BDNF, exercise and the vascular endothelium

Another new paper showing the vascular connection to MS.

New research shows that a 24 week resistance and endurance exercise program increases brain derived neurotrophic factor (BDNF) in people with MS.
link

At baseline, the BDNF concentration of persons with RRMS was 21% lower than healthy controls. Following 24 weeks of intervention, changes in BDNF concentrations differed significantly between exercise group and sedentary group.  In particular, within exercise group, BDNF concentrations increased 13.9% ± 8.8%, whereas it decreased 10.5% ± 4.1% within sendentary group. 

BDNF is called the "Miracle-Gro" for the brain.  It is a very important cerebrovascular protein which protects neurons and allows for neurogenesis, or the growth of new neurons.  BDNF is vital to learning, memory and executive function.

Lower levels of BDNF are linked to Alzheimer's, dementia, depression, diabetes---and now, Multiple Sclerosis.

Cardiovascular researchers have known that exercise increases BDNF levels for quite some time.  Why?  Because BDNF is created by healthy vascular endothelial cells.  Cardiovascular health allows for BDNF creation.  How?  Shear stress--which is caused by blood flow over the lining of our blood vessels--activates the endothelium, and allows for BDNF secretion.
An active, moving body with an active, pumping heart is essential to the brain.
link

When will the tipping point occur?  When will MS specialists refer to the vascular connection to Multiple Sclerosis and begin to look at the endothelium?  When will they prescribe cardiovascular fitness to their patients?   When will they change the dialogue, to include heart health?

Still waiting for them---but you don't have to.
Move as much as you are able.  Incorporate an exercise program, and increase your own BDNF levels today.

Joan

 

Dr. Michal Schwartz was right.

The last hundred years or so, all of neurological disease research has maintained that any immune cells which showed up in the brain were there for one of three reasons:  to protect the brain against infection, in an autoimmune reaction (as in MS) or during an inflammatory attack (as occurs after stroke or ischemia.)  But immune cells as part of a healthy, functioning brain?  Absolutely not!

MS researchers have continued this dogmatic narrative, based on the "successful" development of EAE and immune ablating and suppressing drugs.  They maintain that the brain is immune privileged, and the blood brain barrier is meant to keep immune cells out.  And they've been suppressing the heck out of MS patients' immune cells ever since.

Recent research from the University of Virginia and the Kipnis Lab has called all of this into question.  It now appears that a healthy immune system is connected to the brain,  Exactly as it is in all other organs, via lymphatic vessels which drain into veins.

But even before the U of V publication, there has been one researcher who has single-handedly challenged the dogma on the immune privileged brain.  She has asserted the need for immune cells in our central nervous system.   She has been ridiculed, mocked and ignored--because she has stated that immune cells are supposed to be in the brain to aid, repair and rebuild.  She has published on the premise that immune cells are neuroprotective.
link

Dr. Michal Schwartz of the Weizmann Institute of Science has questioned whether immune ablation and suppression  in multiple sclerosis drugs was the correct approach.  Her research showed that it was essential not to completely stop the immune cells entering the MS brain, but to retrain the cells:  immune modulation, rather than immune suppression.  She continued to publish that immune suppressing drugs had fallen short, that MS continued to progress.  She thought it was impossible that the brain would have given up its ability to be assisted by the immune system.  It simply did not make sense to her.  Why would our most important organ not need the immune cells?
link

Immune ablation and suppression never made sense to me.  Subsequently, I've been following her research ever since Jeff was diagnosed with MS in 2007.  And that's why Jeff has only ever been on Copaxone, which was developed at the Weizmann Institute.  Copaxone retrains the immune cells thought to be causing damage, and leaves the others intact.

Dr. Schwartz likes to quote Abraham Lincoln--
"If you are doing any revolution, do not try to convince your opponents,
if you are right, you don't need it.  If you are wrong, it will not help you."

Dr. Schwartz has been quietly conducting her revolution in Israel, publishing her research in medical journals, and speaking out on the absolute necessity of immune cells in the brain.  As she says, "A healthy mind depends on a healthy immune system."  These so-called lymphocyte "auto-immune cells", which MS drugs sought to inhibit, were the exact same ones her research showed were needed to repair the brain.  And she established her theory of "protective autoimmunity."  Her research continued to show that these cells were needed to create new stem cells.
link

Immune cell suppression and ablation will need to be reconsidered now.

She has been brave enough to keep on this trail.  And now, with the recent U of V research,  it appears she was right all along.
Here's Dr. Schwartz presenting her research in plain English.
Give her fifteen minutes of your time---listen to her revolution.
link


Be careful with serious immune ablating and suppressing drugs, especially while we're still learning about the function of immune cells in the CNS.  If this past week and the U of V research has taught us anything, it's that we simply don't know what we don't know...

be well, be hopeful,
be educated,

Joan

REAL breakthroughs in MS research

It's been a busy month for MS research.  I wanted to give a brief overview of the new publications coming out in vascular journals, linking CCSVI and MS to slowed cerebral blood flow, changes in cerebrospinal fluid flow and coagulation factors.

As much as neurologists and immunologists continue to claim this exploration is dead, finito, over---there are still dozens of publications in press or being published which elucidate the vascular connection of CCSVI to neurological disease.  This exploration is far from over, as more and more international investigators join in the exploration.


1.  The International Society for Neurovascular Disease (ISNVD)--a multi-disciplinary group of researchers, has published their position statement on recommendations for multimodal noninvasive and invasive screening for detection of extracranial venous abnormalities indicative of CCSVI.

The full text is available here:
http://www.jvir.org/article/S1051-0443(14)00746-5/fulltext

This position paper is extremely important, because it addresses the variablity of findings made by other researchers examining impaired venous flow in people with MS---and gives the first ever standardized imaging and evaluation recommendations.  It is written by some of the leading venous and imaging experts in the world.

