can cause a lack of oxygen (hypoxia) in the brain. This slowed perfusion has been linked to fatigue in MS patients.

This "slowed perfusion" has also been linked to other MS symptoms, disability levels, and, in relationship to the perpetual "chicken and egg" questions in MS, there's preliminary research indicating that it starts early (in CIS) and potentially "jump starts" the pathological process in MS. A little bit about each topic.

First off, from Wikipedia a definiton of hypoperfuison aka ischemia: "Ischemia in brain tissue, for example due to stroke or head injury, causes a process called the ischemic cascade to be unleashed, in which proteolytic enzymes, reactive oxygen species, and other harmful chemicals damage and may ultimately kill brain tissue." Now, some research in the other areas.

Hypoperfusion and Other MS Symptoms

Cognitive Functioning
there appears to exist a relationship between decreased white matter perfusion and cognitive dysfunction in patients with MS.

Neuropsychiatric Impairments
Our results suggest a role for tissue perfusion impairment in NP dysfunction in MS.

Hypoperfusion in Normal Appearing White Matter (NAWM), RRMS, PPMS and Link to Disability Levels
Compared to controls, CBF and CBV were significantly lower in all NAWM regions in both PP-MS patients (p values from <0.0001 to 0.001) and RR-MS (p values from <0.0001 to 0.020).

Compared to RR-MS, PP-MS patients showed significantly lower CBF in the periventricular NAWM (p=0.002) and lower CBV in the periventricular and frontal NAWM (p values: 0.0029 and 0.022).

EDSS was significantly correlated with the periventricular CBF (r=-0.48, p=0.0016) and with the periventricular and frontal CBV (r=-0.42, p=0.015; r=-0.35, p=0.038, respectively).

This study suggests that the hemodynamic abnormalities of NAWM have clinical relevance in patients with MS. DSC perfusion MRI might provide a relevant objective measure of disease activity and treatment efficacy.

Maybe an MRI outcome measure of stenting should be results from "DSC perfusion" MRI--just a thought.

Hypoperfusion Starts Early-Present in Normal Appearing White Matter in People with CIS and RRMS
White matter hemodynamic abnormalities precede sub-cortical gray matter changes in multiple sclerosis

Hypoperfusion has been reported in lesions, normal-appearing white (NAWM) and gray matter (NAGM) of patients with clinically definite multiple sclerosis (MS) by using perfusion MRI. However, it is still unknown how early such changes in perfusion occur.

CONCLUSIONS: CBF was decreased in the NAWM of both CIS and RR-MS patients and in the subcortical NAGM of RR-MS patients suggesting a continuum of tissue perfusion decreases beginning in white matter and spreading to gray matter, as the disease progresses.


Hypoperfusion and Early MS Pathology

This topic is a bit trickier and I'm not into debating the "auto-immune" vs. not topic. This is just some fairly current MS research that could be relevant to a discussion of CCSVI, hypoperfusion and MS.

First off, there's substantial research evidence indicating that there are pathological changes in normal appearing white matter(NAWM) and gray matter in people with MS prior to lesion formation--here's some recent info on the "NAWM".

Preactive Lesions in MS
RECENT FINDINGS: Compelling evidence is accumulating for pathological changes in normal-appearing white matter of MS patients, which occur before the actual development of the active demyelinating lesion. Focal disorder has been documented in normal-appearing white matter of MS months to years before the appearance of gadolinium-enhancing lesions.

SUMMARY: Preactive lesions in MS represent early stages in the formation of destructive MS lesions. As many of them spontaneously resolve, they are expected to hold important clues to stop the inflammatory process in MS.

Now, here's info connecting "hypoperfusion" with this initial MS pathology in the NAWM.

Support for Primary Hypoperfusion in MS

This article (freely available) notes the research re NAWM and diffuse abnormalities prior to lesion formation, and indicates that "the underlying basis for hypoperfusion in MS may be related to ischemia from a primary vascular pathology, or, secondary to decreased metabolic demanded from processes such as wallerian degeneration (WD) of axons transected in distant lesions. The distinction between these mechanisms has potentially important implications, because ischemia may be an early and potentially reversible finding, whereas hypometabolism from axonal degeneration would represent advanced and irreversible disease."

