Exciting New MS Treatment!

NEWS RELEASE

A new MS drug appears to alter fluid dynamics and repair the blood brain barrier!
In fact, 63% of the patients treated with Perfuza (toxicmuzab) had no new or enhancing MS lesions at 12 months! In light of recent discoveries of the brain's lymphatic vessels and the connection to venous flow, we are thrilled to be able to offer MS patients a drug treatment which may be addressing CNS fluid dynamics.

Here's more on the impressive results of Perfuza from a recent publication in JAMA---

We found a reduction in the mean number of new brain lesions (corresponding to more lesion- free patients) in the toxicumab group compared with the placebo group at 6 to 12 months. The delayed and positive effect on the magnetic resonance biomarker suggests that toxicumab could affect the dynamic of the blood-brain barrier.

Gadolinium enhancement is a marker of damage to the blood-brain barrier, whose time course depends on lymphatic drainage18 and hence on venous drainage from the skull.19 Previous studies have reported that venous pressure is lowered3 and cerebrospinal fluid dynamics is improved20 after taking toxicmuzab, thereby favoring the drainage of cerebro spinal fluid into the dural veins, which depends on a pressure gradient between the subarachnoid spaces and dural veins.21,22

Another study23 reported that white matter lesion load was inversely correlated with reduced cerebrospinal fluid dynamics, as measured by MRI. In addition, flow improvement through the internal jugular veins owing to toxicmuzab has been reported to improve brain perfusion in patients with RRMS.21 It has also been reported that the development of a new MS plaque was preceded by sustained MRI-detected hypoperfusion before the plaque was identified on MRI.24,25

link

Incredible, right???  Finally.  A drug which can potentially affect the blood brain barrier!
Perfuza (toxicmuzab) may be the greatest money-making MS drug in history.
Projections are now at 2-3 billion for 2018 alone.


Only kidding.

The paper I'm quoting from, verbatim, is the recent JAMA review of angioplasty for CCSVI from the Brave Dreams clinical trial. 

Just replace my made up block buster drug Perfuza (toxicmuzab) with angioplasty to restore venous flow.   And then, write a conclusion and snarky editorial that says that we should not pursue this treatment any further, and that CCSVI research is over.

Even though the conclusion of the paper says that over half of patients saw benefit in cerebral blood flow from CCSVI treatment.

The editorial which goes along with this publication is actually incorrect.  The author of the editorial, Dr. Ari Green***, claims that there was absolutely no benefit in those treated for CCSVI, that there was no reduction in new lesions.  Here, read the editorial for yourselves, and read the paper again, and tell me---isn't this incorrect?
https://jamanetwork.com/journals/jamaneurology/fullarticle/2664000

***Dr. Green has received personal compensation for activities with Inception Sciences, Mylan Pharma, Medimmune, and Bionure. Dr. Green has received personal compensation for serving on the board of Inception Sciences. Dr. Green holds stock and/or stock options in Inception Sciences. Dr. Green has received research support from Inception Sciences, Biogen, and Novartis.  link
Dr. Green's Inception Sciences Company owns the patent for an antihistamine-like molecule thought to remyelinate neurons. I wrote about the absurd hype regarding a 1.3% improvement in visual acuity here:  link

To recap---this published paper from the neurologists of the Brave Dreams trial just proved, conclusively-
1. CCSVI is a real condition in people with MS.
2. There are a variety of venous malformations.  There were patients with closed jugular valves, refluxing blood flow, and hypoperfusion.
3. Venoplasty was able to restore normal flow in 54% of the patients.  Not all malformations can be treated with PTA alone.
4.  63% of treated patients had no new MS lesions on MRI at 12 months.
Doesn't this count for something?  At least additional study?

What is real news? What is fake news?
Is this simply spin or is it something darker?

If a room full of neurologists look at the results from CCSVI venoplasty and conclude 
"The delayed effect of venous PTA 6 months after the procedure on the magnetic resonance biomarker suggests a possibility that PTA may produce benefit for a subgroup of patients with MS. This should be further analyzed and investigated." 

yet still write a conclusion and editorial suggesting CCSVI research be stopped--- what is reality?

Please, tell me.  Honestly, I'm flummoxed.

More ahead.
Joan

Setting the record straight

I want to simply state some facts for my readers.  Because if I don't, journalists and bloggers will continue to create a narrative of the kooky singing wife, who found some crazy researcher online and led the world on a goose chase.  And that's not true.  And it's really hurtful.

Some factual, documented history:

1.  I believed there was a vascular connection to my husband's MS diagnosis from day one.  That would be March 23, 2007, the day we got his serum results from the doctor and I saw so many numbers that were way out of normal range.   Coincidently, my birthday.

2.  Using Jeff's serum results as a point of reference, I went to the library and took out every single book they had on MS, including McAlpine's history of Multiple Sclerosis--which had a section on the long history of the vascular connection.  This is where I first read about Dr. Tracy Putnam.  link The pile of textbooks also included Dr. Swank's research.  Dr. Swank wrote about the connection of MS to the blood.  He published over 100 research papers on MS.  He wrote about capillary fragility, petechiae and hypercoagulation in his MS patients--all of this research rang a lot of bells for me.  link

3.  I was on a forum called "This is MS" in September 2007.  I wrote about Jeff's serum results, hypercoagulation, and postulated on a bunch of research with other people with MS and caretakers.  It was a great community, and we shared papers, programs and MS research.

