Welcome! This blog contains research & information on lifestyle, nutrition and health for those with MS, as well as continuing information on the understanding of the endothelium and heart-brain connection. This blog is informative only--all medical decisions should be discussed with your own physicians.

The posts are searchable---simply type in your topic of interest in the search box at the top left.

Almost all of MS research is initiated and funded by pharmaceutical companies. This maintains the EAE mouse model and the auto-immune paradigm of MS, and continues the 20 billion dollar a year MS treatment industry. But as we learn more about slowed blood flow, gray matter atrophy, and environmental links to MS progression and disability--all things the current drugs do not address--we're discovering more about how to help those with MS.

To learn how this journey began, read my first post from August, 2009. Be well! Joan

Showing posts with label EAE. Show all posts
Showing posts with label EAE. Show all posts

Saturday, March 5, 2016

Boosting Immune Cells

Anne Kingston, reporter and senior writer at Maclean's Magazine, has just published a fantastic interview with pioneering neuroimmunologist Michal Schwartz.   I've recommended Dr. Schwartz's new book, Neuroimmunity: A New Science That Will Revolutionize How We Keep our Brains Healthy and Young, on this blog.  I'm thrilled that Anne not only read the book,  but got in touch with Dr. Schwartz and interviewed her, to learn even more.
http://www.macleans.ca/society/health/a-healthy-immune-system-is-the-key-to-a-healthy-mind/

I found this particular question especially insightful.

Anne Kingston: Your research indicates the immune system needs to be boosted, not suppressed. Doesn’t that run contrary to the immunosuppressant therapies routinely prescribed for many autoimmune diseases?

Dr. Schwartz: I’ve told everyone for a while to be careful when prescribing any anti-inflammatory drug for any neurodegenerative disease. They understand, but don’t have an alternative.


In other words, since there's nothing better, neurologists haven't changed their treatment target.  They understand that immune suppressing drugs (also known as anti-inflammatory) are keeping helpful immune cells away from the brain, but they don't have anything else they can prescribe which is FDA approved.  Here's more on the FDA pay to play system, which is maintaining the current $20 billion a year MS treatment industry.
http://ccsviinms.blogspot.com/2013/10/the-fda-and-multiple-sclerosis.html 

The last several years of research have directly questioned the current MS treatments.   Recent discoveries of the brain's lymphatic vessels and connection to the immune system and the neuroprotective role of immune cells.  The fact that the brain is not immune privileged and needs immune cells to repair the blood brain barrier.  The glaring fact that this immune cell and lymphatic cleansing system is relient on functioning venous drainage system  ---- in light of all of this research, the continued silence of the MS community is deafening.  They carry on as if nothing has changed, still prescribing immune cell sequestering and ablating medications, without a second thought.  They ignore vascular issues and the compounding evidence that cardiovascular lifestyle intervention can modify disease progression.   

Why?  They understand the science, but they don't have an FDA-approved alternative to sell MS patients.

Readers of this blog know that the current mouse model for MS, called experimental autoimmune encephalomyelitis (EAE) is not an appropriate model for MS.  EAE it is initiated by injecting the mice with lots of stuff we certainly don't find in the CNS of humans with MS, in order to create an inflammatory reaction.

Did you know that the MS drug Copaxone was originally created in an attempt to CAUSE the animal model of MS?   It was formulated to give mice EAE?  That's right.
http://www.ncbi.nlm.nih.gov/pubmed/20106343 

Glatiramer acetate (GA) was created in a lab over 40 years ago to cause EAE.   It consists of four synthetic protein compounds combined together to replicate myelin basic protein (MBP.)  Myelin basic protein is what the immune system damages in MS.  So, the idea was, inject the animals with this myelin-like formulation, and the immune system would go to town and attack ---creating an MS-like disease process, and disabling the mice.

What actually happened, however,  was the exact opposite. The animals injected with GA could not develop EAE.  What happened was that this formulation did indeed activate t-cells and boosted an immune reaction,  but these t-cells were not damaging, they were protective.
http://www.jimmunol.org/content/186/4/1887.full.pdf

This is how Copaxone was developed to treat humans--what MS researchers like to call serendipity, I think is essential to understand.  Copaxone is not an immune ablating or suppressing drug, it is an immune boosting drug.