Conclusion:......These findings support the concept of primary ischemia in MS rather than secondary hypoperfusion as a result of WD.

And, don't forget, earlier in this post there's the research that the tissue perfusion starts in the white matter before it proceeds to the sub-cortical gray matter.

All very interesting IMO....hypoperfusion, a side effect if you will of CCSVI, has been linked to MS symptoms (fatigue, cognitive, neuropsychiatric), to RRMS, PPMS and disability levels, has been identified in people with CIS (i.e.,early in the disease process) and early research found the pathological changes in NAWM that precede lesion formation to be attributable to hypoperfusion rather than Wallerian degeneration (which I think would be the most typical MS explanation.)

Comments, observations or other thoughts or ideas on this topic anyone?

I really appreciate all the work and effort Marie, Cheer and others have put into this and want to thank all the "pioneers" as well. Take care all

Sharon
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Postby Rokkit » Sun Jul 19, 2009 8:34 pm

Good grief, that's an unbelievably concise and lucid summary of an enormous amount of research and information. This kind of post is what makes thisisms.com unlike anything else. Thank you!

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Postby cheerleader » Sun Jul 19, 2009 9:23 pm

Hi Sharon,
Terrific to have you come on and put together such a thorough post on slowed perfusion. I believe a return of normal perfusion rate is a very important part of the recovery we've seen in Jeff since his stent procedure. Marie and I actually talked about it at length, starting on page 21 of the long CCSVI thread...things got buried in that thread. But hypoperfusion needs to be understood by all learning about CCSVI.
Keep posting!
cheer
link to hypoperfusion discussion in CCSVI thread


cheerleader wrote:Here's a study from 2005 on MRI imaging of "perfusion" (delivery of arterial blood to the capillary bed) in the MS brain. The authors found that transit time for blood in MS brains was significantly prolonged compared to controls.

Perfusion measures of cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) were analyzed in 75 lesions from 17 patients with the NAWM (normal appearing white matter) of 17 MR imaging negative control subjects as reference.

MTT values were found to be significantly prolonged for the enhancing and nonenhancing MS lesions and importantly for the NAWM in MS patients compared with normal control white matter.


There is a significantly prolonged time it takes for cerebral blood to get in and out of the brain in MS patients, even in normal appearing white matter...compared to controls. There is cerebral blood flow irregularity even prior to lesion formation.

This perfusion-based differentiation would not be apparent by conventional T2-weighted imaging. The magnitude of the prolonged MTT and reduced CBF indicating perfusion deficits for all these focal lesion clusters and the NAWM is provocative in itself and especially so in view of the new pathology literature and the direction it is leading us in determining factors in MS relevant to the microcirculation and ischemia. The authors interpret their findings as a primary vascular pathology rather than reflecting decreased metabolic demand.


Future studies will determine how perfusion measures will be used in demyelinating disease in the reading room. For now there is the opportunity with high-resolution perfusion MR imaging, diffusion MR imaging, and cellular and molecular imaging to look specifically at the normal and abnormal processes occurring at the endothelial level in MS. This will bring us closer to understanding the effects of intervention, including treatments targeting cellular migration and CNS surveillance, vasoreactivity, and the specific "good" and "bad" components of the inflammatory events in MS. This work by Ge et al provokes us to look at the microscopic pathology of MS by MR imaging in new ways. Whether perfusion abnormalities are cause or effect, we are delivered to a fork in the road of considerable interest.

http://www.ajnr.org/cgi/content/full/26/6/1306

To me, this study is further proof of venous insufficiency in MS.

AC
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dx dual jugular vein stenosis (CCSVI) 4/09
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Postby mrhodes40 » Mon Jul 20, 2009 10:36 am

Sharon what wonderful and thoughtful analysis! In looking at this paradigm last winter I kept seeing these things like slowed perfusion and slowed mean transit time and time after time it was a fit with this pathology. The odd thing is there is so much of that kind of data without anyone looking farther into the circulatory system.