4.  Using pubmed and my local library, I eventually came to the intersection between the vascular and immune system I had been searching for---the endothelium.  Using published and peer-reviewed science, I created The Endothelial Health Program for Jeff and shared it on This is MS in the summer of 2008.   I saw a connection between many of his vascular issues (petechiae, high Crp levels, hypercoagulation, high liver enzymes), endothelial dysfunction, and his MS diagnosis.  We found that by changing his diet to a Swank program, increasing his Vitamin D levels, including cardiovascular exercise, thinning his blood with proleolytic enzymes, getting him out in sunshine, reducing work stress, improving his sleep---he was doing much better, he did not have a relapse and his serum results normalized. http://ccsvi.org/index.php/helping-myself/endothelial-health

5.  I wrote to endothelial researchers at USC and Stanford, asking if they had any knowledge of studies or published research on the function of the endothelium in MS.  Both of them e-mailed me back.   I began a correspondence with the researcher at Stanford, because he was the most interested in this connection.  Here is part of his reply.  I have all of the e-mails, if anyone aside from me ever truly wants to get this story correct.

"I enjoyed reading your treatise. 
I quite like the hypothesis that MS is secondary to a derangement of the endothelium of the cerebrovasculature, that results in inflammation and local damage. 
I am also in agreement with your contention that a functioning endothelium is a major key to health. 
Furthermore, I agree that diet and exercise are critical for endothelial health." 

6.  It would be three months later I would send more research to this doctor.  One of the papers was Dr. Zamboni's new publication on CCSVI, which had been shared with me, the "vascular hypothesis gal" on This Is MS.   He was fascinated by the research, and suggested further testing for Jeff.  Here's part of that e-mail.

  "You could get more evidence for cerebral venous abnormalities (I would be particularly concerned about venous stenoses) by MR imaging, with attention to the cerebral veins. "

7.  We would eventually bring Jeff up to Stanford for TESTING to see if he had any venous abnormalities.  It took a few months to schedule, as he was busy composing and we needed to travel from LA to the Bay Area.   He was tested in April, 2009.   My mistake was that I wrote about all of this online, on the This is MS forum.  I should not have done this.  It is my one, deep regret.  But it is also why I continue to blog and write.  Because I feel hugely responsible for what would later happen.

8.   Jeff had serious venous abnormalities, documented on MRV.  link  He had a 99% stenosis in his left jugular vein and an 80% closure of his right.  The doctor we were consulting with felt this was a serious issue for his brain perfusion, and suggested we think about potential treatment.  We went home.

9.  After consulting with other physicians,  Jeff scheduled his venoplasty treatment for May 2009.  He went back up to Stanford and was treated for his venous abnormalities.  He had a profound response on the table---he felt as though the "lights came on" after a stent was opened on his left side.   He came home and slept soundly, without spasms, for the first time in over a year.  He was dreaming again.  He also had a terrible headache the first day, and would develop severe shoulder pain from having his accessory nerve pinched by stents.  These side effects from the treatment would pass, but it was scary.  Again, I wrote about it online.

10.  People read what I wrote, called Stanford, were treated there or tried to get treated elsewhere.  The press picked it up, and the rest is pretty well documented.  What is never reported correctly is that I didn't force an IR to treat Jeff.   We asked him to TEST Jeff for venous abnormalities.  When we saw how bad they were, the IR suggested treatment,  and we eventually agreed.

I never called venoplasty a cure for MS.  I also never meant for people to get hurt, or travel for medical tourism, spend thousands of dollars (as Jeff was covered by our insurance)  or most terribly, to die from complications.  I certainly didn't want to be labeled the crazed wife who forced an IR to treat her husband.  I always said this was only part of living a vascularly healthy life, to encourage healing and strengthen the heart-brain connection.  I never used the word cure.   I started the Facebook group because I was really concerned with how this research was being discussed as a cure.    link  I was also shocked with how vehemently the MS specialists were denying any link to the vasculature.  I wanted people to know this was only a treatment, and it might not be right for them. Which is partially why I stayed online.   That, and a huge amount of pride, I'm sure.  Ego is never a good thing, and I know it complicated this issue.

But in all honesty, all I wanted were answers for the love of my life.  And we hung around because we had hoped this could be helpful to others.  But to be continually portrayed as cure seekers, zealots and wingnuts by the NY Times, the Wall Street Journal, and other publications (which will live online ad infinitum) and to have our names linked to false and incomplete reporting is simply too much.

So, there it is.

Going for a walk with my love, and our 17 yr. old dog, Angel (another medical anomaly)
Have a nice day,

Joan

CCSVI included in Oxford Textbook of Vascular Surgery

"The Oxford Textbook series is the foremost international textbook of medicine. Unrivalled in its coverage of the scientific aspects and clinical practice of medicine and its subspecialties, it is a fixture in the offices and wards of physicians around the world."

The new edition of the Oxford Textbook of Vascular Surgery, edited by Matthew M. Thompson, professor of vascular surgery at St. George's Medical School in London, includes articles from "130 global experts."  The new edition features a full chapter on Chronic Cerebrospinal Venous Insufficiency (CCSVI).  Authored by Dr. Paolo Zamboni, Sergio Gianesini and Erica Menegatti from the University of Ferrara, this chapter is included in a section on diseases of veins and lymphatics.  link

While MS specialists and neuroimmunologists have disparaged and intentionally misrepresented Dr. Paolo Zamboni's vascular studies, he has continued to publish, undaunted.  He, along with the International Society of Neurovascular Disease,  have explored how the venous system affects neurodegenerative disease.  He has improved cerebral venous return using open surgery and venoplasty, and has documented benefits in the health of his patients.  He has created a brand new CCSVI diagnostic center at the University of Ferrara, while collaborating with international space organizations, to understand the affects of microgravity on the venous system.  As I have said before, if rocket scientists collaborate with Dr. Zamboni, why can't MS neurologists?  If the Oxford Textbook editors consider his research expert and important enough to include in this new publication, why the continued naysaying from neurology?

Heartfelt thanks to Dr. Paolo Zamboni and the entire vascular department at the University of Ferrara.  Thank you for continuing your research and exploration, even while confronted with unprecedented hysteria and vitriol from the neurological community.

