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Another abstract from the Vasculab conference
Thanks to our Italian amici, Alessandro and Puccio for sending me this abstract this morning. This abstract is published in the Vasculab program for their 2011 conference in Italy, October 13-14
http://www.vasculab.it/hemodyn2011/pane ... seases.pdf

auth: Marcello Mancini presauth: Marcello Mancini institutions: Institute of Biostructure and Bioimaging National Council of Research Naples

The Cerebral Circulation Time in the evaluation of neurological diseases
abstract: Background -Recent newly developed ultrasound techniques extend our ability to study the cerebral hemodynamics in patients with neurological disease beyond the conventional blood flow velocity analysis. Different ultrasound methods are currently under investigation that either qualitatively or quantitatively describe brain perfusion.

The most widely used technique is bolus kinetics. After applying a ultrasound contrast agent bolus, time intensity curves of the wash-in and wash-out phase of the bolus passage through the brain are registered by imaging at a set frame rate and analyzing the ultrasound intensity in a given region of interest. Based on the time intensity curves, different parameters can be extracted such as peak intensity, time to peak, mean transit time, and incremental time (Fig1).

These parameters can be displayed in a tissue region of interest defined by the examiner. Studies based on histopathological techniques and on MR imaging demonstrate hypoxia-like brain tissue injury or thrombosis of small veins in patients with Multiple Sclerosis (MS).

Applying dynamic susceptibility contrast Magnetic Resonance Imaging, cerebral mean transit time values were found to be significantly prolonged in MS patients. We present the application of contrast enhanced ultrasound (CEUS) to assess global cerebral circulation time (CCT) in patients with multiple sclerosis (MS). The method is based on the assumption that the time required by an ultrasound contrast agent to pass from the cerebral arteries to the veins should be prolonged in patients with vessel disorders.

Methods: We performed CEUS in 82 patients with MS, and 37 controls. The clinical diagnosis was established by neurological evaluation and neuroimaging findings. Impairment was assessed by the EDSS Scale.
Cerebral Circulation Time was defined as the time difference of ultrasound contrast bolus arrival between the carotid artery and internal jugular vein.

Results The MS patients were comparable to control subjects for age, sex, systolic and diastolic blood pressure and heart rate. The artery arrival time was similar in MS group and controls.

The longest and average Cerebral Circulation Times (CCTL,CCTM) were substantially prolonged in patients with MS compared with controls [CCTL MS patients: median (range) 6.5 sec. (3.3-29.2); controls 5.2 (2.57-7.63; p5.8 sec. (2.6-17.5); controls 4.7 (2.5-7.1); p

Conclusions Compared with the healthy control group, MS patients showed a significant prolongation of CCT. Our results suggest that a microvascular or venous outflow impairment could be associated with MS. The CEUS measurement of CCT may be useful tool to disclose cerebral microcirculatory dysfunction in MS patients.

I takes longer for blood to travel from the carotid, thru the brain and back to the bottom of the jugular in pwMS. Alot longer--20-25% longer. In one person with MS, it took almost 30 seconds (that's just scary.) This is yet another study showing slowed perfusion and mean transit time in pwMS.
cheer

Is there any way for this to be a result of MS? I cannot think how lesions and NAWM could slow transit time.

Cece wrote:Is there any way for this to be a result of MS? I cannot think how lesions and NAWM could slow transit time.

Good question, Cece. Slowed mean transit time and hypoperfusion have been noted in MS for many years. It's not new. It could be due to reduced metabolic demand in the brains of pwMS (what many neurologists assert, without proof, and then brush off these studies), but most likely not, as these researchers explain below.
Here is an MRI study from 2004, long before Zamboni, where the radiologists used MRI to measure perfusion and transit time. The link has the complete paper...
http://radiology.rsna.org/content/231/3/645.long

Microvascular Abnormality in Relapsing-Remitting Multiple Sclerosis: Perfusion MR Imaging Findings in Normal-appearing White Matter
Meng Law, MD, Amit M. Saindane, MD, Yulin Ge, MD, James S. Babb, PhD, Glyn Johnson, PhD, Lois J. Mannon, RT, Joseph Herbert, MD and Robert I. Grossman, MD
Dynamic susceptibility contrast-enhanced T2*-weighted echo-planar perfusion MR imaging is a robust and powerful tool for characterizing cerebral microvascular hemodynamics. In this study, we examined the NAWM at the level of the lateral ventricles and found reduced cerebral perfusion in patients with RR-MS compared with cerebral perfusion in control patients. In periventricular, intermediate, and subcortical regions of NAWM, CBF was significantly decreased and MTT was significantly prolonged. These results indicate that there is diffuse hemodynamic impairment throughout the NAWM of patients with RR-MS.