I think the idea of AI MS and perfusion is that the hardened areas and the inflamed endothelium slow the blood flow down. They sort of bought into that hypothesis and did not look deeper.

this
Conclusion:......These findings support the concept of primary ischemia in MS rather than secondary hypoperfusion as a result of WD]

along with this
First off, from Wikipedia a definiton of hypoperfuison aka ischemia: "Ischemia in brain tissue, for example due to stroke or head injury, causes a process called the ischemic cascade to be unleashed, in which proteolytic enzymes, reactive oxygen species, and other harmful chemicals damage and may ultimately kill brain tissue." Now, some research in the other areas.


this is how the destruction can happen independent of immune involvement to begin with, then once that cascade is in effect the immune system will respond vigorously and cause even more damage.

They are looking at using immune suppressives post stroke to try to limit this for better outcomes.


Maybe an MRI outcome measure of stenting should be results from "DSC perfusion" MRI--just a thought.

That's a good idea we could answer this question in a month if a lot of people were tested..........

It'd be pretty hard to argue that CCSVI has nothing to do with MS causation if the perfusion could be changed in moments with a procedure like that and then proven that this is what had taken place.

There goes the argument perfusion issues are secondary to the MS process.... if you can eliminate them instantaneously you just showed that they are not secondary. :idea:

Great post Sharon nice job!
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Postby robbie » Mon Jul 20, 2009 11:21 am

perpetual "chicken and egg" questions in MS,

If the chicken wasn’t first where did the egg come from?
Had ms for over 19 years now.
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Postby Jamie » Mon Jul 20, 2009 11:34 am

The creature inside the egg could be a genetic mutuation from a different species that we now refer to as a chicken.
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Postby Rokkit » Mon Jul 20, 2009 12:13 pm

In another post, someone said their NIH doctor made the point that for CCSVI to be proven causal to MS, you would need to see inflammation resolved on an MRI following repair of stenosis. That makes some sense, but the idea of an "ischemic cascade" introduces more variables. I'm wondering if you would need to repair the stenosis first, then address other damage in the chain of ischemic cascade, and then expect to see inflammation resolve.

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Postby mrhodes40 » Mon Jul 20, 2009 2:19 pm

ischemic cascade introduces more variables


Yes I agree. We do not know how this will all play out. I have not said it in a while but it is possible in my mind some combination treatment will eventually be understood as best.

Imagine this: you are dx'd MS then they give you a good dose of erythropoietin and HCG ( or neupogen or something) to stimulate your stem cells........ while your BBB is still open

a week later you get a dose of Steroid....

then stents.

Total fantasy!! But the idea would be to do some repairative work before closing the BBB up by stopping CCSVI.
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More on Hypoxia and MS

Postby Shayk » Sun Jul 26, 2009 6:39 pm

Hi again--another long post. :roll:

I'm still intrigued with the idea of "early" hypoxia in MS pathology. I've discovered more research that seems to support the idea that hyoxia precedes visbile pathology. Once again, the research is based on evidence in people with MS. A point not to be underestimated IMHO.

Molecular changes in normal appearing white matter in multiple sclerosis are characteristic of neuroprotective mechanisms against hypoxic insult

Now, this is a case where the title of the abstract really says it all. Basically, the research, ala 2003, was a post mortem examination of NAWM in 10 people who had MS. The focus was on identifying molecular changes and gene expression patterns that were upregulated in NAWM prior to lesion formation.

1. They noted the research was relevant because: "The earliest changes that lead to lesion formation are not known" and their research was an effort to help answer that question.

2. Their research indicated that the genes that were upregulated in NAWM were "involved in the maintenance of cellular homeostasis and in neural protective mechanisms known to be induced upon ischemic preconditioning" In other words, I think, the genes that were upregulated were those that would help protect NAWM against future hypoxia.

3. They postulated two possible reasons for their findings: a) "the molecular changes might reflect an adaptation of cells to the chronic pathophysiology of MS", or, b) the molecular changes "might also indicate the activation of neural protective mechanisms allowing preservation of cellular and functional properties of the CNS." Clearly as, the abstract title indicates--they found that the gene expression changes upregulated in NAWM in MS were "characteristic of neuroprotective mechanisms against hypoxic insult".

4. They also found a general neuroprotective reaction against oxidative stress in the NAWM.

5. In their own words "An increased understanding of the underlying mechanisms may lead to the development of new more specific treatment to protect resident cells and thus minimize progressive oligodendrocyte and axonal loss." ??? stents for CCSVI

So, there is research in people with MS, by two different groups, (one posted earlier in this thread) which focused on changes in NAWM prior to lesion formation. Both found evidence implicating hypoxia rather than the sequelae of MS pathology as initiating the changes in NAWM.