CCSVI exists.  Slowed venous return to the heart harms the central nervous system, just as slowed venous return harms every other major organ in the human body.   This is scientific fact.  Whether or not MS specialists choose to acknowledge the science remains a moot point.  Vascular specialists understand this, and will continue to treat patients and push the research forward.  This is how medical science evolves, one peer-reviewed publication at a time, until the stack becomes undeniable.  Financial incentives, pharmaceutical payouts,  cognitive dissonance, and territorial medical silos cannot stop it.

Share this information with vascular specialists at your local universities and hospitals.  Fund research and support groups like the ISNVD.  Insist that "charities" and organizations who purport to be helping people with MS include vascular specialists on their medical advisory boards.  Question the status quo.

And most importantly, do all you can to improve your own heart and endothelial health.  Because this is real-- the heart and brain are connected-- and there are things you can do today to help yourself.  No prescription necessary.

Be well,
Joan

Jugular Veins are Important

Recently published in the Journal of Mutiple Sclerosis, a review paper co-authored by Dr. Paolo Zamboni and Dr. Massimo Pedriali on the "Pathology of the Internal Jugular Vein in Multiple Sclerosis".   The complete paper is available on line for free---and I'd recommend it to all.  It is a very thorough review.

http://www.omicsgroup.org/journals/the-pathology-of-the-internal-jugular-vein-wall-in-multiple-sclerosis-2376-0389-1000160.php?aid=63610

As this review outlines, there are observable and documented differences between the jugular veins of healthy controls, when compared to people with Multiple Sclerosis.  These pathological differences involve the endothelial cells which comprise the veins' lining.  Endothelial cell aptosis (death) and derangement, as seen in MS, changes the ability of the jugular veins to drain.  Valvular and intraluminal abnormalities in the jugular veins of people with MS have hemodynamic implications.  There is a shift in collagen in the jugular veins of people with MS which affects venous compliance.

Veins have received little attention and research, when compared to the study and understanding of arteries.  Certainly, in terms of brain health, the carotid arteries are scanned and studied, and neurology and stroke researchers know that blockages, clots, and impairment in flow can be disastrous to the brain.  There are treatment modalities developed to deal with carotid artery issues---from medications to open surgery, to interventional proceedures.  No one questions the importance of healthy blood flow to the brain.

But the venous system and the removal of fluids from the brain is even more important than previously imagined.

During the past two years, international researchers have described a newly discovered lymphatic drainage system, which has actual draining vessels, and relies on the brain's draining veins.  These vessels take lymph fluid, carrying metabolites, proteins and toxins, out of the brain.  This process is aided by sleep.  This science is brand new.   It has reversed what we once believed was the brain's "immune privilege."
http://ccsviinms.blogspot.com/2015/06/rewrite-textbooks.html

This "stunning discovery" of a lymphatic drainage system relies on the jugular veins.

"Instead of asking, 'How do we study the immune response of the brain?' 'Why do multiple sclerosis patients have the immune attacks?' now we can approach this mechanistically. Because the brain is like every other tissue connected to the peripheral immune system through meningeal lymphatic vessels," said Jonathan Kipnis, PhD, professor in the UVA Department of Neuroscience and director of UVA's Center for Brain Immunology and Glia (BIG). 
http://ccsviinms.blogspot.com/2015/06/a-stunning-discovery.html

The brain is like every other organ in our body---it needs drainage.  Jugular veins are responsible for the exit of blood, cerebrospinal fluid (CSF) and lymph.  Any delays can cause changes to the brain's immune functioning, oxygenation, glucose metabolism and health.  Delays cause neuronal death and inflammation.  Or, what we see in multiple sclerosis.

Dr. Jonathan Kipnis, the discoverer of these lymphatic vessels, will be the keynote speaker at the International Society for Neurovascular Disease.  He will be presenting his research and proposals for studies in MS, alongside Dr. Zamboni and the other members of the ISNVD.

Here's the program.   “How the Extracranial Venous System Influences Neurological Diseases.”

http://isnvd.org/sites/default/files/ISNVD-2016%20meeting%20outline%20program%20guide%209-21-2015.pdf


This is not going away.
jugular veins are important,

Joan



Notice the difference between the top panel---healthy endothelial cells lining the jugular veins in normal controls, compared to the endothelial cells of a person with MS (bottom)

Figure 5: Scanning electronic microscopy. Top panel: regular disposition of the endothelial cells in IJVs of healthy controls, respectively at 800x (right) and 1500x (left). Bottom panel: irregular arrangement of the endothelial cells in the IJV of a MS patient, respectively at 800x (left) and 1500x (right). The cells appear lifted with craters.

Celebration!

UPDATE 2018---Jeff remains MS progression free eleven years after diagnosis, with no new lesions, and a continuation of healing.


Our family has some great news to share!  Jeff's new MRI shows a continued healing of his brain and spine.  His cervical lesions are now "less prominent" than they were on his last MRI in 2012, an indication of remyelination.   He has no new white matter lesions, and, most importantly, his gray matter structures are all healthy and normal, with no signs of atrophy.  This MRI shows actual healing---not placebo---when compared to Jeff's very first MRI in 2007, which showed gray matter atrophy and enhancing lesions on the spine and brain.

It has been 8 1/2 years since Jeff's MS diagnosis, and 6 years since his venoplasty treatment at Stanford.  Jeff remains physically and mentally active, and has stayed on the Endothelial Health Program.  He has had no MS progression.  We do not take Jeff's health for granted.  We are very thankful for the wonderful CCSVI community and researchers, and we consider this blessing of good health something which we are responsible to share. We want to stay involved in the neurovascular community at large, because we remain convinced that it is essential to look at the brain's blood, cerebrospinal fluid and lymphatic flow when evaluating treatments.  