We interpret our findings of diminished perfusion in NAWM as evidence that MS has a primary vascular pathogenesis, and there is histopathologic evidence to support this hypothesis: Adams et al (9) described frequent edematous onion-skin changes and lymphocytic infiltration of vein walls in NAWM without adjacent parenchymal inflammation; this suggests that MS represents a form of subacute or chronic vasculitis that could precede lesion development. Allen and McKeown (46) have also observed perivascular inflammation in areas of macroscopic NAWM.

It is possible that decreased perfusion in NAWM could be related to widespread parenchymal damage in areas that cannot be seen with the spatial resolution at conventional MR imaging—damage that leads to a decreased metabolic demand for blood flow. Arguing against this are the histopathologic evidence that a primary vasculitis is involved and the greater involvement of highly vascular periventricular regions. Ultimately, it is unclear whether areas of abnormal perfusion are precursors of lesions, whether they occur independently of lesion development through a different mechanism, or whether they reflect decreased metabolic demand as a result of primary demyelination. It is also uncertain as to whether progressive subtypes of MS have different degrees of perfusion abnormality or whether qualitatively documenting a certain level of compromise in perfusion would help predict the natural history or progression of disease. Longitudinal studies and further investigation are required to address these questions.

In summary, we believe that our finding of significantly reduced perfusion in the NAWM (ie, a prolonged MTT and a reduced CBF) of patients with RR-MS at dynamic susceptibility contrast-enhanced MR imaging raises the possibility of vascular involvement by the disease process in MS. We are aware of the current technical limitations with this technique, and, even though we must be cautious in not overinterpreting our findings, we will continue to investigate the role of dynamic susceptibility contrast-enhanced MR imaging in understanding MS and hope that our results will stimulate additional studies.

This research was independent-- from NY University Department of Radiology. The researchers were funded by NIH,
cheer

It said the "artery arrival time was similar in MS group and controls." But the time to pass from the artery to the jugular was significantly slower in MS patients. I think the only way this can happen is if the volume of the blood vessels between the artery and the jugular is larger in MSers than in the control group. That's because the blood has to fill those blood vessels before it can get out to the jugular. To me that suggests that a stenosis in the jugulars is causing higher pressure upstream which expands the vessels, thereby increasing the volume. Possibly that could stretch the endothelium to the point where it becomes porous and allows antibodies to pass through the BBB. Of course that's all just speculation on my part.

BTW that should cause all blood vessels upstream of the stenosis to become enlarged including the jugular vein. But I can only recall one person, Ricci, who had that condition. Did anyone else see that condition in their venograms?

can someone interpret that for those of us that dont speak dr language please?

thank you

cheerleader wrote:Slowed mean transit time and hypoperfusion have been noted in MS for many years. It's not new. It could be due to reduced metabolic demand in the brains of pwMS (what many neurologists assert, without proof, and then brush off these studies), but most likely not, as these researchers explain below.
Here is an MRI study from 2004, long before Zamboni, where the radiologists used MRI to measure perfusion and transit time. The link has the complete paper...
http://radiology.rsna.org/content/231/3/645.long

Microvascular Abnormality in Relapsing-Remitting Multiple Sclerosis: Perfusion MR Imaging Findings in Normal-appearing White Matter
Meng Law, MD, Amit M. Saindane, MD, Yulin Ge, MD, James S. Babb, PhD, Glyn Johnson, PhD, Lois J. Mannon, RT, Joseph Herbert, MD and Robert I. Grossman, MD


This research was independent-- from NY University Department of Radiology. The researchers were funded by NIH,
cheer

BTW Dr. Grossman from NYU continues to publish numerous studies on hypoperfusion in MS. I wish he got more publicity, he certainly deserves it. In fact, he addressed primary hypoperfusion (as opposed to secondary hypoperfusion - being caused by something like reduced metabolism) in this study. Check it out. It's one of my favorites.

http://www.ncbi.nlm.nih.gov/pubmed/17416836 "These findings are more consistent with what would be expected in primary ischemia than in secondary hypoperfusion from WD."

