Blood flow matters

If you ever wondered whether blood flow was important to brain health, all you would have to do is read about three new MS drug trials announced in the past month.

All three of these compounds have been shown in EAE mouse trials to reduce symptoms, reduce inflammation and slow progression of MS.  All three have been touted as "neuroprotective."

But all three of these medications have a very similar known method of action (MOA) in humans.  All have been used for years for cardiovascular and stroke patients.  All have an effect on the endothelium and release nitric oxide and lower blood pressure.  All three deal with "hypoperfusion", or reduced blood flow.

They all widen blood vessels, and increase blood flow to and from the brain.

guanabenz-- relaxes blood vessels so that blood may pass through more easily.
http://www.mayoclinic.org/drugs-supplements/guanabenz-oral-route/description/drg-20064106

ibudilast-- increases cerebral blood flow, is a vasodilator
http://www.ncbi.nlm.nih.gov/pubmed/18677969

biotin---decreases blood pressure, increases blood flow, treats ischemia (low O2) after stroke
http://www.ncbi.nlm.nih.gov/pubmed/18179728
http://www.google.com/patents/WO2014016003A1?cl=en



That's right.  MS researchers have learned from Dr. Zamboni's discovery of CCSVI and slowed cerebral blood flow and hypoperfusion in the MS brain.

But they do not want patients to try "alternative treatments"; to have venous malformations treated, or to receive HBOT treatment,  or have atlas adjustments, or to eat better, quit smoking, get UV rays or exercise more.  All of these alternatives have been scientifically shown to increase cerebral blood flow and perfusion.  These alternatives will help people with MS live healthier lives.  But they will not help MS researchers.

MS researchers would prefer it if you would take a pill.  That way, their research labs will remain funded.  That way, they receive finders' fees when you are enrolled in a drug trial.
(Up to $5,000 per patient!)
http://ccsviinms.blogspot.com/2012/04/clinical-trials-and-finders-fees-april.html

That way, they can receive speakers' fees, and have wonderful conferences, and do not have to address the elephant in the room----that the EAE model of MS is not MS.  EAE has been used to create a $20 billion dollar a year drug industry, based on immune modulation and ablation, but has not stopped MS disease progression in humans.

There is most certainly a problem with cerebral blood flow and hypoperfusion in people with MS.  In fact, all diseases of neurodegeneration have hypoperfusion.
http://ccsvi.org/index.php/the-basics/ccsvi-in-other-neurological-diseases

I simply wonder when the MS industry will admit that the new target of "neuroprotection", simply means increasing blood flow to neurons and myelin in the hypoperfused MS brain.

Still waiting,
Joan


This picture on the left is from Dr. Zamboni and Dr. Simka---it illustrates how cerebral blood flow becomes blocked, refluxes up jugular veins and goes to less efficient, collateral veins in CCSVI,  creating hypoperfusion.  I know it's real, because it's what my husband had on MRV (see pic on right)  And there is no pill in the universe that could have restored Jeff's blood flow.  He needed venous repair, and a new lifestyle.  Six years later, no MS progression.  This is real.

Biotin for Progressive MS

UPDATE:  December 2017---

Medday, the company developing high dose biotin for progressive MS, has told the European Medicines Agency that it wishes to withdraw its licence application for the treatment of progressive multiple sclerosis.The European Medicines Agency (EMA) has been examining data on high dose biotin (MD1003, Qizenday) since the application was accepted in September 2016. At a meeting last week, the EMA's Committee for Medicinal Products for Human Use (CHMP) concluded that the clinical data from two trials that enrolled 253 patients was not sufficient(link is external) to assess the effectiveness or the safety of biotin.  link

Recent research and press releases on the use of super-high dosages of biotin (300 mg a day, also known as MD1003) for progressive MS are all over the internet, after moderate improvements in MS symptoms were announced at the annual American Academy of Neurology meeting last week.  MS boards and patient blogs describe how people are considering trying this therapy on their own, by securing high dosages of biotin from compounding pharmacies or health food stores.   But strangely absent from this online discussion is the method of action implied for biotin, which is targeting the results of a decrease in cerebral blood flow, as well as the actual results of pilot studies.  I think it's vitally important to look behind the MS research headlines, and consider the science.  Especially before investing time, money and hope in a new product.