The ISNVD recommends the use of a multimodal noninvasive and invasive imaging approach to optimally identify extracranial venous structural/morphologic and hemodynamic/functional abnormalities indicative of CCSVI. Creation of more quantitative imaging criteria are needed for further characterization of these venous abnormalities. Screening and monitoring of these venous abnormalities with the use of a combined noninvasive and invasive imaging approach should help establish the actual incidences and prevalence of extracranial venous abnormalities indicative of CCSVI in various populations. In addition, a multimodal imaging approach will address whether these abnormalities can cause significant hemodynamic consequences for intracranial venous drainage. The proposed noninvasive and invasive imaging protocols represent a first step toward establishing and validating the criteria for detection and monitoring of extracranial venous abnormalities indicative of CCSVI in open-label or double-blinded randomized controlled studies. The ISNVD recognizes that the rapidly evolving science and growing interest in this field will facilitate a refinement of these protocols in the near future.

2.  Another international collaborative effort looks at cerebrospinal fluid (CSF) dynamics in MS, using phase contrast MRI.  At the helm of this research is internationally recognized imaging expert, Dr. E. Mark Haacke.

This research separated pwMS into two groups, those with stenotic internal jugular veins (ST), and those without stenotic IJVs (NST) Changes in outflow was noted in those with stenotic veins.

The delay between the beginning of beginning of systole and the CSF outflow was higher in ST compared to NST MS. Less IJV flow was observed in ST vs NST MS. None of the measures was different between the different MS phenotypes. These results suggest that alterations of IJV morphology affect both IJV flow and CSF flow timing but not CSF flow amplitude
http://benthamscience.com/journal/abstracts.php?journalID=cnr&articleID=124278

3.  Tying into this impairment of CSF outflow dynamics, another recent publication found that the third ventricle in the brains of those with CCSVI was much larger than in healthy controls on MRI.   The third ventricle is one of four ventricles in the brain, and is filled with cerebrospinal fluid (CSF).  In normal brains it is a narrow cavity and CSF flows freely through in a timely manner.  In those with hydrocephalus or normal pressure hydrocephalus, this ventricle expands.  
http://ccsviinms.blogspot.com/2012/11/normal-pressure-hydrocephalus-once.html

This buildup of fluid can damage the brain.  And the third ventricle is enlarged in those with CCSVI, indicating a lack of timely venous flow is impacting CSF flow.

In the MS–CCSVI group, the third ventricle diameter was 6.2±1.7 mm (from a minimum of 2.5 mm to a maximum of 9.2 mm, with a median of 6.3 mm, and a mode of 6.0 mm). Our data showed that 29 patients (88%) had an increase in third ventricle diameter, whereas only four patients (12%) had physiological size (less than 4 mm) comparable to all healthy control group subjects (27.28%). These results show that the increase in the third ventricle diameter could represent a criterion of positivity of neurological disease in patients with CCSVI.
http://www.dovepress.com/increased-size-of-third-ventricle-in-patients-with-multiple-sclerosis--peer-reviewed-article-JVD

4.  Finally, a group of vascular researchers look at how successful endovascular treatment of CCSVI changes the blood.  The fact that MS is related to higher levels of fibrin, ET1 and other markers of hypercoagulation and endothelial dysfunction has already been firmly established.
http://ccsviinms.blogspot.com/2014/03/blood-matters.html 
http://ccsviinms.blogspot.com/2012/11/whats-blood-got-to-do-with-it-nov.html

This group wanted to see if these blood markers changed, once normal venous flow was established.  They were.  In fact, lower coagulation activation status was associated with a better clinical outcome.  Another connection to the blood and endothelium.

Coagulation activation and endothelial dysfunction parameters were shown to be reduced at 1 month and stable up to 12-month follow-up, and they were furthermore associated with a good clinical outcome. Endovascular procedures performed by a qualified staff are well tolerated; they can be associated with other currently adopted treatments. Correlations between inflammation, coagulation activation and neurodegenerative disorders are here supported by the observed variations in plasma levels of markers of coagulation activation and endothelial dysfunction.
http://journals.lww.com/bloodcoagulation/pages/articleviewer.aspx?mobile=0&year=2014&issue=10000&article=00012&type=Abstract&desktopMode=true

There is much movement in the study of how impaired venous return affects the brain for those with CCSVI/MS, and how treating this impairment improves clinical outcomes.  I live with anecdotal proof.  Jeff is now almost six years past his endovascular treatment and repair of malformed jugular veins and dural sinus.  He is jogging, traveling the world, working more than full-time, with a reversal of gray matter atrophy.  His third ventricle looks normal on MRI, he has had no further MS progression.  His coagulation numbers went from severe hypercoagulation, to normal.

There is a connection.  We will not let this research slip through the cracks.
stay tuned,
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

Understanding Endothelial Dysfunction--learning from Ebola crisis

The horrific outbreak of the Ebola virus in West Africa is causing researchers and physicians around the globe to ask what can be done to slow the death rates in this vulnerable population.

A recent piece in the New York Times, titled "Can Statins Help Treat Ebola?"  is authored by Dr. David S. Fedson, a retired professor of medicine at the University of Virginia.  Dr. Fedson writes about the current crisis of the Ebola epidemic and the short supply of life-saving drugs.  He suggests that there are other treatments, aside from experimental and expensive drugs, that have already been tested in humans, are readily available and can modify the body's response to the virus.

How would these drugs help?  They target endothelial dysfunction.

More than a decade ago, clinicians noted striking similarities between patients with Ebola and those with bacterial sepsis. Both diseases involve severe dysfunction of the endothelial cells that line blood vessels throughout the body. This dysfunction in turn precipitates major abnormalities in blood coagulation. Both can eventually lead to the failure of internal organs, primarily the liver and kidneys, and organ failure often leads to death. 

Researchers have since discovered that abnormalities of endothelial function and coagulation can be modified or reversed by treatment with drugs such as statins, angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs), which were developed to treat patients with cardiovascular diseases and diabetes. 
http://www.nytimes.com/2014/08/16/opinion/can-statins-help-treat-ebola.html?_r=1

Dr. Fedson suggests that strengthening the endothelium with cardiovascular drugs may be the key to stopping organ failure and saving lives in the Ebola outbreak.