Now, here's some mice research (non MS) which highlights the impact of hypoxia on myelin gene expression and oliogodendroglial cells. Again, I think the title speaks for itself.

Hypoxic-ischemic injury results in acute disruption of myelin gene expression and death of oligodendroglial precursors in neonatal mice

Some quotes from the abstract are basically understandable and relevant to MS (H-I = hypoxic ischemic injury).
Our results show that a H--I insult causes a surprisingly swift and dramatic degenerative response in the subventricular layer and adjacent white matter.

Within 3 h after H--I, the programmed cell death cascade was initiated; internucleosomal DNA degradation took place in subventricular and glial cells; oligodendrocyte progenitors died and axonal degeneration in the ipsilateral corpus callosum was extensive.

The swiftness of the subventricular and glial cell degeneration suggests the H--I insult directly targets glia, as well as neurons, and raises the provocative question of whether glia exert damaging effects upon neurons and axons.

...the severity of the H--I insult can be modulated by varying the duration of hypoxia


Also of note, from the latest issue of the International MS Journal and from an article entitled MS: Is It One Disease?(focused on the four lesion types--which hasn't panned out)
"Inflammatory demyelination, the pathological hallmark of active MS, is a ‘late’ event in the newly forming lesion, and is preceded by a uniform pre-phagocytic pathology that suggests early oligodendrocyte injury or loss."


So, it seems to me the feasibility of a link between CCSVI side effects--hypoxia-ischemia and early MS pathology definitely exists:

--There's the research which found hypoxia initiating changes in the NAWM prior to lesion formation

-- There's research which found an upregulation in genes protecting against hypoxia prior to lesion formation.

--Hypoxia-ischemia injury knocked off oligodendrocyte progenitors (myelin forming cells) at least in mice, plus axons degenerated.

--The hypoxia-ischemia injury to oligodendocytes is consistent with the research indicating "oligodendrocyte injury or loss" precedes lesions

Take care all--maybe it's just possible it will all come together....sooner rather than later. 8)

Sharon
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Postby Loobie » Mon Jul 27, 2009 2:45 am

Jamie wrote:The creature inside the egg could be a genetic mutuation from a different species that we now refer to as a chicken.


That's what I'm talking about. I'm serious. "Many scars" are now looking like they are the result of CCSVI. Someone slap me back if I'm oversimplifying, but I'm still learning about this stuff every day.
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Postby cheerleader » Mon Jul 27, 2009 6:06 am

Thanks, Sharon. The changes in normal appearing white matter (NAWM) in MS- which precede lesion formation- and look like hypoxic shock, are the more conclusive evidence of the mechanism behind CCSVI. Thanks for the terrific papers.

We're talking about how these hypoxic changes also initiate the coagulation cascade here:
http://www.thisisms.com/ftopict-7699.html

Thanks for adding more research to the huge pile of confirming facts, Sharon. It certainly does appear to be lining up...
(as a personal aside, it was Jeff's odd blood results after a week at high altitude and his first MS flare that made me look at the blood in the first place. To see evidence of hypoxia before injury and the coagulation cascade- points to his blocked jugulars once again.)

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Postby mrhodes40 » Mon Jul 27, 2009 10:21 am

Sharon another thoughtful post. thanks!

Within 3 h after H--I, the programmed cell death cascade was initiated; internucleosomal DNA degradation took place in subventricular and glial cells; oligodendrocyte progenitors died and axonal degeneration in the ipsilateral corpus callosum was extensive.