Glatiramer acetate, now called Copaxone, was created in a lab at the Weizmann Institute in Israel. Not coincidently, this is the same institute where Dr. Schwartz has been conducting her research.  It would be the discovery of how GA increased the body's t cells and protected axons which would coincide and overlap with her studies.

Boosting immune cells, instead of suppressing them, protects the central nervous system. 

Granted, we now know Copaxone is most certainly not a cure for MS.  Although it blocked EAE in mice, its longterm efficacy in humans with MS is more of a mixed bag.  But what the creation of Copaxone should have instigated, at least in mind, were questions regarding the long-term safety of serious immune ablating treatments for MS and the development of immune boosting and modulating treatments.

"They understand, but they do not have an alternative."

Let's continue to put pressure on MS researchers for alternatives.  For immune modulating treatments, for venous treatments, for cardiovascular therapies, for immune boosting treatments. It's vitally important to study the endothelium, the connection between the vascular and immune systems.

Until we understand more, please be careful with serious immune cell sequestering MS drugs (like Tysabri, Gilenya, Tecfidera) or immune ablating chemotherapies (like Campath and Lemtrada.)   Do everthing you can do to live your best vascularly, endothelially, heart-healthy life.

The research keeps coming in.  And we do not know what we do not know.

be well,
Joan






Sunday, June 21, 2015

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

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.

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












Friday, June 22, 2012

From Dr. Putnam to Astrocytes--MS as a Vascular Disease


June 22, 2012 at 12:04pm

For those who haven't had a chance to read about the history of the beginnings of the MS Society and the founding neurologist, Dr. Tracy J Putnam---here's a bit of background on the vascular history of MS.
http://ccsviinms.blogspot.com/2012/06/dr.html

The very latest research into multiple sclerosis is discovering what Dr. Putnam hypothesized. MS is created by a response from the vascular system to injury. 

New research, published this month, continues Putnam's thesis, at the cellular level.
Something is signaling the vascular cells in the brain.

Here's how it works.
Astrocytes are beautiful, star-shaped cells that live in the central nervous system. ( I love the fact that our smallest cells look like the largest bodies in our solar system.  There's wonderful symmetry in creation.)

Astrocytes are the most abundant cell in the human brain.  One of the most important things astrocytes do is support the endothelial cells in our brain, and maintain the very important blood brain barrier. The blood brain barrier should have tight junctions, that don't allow blood particles into brain or spinal tissue.  (For those new to the idea of the endothelium, please check out the Endothelial Health program I made for Jeff.  It will explain how MS and our blood supply are connected.)

Researchers have recently noted that when the brain is subject to hypoxia, or low levels of oxygen, the blood brain barrier becomes open, or "permeable."  This allows infiltration of blood cells and the immune system, which create damage to the brain.  Please notice that if the blood brain barrier was not open, T and B cells would not have entry.  The immune system isn't just going into the brain, uninvited and without cause.  The gate is wide open.

Blood brain barrier (BBB) permeability is an early and prominent feature of inflammatory CNS conditions, including MS (13), viral encephalitis (14), and traumatic and hypoxic/ischemic injury (15). BBB disruption correlates with neurologic exacerbation, and MS patients with contrast-enhancing plaques are more likely to have irreversible pathology (13, 16). BBB breakdown leads to edema, metabolic imbalance, excitotoxicity, and ingress of factors that potentiate inflammation and inhibit repair (17–20) and facilitates infiltration of T and B lymphocytes, macrophages, and neutrophils (21). In diseases such as MS, current options to restrict relapse severity are limited, and patients may benefit from more selective agents (22).

What is going on?  What signals the astrocytes to open the gate?  Researchers are looking specifically at VEGF--vascular endothelial growth factor.

Studies have identified astrocytes as regulators of BBB induction and maintenance (9–11) and have implicated astrogliosis, particularly induced by IL-1, as a driver of both BBB breakdown and repair (10, 12, 48). The mediators producing the effects of reactive astrocytes are incompletely characterized, and our data revealed VEGF-A as an important astrocyte-derived inducer of BBB disruption and pathology in vivo. Although VEGF-A–induced vascular permeability has previously been implicated in pathogenesis of disorders, including myocardial infarction, CNS hypoxia/reperfusion injury, and tumor growth and metastasis (49), and we and others have previously speculated on its role in BBB breakdown (12, 26), this study is the first to our knowledge to show the significance of astrocyte-derived VEGF-A in lesion pathogenesis and generation of clinical deficit in models of CNS inflammatory disease.