And for those of you who aren't yet Grossman fan-boys like me, check out all his work. It's worth it. http://www.med.nyu.edu/biosketch/grossr03/publications

It said the "artery arrival time was similar in MS group and controls." But the time to pass from the artery to the jugular was significantly slower in MS patients. I think the only way this can happen is if the volume of the blood vessels between the artery and the jugular is larger in MSer than in the control group. That's because the blood has to fill those blood vessels before it can get out to the jugular. To me that suggests that a stenosis in the jugulars is causing higher pressure upstream which expands the vessels, thereby increasing the volume. Possibly that could stretch the endothelium to the point where it becomes porous and allows antibodies to pass through the BBB. Of course that's all just speculation on my part.

BTW that should cause all blood vessels upstream of the stenosis to become enlarged including the jugular vein. But I can only recall one person, Ricci, who had that condition. Did anyone else see that condition in their venograms?

You are assuming that the cerebral blood pressure is a) the same as what is measured the standard way, with a cuff on the arm if b) the people who administrated the test measured it that way, and c) if they did, the cerebral blood pressure is the same in MS and controls. I hope that was intelligible. If it is the same between MS and controls in the brain, as it presumeably was on the arm, then yes, what you say is true. However, since as someone pointed out recently, it will take the path of least resistance, if that is somewhere other than carotids (for instance the rest of the body, including the legs) it may be slower because the stenosis in the jugs has increased the resistance and the blood got more pressurized elsewhere.

That may be bad for your heart, or it may just stretch out your vessels elsewhere, and be OK for a while.

I have noticed one person I know, whose progression has later on included swollen and purple feet. Mine have only recently become swollen, and I hope it goes away. They aren't purple (yet?). If that is the reason, however, the recent discussion of Daflon may be appropriate. Dr. Zamboni and others have said there is increased pressure above the stenosis, but I suspect one of the reasons for progression is that the vessels only get swollen over time, wherever they are.

I remember seeing 3-D MRVs from Dr. Haacke which had veins above the stenosis ballooned out (not by catheter). All over the brain. I don't know how common this is but if it is the case, I don't know what effect a vasoconstrictor would have, because after a while the vessels would fatigue, and maybe get embolisms.

BTW the path of least resistance (maybe in veins more than arteries, but arteries grow corollaries too) is one reason why Rose's guff about there having to be a pressure gradient is just that, guff. He not only has a big mouth, but he doesn't know what he's talking about. Increased pressure also, for some reason, causes, as Dr. Simka points out, expression of ICAM-1, which causes the adhesion of immune cells that Tysabri prevents. The result of that is the immune activity that shouldn't be there. Don't I also remember from the Daflon stuff somewhere that the immune cells are found gathering upstream of the stenosis? Wonder why that would be? (No, I don't.)

Hey, maybe the reason for the inflammation and immune activity is because the endothelium is getting stressed/stretched. Ya think? And doesn't that word stress sound familiar from someplace? I think it causes people to get red faces sometimes. And heart attacks. Wonder if blood pressure is involved? Naaaah.

A blocked major outflow route can cause slowed transit time or slowed perfusion, independent of blood pressure.
The situation is exactly what happens in Budd Chiari, when veins draining the liver are blocked, and the liver slowly dies. It is called venous congestion, and it kills the organ. This happens slowly, due to ischemic injury, high pressure, slowed flow....all the things you are mentioning. There is not one vascular doctor who would ever say that the change in blood flow from normals was due to "decreased metabolic demand" of the liver. They would tell you, the veins are blocked. Open them, and heal the liver. That's what they do, and it works. Normalized blood flow is returned, in many cases, if damage isn't too terrible, the liver can heal. That's why doctors who save the liver in Budd Chiari, like Dr. Lee, understand CCSVI--

Why do we treat the brain differently?
cheer

Current is flow. Voltage is pressure. Resistance is resistance. You can think of vessels as resistors. The circulatory system is a very complex resistor network. The capillary beds are massively parallel high value resistors. The veins, arteries, venules and arterioles are lower value resistors. The heart and the muscles are the power source, fed by sugar and burning oxygen, assisted or hindered by gravity. Excluding evaporation and porousness and osmosis and things like that (spinal fluid: where does that fit in?) the whole thing is a very complex but solvable network. Ohm's law doesn't always cut it in a complex net. Sometimes you need things like the quadratic formula. When things get very non-linear (like with Starling resistors) you are really hosed. But blood pressure and resistance (as in stenosis, which is a narrowing or raising of resistance) have a direct proportionality relationship - Ohm's law. The fact that the fluid is blood and the resistors are tubes of muscle, endothelium, etc, means the math gets a bit more complex, and the resistance is very finely controllable, when you bring in variable diameters, but it's still only about as hairy as rocket science. What happens to the tube (endothelium, smooth muscle, vessel wall, etc.), when it stretches is like a resistor (think of a light bulb filament) getting a lower and lower resistance, until worst case, it pops (the filament burns out).