These very same statins have been suggested as a treatment for secondary progressive multiple sclerosis, as they reduced brain atrophy (from 0.6% to 0.3% per year) in pwMS when compared to placebo.  MS doctors are more accepting of a pill, rather than life-style modification, when treating disease, as a pill can be placebo-controlled and trialled.  And they most certainly never explain why cardiovascular treatments might slow brain atrophy.  But as we have all learned, it's because of blood flow to the brain.
http://www.sciencedaily.com/releases/2014/03/140318190031.htm

In fact, all of the above mentioned cardiovascular drug treatments are now being tested in people with MS, to slow down neurodegeneration and brain atrophy; death of brain tissue due to endothelial dysfunction.  These drugs are not immune modulating---rather, they address blood flow, endothelial function and coagulation.  Here's more on the new medications being tested in MS.
http://ccsviinms.blogspot.com/2013/08/medications-for-ms-addressing-blood.html

What can those with a chronic and progressive disease like MS take away from this deadly Ebola outbreak?   There is a vascular connection to this terrible disease, as there is a vascular connection to MS.  A strong endothelium is the body's best defense.  Keeping the blood vessel lining healthy and impermeable is the surest way to maintain cerebral circulation for those with MS.   Endothelial health will slow brain atrophy and may even reverse it.

But you don't need a statin.  There is much that can be done with lifestyle, nutrition, and exercise.
http://ccsvi.org/index.php/helping-myself/endothelial-health

Here's to more healing ahead!
Joan

Inadequate cerebral blood flow and loss of neurons in MS

A new study was recently been published in the JAMA Neurology journal.  One of the investigators is Yulin Ge, MD--a recent presenter at the International Society for Neurovascular Disease conference.  www.isnvd.org  Dr. Ge has been imaging the MS brain for over a decade at NYU, and he has found many vascular connections to MS.

The study looks at cerebrovascular reactivity, or CVR.  CVR is how the brain reacts or responds  with blood flow when there is vasodilation.  This function is extremely important, as neurons need adequate blood flow to provide glucose and oxygenation.  Without this response of adequate cerebral bloodflow (CBF), the brain will not function properly, and neurons can potentially die.

http://archneur.jamanetwork.com/article.aspx?articleid=1893478

What this new study did to measure CVR was to look at how healthy controls and pwMS responded to a hypercapnia (too much carbon dioxide), which the researchers created by using 5% carbon dioxide gas.  This gas increases cerebral blood flow by creating vasodilation--or a widening of blood vessels.  A healthy endothelium (lining of the blood vessels) would normally respond to hypercapnia by widening vessels and allowing for more blood to flow to the brain.

Patients with MS had a significant decrease of cerebrovascular reactivity compared with controls. This decrease in CRV correlated to gray matter atrophy, but did not correlate with white matter lesions. 

Their conclusion was that there is an impairment in the cerebrovascular pathophysiology in pwMS, and that inadequate blood flow to neurons may indeed be the cause of neurodegeneration in MS.  And that this was a vascular problem, NOT a problem initiated by white matter lesions.

We know that impaired CVR is related to arterial stenosis and occlusion of the blood vessels in the neck.  http://www.hindawi.com/journals/rrp/2012/268483/

Note that this new study did not hypothesize why this is happening in people with MS. But this study could well be related to what the Columbia researchers saw when they damaged the vascular endothelial cells outside the brain.

The Columbia University study, which was published earlier this summer, found that when researchers damaged the vascular endothelial cells lining the blood vessels outside the brain using lasers to cause oxidative stress,  they could disrupt blood flow to the brain and affect neurovascular coupling.  http://ccsviinms.blogspot.com/2014/06/columbia-researchers-provide-new.html

Dr. Zamboni has noted that there is a derangement of the endothelial cell layer in the jugular veins and valves in people with CCSVI/MS.  This loss of endothelial cell integrity could well be causing the decrease in cerebrovascular reactivity seen in people with MS.
http://phl.sagepub.com/content/early/2014/06/27/0268355514541980.abstract

As an anecdotal side note, my husband's gray matter atrophy reversed after he was treated for dural and jugular venous stenosis and began following the Endothelial Health Program.
http://ccsvi.org/index.php/helping-myself/endothelial-health
And he has had no further MS progression since 2007.

The heart and brain are connected, and a healthy endothelium is essential to both.
Something to consider,
Joan

The Cure Mentality

Disease organizations have walks, bike rides and a variety of fund raisers to encourage donations to "Find the Cure!"   While these organizations have been spectacularly successful at raising money and in some instances, improving survivability of disease, they have not found cures.  And this fact brings us to the larger question---

Can we actually cure MS?

Cures exist.  But only for some, not all, of human disease.  We love to say, "There's no cure for the common cold!" and we all know there's no cure for dying.   We also know there isn't a cure for cardiovascular disease and stroke---there's only prevention, angioplasty and rehabilitation.  Still, we expect science to figure it out.  We think that researchers will create one pill, one solution, one therapy, one cure. 

I would like to propose that this focus on the cure for MS is keeping us from actual healing.  

How and when did our "cure mentality" begin?    I believe it was during the 1930s and 40s, when penicillin and the vaccine to prevent polio were introduced to the general public.   This was the era when all the big disease organizations were founded, to make sure these promising new scientific explorations continued. 

I researched this period for an essay on the founding neurologist of the MS Society,  Dr. Tracy Putnam.  He was the researcher who showed the vascular connection to MS in an experiment where he occluded the venous sinus of dogs, and created MS lesions and disability.   Yet his vascular theory of MS was tossed aside for "new" science and the autoimmune theory of MS, based on research by a co-creator of the polio vaccine, Dr. Thomas Rivers.  

Why did this happen?  Why didn't researchers follow up on Dr. Putnam's findings?   Because the vascular theory of MS did not produce an immediate "cure."  Patients and advocates expected nothing less. 