I simply do not think it's wise to take mega-doses of biotin.  Although I do think it's important to deal with slowed cerebral blood flow in the MS brain.  Please take 5 minutes to read this note, and I believe you might feel the same way.

I first wrote about biotin at the beginning of April, on the CCSVI in MS Facebook page, after one of our administrators posted a link to an abstract.
High doses of biotin in chronic progressive multiple sclerosis: A pilot study.

http://www.ncbi.nlm.nih.gov/pubmed/25787192

Here's what I posted below the link from Sandro:
"Biotin is also known as vitamin B7. It is found in peanuts, leafy green veggies and egg yolks. It is naturally produced by healthy intestinal bacteria. Smoking and drinking can deplete it. Thanks to Sandro for this link.  
All of these ideas can be found in the Endothelial Health Program, which recommends probiotics, B vitamins, dietary increases in leafy veggies, and smoking cessation. It's not a pill, it's a lifestyle. Joan"

At that time, readers were asking for more information, so I dug a bit deeper and found the patent application for this new "drug."
http://www.google.com/patents/WO2014016003A1?cl=en

"A pharma company is patenting this high dosage of biotin, to market this vitamin as a drug. Here's the patent. I suggest you read it, it is enlightening. They are also patenting this "drug" for ischemic stroke damage and hypoperfusion. Drug companies understand the vascular connection."


In fact, if you read the entire patent application, the method of action for high dosages of biotin in multiple sclerosis is explained--biotin is targeting the damage from ischemia.  This vitamin addresses the results of  decreased cerebral blood flow, which creates ischemia, oxidative stress and reduced ATP production in the brain's cells.  From the patent application:

 The major responsibility for the evolution of the ischemic penumbra is the status of local cerebral blood flow. It is assumed that a decrease in cerebral blood flow yields reduced ATP production and failure of Na+/K+ pumps, increasing extracellular glutamate and activating glutamate- mediated channels, ending in an increase of intracellular calcium that is deleterious for the cell. It is widely accepted that the ischemic penumbra is a target for neurorepair and neuroprotective therapies.

Once again, we see quite clearly that drug companies understand the fact that the MS brain is hypoperfused and suffering from ischemia.  They know there is a vascular connection in MS, and that the damage to the MS brain is very similar to ischemic stroke.  

The results of the biotin study were somewhat compelling, but I was surprised at how many people were ready to take high doses of a vitamin, without understanding the mechanism of action, or the fact that this treatment was created for a very specific type of MS--mainly optic neuropathy.  In fact, the major improvements in patients in the trial were not in motor abilities, but in vision.  The changes is EDSS were incredibly minor. All of this information is very specifically addressed in the patent application.

I've often said that it is much easier to placebo control one compound, one drug, one treatment modality at a time, rather than an entire lifestyle. Because of this fact, drug companies are able to test high dosages of biotin in the gold standard method, against placebo,  and publish results.  But this does not mean that the best method of addressing the damage of a hypoperfused brain is high dosages of biotin.

There are side effects noted with high dosages of biotin, and serious interactions with other drugs.

Interactions. Biotin negatively interacts with anti-seizure medications and medications that help lower cholesterol, causing these medications to work less effectively. While biotin is helpful in regulating your metabolism and blood sugar levels, it can have a distinct effect on the overall blood glucose level in your body. If you are taking medications like cholesterol medication or anticonvulsants or treating a condition like diabetes, taking biotin can have an impact on your symptoms.
http://www.md-health.com/Biotin-Side-Effects.html



Best results are found in a complete lifestyle approach, with cardiovascular exercise, physical therapy, whole food nutrition full of leafy greens and phytonutrients from plants, stress reduction, probiotics,  UV ray therapy, vitamin D supplementation, vitamin B supplementation, smoking cessation, hydration, adequate sleep,  and addressing venous malformations which may be impacting cerebral blood flow.