This is the first study that has noted the importance of astrocyte derived VEGF in the formation of lesions and brain damage in a model of MS.

Please note the other diseases that have VEGF created "vascular permeability"--hypoxia and myocardial infarction--are vascular diseases.  VEGF-a is activated in situations where there is low oxygen, and the organ begins to suffer the effects of low O2.

So, what is VEGF and why does it matter in MS?  

Vascular endothelial growth factor (VEGF) is a chemical signal produced by cells that stimulates the growth of new blood vessels, called "angiogenesis."  This is part of a system which restores the oxygen supply to tissues when blood circulation is inadequate.

VEGF's normal function is to create new blood vessels during embryonic development, new blood vessels after injury, and new vessels (collateral circulation) to bypass blocked vessels.

Here is a rather pejorative look at the vascular connection, written in a condescending tone by a group of German Neurologists-- 

Vascular pathology in multiple sclerosis: mind boosting or myth busting?
The idea of MS being a vascular disease is not new. In the 1930s T.J. Putnam proposed venous obstruction as the primary alteration in MS [7]. Given the venotopic localization of MS plaques, this hypothesis has been discussed on and off ever since. In 2007 an Italian group headed by P. Zamboni added new fuel to the fire by demonstrating that venous blood flow alterations can be found at a high frequency in MS patients [5]. 

While the concept of CCSVI has gained much attention in the field of MS research and in particular among MS patients, there is increasing evidence that the relation of venous changes to the pathophysiology of MS may not be as simple as initially described. Most importantly, new MR imaging techniques add to the notion of vascular changes in MS, yet again raise doubts whether these alterations are cause or rather consequence of the disease process.

(At the end of the article, the authors state they have nothing to disclose, yet all of them have participated in many MS drug trials. Drugs which are based on the EAE immune model of MS-  Dr. Linker has received personal compensation for activities with Bayer Health Care, BiogenIdec, Merck Serono, Novartis and TEVA Pharma. Dr. Linker has received research support from BiogenIdec, Novartis and TEVA Pharma.)

Why is it only neurologists who believe some "mystery mechanism" disease process is behind VEGF activation, blood brain barrier disruption and inflammation---when we have other models of vascular disease in vivo, such as stroke, which illustrate how hypoxic injury creates this scenario

If MS specialists want to continue to pretend there is no vascular involvement in MS, and that MS is a disease of a mysterious and crazed immune system,  they can keep saying it-- and creating, testing and selling the drugs.  But the truth is, all of the research continues to point to the importance of the endothelium and the vascular response of the body to injury of the brain.  

What's causing the injury?  Slowed flow through the brain, hypoperfusion, low O2 and glucose levels from collateral venous return?   Makes sense to me.   More to come.

Joan


Tuesday, June 19, 2012

The History of the National MS Society--founded by Dr. Tracy Putnam


June 19, 2012 at 8:27am

The history of the National Multiple Sclerosis Society in the United States is told in a very specific way, in a brochure published on the NMMS page.   Their focus is on the immunology of MS, the EAE mouse model and the subsequent MS immune suppressing treatments.

With remarkable foresight, the very first research grant from what was then called The Society for the Advancement of Multiple Sclerosis Research was awarded to study the immunology of MS—the relationship between the body’s immune system and the central nervous system (the brain and spinal cord). 
http://www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Brochures/Brochure-History-of-Multiple-Sclerosis.pdf

However, this is only part of the history.  The NMMS leaves out the real beginning.  Sylvia Lawry started the MS Society to help her brother who had MS.  She found the greatest medical mind of her generation, MS specialist and neurologist Dr. Tracy Putnam, and asked him to lead her new association.  Yet Dr. Putnam is never mentioned by the National MS Society.  It was Dr. Putnam who invited Dr. Elvin Kabat to work on MS research with him at Columbia University,  and hired this young researcher in 1940.  He was responsible for helping select him for the first research grant made by the MS Society.  Yet Dr. Putnam is no longer mentioned by the NMMS.
http://www.annualreviews.org/doi/pdf/10.1146/annurev.iy.01.040183.000245

Why does the NMMS leave out Dr. Putnam?  Perhaps because his entire career he stated that MS had a vascular component.