Dr. Putnam used newly developed blood thinners to treat MS, and the disease still progressed in some.  Patients and advocates grew weary and looked for new answers.  They turned to the young and successful pioneering scientist, Dr. Rivers.  He created the EAE mouse model of MS, which is still used 70 years later--even though, ironically, it has not produced a cure.  Instead, EAE has been used to create a 20 billion dollar a year industry for pharmaceutical treatments for MS.
link

What if Dr. Putnam was right?  What if MS is a cerebrovascular disease that can be treated, modified and possibly prevented?

Sadly, CCSVI treatment was touted as a potential cure by the press and many patients,  even though Dr. Zamboni and all the pioneers had never claimed this.  We knew it was a treatment and only part of a whole new vascularly healthy lifestyle.  Jeff and I were so discouraged when the New York Times chose to portray us as cure-seekers, and completely misrepresented the research.  
link

Today, we have a similar furor growing over stem cell treatment.  Although stem cell treatments that require immune ablation and chemotherapy have proven harmful, and have not stopped disease progression or brain atrophy in progressive patients.
link


Why do we still look to immunologists and MS specialists for the cure?

We now know that MS is not a genetic disease.  There is not one gene that causes MS. Scientists have located the MHC gene and other loci that raise the potential to develop MS-- but only 4% of people with MS have MHC, with over 200 risk loci identified.  Not exactly a smoking gun. link

And we know MS is not purely autoimmune, like the EAE model used in mice, or we would have a cure by now.  Because copaxone and other drugs have been touted as reversing EAE in mice, but not humans.  link

We do know that MS is affected by environmental factors.  
Proven, scientific links to MS susceptability and progression have been found in low vitamin D levels, low sun/UV exposure, eating processed foods and transfats, cigarette smoking, obesity, stress, lack of exercise and movement, lack of sleep,  and hypoperfusion or slowed blood flow in the brain.

As these Australian researchers have published---prevention may be the best path to healing and disease prevention for MS.
In the face of imperfect and non-curative treatments, understanding the role and mechanisms of action of environmental exposures is highly important as these are potentially preventable.  link

There are things to be done to improve our health.
Could we consider our goal to be prevention, disease cessation and healing, instead of a cure?

What if we took all that energy, money and time we voluntarily give to the disease groups that have continually promised us a cure and reinvested it back into our own lives and our community?

How about using that money to start buying more organic fruits and veggies--and skipping the MS Society hamburger and milkshake fundraiser?   (yes, sadly, this is a real fundraiser.)  link

What if we use our few good hours of daily energy to get physical therapy, take a walk, go to the gym and keep moving our whole bodies?  link

Toss out the cigarettes, and chew on carrot sticks?
link

What if we went outside for 15 minutes, and soaked up some of those nitric oxide releasing UV rays and raised our vitamin D levels naturally?
link

How about meditation instead of frustration?   Deep breathing and deep sleep?
link

Could we heal?  Could we change our disease course?  Science gives us a resounding "yes!!"   As do many medical researchers including Dr. Terry Wahls, Dr. Ashton Embry, Dr. George Jelinek and the late Dr. Roy Swank.

Jeff would tell you these lifestyle changes work.  And his MRI proves he is healing.  His gray matter now looks normal on MRI.  He is not cured--he still has some damage from his first bad flare and neuropathic pain, he still has damage due to "MS".  But it is not getting worse.  His MS is not progressing.  His brain and spine are healing, using venoplasty for CCSVI and the Endothelial Health Program.  link

When we simply sit and wait for a cure and don't change the things we know we can change, we abdicate our power.  We give away our own innate ability for healing.

Wishing everyone who reads this blog hope and true healing,
Please stay in touch with me, and let me know what is helping you to heal.
It's not about blame for the past, it's about real hope for the future.  
We're all in this together--and I remain a cheerleader,

Joan

Report from the AAN conference---What Do They Know?

Please read the transcript and/or watch this Medscape video from the recent American Academy of Neurology's 66th Annual Meeting in Philadelphia.  It is sobering.

http://www.medscape.com/viewarticle/825066#1
(You can join for free to view the videos and read articles.)

All of the panelists are MS specialists.  These are the experts. 

In it, we learn that:

1. MS disease progression and disability appear to be tied to brain atrophy, not new lesions or relapses.
A drug for MS, called laquinimod, appeared to help slow disease progression and atrophy in MS, although it had no effect on relapses and lesions.  In fact, laquinimod failed to slow relapses or lesions any better than placebo in the initial trial of RRMS.   No one really knows how laquinimod works.  That's right, the Mechanism of Action (MOA) is unknown.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3825117/

It could be that laquinimod is increasing brain derived neurotrophic factor (BDNF) and preserving neurons.   Increasing BDNF is known to help the brain by preserving brain tissue.
You can increase BDNF levels yourself, without laquinimod--by exercising.
http://www.ncbi.nlm.nih.gov/pubmed/21198979

Bottom line--the MS specialists really aren't sure what is going on, or why laquinimod worked....but they'll be happy to try it out on people with progressive MS.  And as their disclosure statements show us, all of them have received honoraria, speakers fees, consultant fees and funding from Teva Neuroscience, the company developing laquinimod.


2. Genetics really do not play into the risk of developing MS.  The new genes associated with MS only add about 1% more to risk of susceptability.  Genetics studies have, for the most part, been a dead-end.

3. In fact, environmental factors, like sunlight exposure, vitamin D and Epstein Barr exposure, appear to be more important.  

4. Smoking is not good for people with MS.  It hastens disease progression.  There are lifestyle changes that people can make, which will slow disease progression.  And smoking appears to be the most "modifiable" risk.  Why is smoking bad for people with MS?  They don't know.  It could be how the "mucosa of the lungs interacts with the immune system during smoking."  

Or it could be, hmmm...just maybe... how smoking, a known risk factor for stroke and cerebrovascular disease, impairs blood flow and oxygenation of the central nervous system?
http://www.nature.com/jcbfm/journal/v16/n4/full/9590091a.html
http://jap.physiology.org/content/35/6/820


Watch this video and see behind the curtain of the great and powerful Oz.  View the emperor in all of his regal clothing.  These guys are basically saying, we don't know what MS really is or what to do about it.  If I have learned anything about MS in the seven years since Jeff's diagnosis, I have learned that the EAE model of MS is wrong, and the current treatment of MS is not helping patients live longer, more vital, less disabled lives.
Here is more on the futility of EAE in MS research.

