Short term change in blood flow causes lesions...

[Anonymoose]

Another random goody found today.
http://brain.oxfordjournals.org/content/127/1/111.full

In fact, a steep regional increase of CBV and CBF compared with the contralateral side could be detected up to 3 weeks prior to the breakdown of the BBB and subsequent contrast enhancement, indicating a dominant role of the vasculature preceding the inflammation of white matter tissue.

In multiple sclerosis, vasogenic oedema and an increase of extracellular space in combination with myelin breakdown and tissue structure disruption were reported to result in increased ADC values in both, NAWM (Rocca et al., 2000; Werring et al., 2000; Cercignani et al., 2001; Caramia et al., 2002), and acute and chronic lesions (Tievsky et al., 1999; Filippi et al., 2000). Interestingly, a prominent perfusion increase was found prior to a significant increase in ADC in the present study. The peak of the CBV was followed by a gradual decline over 20 weeks, before it decreased more rapidly, and, in case of development of T1‐hypointensity (‘black hole’), remained below baseline. The initial elevation can presumably be explained by inflammation‐related vasodilation in the acute stage, whereas the decreased perfusion in later stages of the lesion might be due to the development of a (hypometabolic) gliotic scar, which is indicated by reduced N‐acetyl‐aspartate (NAA)/creatine ratios in magnetic resonance spectroscopy in T1‐hypointense lesions (van Walderveen et al., 1998; Li et al., 2003).

So...to me...this kind of takes ccsvi out as a cause for MS lesions. The blood flow issues related to the creation of ms lesions are short-lived. CCSVI is a constant issue. Am I thinking wrong here?

[cheerleader]

That's the hyperperfusion that happens right before lesion formation, which is short-lived, and can potentially be explained as the result of reperfusion injury (the body attempting to re-perfuse an ischemic area of injury) if we view CCSVI creating ongoing venous insufficiency.

Here's some info I wrote up on this from Facebook, Anony. Notice it includes the exact same paper you referenced. Dr. Dake has spoken about this.

Dr. Dake mentioned in a presentation at ISNVD how hyperperfusion (otherwise known as reperfusion injury) occurs before an MS lesion forms. He referenced this paper, which discusses how this perfusion change happens before the break in the blood brain barrier, before the immune system entry, before demyelination. The very first step is a change in perfusion. I wanted to know--why?
http://brain.oxfordjournals.org/content ... 1.full.pdf

Reperfusion injury is not the complete MS disease process. It is a reaction to an event. I believe MS relapses are not MS, they are the early part of the disease. The MS neurodegenerative proces continues underneath into progressive MS. This is why gray matter atrophy is a better marker of disability and MS progression, rather than white matter lesions.

Reperfusion Injury and Multiple Sclerosis relapses share:

1. Demyelination -- Loss of myelin occurs after nerves have blocked bloodflow, low O2 and glucose, and then a return of bloodflow. Reperfusion causes demyelination of nerves-
Perivascular demyelination and intramyelinic oedema in reperfusion nerve injury.
http://www.ncbi.nlm.nih.gov/pubmed/7961132
Acute inflammatory demyelination in reperfusion nerve injury
http://www.ncbi.nlm.nih.gov/pubmed/10632103

2. Blood brain barrier disruption--the blood brain barrier becomes permeable, and endothelial tight junctions are altered in reperfusion injury.
Reperfusion-induced injury to the blood-brain barrier after middle cerebral artery occlusion in rats.
http://www.ncbi.nlm.nih.gov/pubmed/8042219
Blood-brain barrier disruption and matrix metalloproteinase-9 expression during reperfusion injury: mechanical versus embolic focal ischemia in spontaneously hypertensive rats.
http://www.ncbi.nlm.nih.gov/pubmed/12411666

3. An excessive innate immune response--immune cells are called in
Association of immune responses and ischemic brain infarction in rat.
http://www.ncbi.nlm.nih.gov/pubmed/11435927
Naturally Occurring Autoantibodies Mediate Ischemia/Reperfusion-Induced Tissue Injury
http://www.landesbioscience.com/curie/chapter/5117/