Dr. Tracy J. Putnam created an animal model of multiple sclerosis by occluding the venous sinus in dogs.  He believed MS was a disease of blocked venous blood flow, which created the immune response in the central nervous system.  

Dr. Tracy Putnam, American neurologist and chair of the medical advisory board for the National MS Society, experimented by obstructing venous outflow in dogs, only to find that the dogs quickly developed brain plaques similar to those found in MS patients. Putnam wrote about his observation, “The similarity between such lesions [in dogs] and many of those seen in cases of multiple sclerosis in man is so striking that the conclusion appears almost inevitable that venular obstruction is the essential immediate antecedent to the formation of typical sclerotic plaques.”
http://archneurpsyc.jamanetwork.com/article.aspx?articleid=646487
http://jnnp.bmj.com/content/s1-17/67/193.full.pdf
http://archneurpsyc.jamanetwork.com/article.aspx?articleid=648079

He is absent from the NMMS history.  But we need to remember his name.

Here is a story about the founding of the National MS Society, printed in Time Magazine in 1946---

Time Magazine, 1946  "The Mystery Crippler"

The patient first notices a pins-&-needles sensation in his legs. After a time his head and shoulders may twitch, his eyeballs roll wildly, he sees double, reels when walking, stumbles in his speech, from time to time is seized by uncontrollable laughing or crying jags. In advanced stages he may be paralyzed.

The patient is not drunk. These are symptoms of a mysterious, widespread disease known as multiple sclerosis, a disorder of the nervous system. Doctors have recognized it for nearly 100 years (the German poet Heinrich Heine is believed to have died of it), but they have never discovered its cause or cure.

Last week the first concerted attack on the disease was launched by a new organization started by multiple sclerosis sufferers. Based in Manhattan, the Association for Advancement of Research on Multiple Sclerosis has enlisted some of the top U.S. neurologists (honorary chairman: Dr. Tracy J. Putnam, director of Columbia University's Neurological Institute).

Dr. Tracy J. Putnam was the Director of Columbia University's Neurological Institute and the leading expert on Multiple Sclerosis in early 1946, when the Time Magazine article was published.   Putnam was a neurosurgeon and a neurologist.  He was the first major researcher to go public with a theory for MS.  But by the end of the 1940s, he was forced to resign from Columbia and left New York and his academic career.  Why?  One reason is because Dr. Putnam did not cure MS.

Senator Charles W. Tobey of New Hampshire sponsored the National Multiple Sclerosis Act, which began hearings before the Senate Subcommittee on Health of the Committee on Labor and Public Welfare on May 10, 1949. Senator Tobey's own daughter had multiple sclerosis, and he sought the advice of the National Multiple Sclerosis Society in composing the legislation. When the proposal for a National MS Research Institute was included in hearings on a National Health Plan in the House of Representatives in 1949, Ralph I Straus, the president of the NMMS, gave testimony, as did Senator Tobey, Mrs. Lou Gehrig and Dr. Tracy Putnam, as well as a number of other doctors, family members and patients.

They were not entirely in agreement. Most of the laypeople present stated that no progress whatsoever had been made in the "fight" against MS and demanded the kind of government interventions that had made possible the mass production of penicillin, which in turn was credited tor the sustained health of Allied troops invading Nazi Europe. Putnam, who had been an active participant in MS research for the last two decades, was confronted by a discontented public who did not seem to know about the progress he and others had achieved since Cruveilhier and Carswell.

Putnam was the first major researcher to go public with a theory of MS cause and the prospect of a treatment in 1942, but in 1949 he could not claim great success for this treatment. Though he described further research into other medications, he was facing people who wanted results, no hypotheses. 
From "Multiple Sclerosis through history and human life" by Richard M. Swiderski- page 159  

Dr. Putnam had his hypothesis of blocked veins, but he did not have success in curing MS with newly discovered anticoagulants.  The public wanted results.  They wanted a penicillin for MS.  They wanted a vaccine, like the polio vaccine.  They wanted a cure.  