"... a false orthodoxy claiming that multiple sclerosis is an autoimmune disorder has developed and formed the present basis of treatment, drug trials and research. The outcome of this misplaced creed has been truly catastrophic.” 

http://www.expert-reviews.com/doi/pdf/10.1586/ern.10.69

However, I have witnessed how pioneers who actually have MS---people such as Dr. Terry Wahls, Dr. George Jelinek and all of you---have taken measures into your own hands.  You have found the direct correlation of your disease to slowed cerebral blood flow from venous malformations.  You have had venoplasty and changed your lifestyles.  You are getting more sunshine, UV rays and vitamin D.  You have quit smoking, started moving more.  You have gotten off sugar and gluten,  are eating more whole foods and are dealing with life's stresses.   You are healing your gut with whole foods and probiotics.  You are lessening your exposure to toxins.  You are healing your endothelium! You have explored other avenues and differential diagnoses.

And you are living, wonderful, anecdotal proof of the ability to slow, stop and reverse MS disease progression!  Proof of the fact that there are things we can do to reduce inflammation and maintain gray matter.  Lifestyle changes, like smoking cessation, exercise and nutrition-can really make a difference.

Don't wait another minute, let alone a decade, for these guys to figure it out.  Take care of yourself, today!

Joan

New research on UV rays and MS symptom reduction

Most of you know about my suggestion that people with MS seek UV ray therapy, by spending ten to fifteen minutes in sunshine daily, or using UVB phototherapy in less sunny locales.  Not just to maintain healthy Vitamin D levels, but to boost levels of Nitric Oxide (NO).

I first wrote about this in the Endothelial Health Program in 2008.  We make sure Jeff gets his daily rays (as well as daily exercise and phytonutrients.)  Here's the program again, for new readers.
http://ccsvi.org/index.php/helping-myself/endothelial-health

In the following note, I wrote about the ground-breaking, Noble prize winning research of Dr. Furchgott--he discovered the importance of Nitric Oxide and the process of "photorelaxation" or the vasodilation that occurs thanks to UVB rays.

Dr. Furchgott discovered the process of photorelaxation over 40 years ago.  What he noted in the lab was that exposure to UV rays changed the endothelium, encouraging nitric oxide production and vasodilation of arteries.  

http://ccsviinms.blogspot.com/2013/06/photorelaxation-uv-rays-and-ccsvi-june.html

It would be decades later Dr. Richard Weller discovered exactly how UVB rays released nitrates via our skin--and explained how this could explain the connection of latitude and heart disease.

Dr. Richard Weller of Edinburgh University reports on research finding that when skin is exposed to UV rays for 20 minutes, vasodilating nitric oxide is released.  This effect is independent of vitamin D levels--and may explain why even if D levels are raised by supplementation, the full benefit is not received.  

http://www.medicalnewstoday.com/articles/260247.php

So, I was understandably interested to see a group of neurologists looking at the effect of UVB rays on people with MS.  

http://www.ncbi.nlm.nih.gov/pubmed/24771567

The neurologists first look at the murine model of MS, called EAE.  But, as Dr. Weller explains in his wonderful TED talk---mouse models do not work when we're discussing UVB rays and their affect on humans....because mice do not process UV the same way we do.  They do not have the same skin.  After learning this, Dr. Weller did all of his research on his student lab assistants, and as he quips, "They are cheap, and no one pickets you saying, save the lab assistants!"

Here's Dr. Weller on his discovery of what UVB rays do in humans.  If you haven't watched this TED talk yet--please do!  You'll thank me later.  (For a scientist, he's really entertaining!) 

http://www.ted.com/talks/richard_weller_could_the_sun_be_good_for_your_heart

Alright, back to the new paper from the Department of Neurology in Munster, Germany, which is titled:
UVB light attenuates the systemic immune response in CNS autoimmunity.

http://www.ncbi.nlm.nih.gov/pubmed/24771567

Here's what they saw in humans....an anti-inflammatory response in MS due to UV ray exposure.

Additionally, patients with relapsing-remitting MS were treated with narrowband UVB phototherapy. Immunomodulatory effects were examined in skin biopsies, serum samples and in immune cells of the peripheral blood. 

Results: Regulatory T cells (Tregs), which are induced locally in the skin-draining lymph nodes in response to UVB exposure, connect the cutaneous immune response to CNS immunity by migration to the sites of inflammation (blood, spleen, CNS). Here, they attenuate the inflammatory response and ameliorate disease symptoms. Treg-inducing tolerogenic Dendritic Cells (DCs) were further necessary for induction of this systemic immune regulation by UVB radiation since ablation of Langerhans cells abolished the UVB-induced phenotype. MS patients treated with UVB phototherapy showed an increase in induced Tregs and tolerogenic DCs accompanied by the downregulation of the T-cell effector cytokine interleukin (IL) -21. The treatment further induced elevated serum levels of vitamin D. Interpretation: Local UVB radiation of the skin influences systemic immune reactions and attenuates systemic autoimmunity via the induction of skin-derived tolerogenic DCs and Tregs.

Now, in English :)  When people with MS were exposed to UVB rays, their lymph nodes responded by sending out regulatory t cells to areas of inflammation.  These Treg cells are"good guys."  They calm inflammation.  And Tregs are enhanced by UVB rays via skin cells.  People who got UVB rays had a reduction of MS symptoms.  No prescription necessary.

That's right---neurologists are telling us that UVB rays helped pwMS! 