TAKEN WITH this section from another paper on a person who died 17 hours into an MS attack FROM HERE

The most striking feature apparent in myelin-stained sections was that there was relatively little loss of myelin throughout the lesion (see Fig 1). In broad areas within and extending from the lesion, myelin sheaths showed only a slight reduction in staining intensity,whereas all normal appearing oligodendrocytes were re-placed by apoptotic oligodendrocytes, that is, oligodendrocytes with shrunken nuclei and annular or compact condensation of nuclear chromatin. Thirty percent oF the affected cells showed commencing nuclear fragmentation (“nuclear body” formation) with approximately 10% showing condensed cytoplasm and round-ing up of the cell body, both features typically associated with apoptotic cell death


This paper that I have mentioned before dissected a brand new lesion after the person had died. The microscope revealed not an immune system gone wild but oligodendrocytes that had died. The author of this paper a famous MS researcher no longer believes MS is autoimmune as a result of this clear finding. Taken with Sharon's reference it supports the possibility of the CCSVI model.


...the severity of the H--I insult can be modulated by varying the duration of hypoxia


This is key because CCSVI can cause very mild hypoxia as a kind of secondary phenomenon, it is not gross ischemia as it would be in a stroke for example. To the idea of the ischemic preconditioning of the tissue adjacent to the involved veins in NAWM make sense....in other words in areas with small amounts of reflux that are not yet enough to cause a visible lesion, you could have enough hypoxia to trigger the protective mechanism as quoted in Sharon's materials.

THese kinds of papers and findings are why I believe the CCSVI model is likely correct. Not because stenosis is seen in MS, but because it appears in reviewing these kinds of known MS findings, stenosis can cause the kinds of changes that are well documented in MS, many of which are inadequately or poorly explained by the AI model.
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Postby Jamie » Mon Jul 27, 2009 11:41 am

We haven't even got a NAME for MS just an observation of the result of the disease, i.e. Many Scars.
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Postby jimmylegs » Mon Aug 10, 2009 6:19 am

hi i'm just on a kick posting this abstract in a few places where altitude is mentioned:
i was looking up something unrelated on selenium and infection, something in an abstract switched me on to selenium and hypoxia, and unexpectedly i came across this abstract on selenium, hypoxia, and high altitude:

At high altitudes, the reactive oxygen species are continuously generated as a consequence of low oxygen partial pressure (hypoxia), which causes tissue damage. The body's defence system to combat the oxidative stress (e.g., anti-oxidant enzymes, free radical scavengers such as vitamin C, vitamin E, beta-carotene, reduced glutathione and minerals such as selenium, etc.) may diminish. In the present study, the antioxidant effect of selenium (Se) in reducing the hypoxia-induced oxidative stress was evaluated by exposing male albino rats to hypoxic stress in a decompression chamber. Exposure to hypoxia resulted in an increase in malondialdehyde (MDA) levels in plasma and tissues and a concurrent decrease in blood glutathione (GSH), glutathione peroxidase (GPx), plasma protein and plasma selenium content when compared with controls. Haemoglobin concentration (Hb%), red blood corpuscles (RBC) and white blood corpuscles (WBC) count were also increased in the hypoxia-exposed group. Selenium supplementation to animals reversed the trend. There was a significant decrease (P < 0.001) in MDA and subsequent increase in plasma and tissue GSH levels. Similarly the blood and tissue GPx and plasma protein also increased significantly in the Se supplemented animals compared with control animals. The Hb%, RBC and WBC counts showed no significant difference between Se-fed and control rats. These results suggest that selenium may help in reducing the lipid peroxidation during hypoxia.


here's something else interesting too (actually this map is hard to interpret because there are three shadings on the map none of which look very exactly like the two shadings in the caption?? gotta find a better one):
Image
i already posted this link on the geographic distribution thread; it's worth a look: <shortened url>

and on the other hand:
May 20, 2009
Americans with diabetes have high levels of selenium in their bodies, prompting some health experts to suspect that it could contribute to development of the disease. In response to their new findings, a research team has recommended that U.S. residents stop taking supplements that contain selenium.

that's pretty weird, that selenium is low in ms, finland has high ms, low soil selenium, and yet the highest diabetes, and selenium is high in diabetes patients. what gives.
interesting though, that they don't bother to mention the illnesses where selenium status has been found to be low, and advise individuals to check their own status - just make a sweeping 'don't take it' statement regardless of individual circumstance...
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Postby skydog » Thu Nov 05, 2009 4:52 pm

Bumping this for the newbies and to refresh the memories of the rest. Not a dead horse, Lots of very important info in the Shayk/Sheron posts. Bumping up the good stuff needs to continue. Back to the roots of how we arrived to this point for others to see. M
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