This is the primary reason why the research focus went to the EAE model of MS, created by Dr. Thomas Rivers at the Rockefeller Institute.  Rivers has worked on the polio vaccine, and his research was perceived as the "future."  He had discovered, while working on the polio vaccine, that immune cells, once activated by a foreign agent, could enter the central nervous system of monkeys and cause demyelination.
http://centennial.rucares.org/index.php?page=EAE

Putnam had his published research and a trial in pwMS using the drug dicoumarin.  This drug had just been discovered in 1941; it was a blood thinner created from spoiled clover.  It was found to be useful in dissolving blood clots.  Dicoumarin was helpful for relieving symptoms in people with MS, but it was not the hoped for cure.  The disease continued to progress.  At that time, there were no surgical or venoplasty treatments to address venous stenosis, nor were there machines to see venous occlusion in humans.


It is important to state that this is why neurologists say, "We've already been down the vascular path in MS research.  It was a dead end."  Because Dr. Tracy Putnam did not cure MS with a newly discovered blood thinner in the 1940s.   And the focus and research money went to neuroimmunology, creating a 20 billion dollar a year treatment industry.

Dr. Putnam had a decade for his vascular research.  The EAE autoimmune mouse model of MS has had over seven decades, and there is still no clearly defined disease aetiology for multiple sclerosis.

Who was this brilliant man, and why has he been removed from the story of NMMS multiple sclerosis research history? 

Dr. Putnam assumed the Directorship of Neurological Unit at the Boston City Hospital in 1934 as Professor of Neurology at Harvard. His intellect, scientific bent, and exceptional teaching and writing skills, all developed to the fullest in the exceptional period of Harvard’s eminence in the neurosciences, soon catapulted him into the international prominence. 

During his research years at Harvard, he developed novel fields of study and surgical approaches to neurological disorders, he developed novel ideas about subdural hematoma, hydrocephalus, motor disorders and epilepsy, and participated in the early studies with Houston Merritt and others, eventually developing the drug Dilantin as he described in his book in 1970 “The Demonstration of the Specific Anticonvulsant Action of Diphenylhydantoin and Related Compounds.” He was appointed Professor of Neurology, Professor of Neurological Surgery, and Director of the Neurological Institute of New York in 1939, just before the onset of World War II and the departure of a number of the talented younger people who he brought as supporting staff to New York. 

Dr. Putnam’s years at the Neurological Institute of New York were not happy ones for him, since World War II decimated the younger and potentially helpful members of his staff, and his gentility and generosity of spirit were commonly misunderstood as weakness and vulnerability.

He was beset by administrative and wartime personnel problems while at the same time maintaining a major editorship in Neurology and important governmental responsibilities. 

Because of the various pressures and other factors, he moved to California in June 1946 to become Director of Neurology at the Cedars of Lebanon Hospital. As Dr. Edward Schlesinger* has written, “Rarely has an individual brought so many talents to neurology and neurosurgery, or pointed out so many directions of ground-breaking research. Unfortunately, coincidences of time and place exacted a catastrophic toll on his career and he died on March 29, 1975.” 

There were rumblings about Dr. Putnam.  He had hired many "non-Aryan" neurologists on the Columbia staff.  He had brought in Jewish researchers, like Elvin Kabat, to help him understand MS.  Putnam did not care about racial or religious divides.  He only wanted to work with the best and brightest.   For those of us who were not living during this time, it may be hard to comprehend, but anti-semitism in the US was very prevalent.  Here is more on this part of the history in Dr. Putnam’s story.

Dr. Putnam was forced to resign in 1947, ending his career at Columbia. Colleagues at the time suspected several reasons, including a lack of administrative skills, enemies on the staff and the conflicts that arose from having a neurosurgeon running a neurological institute.

But Dr. Rowland unearthed another explanation. A New York newspaper of the era, called PM, reported in 1947 that Dr. Putnam had been told to fire all of the “non-Aryan” neurologists, something he was unwilling to do.

Dr. Rowland corroborated this story when he discovered a 1961 letter written by Dr. Putnam to a fellow physician. Dr. Putnam reported that Charles Cooper, then head of Columbia’s affiliated hospital, Presbyterian, had told him in 1945 “that I should get rid of all the Jews in my department or resign.”

Quotas for Jewish medical students and physicians disappeared fairly rapidly after World War II, partly in response to Nazi atrocities against the Jews. But Dr. Putnam’s quiet advocacy on behalf of Jewish physicians when such a stance was unpopular should not be forgotten.

