a publication on normal cerebral outflow

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

Postby Leonard » Sun Jan 02, 2011 11:28 pm

Thanks so much Cece for the glucose lead. I think we have solved or at least come close to solving the MS mystery. My hypothesis now goes as follows:

MS is caused by an insufficient glucose level in the brain or parts of the brain. This causes neurons to go into a dormant mode, and eventually, when seriously undernurished for a long period of time, axonal death. The immune system and this very advanced mechanism (ref your first posting of this thread) will clean up the mess. That's when we start see the scars.

The low glucose condition in the brain or parts is caused by an insufficient flow of the blood. This causes poor oxygen and glucose volume to pass through the vessels. The long for sugar and elevated glucose levels in the blood by MS patients point to a relation with the glucose, with symptoms as candida and yeast occuring more frequently (ref: book Judy Graham). Also the faster recovery of functions on intake of sugar/glucose.

Stenoses in the veins also cause refluxes in the deep cerebral veins and iron depletion on the vessel walls (you can see this on 7T MRI) and this further inhibits glycose transport through the affected parts of the BBB. Iron depletion is a normal phenomenon in organs and limbs in case of problem with the drainage. By opening up the veins in the drainage, as Zamboni does, the normal blood flow restores, and the BBB function may restore to normal. The increased blood flow during pregnancy and stop of MS progression adds to the plausability. The low fat/Swank diet and the use of blood thinners/anti-clotting also help improve the blood flow with the same positive effects

But then there also the vitamine D connection. A high level of Vitamine D during the first 3 months of pregnancy of your mother and/or sufficient Vit D during your childhood (when the vessel walls grow to adult) are important because the Vitamine D will "interlock" in the vessel walls and your BBB. This will help to pass the glycose from the blood stream through the BBB to the neurons. Therefore some people who have stenoses and a low blood flow but high Vitamine D will still provide enough glucose to their neurons, thus will not experience the MS symptoms, at the very least not as quick as those with low Vit D.

What lessons may we draw:
1. get the veins opened and restore the normal blood flow.
2. for the pharma industry, start develop medication that may help improve the glucose transport across the BBB (if you have not already started)

All the pointers seem to point to the right direction. It seems we have the major pieces of the puzzle and they seem to come together quite nicely. I think we should develop an argumentaire/position paper on this. I am not a medical person or a native speaker, so perhaps others could take a lead here.

Thank you all for your contributions. This forum has been a life line for me over the last year.
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Postby pairOdime » Mon Jan 03, 2011 4:27 am

A hit on PubMed for "glucose and blood brain barrier"...of course there is a big difference between utilization of glucose that is available and limited availability of glucose due to impaired cerebral venous flow.

Neurochem Int. 2010 Dec 3. [Epub ahead of print]
Modeling neurodegenerative disease pathophysiology in thiamine deficiency: Consequences of impaired oxidative metabolism.
Jhala SS, Hazell AS.

Department of Medicine, University of Montreal, Montreal, Quebec, Canada.

Abstract
Emerging evidence suggests that thiamine deficiency (TD), the cause of Wernicke's encephalopathy, produces alterations in brain function and structural damage that closely model a number of maladies in which neurodegeneration is a characteristic feature, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, multiple sclerosis, along with alcoholic brain disease, stroke, and traumatic brain injury.

Impaired oxidative metabolism in TD due to decreased activity of thiamine-dependent enzymes leads to a multifactorial cascade of events in the brain that include focal decreases in energy status, oxidative stress, lactic acidosis, blood-brain barrier disruption, astrocyte dysfunction, glutamate-mediated excitotoxicity, amyloid deposition, decreased glucose utilization, immediate-early gene induction, and inflammation.

This review describes our current understanding of the basis of these abnormal processes in TD, their interrelationships, and why this disorder can be useful for our understanding of how decreased cerebral energy metabolism can give rise to cell death in different neurodegenerative disease states.
It's a paradigm shift
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Postby pairOdime » Mon Jan 03, 2011 4:42 am

An example of the possible impact of limited glucose availability or impaired utilization....

Psychopharmacology (Berl). 2010 Nov 16. [Epub ahead of print]
Inhibitory effects of alcohol on glucose transport across the blood-brain barrier leads to neurodegeneration: preventive role of acetyl-L: -carnitine.
Muneer PM, Alikunju S, Szlachetka AM, Haorah J.

Laboratory of Neurovascular Oxidative Injury, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198, USA.

PURPOSE: Evidence shows that alcohol intake causes oxidative neuronal injury and neurocognitive deficits that are distinct from the classical Wernicke-Korsakoff neuropathy. Our previous findings indicated that alcohol-elicited blood-brain barrier (BBB) damage leads to neuroinflammation and neuronal loss. The dynamic function of the BBB requires a constant supply and utilization of glucose. Here we examined whether interference of glucose uptake and transport at the endothelium by alcohol leads to BBB dysfunction and neuronal degeneration.