There is no one miracle pill or supplement or drug which can replicate the results of a complete lifestyle.

Here's the complete program I created for Jeff, which takes all of this into account.  It was created to deal with oxidative stress, hypoperfusion and energy depletion in the brain.
http://ccsvi.org/index.php/helping-myself/endothelial-health

The Endothelial Health Program was created to increase cerebral blood flow, via healthier blood vessels and cardiovascular function.  All of the steps are proven, scientifically, to increase cerebral blood flow and oxygenation of the brain.  It is preventative and reparative medicine.  And it works.  Jeff's going strong, now 8 years past his MS diagnosis, with no MS progression and a reversal of brain atrophy on MRI.  He's still jogging and working full days. Always consult with your own physician before beginning a new lifestyle program.  Jeff works with our GP, to make sure all of his blood numbers are good, and that he is doing well on his program.

Be well, be hopeful, but understand that there is not one pill or compound or vitamin that will ever replace a multi-modal, systems approach to healing.

Joan

MS "breakthrough" research--On/Off Switch!!!

I am sick and tired of reading news stories about some "new MS breakthrough" which uses the EAE mouse model of MS and describes MS as an autoimmune disease.  It is as though the immunology research community believes that if they just keep acting like they are busy discovering things (where they have been looking for 70 years and finding nothing about disease etiology) they can keep getting funding for their labs, and keep people with MS thinking there is momentum.

The latest in a sea of sameness is the Bristol University crap about an "on/off switch" for the immune response to MS.

Here's the full paper, published in Nature---for those who like to read published research, rather than press releases full of hyperbole and BS.

http://www.nature.com/ncomms/2014/140903/ncomms5741/full/ncomms5741.html

In reading the paper, we learn that this new "breakthrough" is remarkebly reminiscent of Copaxone treatment, in which killer T cells are said to be modulated to helpful T cells by means of exposing them to an antigen (in Copaxone's case, that's a mimic of the proteins found in myelin basic protein---glatiramer acetate.)  This particular "new breakthrough hope"  therapy is going after CD4+ T cells, using injected peptide epitopes, rather than intact antigens--which are said to be "more effective."

Again, all of the testing was done on the mouse model, EAE.  Not humans with MS.

As reviewed elsewhere23, 45, peptide epitopes targeting ​CD4+ T cells have distinct advantages over intact antigens, and yet the mechanism by which peptide therapy prevents and treats ongoing autoimmune and allergic diseases is poorly defined. Mucosal routes of administration have proven safe and effective in animal models of allergy and autoimmunity, but have not translated well to the clinic. Here we demonstrate that the s.c. route of administration is more effective than the i.n. route, with a 1,000-fold lower dose of antigen being effective for anergy induction when compared with previous studies17, 18. As noted17, the efficacy of tolerance induction and disease prevention depends on signal strength. In this study, all aspects of inflammatory T-cell function, including proliferation, inflammatory cytokine secretion and encephalitogenicity were suppressed, whereas the ability of cells to secrete ​IL-10 and suppress EAE increased in a dose-dependent manner. ​IL-10 clearly serves as a promising mediator of effective antigen-specific immunotherapy1, 12.

But muting or changing the inflammatory response of CD4 + T Cells isn't really explaining why they are there in the first place, or how come this exact same cellular response shows up in ischemic stroke, slowed cerebral blood flow and reperfusion injury in humans.

That's right!!  CD4+ T cells show up after stroke, ischemia, and reperfusion injury.  These cells are responding to slowed blood flow in the brain, or hypoperfusion.