MS is an inflammatory disease in which neurodegeneration and gray matter loss is the only correlate to disease progression.  The autoimmune hypothesis remains unproven.  All of the current drug treatments---now, a $20 billion a year industry--- are based on the EAE mouse model of MS, which relies on stopping immune activation in the central nervous system, and uses white matter lesions to measure "success" of a disease modifying med.  None of these meds have been shown to stop MS disease progression.

New research on the brain continues to come in, and points to the brain's reliance on the major draining veins to maintain gray matter structures.  MS specialists remain intransigent;  by refusing to consider how slowed venous flow and endothelial dysfunction might be affecting their patients' brain health.

Yet the evidence continues.  Outspoken advocates who have treated their own MS with cardiovascular means of diet, exercise and lifestyle changes continue to speak out and gain followers.  These individuals are pointing the way to health and healing for the MS brain.

Dr. Terry Wahls  http://terrywahls.com

Matt Embry  http://www.mshope.com

Dr. George Jelinek  http://www.overcomingmultiplesclerosis.org

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


Even though each program has specific dietary differences (paleo, anti-allergen, low fat)---it's important to notice the lifestyle measures which these programs SHARE.

1. Healthy, whole foods, with plenty of colorful organic fruits and vegetables
2. Removal of processed foods and transfats
3. Smoking cessation
4. Increased intake of Vitamin D with UV ray exposure and supplementation
5. Regular cardiovascular exercise
6. Meditation or some form of stress relief
7. Consideration of the blood, CSF and lymphatic flow to and from the brain
8. Good quality and regular sleep
9. Maintaining a healthy weight
10. Addressing microbiome health with probiotics

There are things that can be done today, to help the brain heal.  Will these measures "cure" or "end" MS?  None of us know that for sure.  There may well be genetic factors which contribute to highly progressive MS, that cannot be completely addressed by these programs.  But we now have years and years of evidence compiling---Matt Embry is out the furthest with 20 years of no disease activity, George Jelinek is at 16 years, and Terry Wahls and Jeff are at eight years.

These numbers are impressive, and they matter.
Please be encouraged (which literally means, to give heart!!!)
The heart and brain are connected, and it's possible to take care of them.
You can do it, one day at a time,

Joan and Jeff

MS News--It's deja vu, all over again

Following neurology headlines since Jeff's MS diagnosis 8 years ago--I've seen many exciting research developments in understanding the human brain.

Recent examples of game-changing research include
The discovery of the brain's lymphatic cleansing system, which occurs when we sleep.
http://ccsviinms.blogspot.com/2015/04/glial-cells-glymphatics-and-nedergaard.html

The discovery of the brain's lymphatic vessels, which mean that the brain is not immune privileged, and immune cells are needed in the CNS to insure brain health.
http://ccsviinms.blogspot.com/2015/06/rewrite-textbooks.html

And all of the discoveries made into the vascular connection to diseases of neurodegeneration published by the International Society for Neurovascular Disease (ISNVD)
http://ccsviinms.blogspot.com/2015/03/2015-isnvd-conference-abstracts.html

Meanwhile, MS research spins on a hamster wheel of repetition and dismal lack of progress.  It's been the same, sad headlines for the past eight years.   Nothing about disease etiology.  There is a complete disconnect between what is happening in neuroscience, and what is happening in MS treatment.

Here are today's MS "News" headlines--- (we've seen these over and over again)

PML, the deadly reaction to the JC virus found in immune-compromised individuals, is now being diagnosed in patients on MS drugs Tecfidera, Gilenya and Tysabri.
http://www.medpagetoday.com/Neurology/MultipleSclerosis/52930

White matter lesions are not meaningful in understanding MS progression, and gray matter disease is more closely tied to disability progression.
http://www.nature.com/nrneurol/journal/vaop/ncurrent/full/nrneurol.2015.140.html

Salt, lack of vitamin D and environmental factors like smoking contribute to MS progression, but MS specialists are not sure why.  Even though cardiovascular researchers already know these factors all contribute to endothelial dysfunction.  The heart-brain connection is continually ignored by MS research.
http://www.eurekalert.org/pub_releases/2015-08/foas-hsi080515.php
http://www.independent.co.uk/life-style/health-and-families/five-ways-to-boost-your-vitamin-d-levels-10437766.html
http://www.mstrust.org.uk/news/article.jsp?id=6850

And in a bumbling show of complete disregard for the cardiovascular connection to brain health, the MS Society of Canada asks Canadians to pledge to eat super-sized portions of french fries to "EndMS"!!!!!  You could not write this stuff, folks.   Simply unbelievable.
http://www.weightymatters.ca/2015/08/multiple-sclerosis-society-of-canada.html





What I find most troubling is that nothing has changed the $20 billion dollar a year MS treatment machine.  Drugs with harmful side effects, which calm inflammation but DO NOT address gray matter loss or disease progression, continue to be prescribed as "gold standard" treatment.    Patients are not being told that lifestyle changes-- such as exercise, vitamin D supplementation and UV ray exposure, whole food nutrition, limiting processed foods and transfats, not smoking, and getting good sleep--are all scientifically shown to make a difference in disease progression and calm inflammation in a less risky way.  Advocates who try to help people understand this, like Matt Embry, are sent cease and desist copyright infringement letters by the MS Society.  And no one, with the exception of the ISNVD and Dr. Zamboni, and advocacy groups like CCSVI Alliance, Direct-MS and the NCS, is discussing the vascular connection to MS.

MS research labs are funded, MS specialists get their speaking and consultation fees from pharma, the stock market and investors continue to follow MS drugs, MS Society leaders are paid, funds are raised from people eating french fries---- money is being made off of MS patients.
Yet no one is pursuing disease etiology.

I've talked to many researchers over these past years, and they are all frustrated by the lack of initiative and funding available to them.

Jeff and I are traveling, working, back to our careers and lives.  I keep blogging, hoping that drawing attention to research on the vascular connection might help someone.  Every month or so, I check the MS research headlines, and see the same ol' same 'ol.  Deja vu, all over again.