In fact, we already know this happens.  It's why UV ray phototherapy is used for patients with psoriasis.  UV light increases Treg cells, which in turn reduce inflammatory cells.
http://www.medscape.com/viewarticle/814678_5

How, exactly, does this happen?  Although it's not mentioned here, other researchers have explained it ...Wait for it.....it's Nitric Oxide!

http://www.sciencedirect.com/science/article/pii/S1089860312000870

http://www.jimmunol.org/content/early/2013/05/28/jimmunol.1202580.abstract
http://www.ncbi.nlm.nih.gov/pubmed/23720815

Nitric Oxide (NO), the marker of endothelial health, is also responsible for helping those treg cells leave the lymph nodes and head to sites of inflammation, calming MS inflammation and symptoms.  The same Nitric Oxide that Dr. Weller has shown to be released from human skin cells by UVB rays.  It's all connected.

The endothelium is the interface between our vascular and immune systems.  The lining of our blood vessels connects every inch of our body.  Nitric Oxide is essential for our health.  And we can boost NO with nutrition, lifestyle, exercise, meditation, and sunshine.

http://www.ccsvi.org/index.php/helping-myself/endothelial-health

I continue to hope that neurologists will reach out across the aisle, and work with endothelial specialists, to understand the intricate interplay between our vascular and immune systems. To move beyond the credo of EAE and autoimmunity, which may exist in mice, but not in men.  To understand the connection of the heart and the brain, via the vasculature.  The ISNVD is looking at this connection, and they want neurologists to join them.

It's all there.

Sunny days ahead,

Joan

A Single Step

There is a paradigm shift which is happening in our understanding of human health and disease.  More and more, researchers are looking at how our everyday movement is impacting our health.

There is a difference between supervised exercise training, physical therapy, and "lifestyle activity".  For years, people with MS have been encouraged to seek physical therapy.  But they have not been encouraged to simply move more.  For those with MS who are still able to take steps and walk, I'd like to offer some information, encouragement and cheerleading.

The MS activity paradigm is changing.  Here is a recent abstract on this topic:

Lifestyle physical activity in persons with multiple sclerosis: the new kid on the MS block.

Supervised exercise training has substantial benefits for persons with multiple sclerosis (MS), yet 80% of those with MS do not meet recommended levels of moderate-to-vigorous physical activity (MVPA). This same problem persisted for decades in the general population of adults and prompted a paradigm shift away from "exercise training for fitness" toward "physical activity for health." The paradigm shift reflects a public health approach of promoting lifestyle physical activity through behavioral interventions that teach people the skills, techniques, and strategies based on established theories for modifying and self-regulating health behaviors. This paper describes: (a) the definitions of and difference between structured exercise training and lifestyle physical activity; (b) the importance and potential impact of the paradigm shift; (c) consequences of lifestyle physical activity in MS; and (d) behavioral interventions for changing lifestyle physical activity in MS. The paper introduces the "new kid on the MS block" with the hope that lifestyle physical activity might become an accepted partner alongside exercise training for inclusion in comprehensive MS care.

http://www.ncbi.nlm.nih.gov/pubmed/24603882

What is the difference between exercise training and "physical activity for health"? 

Many of us may exercise and train at the gym or at home.  We lift weights, swim, do yoga, stretching----but then, for the rest of the day, we are seated.  Doctors and researchers are noting that people simply do not walk anymore.  And this is a problem.

There is a new movement many of you may have been reading about.  For those who are still able to walk, it may be in your best interest to see if this program is something you can incorporate in your life.

It's called the 10,000 Steps A Day Program.  Walking 10,000 steps is the goal doctors and the surgeon general would like us to have. 

 If you're just getting started, 10,000 steps a day probably seems enormous. Don't worry––it won't take long to reach it! According to research into activity levels, anything under 5,000 steps a day is considered to be a sedentary lifestyle, and it isn't until you reach 10,000 steps a day that you're considered to be "active".^[1][6] It is recommended that you begin walking as much as feels comfortable to you, then aim to walk in increments of 1,000 to 2,000 steps more each week until you're comfortably at 10,000 steps a day.^[7] There is nothing stopping you walking more than this each day, but the aim is to always make 10,000 steps.

http://www.wikihow.com/Walk-10,000-Steps-a-Day

For me, 10,000 step equals about four miles of walking.  How do I know this?  I've been using a pedometer for a couple of months now. Mine is a free app called Pedometer++ on my iphone.  But you can use any type of pedometer that works for you.  I was surprised at how few steps I had been taking!  Getting to 10,000 a day has taken a real, concerted effort for both me and Jeff.  Jeff is active, but he spends most of his day at his desk, writing music.  And I spend most of my time writing or singing.  We really have to go on longer walks every day to reach the 10,000 step goal.  We're parking the car further from the store, taking stairs, simply moving more during the day.  And we're finally reaching the goal.  Our son is home for spring break, and he has the same pedometer.  He walks about 12,000 steps a day, getting around his campus....but since he's been home with his folks, he's been sitting around more.  We all went on a long walk last night, and made our goals.

The truth is, most people, even healthy people, are simply not taking enough steps.  We've become a sitting society.

Sitting has been getting a lot of attention lately, to the point that there’s a new adage: “Sitting is the new smoking.” In addition to encouraging everyone to sit less, people are specifically encouraging exercises during TV watching and during work hours, with walking meetings and standing desks, as ways to decrease sedentary time.

“The real problem is that we are raising sedentary children,” said one of the researchers, Pamela Semanik, assistant professor of adult and gerontological nursing at Rush College of Nursing. “It’s so insidious in our culture.”

At her workplace, where people see the results of not moving, people have changed their ways, she said, adding that she has sold her car and reads medical journal articles on a treadmill.

The researchers in the current study said as many as 5.3 million annual deaths worldwide are related to insufficient activity.

http://www.latimes.com/science/sciencenow/la-sci-sn-sedentary-disability-20140219,0,7209026.story#ixzz2vshgBlk7

So, what to do?

I'd like to paraphrase a familiar quote.  The Journey of 10,000 steps begins with a single step.

Be encouraged!  Move more, to whatever extent you are able.  Get a pedometer, and follow your results.  And let me and our MS community know how you're doing!