4. An excess of free radicals, oxidative stress and partially reduced oxygen species are found in both reperfusion injury and Multiple Sclerosis
Oxidative Stress in Multiple Sclerosis
http://www.ncbi.nlm.nih.gov/pubmed/20120717
Mechanisms of Oxidative Damage in Multiple Sclerosis
http://www.hindawi.com/journals/ad/2011/164608/
The role of oxidants and free radicals in reperfusion injury
http://cardiovascres.oxfordjournals.org ... 2/181.full

5. Endothelial Dysfunction as evidenced by elevated levels of endothelin-1 in plasma
Increased endothelin-1 plasma levels in patients with multiple sclerosis.
http://www.ncbi.nlm.nih.gov/pubmed/11315981
Extraocular blood flow and endothelin-1 plasma levels in patients with multiple sclerosis.
http://www.ncbi.nlm.nih.gov/pubmed/12646761
Endothelin-1 is involved in the pathogenesis of ischemia/reperfusion liver injury
http://onlinelibrary.wiley.com/doi/10.1 ... 9/abstract


+++++++++++++++++++++++++++++++++++++++++++++++++

Reperfusion injury has been studied extensively on the arterial side. Like most medical research, the study of the veins and venous return is lacking. But I did find one interesting study that showed how reperfusion injury happens after rats' intestinal veins were blocked and venous hypertension above the blockage occured--

Elevated venous pressure can be associated with severe tissue injury. Few links, however, between venous hypertension and tissue damage have been established. We examined here the effects of micropressure elevation on the outcome of venular occlusion/reperfusion in the mesenteric microvasculature of male Wistar rats. One hour of venular occlusion (diameter approximately 50 microm) by micropipette occlusion followed by reperfusion were carried out with sham surgery without occlusion as control. Leukocyte rolling, adhesion, and migration, oxygen radicals detected by dichlorofluorescein (DCF), and parenchymal cell death detected by propidium iodide (PI) were recorded simultaneously in the same vessel at a location upstream of the occlusion site with elevated micropressure and at a downstream location with low micropressure.
The number of rolling, adhering, and migrating leukocytes increased on the upstream side of the occlusion to a higher level than downstream of the occlusion site.

Microhemorrhages of blood cells into the mesentery interstitium were observed only on the upstream side of the occlusion. These results indicate that an elevation of the venular blood pressure during occlusion/reperfusion exacerbates the inflammatory cascade and tissue injury. Venous occlusion may constitute an important mechanism for tissue injury.
http://www.ncbi.nlm.nih.gov/pubmed/11893575

I think that on top of this ongoing process of neurodegeneration in MS, there are intermittent ischemic events which take these glucose and O2 levels dipping even lower--events like an illness, a trip to high altitude, stress, an injury, giving birth, a bacterial infection--and when the event is over, the reperfusion cycle begins--what we call an exacerbation or "MS flare."

I believe this is why many pwMS can directly tie their relapses to times after viruses, stress, lack of sleep, etc. These events become the straw that break the camel's back. And once these events end, reperfusion injury happens. It's a damaging one/two punch.
https://www.facebook.com/note.php?note_ ... 0489747211

cheer

[Anonymoose]

Thanks for another outstanding explanation.

The one thing that doesn't quite work in my head at the moment (okay...lots of things don't work in my head), is the connection being made between reperfusion after complete blockage of blood flow for hours and what happens as a result of reduced blood flow. It can't be the same thing...the difference between going on hunger strike and going on a diet. What am I missing here?

[cheerleader]

The theory I put out there is that it is an "event" which creates a temporary and dangerous level of hypoxia.
CCSVI primes the pump, by creating a chronic slowed cerebral bloodflow, and then some environmental factor causes glucose and O2 levels to dip too low. This initiates the reperfusion response.

I think that on top of this ongoing process of neurodegeneration in MS, there are intermittent ischemic events which take these glucose and O2 levels dipping even lower--events like an illness, a trip to high altitude, stress, an injury, giving birth, a bacterial infection--and when the event is over, the reperfusion cycle begins--what we call an exacerbation or "MS flare."

I believe this is why many pwMS can directly tie their relapses to times after viruses, stress, lack of sleep, etc. These events become the straw that break the camel's back. And once these events end, reperfusion injury happens. It's a damaging one/two punch.

But this is all just hypothetical. It will be up to the researchers studying CCSVI to find the correlation. Dr. Schelling believes relapses are due to thoracic venous "back jets" causing temporary venous congestion and initiating reperfusion...which makes sense, too. Only time and more research will tell.
cheer