In the next few months, I will be posting links to my new podcast.  It will feature interviews with doctors and researchers who are passionate and committed to helping people heal.  I'll have more information available as I get further along in the process.  It will be available, for free, on iTunes and linked on a webpage.

I do not want to see the same stagnating MS headlines and failed treatments eight years from now--and I know none of you do, either!  We owe it to this wonderful MS community, we owe it to our children and their children.  If you have ideas for doctors, researchers or topics you'd like to hear addressed, please leave me your suggestions! I'll be speaking to functional medicine doctors, researchers and advocates.

Let's all be the change we wish to see, and get off the hamster wheel,
Joan

Rewrite the textbooks

UPDATE: October 2017  
Confirmation of the Kipnis Lab and University of Helsinki finding in humans.  
Researchers at NIH see the actual lymphatic vessels in the human brain. 

“We literally watched people’s brains drain fluid into these vessels,” said Daniel S. Reich, M.D., Ph.D., senior investigator at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and the senior author of the study published online in eLife(link is external). “We hope that our results provide new insights to a variety of neurological disorders.”   link

                                                   *******************

The Journal of Experimental Medicine said it best in their recent tweet:

"The CNS is considered an organ devoid of lymphatic vasculature." Ed. note: "NOT"

Not. Decades of medical theory which considered the brain as different from other organs of the body and without lymphatic drainage system were, well, simply wrong.

The University of Helsinki has independently published a paper in the Journal of Experimental Medicine which confirms the University of Virginia's paper on lymph vessels published just two weeks ago. Both universities have found:
A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules

link

How have researchers had it SO WRONG for SO LONG?

If you're like me, you figured that neuroscientists had looked long and hard for any signs of lymphatic drainage surrounding the brain, and had proven that it simply didn't exist, and that the brain was indeed immune privileged, and separate from the rest of the body's peripheral immune system.

“Any neuroscience textbook that has ever been written will say that the central nervous system is devoid of a lymphatic system and that is one of the reasons the brain is immune privileged,” Louveau said. “When we started our project, our question was if there are so many immune cells surrounding the brain, how do they traffic there? By addressing this question we found vessels that weren’t supposed to exist. They were very well hidden and we think that is why it took so long to discover them.”

link

In fact, the whole concept of immune privilege of the brain and lack of lymphatic drainage was created 70 years ago and hasn't changed much in ensuing years.   This was around the same time EAE was created as the animal model for MS.  Why hasn't there been more exploration until recently?   I believe one reason is because the old theories have made people very rich.

Let's learn the history:
The theory of  immune privilege was invented to explain why foreign tissue grafts placed on brain tissue didn't cause an immediate immune reaction, as similar grafts did in other parts of the body, like the skin.  It was believed that antigens in the brain were concealed from the immune system by the blood brain barrier.  That's why it was assumed that when immune cells showed up in the brain--if they weren't there fighting an infection or as an inflammatory reaction after a stroke---there could only be one explanation--it was some sort of "auto-immune"and destructive inflammatory reaction.  

This theory of immune privilege was developed in the 1940s and became the foundation of transplantation immunology---or the reason why we need to block the immune system when patients receive a donated organ or a skin graft.  The body's immune response needs to be turned off, so that it will not reject the foreign tissue.  This process was discovered by Sir Peter Medawar, who wanted to understand how to help skin grafts survive.

Sir Peter Medawar, whose experiments in the 1940s established the basic rules of transplantation immunology [2], placed skin and or other types of grafts in the anterior chamber of the eye and the brain [3]. Observing that many of these grafts, unexpectedly, survived for prolonged intervals of time, he invented the term ‘immune privilege‘ to refer to the unexpected and prolonged acceptance of solid tissue grafts at specialized sites in the body. At the time, it was believed that the brain and eye lacked lymphatic drainage pathways, and that both organs resided behind stringent blood-tissue barriers. In light of this knowledge, Medawar proposed that immune privilege results from ‘immunologic ignorance’ because, on the one hand, in the absence of lymph pathways antigens could not escape from the eye, and on the other hand, immune effectors in the blood could not pass the vascular barrier to enter the sites where antigen resides. He speculated that antigenic material placed in privileged sites is sequestered from the immune system, and that the system remains unaware of the existence of grafts in privileged sites. link

This speculation on immune privilege has continued on for seven decades, mostly due to the fact that no one could find any lymphatic drainage pathways or understand how or why immune cells might get through the blood brain barrier.  

Not coincidently, the EAE model for MS was developed around the same time as the theory of immune privilege, as an example of how t-cells could break through the blood brain barrier and attack the brain in an auto-immune reaction.  It has been a prevailing theory in MS treatment development, which has also never been proven.  Another 70 year old theory which has lead to disastrous assumptions about the brain.


The presence of mild scant lymphocytic infiltrates in the demyelinating lesions has been generally interpreted as the evidence of an inflammatory autoimmune process. Because specific T-cell mediated autoimmunity can be reproduced in animals after myelin protein sensitisation (Experimental Allergic Encephalo- myelitis (EAE)) it has been assumed (but never proven) that a similar T-cell driven immune mechanism is responsible for demyelination in MS. 

