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

Saturday, June 30, 2012

UBC research on natural course of MS

June 30, 2012 at 10:34am

There is a new paper from the neurological division of UBC on the natural improvements and disease course that occur in pwMS who are NOT treated with disease modifying drugs.  This data uses measurements from patients' birth, rather than MS onset.  Researchers call these patients who never received disease modifying drugs "treatment naive"--and there are not many of these folks around to study anymore, so this paper is very important.

 Here is what the study showed, from a recent presentation by lead investigator Professor Helen Tremlett:

The natural history of MS and implications for clinical practice
Professor Helen Tremlett, University of British Columbia Hospital, Vancouver, opened the conference with an overview of long-term natural history studies of MS in British Columbia. Data from this large cohort suggested progression of MS is slower than previously thought, which has implications for designing clinical trials and determining the long-term effectiveness of disease modifying therapies (DMTs).

Data demonstrated that by measuring time to outcomes from birth rather than from onset of MS men and women have similar disease outcomes (time to reach EDSS 6); an older age at onset is favourable; relapses do not affect long-term disability outcomes and early relapses only impact progression over the short-term. Whilst young patients with MS may gain long-term benefit from treatment with DMTs, older people may find limited benefit. Interestingly, MS relapse rates naturally decrease over time and a five year relapse-free period was common (occurring in 77% of people with relapsing remitting MS) independent of drug therapy.

Please note, this is all new info, and goes against common and current thought about MS disease progression--

Men and women have similar disease outcomes.
Older age at onset is favorable
Relapses do not affect long term diability
It's common to go 5 years without a relapse.
Relapse rates decrease over time, and older people will find limited benefit in DMTs.

Monday, June 25, 2012

Multiple Sclerosis: Hypoperfusion/Reperfusion Theory

June 25, 2012 at 1:47pm

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

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

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

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

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

The relatively new concept of neurovascular unit (NVU) helps to clarify the hemodynamic changes due to the intricate interplay between cerebral blood flow (CBF) and vasoactive factors. Several studies have demonstrated the importance of endothelial factors, their neurovascular interaction, and that vascular changes are also highly conducive to neurodegenerative changes and clinical impairment.1013 Cerebral hypoperfusion and vascular factors are strictly involved in neurovascular dysfunction, vascular oxidative stress, and relative tissue hypoxia, well in advance of any demyelinating lesions. Changes in capillary resistance and neurovascular function may, in fact, represent important common denominators for conditions that increase the risk of developing both demyelinating lesions and progressive MS forms. https://journals.sagepub.com/doi/full/10.1177/1177271918774800

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

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

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

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

Dr. Michael Dake mentioned in a presentation at International Society for Neurovascular Disease (ISNVD) how "hyperperfusion" (otherwise known as reperfusion injury) occurs BEFORE an MS lesion forms.   He referenced this paper, which discusses how this perfusion change happens before the break in the blood brain barrier, before the immune system entry, before demyelination. The very first step is a change in perfusion.  I wanted to know--why?

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

We are learning more and more that gray matter loss, or brain atrophy,  is a reliable method for monitoring the neurodegenerative process in MS.  Gray matter loss and death of neurons begins from the inception of the disease and continues with increasing disability.  It is linked, only modestly, with white matter lesions. This is why the current medications which suppress the immune system do not stop MS, and are not effective in progressive MS.
We already know that pwMS have lower levels of glucose and O2 being delivered to their brain and spinal tissue, due to hypoperfusion, which can cause neurodegeneration and mitochondrial dysfunction.

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

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

I think that on top of this ongoing process of neurodegeneration,  there are intermittent ischemic events which take these glucose and O2 levels dipping even lower--  events like an illness, a trip to high altitude, stress, an injury, giving birth, a bacterial infection--and when the event is over, the reperfusion cycle begins--this is what we call an exacerbation or "MS flare."  

I believe this is why many pwMS can directly tie their relapses to times after viruses, stress, lack of sleep, etc. These events become the straw that break the camel's back.  And once these events end, reperfusion injury happens. It's a damaging one/two punch.

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


Reperfusion Injury and Multiple Sclerosis relapses share:

1.  Demyelination -- Loss of myelin occurs after nerves have blocked blood flow, low O2 and glucose, and then a return of blood flow.  Reperfusion causes demyelination of nerves.
Perivascular demyelination and intramyelinic oedema in reperfusion nerve injury.
Acute inflammatory demyelination in reperfusion nerve injury

2.  Blood brain barrier disruption--the blood brain barrier becomes permeable, and endothelial tight junctions are altered in reperfusion injury.
Reperfusion-induced injury to the blood-brain barrier after middle cerebral artery occlusion in rats.

Blood-brain barrier disruption and matrix metalloproteinase-9 expression during reperfusion injury: mechanical versus embolic focal ischemia in spontaneously hypertensive rats.

Ischemia-Reperfusion Injury in Stroke

3. An excessive innate immune response--immune cells are called in 
Association of immune responses and ischemic brain infarction in rat.
Naturally Occurring Autoantibodies Mediate Ischemia/Reperfusion-Induced Tissue Injury

4. An excess of free radicals, oxidative stress and partially reduced oxygen species are found in both reperfusion injury and Multiple Sclerosis
Oxidative Stress in Multiple Sclerosis
Mechanisms of Oxidative Damage in Multiple Sclerosis 
The role of oxidants and free radicals in reperfusion injury

5. Endothelial Dysfunction as evidenced by elevated levels of endothelin-1 in plasma 
Increased endothelin-1 plasma levels in patients with multiple sclerosis.
Extraocular blood flow and endothelin-1 plasma levels in patients with multiple sclerosis.
Endothelin-1 is involved in the pathogenesis of ischemia/reperfusion liver injury

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

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

Functional impairment of lymphatic drainage from the CNS after ischemic stroke may lead to rapid neuronal cell death due to the accumulation of toxic metabolites in the brain parenchyma.