Here are stroke and vascular researchers discussing CD4+ T cells and the immune reaction to stroke and vascular issues in published research.  Perhaps we should let them know that stroke or reperfusion injury is an autoimmune disease that can be turned on or off!

For instance, lymphocytes from stroke survivors show more activity against myelin than the lymphocytes from patients with multiple sclerosis. In addition, myelin-reactive T cells are found in higher numbers among patients with cerebrovascular disease. These data thus provide evidence that a cellular immune response to brain antigens occurs following stroke.
http://stroke.ahajournals.org/content/41/10_suppl_1/S75.full


These findings indicate that CD4⁺ and CD8⁺ T lymphocytes, but not B lymphocytes, contribute to the inflammatory and thrombogenic responses, brain injury, and neurological deficit associated with experimental stroke
http://circ.ahajournals.org/content/113/17/2105.long

These findings implicate a CD4+ subset of T lymphocytes as key mediators of early inflammatory responses after renal  ischemic reperfusion  injury. 

http://www.scielo.br/pdf/bjmbr/v40n4/6420.pdf


I have a novel suggestion for researchers---why not look at the connection of MS to stroke, the vascular endothelium, CCSVI and reperfusion injury?  Why not understand this cellular response in non "auto-immune" diseases?

Now that would be a REAL breakthrough,
Joan

Why mouse models of stroke and MS don't work

April 22, 2012 at 8:51am

MS is not the only neurological disorder which has a flawed rodent model.  Turns out, stroke researchers just aren't happy with their mouse model, either.  Why?  Because the immune response after stroke is different in mice and people.

EAE is not MS in humans.  

Believe it or not, the current MS drugs cure mice of EAE.  But they sure do not cure people of MS.  

What's the problem?   There are many problems with the EAE model.    

Here's my favorite description of what's wrong with EAE, from Dr. Michael Dake--

"There's an animal model, but it's not really, unfortunately, like most animal models, it's not really a human model.  Basically, you take like a mish of ground up spinal cord and brain from some other species, you mix it with some oily substance, some TB bacilli, and some bordatella pertussis, some whooping cough toxin, and inject it into peridium,  and what you get is this whopping inflammatory response, and that's good because you get the accelerated disease process, but obviously in humans, it's a much more chronic and progressive thing."

People with MS haven't had this cocktail of viruses injected into their brains.  (Good thing!)

But there's much more. The immune system of rodents and humans are very different, too.

Stroke researchers understand that their rodent models are not working.  

This is because the immune reaction after ischemia is very different in rodents when compared to humans. 

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

Here is a recent paper on the problem with the rodent model of stroke--and the difference in the immune response in mice and men.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085747/

Important to note---the immune system responds after stroke, just as it does in MS.  Ischemic injury, or lack of oxygen to brain tissue, calls in the immune system to clean up dead cells.  This happens in all mammals.

The rodent immune cell composition is remarkably different from that of humans.

Specifically, rodents have a lymphocyte predominance with a 1:5 ratio of neutrophils to lymphocytes.

Humans have a 2:1 ratio of neutrophils to lymphocytes.

What does this mean?  Time for some explaining.

Neutrophils and lymphocytes are both types of white blood cells that make up the innate immune system of all mammals.

Ischemia, MMPs and Myelin loss

December 16, 2010 at 10:47am

Continuing the exploration of the "auto-immune" reaction of the body in situations of slow blood flow, oxidative stress and lowered oxygen levels in the brain--we learn that  myelin breakdown is not unique to MS.  It happens in dementia, Alzheimer's, ischemic stroke, carbon monoxide poisoning and cerebrovascular disease.   

There is recent research on myelin loss in ischemia. 

This paper studies how matrix metalloproteinases (MMPs) are involved in this process--

MMPs:   A member of a group of enzymes that can break down proteins, such as collagen, that are normally found in the spaces between cells in tissues.   Matrix metalloproteinases are involved in wound healing, angiogenesis, and tumor cell metastasis.