The acceptance of EAE as a model for MS is an unfortunate error that has its basis on faith rather than science. Whilst EAE is a good example of an experimental organ-specific autoimmune disorder in animals, it cannot be accepted as a model for MS for a wide variety of reasons. This is particularly important in relation to the development of MS pharmacotherapy. We have analysed the literature on immune-modifying therapy in MS and it is clear that none of these agents can qualify as a candidate therapy under scrutiny.
link


The brain's relationship to the peripheral immune system is obviously much more communicative and complex than previously imagined.  The discovery of lymphatic vessels by neuroimmunologists means we need a do-over in MS research, as this science writer comments:

This data suggests that brain immune surveillance communicates with the immune system and can generate adaptive immune responses. The authors infer that previously characterized glymphatic washing of the brain likely connects to the lymphatic system; a testable hypothesis. The authors further suggest that this system will change the way we think about neurological disorders such as multiple sclerosis and Alzheimer’s.

link

The fact that MS has no disease-specific immune target,  no specific antigen, and does not look like EAE in mice, should give us all pause.   There has never been any concrete, scientific proof that MS is an autoimmune disease.  Just a theory,  which has been used to create a 20 billon dollar a year industry.  And that theory has completely unravelled.  The question is, will MS researchers let go of pharma money, in order to pursue the true etiology of MS?

If the brain requires immune cells for neuroprotection, stem cell regeneration and plasticity, than what are we doing suppressing the immune system with MS drug therapies?  What if this immune reaction is, as Dr. Michal Schwartz's research has shown, "protective", and should be modified, not stopped?  (notice that this paper was co-authored by Dr. Kipnis, a PhD graduate of the Weizmann Institute of Science, who now heads up the Kipnis Lab at the Univeristy of Virginia where these lymphatic vessels were discovered.)

For decades, several axioms have prevailed with respect to the relationships between the CNS and circulating immune cells. Specifically, immune cell entry was largely considered to be pathological or to mark the beginning of pathology within the brain. Moreover, local inflammation associated with neurodegenerative diseases such Alzheimer's disease or amyotrophic lateral sclerosis, were considered similar in their etiology to inflammatory diseases, such as remitting relapsing-multiple sclerosis. The ensuing confusion reflected a lack of awareness that the etiology of the disease as well as the origin of the immune cells determines the nature of the inflammatory response, and that inflammation resolution is an active cellular process. The last two decades have seen a revolution in these prevailing dogmas, with a significant contribution made by the authors. Microglia and infiltrating monocyte-derived macrophages are now known to be functionally distinct and of separate origin. Innate and adaptive immune cells are now known to have protective/healing properties in the CNS, as long as their activity is regulated, and their recruitment is well controlled; their role is appreciated in maintenance of brain plasticity in health, aging, and chronic neurodevelopmental and neurodegenerative diseases.
link

Israel Steiner, a neurologist at the Hadassah University Hospital in Jerusalem, agrees that EAE has blocked "effective progress" for decades. He thinks alternative theories should be put to the test. "I definitely believe it's high time to reconsider the entire field. It has not led us into understanding the disease or to a better therapy for patients," he says. 

"Many people in the community who do not have a vested interest in the autoimmune hypothesis share my views, but I'm not sure they would like to step out."  

New Scientist vol 176 issue 2369 - 16 November 2002, page 12 

Dr. Steiner would later publish the paper:  Experimental allergic encephalomyelitis: A misleading model of multiple sclerosis  link

The MS neurologists with "vested interest in the autoimmune hypothesis" were the very same ones who shut down CCSVI research before it could even begin, or be done correctly.  They were the first to say that veins would have nothing to do with MS, that it was an autoimmune disease, that the brain's drainage system was unimportant.  They created the narrative that those of us pleading for collaboration with Dr. Paolo Zamboni and the International Society of Neurovascular Disease (www.isnvd.org) were wackos, a fringe element, a Facebook/YouTube phenomena that would pass.  

But they were wrong.  The brain's venous system is most certainly important for efficient drainage of CSF, blood and now, lymph.  And the brain's immune system appears to be intimately tied to venous flow of the brain via newly discovered lymph vessels.  link 

In fact, the two large lymph vessels which collect the lymph drainage from the brain, head and neck can enter the blood stream at the internal jugular vein, the subclavian vein, or the junction of these two veins, called the venous angle.  Lymph relies on the low pressure venous system for drainage. To say that this discovery has "nothing to do with CCSVI" is to blatantly ignore physiology.  For patients, or neurologists, who would like to learn more about lymphatics:  link

The writing is on the wall, in medical journals, blogs and even twitter.

And we are all watching, reading, and waiting.

Time to rewrite the textbooks and help people heal,

Joan

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.

2015 ISNVD Conference Abstracts---research breakdown

The International Society for Neurovascular Disease (ISNVD) will be convening for the 5th Annual Conference in Naples, Italy at the end of March.  Abstracts for the presentations have been made available online here:
http://isnvd.org/d/sites/default/files/Invited%20Speaker%20abstracts%20-%20all.pdf

There are many more new presenters and international researchers attending this conference.  The ISNVD continues to grow in its membership and influence.

While neuroimmunologists stubbornly insist that there is no connection between diseases of neurodegeneration and circulation, this illustrious group of international researchers is showing that we are only at the beginning of understanding the impact of blood flow on brain health.

Here is my layperson's breakdown of the research abstracts and presentations.


2D and 3D analysis of vessels in the retina and the brain
Prof. Bart ter Haar Romeny, Ph.D.1,2
1Eindhoven University of Technology, Eindhoven, the Netherlands 2Northeastern University, Shenyang, China
This research is using the imaging of blood vessels in the eye's retina to get a picture of how blood is circulating throught the central nervous system. The blood vessels in the retina give an early picture of how brain diseases and breakdown of the blood brain barrier might be developing. Scanning the eye is easier and more cost-effective, as well.

Venous dysfunction and neurodegenerative diseases
Chih-Ping Chung MD PhD
Taipei Veterans General Hospital, National Yang Ming University, Taipei, Taiwan
Dr. Chung and his group have been studying the venous vasculature in relationship to brain disorders for over a decade. He has spoken at a few of the ISNVD conferences now. His new research focuses on how venous abnormalities are linked to white matter changes and how venous drainage impairment leads to dysfunction in Alzheimer's Disease.