Stenosis must cause higher pressure, or slower flow. One or the other, no way around it (so to speak).

The path of least resistance is a fundamental principle of physics.

Results The MS patients were comparable to control subjects for age, sex, systolic and diastolic blood pressure and heart rate. The artery arrival time was similar in MS group and controls.

blood pressure was not a factor in this study. They considered it, and it was a non-issue. We've seen CCSVI in those with high, low and average BP. We've seen CCSVI in the overweight, the fit, those with heart disease, those with mitral valve prolapse, and those, like my hubby, with fantastic, healthy hearts and perfectly normal blood pressure.

There are great threads on fluid dynamics with Dr. Beggs and Dr. Tucker, one eye. And you have many excellent points regarding fluid dynamics. But in this study, blood flow was slowed, perfusion was slowed, MTT was slower without any difference in BP. Yes, it was measured with an arm cuff, because that's all we got Hopefully, Dr. Haacke's studies will open the door on cerebral blood flow in CCSVI, and give us new markers. But we don't have them, yet.
cheer

What I was getting at is that they may not have measured blood pressure in the brain itself. A cuff uses sounds heard in the arm, usually. The noises may be different in the brain (on the other side of the neck).

The cuff also puts a varying pressure on the blood vessels, and I assume that the noise changes as the pressure changes. Too bad we can't compress vessels in the head, but thanks, anyway. Plethysmography, on the neck, using a strain gauge, might be preferable in both cases (anybody taken out a patent?), but it's only on the brain side if it's above any stenoses.

Anyway, depending on how long it's been, and how many corollaries have succeeded, there may or may not be a significant pressure gradient. One reason for remission, followed by no let-up? There must be a limit to the growth of new veins, I would think.

scary item, this one...

In the study of fluid dynamics ..... PRESSURE is simply defined as "resistance to FLOW."

As I explained earlier in my garden hose example ...... you have - EITHER- flow ....or pressure .

As fluid dynamics can be overwhelming to understand ..... I offer a simple to understand explanation of CCSVI .........

Here goes ......

Picture a tall 100 story building . At the top of this building is a floor [ room ] that holds exactly 100 people at full capacity . Not 99 . Not 101 . but 100 exactly. A finite number.

On opposite sides of this buildng there are elevators . One exclusively goes UP , and the other on the opposite side ..... exclusively goes DOWN.

Each elevator holds exactly 10 people at full capacity.

When operating normally , the UP elevator shoots to the top , and 10 people exit . There is room for them .... as 10 people just left on the DOWN elevator.

Over and over .... this cycle happens.

Until something odd happens . For some reason the down elevator starts to stop and go . Some people get off on the 85th floor and using the stairs [ collateral routes] make their way down. It might slow or stop again .

Meanwhile the people waiting to go UP ..... are left waiting ....they need a full load of 10 before they go up [ .....it's a circuit ... ] . So are the 100 people waiting on the top floor . The situation quickly becomes a problem. They were told they would only be held for 10 minutes ....... not an hour ....

The building engineers define the problem as the down side trip. Why is the elevator not bringing 10 people to the ground floor in one swoop ? Most if not all of the DOWN passengrs are getting off at various floors ..... and slowly walking down the stairs . And slowly getting back into the UP lineup.

This is CCSVI.

Be glad some neurologists chose Neurology over Engineering .



Mr.Success

so does this have an effect on CSF flow? increase or decrease?

I recently posted some information regarding what happens to your brain , by pressing on the cartoid artery . This is the " up " elevator I just mentioned.

It is estimated to take between 3 to 10 seconds to lose consciousness.

This clearly demonstrates the importance of blood flow INTO the brain.

This also clearly demonstrates how delicate this organ is to any abnormal function.

How is it possible for anyone to not draw a conclusion , that blood OUTFLOW is just as important ?

We now have clear proof of abnormal blood flow function ...... using a variety of methods .

Dr.Zamboni say's ... Let's fix the DOWN elevator .

The Neurologist's say ....... No ..... let's just medicate those stuck on the top floor ...


I'm getting tired of their bullshit .........


Mr.Success [ Civickiller ....... I have no theory or idea yet .....on CSF ]