MATERIAL AND METHODS: We tested the hypothesis in cell culture of human brain endothelial cells, neurons and alcohol intake in animal by immunofluorescence, Western blotting and glucose uptake assay methods.

RESULTS: We found that decrease in glucose uptake correlates the reduction of glucose transporter protein 1 (GLUT1) in cell culture after 50 mM ethanol exposure. Decrease in GLUT1 protein levels was regulated at the translation process. In animal, chronic alcohol intake suppresses the transport of glucose into the frontal and occipital regions of the brain. This finding is validated by a marked decrease in GLUT1 protein expression in brain microvessel (the BBB). In parallel, alcohol intake impairs the BBB tight junction proteins occludin, zonula occludens-1, and claudin-5 in the brain microvessel. Permeability of sodium fluorescein and Evans Blue confirms the leakiness of the BBB. Further, depletion of trans-endothelial electrical resistance of the cell monolayer supports the disruption of BBB integrity. Administration of acetyl-L: -carnitine (a neuroprotective agent) significantly prevents the adverse effects of alcohol on glucose uptake, BBB damage and neuronal degeneration.

CONCLUSION: These findings suggest that alcohol-elicited inhibition of glucose transport at the blood-brain interface leads to BBB malfunction and neurological complications.
It's a paradigm shift
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Giant Leaps From A Few Papers !!

Postby MarkW » Mon Jan 03, 2011 9:14 am

An interesting paper, thanks Cece.
MS is a very complex disease, highly unlikely to to have a single cause, rather multifactors interacting to provoke the disease in genetically predeposed people.
The first step of MS appears to be death of myelin cells, not nerves. Any causation theory needs to explain what triggers the death of these cells and provide evidence of the explanation.
I suggest that it is a waste of effort to try to explain MS with current data. CCSVI syndrome is a diagnosable and treatable symptom of MS, why go further and annoy MS specialists who can knock down these theories ???

MarkW
Mark Walker - Oxfordshire, England. Registered Pharmacist (UK). 11 years of study around MS.
Mark's CCSVI Report 7-Mar-11:
http://www.telegraph.co.uk/health/8359854/MS-experts-in-Britain-have-to-open-their-minds.html
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Postby Leonard » Mon Jan 03, 2011 10:46 am

MarkW, where I would agree on your last point (i.e. no need to upset the neurologists as we can daignose and treat ccsvi), and I would even agree that MS is complex disease with various factors interacting, I am less convinced that MS is unlikely to have a single cause. In fact, it may well have that single cause (I believe a low glucose condition seems a plausible candidate) that sets off the chain of reaction.

I am also less convinced by the fact that the first step is the myelin; this is the old dogmatic believe. I googled a bit on microglia and myelin and indeed got many rather recent papers and a huge complexity, incidently also stressing the need to review or revisit the old model. I am not convinced that the neurons and myelin can be separated that easily when microglia intervene.

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Postby Cece » Mon Jan 03, 2011 7:50 pm

I wouldn't put aside the cerebral hypoxia side of the equation, but I think the cerebral hypoglycemia side is under-explored.

pairodime, I have to touch up on some basics before I can understand the research you've posted, but it is all of interest.

How does glucose get into the brain? How closely matched are the glucose needs of the brain and the glucose in the bloodstream of a healthy nonCCSVI person, is there glucose to spare or is it pretty close? Is this an argument for losing weight, so that our bodies will take less of the available bloodstream glucose and leave more for our brains? What is the role of vitamin D in glucose uptake across the BBB?
2. for the pharma industry, start develop medication that may help improve the glucose transport across the BBB (if you have not already started)

I think this is a very valid direction. They can even test it in mice. I wouldn't expect it to do much in the EAE mice, since they have normal blood flow, but there are the CCSVI mice debuting this spring at ISNVD. :D

If you overshot with the pharmaceuticals and got too much glucose into the brain, what would that do?
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Postby CD » Mon Jan 03, 2011 8:06 pm

I find this topic interesting. I am hypoglycemic. I always got the shakes, feel weak and get the chills, with a near faint feeling when my sugar drops. I found if I carry a kit-kat or some fast sugar like Necco's, I am fine in a minute or two.

As a kid I did faint, they said probably anemic, way back in the stone ages, and being female of course.

My sugar level was always borderline low, now my 5 hour GTT (Glucose Tolerance test) level is 39 after the 5 hrs. After sitting in the lab waiting out the test, I get the symptoms back in three hours, after drinking that sugary stuff. Then I suffer for two more hours being so weak. I hate that test.

I now have a blood meter to stick myself to make sure my level is not that low. I am never hungry, but eat okay. My weight never changes.