Blood storage within the intracranial space and its impact on cerebrospinal fluid dynamics

Clive B Beggs 1, Simon J Shepherd 1, Pietro Cecconi 2 and Maria Marcella Lagana 2Medical Biophysics Laboratory, University of Bradford, Bradford, BD7 1DP, UK  Fondazione Don Carlo Gnocchi ONLUS, IRCCS S. Maria Nascente. Milan, Italy 
This study measured blood flow throughout the cardiac cycle by using MRI to visualize the flow in the necks of 14 healthy adults.  This study found that it is cerebrospinal fluid (CSF) which controls the volume changes inside the brain.  CSF interacts with the cortical veins to facilitate how much blood is stored.  This is an important finding, because any disturbance in venous outflow of blood and CSF will change the blood storage inside the skull, potentially leading to reduced cerebral circulation.

Advances in Treatment Strategies of Extracranial Venous Disease
Hector Ferral, MD
Senior Clinical Educator NorthShore University Health System
Dr. Ferral has been treating people with CCSVI for a few years now. He has also been an attendee and presenter at the ISNVD before. His new presentation will be looking at the technical advances being made in vein measurement and treatment of CCSVI.

Imaging of Brain Microvascular Disorders: lessons from the CADASIL model.

Hugues Chabriat, MD PhD;Department of Neurology, GH Lariboisiere, APHP, INSERM UMRS1161, University Paris 7 Denis Diderot, Paris France.
This research uses imaging to look at how the small vessel disease related to stroke and dementia develops and progresses.

Endothelin- 1 as a potential target for chronic brain hypoperfusion
Jacques De Keyser, MD, PhD, Free University of Brussels (VUB), Department of Neurology, Brussels, Belgium
This study is near and dear to my heart, as it is looking at how ET-1, a marker of endothelial dysfunction, is related to slowed blood flow in the brain, called hypoperfusion. People with MS have much higher levels of ET 1 in their blood than normals, and much slower cerebral blood flow. We also see this marker elevated in a number of neurodegenerative diseases, like Alzheimer's. In this study, the researchers used bosentan, a blood pressure medication, to treat ET 1 levels. This treatment increased cerebral blood flow in pwMS, and lowered ET-1 levels. (But bosentan has side effects, and is not easy on the liver. Much better, in my opinion, to lower ET-1 levels by addressing endothelial dysfunction, through diet, exercise, and lifestyle.)

TBI and hemodynamic changes in the brain
James R. Stone, MD, PhD
This presentation is looking at how traumatic brain injury induces ischemia, or a low-oxygen state, in the brain. TBI also changes cerebral blood flow and can cause a break in the blood brain barrier, igniting the immune system. New research is showing how explosive devices can cause TBI, even without direct physical contact.

Ultrasound contrast imaging of brain hemodynamic and perfusion Marcello Mancini, M.D.
Institute of Biostructure and Bioimage – CNR
Naples, Italy

This presentation will be looking at how new MRI and ultrasound technologies are allowing researchers to view cerebral circulation in MS.  People with MS show signs of hypoxia (low oxygen) injury and thrombosis (small clots) in the small veins of the brain. New technologies are allowing us to see that cerebral transit time is slowed in MS. 

Imaging of the Microvasculature
E. Mark Haacke, PhD 
Dr. Haacke, a presenter at all of the ISNVD conferences, returns this year to discuss how his invention of susceptibility weighted imaging (SWI) and MRA can be used to study the neurovascular system, and clarify the relationship between the venous sytem and CSF.


Update in computational fluid modelling of the brain
Mauro Ursino
This presentation is using mathmatical and computer models to simulate the complex mechanisms affecting cerbral circulation. Using these models shows how postural changes and stenosis in extra cranial arteries and veins can change upstream intercranial circulation.

Clinical Applications of Venous Treatment
Dr. Michael Dake, Stanford University

Dr. Dake, last year's ISNVD president and a founding member, will be presenting on the contributions of 2014 studies which have enhanced understanding of how endovascular and open surgical treatment of venous abnormalities has affected patients with MS, Alzheimer's disease, Parkinson's, POTS and other pathologies.

The Heart Brain Connection
MJ Daemen
Dr. Daemen is the keynote guest speaker. He is a neurocardiologist, a member of a new field of experts who are bringing together an understanding of how the heart and brain affect each other. As a member of the Dutch Heart Foundation, his group is looking at how cardiovascular disease is influencing cognitive function and cerebral circulation.

A NOVEL SONOGRAPHIC METHOD FOR REPRODUCIBLE JUGULAR VEIN PULSE WAVE ASSESSMENT
Paolo Zamboni, Francesco Sisini, Erica Menegatti, Giacomo Gadda, Mirko Tessari, Mauro Gambaccini
Vascular Diseases Center, University of Ferrara, Ferrara, Italy 

Dr. Zamboni's group is using ultrasound in the B mode (brightness mode) to measure the pulse wave in the jugular vein.  The way that the wave form looks is currently used to monitor for heart disease, however Dr. Zamboni's group is using this technique to find CCSVI.

Is there a role for mast cells dependent synthesis of Endothelin-1 in neurodegenerative diseases?
Pedro D’Orléans-Juste-1, Louisane Desbiens, Denis Gris-2
Departments of Pharmacoly-1 and of Pediatrics-2, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, PQ, Canada

We know that levels of ET-1 (a marker of endothelial dysfunction) and mast cells (tissue cells of the immune system) occur in higher levels in people with MS.  This study uses the mouse model of EAE as well as a human isoform to study how mast cells found in the vicinity of spinal lesions are involved in the synthesis of ET-1.

Venous abnormalities in Meniere's Disease

P.M.Bavera; P. Cecconi; D. Alpini; F. Di Berardino 

This presentation will be using slides to show the correlation and differences between Meniere's Disease and MS, in regards to CCSVI imaging.  There are specific characteristics to the venous abnormalities seen in Meniere's.