In MS---

Multiple MMPs are elevated in human neurologic diseases.  In the setting of MS, it has been shown that serum MMP-9 levels are increased in patients with clinically isolated syndrome (CIS) compared with normal control subjects and are further elevated in patients with clinically definite MS (CDMS) compared with patients with CIS.   In addition, serum MMP levels increase markedly between onset of neurologic symptoms and development of CDMS, whereas levels remain unchanged in subjects with CIS who do not develop CDMS. Other studies have documented elevations of MMP-9 and other MMPs in the serum, CSF, and brain of patients with MS compared with controls.

http://www.direct-ms.org/pdf/ImmunologyMS/Yong%20Exper%20models%20neurodegen%20Neurology%2007.pdf

In Ischemia--

Divergent role for MMP-2 in myelin breakdown and oligodendrocyte death following transient global ischemia.

Walker EJ, Rosenberg GA.

Departments of Neurology, Neurosciences, and Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.

Abstract

Transient global ischemia causes delayed white matter injury to the brain with oligodendrocyte (OLG) death and myelin breakdown. There is increasing evidence that hypoxia may be involved in several diseases of the white matter, including multiple sclerosis, vascular dementia, and ischemia.

Matrix metalloproteinases (MMPs) are increased in rat and mouse models of hypoxic hypoperfusion and have been associated with OLG death. However, whether the MMPs act on myelin or OLGs remains unresolved. We hypothesized that delayed expression of MMPs caused OLG death and myelin breakdown. To test the hypothesis, adult mice underwent hypoxic hypoperfusion with transient bilateral occlusion of the carotid arteries. After 3 days of reperfusion, ischemic white matter had increased reactivity of astrocytes and microglia, MMP-2 localization in astrocytes, and increased protein expression and activity of MMP-2. In addition, there was a significant loss of myelin basic protein (MBP) by Western blot and caspase-3- mediated OLG death. Treatment with the broad-spectrum MMP inhibitor, BB-94, significantly decreased astrocyte reactivity and MMP-2 activity. More importantly, it reduced MBP breakdown. However, MMP inhibition had no effect on OLG loss. Our results implicate MMPs released by reactive astrocytes in delayed myelin degradation, while OLG death occurs by an MMP-independent mechanism. We propose that MMP-mediated myelin loss is important in hypoxic injury to the white matter.

http://www.ncbi.nlm.nih.gov/pubmed/19830840

Blood Flow and white matter lesions

August 27, 2010 at 10:58pm

The idea that MS is related to hypoperfusion, or slowed blood flow, is not new.

Here's is Dr. Juurlink's proposal from 12 years ago--

http://www.ncbi.nlm.nih.gov/pubmed/9824835

Hypoperfusion in the MS brain explained:

"Hypo"; meaning under or sub-par and "perfusion"- meaning the delivery of blood to the capillary bed.

In MS brains, there is a below normal delivery of blood into brain tissue.  Neurologists have never given a good explanation as to why this happens.  Here's a great paper that looks at this phenomena.

(terms to know -NAWM  is normal appearing white matter, or healthy myelin.  

Ischemia means a lack of oxygen or hypoxia.)

http://www.nature.com/jcbfm/journal/v28/n10/full/jcbfm200872a.html

"Accumulating evidence indicates that there is a decreased perfusion throughout the NAWM (normal appearing white matter) in patients with MS. It occurs in both relapsing–remitting and primary progressive MS, strongly suggesting that it represents an integral part of the disease process. Ischemic changes might be involved in the development of a subtype of focal demyelinating lesions (type III lesions). There appears to be a relationship between reduced white matter perfusion and cognitive dysfunction in patients with MS.