We're all in this together,

Joan

Multiple Sclerosis: Hypoperfusion/Reperfusion Theory

June 25, 2012 at 1:47pm

I wanted to put together the research I've compiled considering multiple sclerosis as a disease of primary neurodegeneration due to hypoperfusion, with secondary reperfusion injuries.  I felt it was important to document and organize the scientific research. I also want your input and thoughts.

The reason why MS relapses and remits during the onset of the disease has been difficult to understand, and impossible to replicate in animal models of MS.  EAE, the current animal model for MS, is not like MS.  EAE is more akin to ADEM, in that it does not relapse and remit.  EAE is an ongoing immune reaction.  https://www.msard-journal.com/article/S2211-0348(14)00063-7/fulltext

I believe stroke and cardiovascular researchers may be better able to create models of MS using perfusion--or blood flow.  Stroke specialists, like Dr. Peter Stys, have been questioning the autoimmune theory of MS, and suggesting that the immune reaction may be secondary.    link

Most of us have heard the word hypoperfusion in relation to multiple sclerosis.  The slowed perfusion or less than normal blood flow we see in the MS brain has been documented.  Researchers have shown how people with MS have less cerebral blood flow than normal people, which creates an ongoing low level ischemic environment.  

http://www.ajnr.org/content/early/2018/01/11/ajnr.A5504

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3619305/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3649777/

And researchers are finally now discussing how the hypoperfused MS brain is responding to lowered blood flow.

The relatively new concept of neurovascular unit (NVU) helps to clarify the hemodynamic changes due to the intricate interplay between cerebral blood flow (CBF) and vasoactive factors. Several studies have demonstrated the importance of endothelial factors, their neurovascular interaction, and that vascular changes are also highly conducive to neurodegenerative changes and clinical impairment.^10–13 Cerebral hypoperfusion and vascular factors are strictly involved in neurovascular dysfunction, vascular oxidative stress, and relative tissue hypoxia, well in advance of any demyelinating lesions. Changes in capillary resistance and neurovascular function may, in fact, represent important common denominators for conditions that increase the risk of developing both demyelinating lesions and progressive MS forms. https://journals.sagepub.com/doi/full/10.1177/1177271918774800

Stroke researchers understand the process of ongoing cerebral ischemic stress causing white matter damage. 

Compared with gray matter, white matter of the brain is more sensitive and susceptible to ischemic stress because of its relatively limited blood supply.73 In addition, DM can induce white matter damage, as well as aggravate white matter injury after stroke.73 DM stroke patients are prone to developing earlier and exacerbated white matter hyperintensities compared with non-DM patients.74 Vascular dysfunction including BBB disruption that leads to leakage of serum components into the white matter can also induce white matter damage.75The white matter in the brain is also highly sensitive to inflammatory responses, which can injure the white matter directly as well as indirectly by damaging the BBB and/or creating an inhospitable environment for axonal/myelin regeneration.76 https://www.ahajournals.org/doi/pdf/10.1161/JAHA.117.005819

It was a published theory of Dr. Bernhard Juurlink which first prompted my exploration into hypoperfusion and MS.  I read his 1998 hypothesis paper in 2007, after Jeff returned from a trip to high altitude with dozens of lesions and an MS diagnosis.

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


After ischmic events, the brain is reperfused.  Reperfusion simply means to redeliver blood. Reperfusion is a good thing and a bad thing.  Reperfusion can be a natural occurrence; it returns blood to tissue after there is an event which slows blood flow, like a stroke or ischemia.  Reperfusion brings essential O2 and glucose to cells after such an event, but it also brings inflammation and the immune system with it.  Blood returns to the area of tissue where it had been absent, at a cost.

http://www.ajnr.org/content/25/8/1342

Dr. Michael Dake mentioned in a presentation at International Society for Neurovascular Disease (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/127/1/111.full.pdf

I believe reperfusion injury explains the relapsing remitting course of early MS and ties together research into collateral circulation and hypoperfusion in the MS brain. There will be an explanation as to how this theory functions in progressive MS at the end of this note. 

We are learning more and more that gray matter loss, or brain atrophy,  is a reliable method for monitoring the neurodegenerative process in MS.  Gray matter loss and death of neurons begins from the inception of the disease and continues with increasing disability.  It is linked, only modestly, with white matter lesions. This is why the current medications which suppress the immune system do not stop MS, and are not effective in progressive MS.

http://www.neurology.org/content/68/24/2161
https://www.ncbi.nlm.nih.gov/pubmed/29741648
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209326
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4706325/

We already know that pwMS have lower levels of glucose and O2 being delivered to their brain and spinal tissue, due to hypoperfusion, which can cause neurodegeneration and mitochondrial dysfunction.

http://www.ncbi.nlm.nih.gov/pubmed/19388109

http://msj.sagepub.com/content/early/2012/02/21/1352458512438455.abstract

Right now, the debate as to whether this hypoperfusion is primary, or hypoperfusion is simply a result of an unknown disease process we call "MS".    On that note, here is research stating the hypoperfusion seen in the MS brains looks like primary ischemia, or low oxygen.

http://www.ncbi.nlm.nih.gov/pubmed/17416836

Lower levels of O2 and glucose delivery can be correlated to hypoperfusion caused by venous insufficiency.

http://www.biomedcentral.com/1471-2377/11/128/

http://www.ncbi.nlm.nih.gov/pubmed/21958625

I think that on top of this ongoing process of neurodegeneration,  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--this is 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.

Reperfusion injury is NOT the complete disease.  It is a reaction to an event.  MS relapses are not MS. Relapses are a reaction to an event.  The MS neurodegenerative process continues underneath.  Let's look at how an MS relapse is like reperfusion injury.

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

Reperfusion Injury and Multiple Sclerosis relapses share:

1.  Demyelination -- Loss of myelin occurs after nerves have blocked blood flow, low O2 and glucose, and then a return of blood flow.  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

Ischemia-Reperfusion Injury in Stroke

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031777/

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/content/70/2/181.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/10.1002/hep.1840190319/abstract

6. NEW RESEARCH 2019 which considers newly discovered CNS lymphatic vessels.  Impaired cerebrospinal fluid (CSF) drainage in the central nervous system, due to malfunction of neurovascular unit (NVU) after ischemia, may lead to neuronal cell death and reperfusion injury.