Another one of the Jewish MS researchers Dr. Putnam worked with and supported was Alexandra Adler-

Adler also contributed to the understanding of the neurological basis of multiple sclerosis. Adler and the Harvard neurosurgeon Tracy Jackson Putnam (Putnam & Adler, 1937) conducted a post-mortem study of the brain of a woman diagnosed with multiple sclerosis, demonstrating that cerebral plaques characteristically spread in a rather odd, specific relationship to large epiventricular veins and bizarrely altered the affluents of these veins. Illustrations from this article are routinely reproduced in the medical literature on multiple sclerosis.

Dr. Tracy Putnam left Columbia University and academia behind.  He moved to Beverly Hills, CA, and became Director of Neurology at the Cedars of Lebanon Hospital. and also began a private practice as a neurosurgeon and neurologist.  He continued to treat MS patients with anticoagulants. But he was a broken man.  He was bitter over his treatment at Columbia, he was disheartened that his research had been dismissed. He kept very detailed records on the MS patients he treated with anticoagulation therapy.  He cared deeply about his patients, and wanted to be able to offer them more help and hope. 

I've thought about Dr. Putnam many times during the past four years, wondering how he would respond to Dr. Schelling's book or the new doppler ultrasound technology and Dr. Zamboni's discovery of intraluminal venous malformations in people with MS and treatment with venoplasty.  

My husband had an occluded venous sinus, just like Dr. Putnam's poor dogs.  His sinus was stented and normalized flow has been returned.  He has had no MS progression, no new lesions, and reversal of his gray matter atrophy since treatment. 

We can see the parallels --the tossing aside of Dr. Putnam's research after a lack of a "cure" and the discontent with Dr. Zamboni's CCSVI research and the lack of an immediate cure.  I worry that the immunological side of MS is given all of the research money and time, while the vascular connection remains underexplored and underfunded.   I worry that the focus on a "cure" is put before the understanding of MS pathogenesis.  How can we cure what we do not understand?  It bothers me that there is not more curiosity in the neurological world regarding truncular venous malformations and hypo perfusion.   As regular people, we can see the direct connection from Dr. Putnam's studies on veins in dogs, to Dr. Zamboni's discovery of intraluminal malformations in jugular veins, and the hemodynamic changes in blood flow in people with MS.  Why is there not more curiosity in MS specialists?  Where are the Tracy J. Putnams?

Let's keep Dr. Putnam's research and humanity alive.  He may not be included in the National MS Society pages as a hero, but we can honor him in our own ways.  By telling his story, by encouraging multi-disciplinary collaboration in MS research, by caring about those with MS, and by believing that the best and brightest- no matter their heritage, background or medical training-should be allowed to explore and understand this disease.  (and maybe you can give to  the ISNVD www.isnvd.org and CCSVI Alliance, and help us carry on this work   www.ccsvi.org)

Thank you, Dr. Putnam.
Joan




Sunday, April 22, 2012


Why mouse models of stroke and MS don't work

April 22, 2012 at 8:51am

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

EAE is not MS in humans.  
Believe it or not, the current MS drugs cure mice of EAE.  But they sure do not cure people of MS.  
What's the problem?   There are many problems with the EAE model.    
Here's my favorite description of what's wrong with EAE, from Dr. Michael Dake--

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

People with MS haven't had this cocktail of viruses injected into their brains.  (Good thing!)
But there's much more. The immune system of rodents and humans are very different, too.
Stroke researchers understand that their rodent models are not working.  
This is because the immune reaction after ischemia is very different in rodents when compared to humans

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

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

The rodent immune cell composition is remarkably different from that of humans.
Specifically, rodents have a lymphocyte predominance with a 1:5 ratio of neutrophils to lymphocytes.
Humans have a 2:1 ratio of neutrophils to lymphocytes.

What does this mean?  Time for some explaining.
Neutrophils and lymphocytes are both types of white blood cells that make up the innate immune system of all mammals.

Thursday, December 8, 2011

How does the new gray matter research apply to CCSVI?



December 8, 2011 at 10:21am

If you haven't read yesterday's rather paradigm-shifting news about MS and the gray matter, look down a couple of posts.