Reperfusion has been studied extensively on the arterial side.  However, the all important lymphatic drainage mentioned in the paper linked above, occurs on the venous side.   Like most medical research, the study of the veins and venous return is lacking, and stroke researchers admit this is a problem in understanding the full impact of reperfusion injury. 
Although most experimental studies target arterial aspects of recirculation in stroke, a few have focused on the venous side. In contrast to studies of cerebral artery occlusion, which are methodologically more consistent among different laboratories, studies of venous thrombosis models are at an early stage of development and lack standardization, which greatly complicates comparison of results from different laboratories. Furthermore, most published studies have focused either on arterial or venous components, and very few have examined both arterial and venous components in studies of recirculation. Therefore, a goal of the present commentary is to emphasize that both arterial and venous components should be considered in studies of acute ischemic and hemorrhagic stroke.
Overall, the “recirculation” concept strongly suggests that stroke treatment paradigms need to address venous outflow from the brain in relation to arterial inflow. Therefore, to minimize potential brain swelling and reperfusion injury for severe stroke patients, we need to consider carefully venous pressure and outflow, potential arterial smooth muscle and venous endothelial phenotype changes, possible pre-existing venous sinus hypoplasia, and in particular, if nimodipine will be used.

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

Elevated venous pressure can be associated with severe tissue injury. Few links, however, between venous hypertension and tissue damage have been established. We examined here the effects of micropressure elevation on the outcome of venular occlusion/reperfusion in the mesenteric microvasculature of male Wistar rats. One hour of venular occlusion (diameter approximately 50 microm) by micropipette occlusion followed by reperfusion were carried out with sham surgery without occlusion as control. Leukocyte rolling, adhesion, and migration, oxygen radicals detected by dichlorofluorescein (DCF), and parenchymal cell death detected by propidium iodide (PI) were recorded simultaneously in the same vessel at a location upstream of the occlusion site with elevated micropressure and at a downstream location with low micropressure.
The number of rolling, adhering, and migrating leukocytes increased on the upstream side of the occlusion to a higher level than downstream of the occlusion site.

Microhemorrhages of blood cells into the mesentery interstitium were observed only on the upstream side of the occlusion. These results indicate that an elevation of the venular blood pressure during occlusion/reperfusion exacerbates the inflammatory cascade and tissue injury. Venous occlusion may constitute an important mechanism for tissue injury.
(note the upstream microhemorrhages caused by venous hypertension in this study.  These tiny, pinpoint spots of blood escaping into tissue might be linked to the iron deposition and hemosiderin we find in the MS brain.)


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

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

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

In the past, MS has largely been considered a chronic inflammatory and demyelinating disease, driving most of the research and treatment development towards targeting the immune system. As of now, disease modifying therapies for MS are limited to various anti-inflammatory agents that reduce acute inflammatory lesions, clinical relapses and disability progression in RRMS. These anti-inflammatory agents, however, do not completely prevent axonal injury and are largely ineffective in treating progressive MS.
The recent resurgence of MS research focused on axonal degeneration mechanisms has resulted in convincing experimental evidence and potential treatment targets. As reviewed above, mitochondrial function is crucial in preserving axonal integrity in both acute inflammatory and progressive stages of MS. Therefore, therapies that protect mitochondria and enhance their functioning warrant investigation.

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

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

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


A brief recap:

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

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

But, as you all know by now---I'm not a doctor.  I just hate MS.  And I want more answers.
Please, let me know your thoughts, and please share with medical people and researchers you may know,  what part of this theory is lacking?  Does this make any sense?  How should research move forward?


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.

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.


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). 

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.

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.”

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.

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.

Friday, June 1, 2012

You can change your cells

June 1, 2012 at 8:10am

Just like stem cell science, we're going to be hearing a lot about epigenetics.  Epigenetics is the study of changes in gene expression. "Epi" simply means outside of or above.

These patterns of gene expression are governed by the cellular material — the epigenome — that sits on top of the genome, just outside it. It is these epigenetic "marks" that tell your genes  to speak loudly or whisper. It is through epigenetic marks that environmental factors like diet, stress and prenatal nutrition can make an imprint on genes that is passed from one generation to the next.

This new avenue of research looks at how environment changes our genes, by switching them on or off--this includes what we eat and drink, what we come in contact with, and how we move and handle stress.  How we live our lives can create and change our genes.

We used to believe that there was no outside influence that could effect our genes.  What you were born with was what you had for the rest of your life.  And this is true in many instances.  Your baby blue eyes are thanks to Grandma. But Grandpa's diabetes or heart disease aren't your destiny.

This is why identical twins can have different diseases.  We see this in cancer, heart disease and MS.

Recent research has shown that, just like cardiovascular disease,  there is not one specific gene related to multiple sclerosis.  The closest researchers have come is to isolate the HLA locus and the MHC gene.  But only 4% of pwMS have this gene. This has lead some researchers to posit that MS may be an epigenetic disease-

For an excellent article, published just last month on epigenetics and MS--

There's something you can do to change your own cells.  Today.  Honest.