In the adverse event of ischemia, pericytes around capillaries constrict, eventually leading to pericyte death in rigor and could cause neutrophil trapping in the arterioles. These findings suggest reconsideration of neutrophil involvement in ischemia and reperfusion. Rather than acting neurotoxic, neutrophil accumulation in arterioles may have an impact on the vascular function including CSF drainage recently shown to occur along these pathways.15,116 In fact, cerebral ischemia results in impaired fluid clearance along the perivascular spaces in the affected cortex117 underscoring a neutrophil-induced malfunction of the NVU in I/R.

Functional impairment of lymphatic drainage from the CNS after ischemic stroke may lead to rapid neuronal cell death due to the accumulation of toxic metabolites in the brain parenchyma.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6111395/

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

Reperfusion has been studied extensively on the arterial side.  However, the all important lymphatic drainage mentioned in the paper linked above, occurs on the venous side.   Like most medical research, the study of the veins and venous return is lacking, and stroke researchers admit this is a problem in understanding the full impact of reperfusion injury. 

Although most experimental studies target arterial aspects of recirculation in stroke, a few have focused on the venous side.49 In contrast to studies of cerebral artery occlusion, which are methodologically more consistent among different laboratories, studies of venous thrombosis models are at an early stage of development and lack standardization, which greatly complicates comparison of results from different laboratories. Furthermore, most published studies have focused either on arterial or venous components, and very few have examined both arterial and venous components in studies of recirculation. Therefore, a goal of the present commentary is to emphasize that both arterial and venous components should be considered in studies of acute ischemic and hemorrhagic stroke.

Overall, the “recirculation” concept strongly suggests that stroke treatment paradigms need to address venous outflow from the brain in relation to arterial inflow. Therefore, to minimize potential brain swelling and reperfusion injury for severe stroke patients, we need to consider carefully venous pressure and outflow, potential arterial smooth muscle and venous endothelial phenotype changes, possible pre-existing venous sinus hypoplasia, and in particular, if nimodipine will be used.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718333/

I did find one animal study which looked at venous hypertension as a complicating factor in reperfusion injury

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

(note the upstream microhemorrhages caused by venous hypertension in this study.  These tiny, pinpoint spots of blood escaping into tissue might be linked to the iron deposition and hemosiderin we find in the MS brain.)

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

This theory continues--when MS becomes progressive and relapses no longer occur,  it is because the body has been conditioned--- trained from years of hypoxia and low levels of O2 and the recurrent reperfusion. Eventually, as the body ages, this reperfusion response no longer happens.  It burns out.  There is no more white matter damage---but the low levels of O2 and glucose are still causing mitochondrial dysfunction, neuronal and axonal death.  

Hypoperfusion becomes worse, as the body ages and becomes more inactive.  MS continues to progress, even without the reperfusion injury seen during the RRMS days.  Gray matter continues to atrophy- even if there is no demyelination, inflammation or damage to white matter. 

The underlying disease process---low levels of O2 and glucose to CNS tissue, causing neurodegeneration--has remained the same.  MS progresses.  Gray matter atrophies.   But the period of reperfusion injury eventually stops happening, due to conditioning.  There are no more relapses.  The disease moves into the progressive phase.

In the past, MS has largely been considered a chronic inflammatory and demyelinating disease, driving most of the research and treatment development towards targeting the immune system. As of now, disease modifying therapies for MS are limited to various anti-inflammatory agents that reduce acute inflammatory lesions, clinical relapses and disability progression in RRMS. These anti-inflammatory agents, however, do not completely prevent axonal injury and are largely ineffective in treating progressive MS.

The recent resurgence of MS research focused on axonal degeneration mechanisms has resulted in convincing experimental evidence and potential treatment targets. As reviewed above, mitochondrial function is crucial in preserving axonal integrity in both acute inflammatory and progressive stages of MS. Therefore, therapies that protect mitochondria and enhance their functioning warrant investigation.

http://www.biomedcentral.com/1741-7015/9/22/

The current drugs are treating the body's natural response of reperfusion, and the resultant immune activation.  But they do not address the diffuse cerebral hypoxia and lowered glucose transport which remain.  And that's why MS continues to progress.  

Dr. Zamboni sought to treat this hypoperfusion caused by venous malformations and collateral circulation.  He used venoplasty to increase perfusion and blood flow by allowing the body to use the jugular veins, rather than less efficient collaterals.  It's worked for many people, but not all---we obviously need more research.  

This hypoperfusion/reperfusion theory also explains why HBOT treatment, nutrition, antioxidants,  smoking cessation, exercise, stress reduction and vascular approaches help those with MS to receive stability and remission.  These measures provide balance to the body, enable more energy and O2 to be delivered to the central nervous system and help the body avoid these ischemic events which call in the reperfusion response.  These treatments directly address cardiovascular health and the heart-brain connection.

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

A brief recap:

Venous insufficiency, arterial issues, or cardiovascular problems cause primary hypoperfusion of the MS brain. This leads to lowered glucose and O2 delivery to the CNS.  During the RRMS stage of the disease, the body responds to events which lower levels of O2 with reperfusion. This creates venous hypertension and reperfusion injury. The immune system is activated. Lesions form. MS progresses.  As the body slows down with increasing disability and age, hypoperfusion worsens, axons and neurons continue to die.  Gray matter atrophies.  It's a vicious cycle.

How to stop the cycle?  Addressing venous insufficiency or cardiovascular issues. Oxygen therapy.  A whole food diet full of nutrients and plant-derived antioxidents.  Regular exercise to improve cardivascular health.  Lifestyle modifications including stress reduction, meditation, smoking cessation.  Potential immuno therapy to avoid reperfusion injury during RRMS stage.

But, as you all know by now---I'm not a doctor.  I just hate MS.  And I want more answers.

Please, let me know your thoughts, and please share with medical people and researchers you may know,  what part of this theory is lacking?  Does this make any sense?  How should research move forward?

Joan