In a nutshell--researchers from the Cleveland Clinic,  Mayo Clinic, and also Yale- have come forward with new evidence that confirms decades worth of research showing that MS is not primarily an autoimmune disease of the white matter, it is first a disease of gray matter.

The researchers admit that they do not know how current disease modifying drugs address cortical brain damage, and there are no current therapies created for this purpose.  This is most likely why MS disease progression continues while patients are on the drugs, even though relapse numbers may be diminished.  This is why gray matter atrophy is the biomarker for MS disease progression.

_________________________________________________

 How does that fit in with Dr. Zamboni's discovery?  
The gray matter uses 94% of the brain's oxygen supply.  Because of this, gray matter is especially sensitive to any low oxygen environment.

The gray matter is densly packed with blood delivering capillaries.  The blood is what gives gray matter it's color and density.  Any endothelial dysfunction in this region can increase the risk of damage.  Any refluxive flow, break in the blood brain barrier, any iron or heme deposition into brain tissue from microvascular leakage, can affect this part of our brain and create inflammation.

In other words---adequate blood flow and perfusion is essential in this area of the brain.  For delivery of nutrients and oxygen, for removal of waste, for shear stress to maintain a healthy blood brain barrier.  Venous insufficiency and reflux is disasterous to the gray matter and can create inflammation.

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Many of the doctors involved in CCSVI research (Haacke, Hubbard, Dake) have written about the deep cerebral drainage of the cortex, and how this can be impacted by venous insufficiency.

Tuesday, June 28, 2011


The autoimmune theory of MS; Doctors ask, "Have we got it horribly wrong?"

June 28, 2011 at 9:37am

Have we got it horribly wrong? 

 The fact that an opinion has been widely held is no evidence whatever that it is not utterly absurd; indeed in view of the silliness of the majority of mankind, a widespread belief is more likely to be foolish than sensible.
Bertrand Russell*

"The Pathogenesis of MS revisted."  
The Full paper is available here (this is one to print out and share.)

Here is a review of this critical paper in an issue of the New Scientist from 2002
New Scientist vol 176 issue 2369 - 16 November 2002, page 12 

It's not surprising there's no cure for multiple sclerosis. Researchers have been studying the wrong disease for over a century, argue a few rebels.  

THE century-old assumption that multiple sclerosis is an autoimmune disease is under attack. Treatments based on the autoimmune theory have failed so miserably, say a group of doctors, that it is time to look for other explanations.

In a lengthy review to be published next week in The Journal of the Royal College of Physicians of Edinburgh, the three neurologists dispute the received wisdom that the disease wreaks its havoc when immune cells attack and destroy myelin protein, which insulates nerves and helps them conduct signals. Instead, they back an emerging theory that MS is caused when support cells called astrocytes malfunction, perhaps as a result of genetic and environmental triggers.
 (NOTE:  One well-documented environmental cause of astrocyte malfunctioning is hypoxia, or low oxygen in the brain)

Many mainstream MS researchers contacted by New Scientist have poured scorn on the review. But a few agree it's time for a rethink.

Peter Behan and Abhijit Chaudhuri at the University of Glasgow and Bart Roep of the Leiden University Medical Centre pull no punches in their attempts to demolish the prevailing theory. They begin by attacking the animal experiments that have underpinned the autoimmune theory since the late 19th century.

Tuesday, May 17, 2011


EAE in mice vs. the new Stanford animal model of CCSVI by Dr. Michael Dake

May 17, 2011 at 7:39pm
Here is part of Dr. Dake's lecture from the Hubbard Foundation conference:

First, Dr. Dake explains how the current model of EAE is created in mice.  It is a rather convoluted procedure--

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

So, what we've done is taken mice and ligated (the jugular veins)  and we're going to move now up to marmosets, because that's the next level of the species, and marmosets you can actually partially occlude the veins and keep them open without totally ligating them.

 And these mice and their veins, we've got a recipe that we think is right where we want it.  We're starting to see not only clinical performance differences between mice that are ligated and mice that aren't  ligated, but now there's a way to tomographically, in a little mouse brain, to make these wafer thin micron sections thru the whole brain and we're learning a whole lot.  I think it's going to be very interesting as we move up to a larger model to really see....but we think that we're seeing an accentuation of the venous ligation on the disease process."