Advances in Idiopathic Intracranial Hypertension Pathogensis: a Focus on Sinus Venous Stenosis
Roberto De Simone, Angelo Ranieri
Headache Centre  Dpt. of Neurosciences, Reproductive Sciences and Odontostomatology University of Naples “Federico II”

This research is focusing on how stenosis of the venous sinus is related to idiopathic intracranial hypertension (IIH)  There is a feedback loop which appears to occur in this situation.  The venous sinus collapses, cerebrospinal fluid pressure builds, which creates more compression.  Endovascular stenting of the venous sinus is a currently approved treatment to end this cycle of stenosis and hypertension.

In Endothelial function, the glymphatic system and New Drug Development
Endothelial dysfunction in neurodegenerative disease
J. Winny Yun, Emily Stevenson, Seiichi Omura, Fumitaka Sato, Ikuo Tsunoda, Alireza Minagar, Felix Becker, Trevor Castor, Adam Xiao, J. Steven Alexander, LSUHSC-Shreveport Molecular and Cellular Physiology, Microbiology, Virology, Neurology, Shreveport, Louisiana, USA.
Dr. Steven Alexander from LSU returns to the ISNVD to again discuss the endothelium in neurovascular disease. There is a vascular association of specific biomarkers found in MS. This new research is looking for a means to regulate these neurolymphatic markers, to help those with neurovascular diseases.

Fluid Dynamic Influences on Cerebrovascular Endothelial Activation Responses
Dr. Alexander and the LSU team look at how blood flow over endothelial cells affect their health. Laminar shear stress (regular blood flow) over endothelial cells is essential to their function. Disrupted flow causes endothelial cells dysfunction and death. Shear stress alterations could lead to a break down of the endothelial layer in the brain, and create a disturbance in the blood brain barrier and inflammation.

Cardiovascular risk factors and neurodegenerative disorders
Dr. Robert Zivadinov
Buffalo Neuroimaging Analysis Center, Department of Neurology, University at Buffalo, State

This research finds an association with cardiovascular risk factors (smoking, obesity, inactivity, high blood pressure) and MS.  MS patients who had one or more CV risk factors had higher lesions loads and more brain atrophy.

Avanti!

Joan

Putting the Pieces Together

In my last blog post, I asked WHY cerebral circulation time might be doubled in people with MS.  In this post, I'm going to attempt to answer this question, using recent peer-reviewed research.  Because the answers are out there, we just need to put the pieces together.

A recent study published in JAMA Neurology Journal by Yulin Ge, MD showed how pwMS had impaired cerebrovascular function.  Dr. Ge is a member of the International Society for Neurovascular Disease.  Dr. Ge has been imaging the MS brain for over a decade at NYU, and has found many vascular connections.

Impaired Cerebrovascular Reactivity in Multiple Sclerosis
http://archneur.jamanetwork.com/article.aspx?articleid=1893478

Now, to explain what Dr. Ge and his fellow researchers at NYU found.  CVR is how the brain reacts or responds with blood flow when there is vasodilation in blood vessels.  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.

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.  Something was wrong with the blood vessels response.  Increased blood flow did not happen when it was needed.

Impaired CVR would most certainly cause a delay in cerebral circulation time!  These two conditions are intertwined.

Another study on impaired CVR looked at why this might be happening.
A Columbia University study, published last summer, found that when researchers damaged the vascular endothelial cells lining the blood vessels 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

Did you catch that??
Damaged endothelial cells in blood vessels changes neurovascular coupling, and cerebral blood flow is reduced.

“Our latest finding gives us a new way of thinking about brain disease—that some conditions assumed to be caused by faulty neurons could actually be problems with faulty blood vessels,” Hillman adds. “This gives us a new target to focus on to explore treatments for a wide range of disorders that have, until now, been thought of as impossible to treat. 

Endothelial cell death and dysfunction may well be the cause of slowed cerebral blood circulation time in MS.  That's all it took in the Columbia study--frying the endothelial cell layer with lasers and slowed down cerebrovascular reactivity, because the endothelial layer could no longer respond with vascodilation and more blood flow to the brain. This is endothelial dysfunction.

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 cells could well be causing the decrease in cerebrovascular reactivity seen in people with MS.  And it is caused by CCSVI.
http://phl.sagepub.com/content/early/2014/06/27/0268355514541980.abstract

Here are my proposed steps as to why pwMS have delayed cerebral circulation time.

1. Loss of laminar flow, refluxive blood flow and oxidative stress causes endothelial cell death and dysfunction in the vessel walls of both arteries and veins.
2. Without endothelial cells in blood vessels, cerebrovascular reactivity is decreased.
3. This decrease in CVR leads to a slowed cerebral circulation time.
4. Slowed blood flow leads to neuronal cell death and brain atrophy, as well as an hypoxic situation which creates white matter lesions and inflammation.  Voila.  MS.


The research is out there.  If someone could please send this to "The Mouse Doctor" at Barts--he is not taking any responses from me on his blog.  But at least he is FINALLY looking at blood flow.
http://multiple-sclerosis-research.blogspot.com/2015/02/is-ms-starving-brain.html

Of course CCSVI could be implicated in CVR and slowed cerebral circulation time in MS.
How to learn more?  Test patients, like my husband, who have had venous malformations repaired and see if their cerebral circulation time is closer to normal.  My husband's reversal of gray matter atrophy as shown on MRI would seem to imply that there has been healing.

If you want some GREAT news---Dr. John Cooke's team is now figuring out how to create healthy new endothelial cells from fibroblasts, which could then be implanted in patients.
http://www.genengnews.com/gen-news-highlights/fibroblast-transformed-endothelial-cells-show-promise-for-damaged-tissue-repair/81250576/

But what do I know?
It's only been seven years since I contacted Dr. Cooke at Stanford and asked him what he thought about endothelial dysfunction in MS.
http://ccsvi.org/index.php/helping-myself/endothelial-health
Joan