Ge et al (2005) interpreted the hypoperfusion in NAWM as a vasculopathy in the context of the perivascular inflammations that occur in focal MS lesions. However, although inflammatory infiltrates in MS are typically located around small- or medium-sized veins (Adams, 1989) and in the perivascular spaces surrounding arterioles (Gay, 2006; Gay et al, 1997), microvessel thrombosis is only exceptionally being observed within these lesions (Aboul-Enein and Lassmann, 2005; Wakefield et al, 1994)."

So, this paper comes pretty close to saying that this slowed perfusion and white matter lesions could be created by slowed blood flow and a lack of oxygen in the brain.  This is exactly what Dr. Juurlink was proposing.

Here's a study that shows that white matter lesions in rats were formed when cerebral hypoperfusion was created in their brains.

http://www.ncbi.nlm.nih.gov/pubmed/13680276

"Cerebrovascular white matter lesions represent an age-related neurodegenerative condition that appears as a hyperintense signal on magnetic resonance images. These lesions are frequently observed in aging, hypertension and cerebrovascular disease, and are responsible for cognitive decline and gait disorders in the elderly population. In humans, cerebrovascular white matter lesions are accompanied by apoptosis of oligodendroglia, and have been thought to be caused by chronic cerebral ischemia. In the present study, we tested whether chronic cerebral hypoperfusion induces white matter lesions and apoptosis of oligodendroglia in the rat. Doppler flow meter analysis revealed an immediate reduction of cerebral blood flow ranging from 30% to 40% of that before operation; this remained at 52–64% between 7 and 30 days after operation. Transferrin-immunoreactive oligodendroglia decreased in number and the myelin became degenerated in the medial corpus callosum at 7 days and thereafter."

There is NO NEED for any auto- immune system activation to create white matter lesions or myelin destruction.  NONE.  Dr. Juurlink knew this.  Many doctors who study stroke know this.   All that is needed is slowed blood flow.  

Did you know that most elderly people have white matter lesions in their brains?  We don't see them, because they are not routinely given MRIs.  But it's a known fact that the aging brain has slower perfusion, slower circulation and decreased blood flow, resulting in less oxygenation.  Why has the correlation of circulation in MS and other neurodegenerative diseases been ignored?  This chaps my hide.

Here's a paper where they created white matter lesions in rats' brains by clamping their carotid arteries closed.  Remember, the arteries bring the blood in, the veins take it out.  Slowed perfusion can be created by slowed delivery of blood, or slowed removal.  It works both ways.

http://www.ncbi.nlm.nih.gov/pubmed/11743996

Notice in this study, the first areas of white matter lesions were on the optic nerve after only THREE DAYS of ligation.  This mimics the order of problems we see in pwMS. RRMS patients typically present with vision problems first and show white matter lesions.

"Cerebral white matter (WM) lesions are observed frequently in human ischemic cerebrovascular disease and have been thought to contribute to cognitive impairment. This type of lesion can be experimentally induced in rat brains under chronic cerebral hypoperfusion by the permanent occlusion of both common carotid arteries. However, it remains uncertain whether chronic ischemia can damage both the gray and white matter, and whether it can induce demyelination with or without axonal damage. Therefore, we examined axonal damage using immunohistochemistry for the amyloid β/A4 precursor protein (APP), chromogranin A (CgA) and demyelination using immunohistochemistry for the encephalitogenic peptide (EP) in this model. Severe WM lesions such as vacuolation and the loss of nerve fibers appeared in the optic nerve and optic tract after 3 days of ligation, and less intense changes were observed in the corpus callosum, internal capsule, and fiber bundles of the caudoputamen after 7 days with Klüver–Barrera and Bielschowsky staining. These WM lesions persisted even after 30 days. The APP, CgA, and EP-immunopositive fibers increased in number from 1 to 30 days after the ligation in the following WM regions: the optic nerve, optic tract, corpus callosum, internal capsule, and fiber bundles of the caudoputamen. "

When neurologists say that Dr. Zamboni's research is not based on fact....give them a lecture on hypoperfusion and white matter lesions.  This is science, this is fact, this is real.

Joan