I am guessing my brain is being deprived of needed sugar and an energy boost? MS related?
CD

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Postby Cece » Tue Jan 04, 2011 7:17 am

CD, any changes in how your hypoglycemia affects you since you've had the procedure?
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Postby CD » Tue Jan 04, 2011 5:03 pm

Cece,
It's hard to tell, sorry to say. My PCP's vacation substitute doctor, put me on Diovan for moderately high BP while I had my INR blood draw two weeks ago.

Yet, my PCP thought my BP was fine for my age and also my BP can be low one time and higher the next, on it's own.

So, now the Diovan makes me dizzy and nauseous. But those seem to be different symptoms from my low BS problem. I don't feel faint, shaky or the cold-sweat feeling chills I used to get. Maybe I am so used to dealing with it, I just pop a sweet cookie in my mouth with my coffee. :)

My meter readings are within the normal level 70 to 79 non fasting. Two hours after eating it is a bit higher but not out of range. Nothing near a diabetic reading, and not too low. It seems controlled, whether by me and habit, or the food intake times. I don't let too many hours pass before not eating something.

I have to take a re-check of a few Thyroid blood tests soon. I have low thyroid function, thank you MS, and will have to fast. So I will let you know if I get the low BS drop feelings back during the fast.

I had to fast before the CCSVI procedure so they put some glucose in the IV bag for me. They tested my sugar and clotting time before the procedure.

I'll get back to you. The Diovan my body should get used to in time. My BP can drop very quickly and the causes the dizziness. Also it has given me postural dizziness, upon rising too fast. Oh the fun, NOT!

I think my thyroid is better since CCSVI. I do take Synthroid, but it was tender for years and slightly enlarged (goiter with nodules). I believe the jugulars drain into the Thyroid veins?- and they were blocked in that area, both Jugs. My thyroid feels great.

My back of head, neck and shoulder pain is gone too since the procedure. I had that for eons. I have been noticing a few nice bonus benefits since the procedure, with my other diseases/ disorders.
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Postby Cece » Tue Jan 04, 2011 5:23 pm

The collaterals off of the jugulars and some of the alternate drainage routes drain through the thyroid. It's a really vascular-rich gland.

After so many issues and a second procedure it is good to hear you're experiencing benefits.

And, yes, there may be things to learned from you on the glucose-ccsvi connection, keep us posted if you notice anything. :)
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Postby CD » Tue Jan 04, 2011 5:45 pm

Image

From Wiki..Thyroid area is interesting to me.
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Postby Leonard » Wed Jan 05, 2011 5:38 am

The Vitamine D relationship with MS may find a connection here, and probably is a bit more complicated than Vit D just being an enabler for glucose transfer across the BBB:

http://www.hindawi.com/journals/ije/2010/351385.html

Coincidence or not: my father had some signs of MS, difficulty walking the stairs, needed to eat an apple (glucose) to keep going, when he was around 60 years of age. He was diagnosed with diabetes type 2 around that same time. He is 83 years old now and in good health, and keeps his diabetes (and blood sugar) under control through medication (one pil every day).

After he was diagnosed with diabetes type 2, I never really heard about problems of disability of his leg. I find a bit strange. Why? His blood sugar down, intracellular calcium down, enhanced insulin mediated glucose transport??? Would this suggest a relationship between MS and diabetes 2? Would this suggest that elevated glucose levels - as MS patients we may seek to get some relief by sugar/high glucose level - work against us because on the long term intracellular calcium will be elevated and insulin action necessary for glucose transport inhibited?

afterscript: I just googled on a presumed rleationship between MS and diabtes type 2: and yes it is there!!! http://care.diabetesjournals.org/conten ... 984.1.full

It may be another important piece of the puzzle! And it may in fact hint at a possible medication to improve glucose transport.

Whow, it seems these social fora, the google search engine and wikipedia have really changed the rules of the game.
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Postby Cece » Wed Jan 05, 2011 6:27 am

Leonard wrote:afterscript: I just googled on a presumed rleationship between MS and diabtes type 2: and yes it is there!!! http://care.diabetesjournals.org/conten ... 984.1.full

here's a quote from there:
Also, there is evidence of disruption of myelin due to changes in glucose levels (2).

what evidence, disrupted how, through what sort of changes in glucose levels?
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Postby Leonard » Wed Jan 05, 2011 6:38 am

My best guess would be that elevated glucose levels in the blood are not good and may in fact accelerate the disability/demyelination process. It may result in elevated intracellular calcium and inhibit insulin action necessary for glucose transport.

Isn't it about time that the medical professionals jump on this? They can not let us swim like this, that is irresponsible.
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Postby Leonard » Wed Jan 05, 2011 11:11 pm

On reflection, the high glucose levels in the blood may be a consequence of something else. Like patients seeking compensation for the bad transport of glucose.
Underlying may be the diabetes type 2 deficiency of insulin resistance and inhibited glucose transport. This may then cause the myelin death and a lot more.
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