No words to describe how much I respect this man.  He listened to us and was interested, treated my husband's venous malformations,  and continues to speak out on CCSVI.  Thanks, Dr. Dake.


Tuesday, April 13, 2010

Cognitive Dissonance and Credo


April 13, 2010 at 9:06am

My dear friend Marie, who has secondary progressive MS and was the second person treated at Stanford for venous malformations, taught me a very important concept when we started this journey together. 
"Joan, CCSVI and the vascular connection to MS will be tough for neurologists to accept. They will have cognitive dissonance."

As a musician, dissonance is something I know about. Hit two adjacent notes on the piano, and you get a dissonance. They "rub" each other. Move your fingers apart, to play a major third, and the ear is happier. You get consonance, resolution, or harmony.

Cognitive dissonance is when two opposing ideas rub in your brain at the same time, just like those notes.  This causes discomfort, so we humans try to avoid thinking about these things.
Some practical examples-
I know smoking is bad for me, but I'm addicted and need this cigarette.
The person I voted for is doing some pretty terrible stuff, but I picked them, so I have to keep supporting them.
I know this burger and fries aren't great for my health, but they are delicious, so the hell with it.
Yeah, that player may have beaten up his wife, but my team is having a great season, so I'll cheer for him.

The brain needs one of these ideas to win over the other, since both realities co-existing is painful.

Having a teenager in our house makes us deal with cognitive dissonance every single day.
"Mom, I know you tell me God is a loving creator, but why does He allow so much pain and suffering? What about Haiti???  What about Syria?  Does God will that?

Because Jeff and I are Christian, we point our son to the New Testament, where we learn that Jesus came, not as a wealthy and powerful king, but as a poor, suffering servant. He taught us to take care of others first, before pursuing our personal happiness, and that pain is a natural part of life, but it is never in vain.  If we were Jewish, we would point him to the Torah, and teach him that life is full of suffering, but we respond by caring for others, following the law, and worshipping our Creator. If we were Buddhist, we'd teach him about detachment from earthly cares and the path to enlightenment. Muslim; we would point to the Qur'an and how the Prophet came to teach us to care for others and worship Allah. If we were atheists, we'd agree with him; how could a loving God let so many people suffer? Religion (or the lack of) can often provide a solution to the cognitive dissonance of life. So can philosophy, so can therapy, so can nature.

I mention religion, because right now in Toronto, a medical establishment has gathered to profess their group "credo", which simply means "I believe."  These neurologists believe in the theory proposed in the 1940s by Dr. Rivers: that MS is an autoimmune disease best modeled in mice by EAE. All of the medications and therapies they offer are based on this credo. All of the lectures they attend, all of the textbooks and research written, all of the speakers, and all of the fine meals are financed by this credo.

And now here come a bunch of outsiders asking that they open up their minds to another viewpoint. MS could be caused by a malformation in the venous system--as evidenced by reflux of blood and stenosis in most MS patients. Cognitive dissonance is the result. How can their theory stand up to a completely new model? These two thoughts cannot co-exist in the mind, so one must be annihiliated. Guess which one they are going to kill?

In the beginning of all of this, I had hoped that the neurologists would be thrilled to investigate a new model of MS...afterall, they are healers, and surely they want to look into any theories of the potential causation of MS, right? But in talking with Dr. Schelling, I learned from history. Nothing has really changed in thirty years, except everything has changed.

We now have each other thru the internet, and the potential to take this research (which is compounding evidence daily) to vascular doctors and interventional radiologists. They do not have any conflicting views, no cognitive dissonance for them. They are willing to test this new theory, because it makes sense to them. They see how neurovascular diseases work everyday. They understand the importance of venous return. We have consonance. Harmony.

I've included a recording to listen to....I love ancient music, because the idea of dissonance transforming into harmony is so beautifully illustrated in this era. Gesualdo was considered "crazy" in his time, because of the dissonances he used in his compositions. Listen to how the rough, unexpected notes, rubbing against each other, give way to consonance and resolution.

Remember cognitive dissonance when you try to explain CCSVI to your neurologist. Feel compassion for them.  This is going to be a very difficult concept to consider. Try to find a doctor who understands what you are looking for. If your neurologist is open minded enough to accept the rub of dissonance--you are a lucky individual!

Joan