The latest buzzword in MS research---"smo(u)ldering"

MS researchers are considering the ongoing deterioration that occurs in the MS brain, even when patients are treated with current MS medications.  This leads to ongoing progression, damage beyond lesions and relapses which may be related to gray matter atrophy. The new term used to describe this underlying process is "smoldering (or smouldering) disease".  Literally, smoke, but no flame.

Maybe you've also seen many articles on this new "discovery"--which has come about because the current MS drugs are not arresting disease progression, and this offers a new drug target.

Despite therapeutic suppression of relapses, multiple sclerosis (MS) patients often experience subtle deterioration, which extends beyond the definition of "progression independent of relapsing activity." We propose the concept of smouldering-associated-worsening (SAW), encompassing physical and cognitive symptoms, resulting from smouldering pathological processes, which remain unmet therapeutic targets. We provide a consensus-based framework of possible pathological substrates and manifestations of smouldering MS, and we discuss clinical, radiological, and serum/cerebrospinal fluid biomarkers for potentially monitoring SAW. Finally, we share considerations for optimizing disease surveillance and implications for clinical trials to promote the integration of smouldering MS into routine practice and future research efforts.  https://pubmed.ncbi.nlm.nih.gov/39051525/

Long time readers of the blog will recognize my questioning this very situation----the ongoing disease progression and loss of grey matter in "treated" MS patients.  In 2012,  I put together a theory of hypoperfusion and reperfusion injury to address the ongoing, unseen disease progression.  

Hypoperfusion/Reperfusion Injury in MS

 https://ccsviinms.blogspot.com/2013/09/multiple-sclerosis-hypoperfusionreperfu.html

Even though I am not currently writing for this blog, I do check it occasionally--and have noted that people are still finding it and reading the posts.  In fact, over a million readers from all over the globe have read a variety of posts since I began writing.  Just today, there were 259 readers, yesterday there were 1223.  Over 30,000 unique readers check out the blog posts each month.  Obviously, there is still an interest in the vascular connection to MS.  

In this new era of AI--I am able to ask the computer/hive mind what it thinks about "smoldering disease" in MS being related to hypoperfusion and hypoxia in the MS brain.  

And AI seems to think it might be something worth exploring!  Perhaps this theory might be worth investigating.  

Yes, there's a strong connection between 

smoldering disease in Multiple Sclerosis (MS) and hypoperfusion (reduced blood flow) leading to hypoxic injury (damage caused by a lack of oxygen). 

Here's how they are related:

• Smoldering lesions: These are chronic, active MS lesions characterized by ongoing low-grade inflammation and tissue damage, contributing significantly to disease progression and disability accumulation, even when there are no outward signs of a relapse.
• Hypoperfusion in MS: Research indicates that many individuals with MS experience widespread cerebral hypoperfusion, meaning reduced blood flow to their brain. This hypoperfusion can lead to areas of oxygen deficiency (hypoxia).
• Hypoxia and Inflammation Cycle: Hypoxia and inflammation are closely intertwined in MS. Hypoxia can exacerbate inflammation, while inflammation can trigger hypoxia by damaging blood vessels and impairing blood flow regulation. This creates a vicious cycle that contributes to MS disease progression.
• Smoldering Lesions and Hypoxia: Hypoxia may play a crucial role in the development and persistence of smoldering lesions, particularly pattern III lesions which show similarities to hypoxic/ischemic lesions. Studies suggest that chronic inflammation associated with smoldering lesions, especially those containing iron-laden microglia/macrophages at their edge, could contribute to local tissue hypoxia and chronic damage. 

In summary: The concept of smoldering MS highlights the chronic, ongoing nature of the disease and suggests that mechanisms like hypoperfusion and subsequent hypoxia are likely involved in driving this persistent damage and contributing to long-term disability, even in the absence of relapses. 

Vascular endothelial dysfunction associated with severity in MS

I wanted to provide a recent research round-up on the connection of MS to vascular health, specifically how endothelial dysfunction contributes to MS progression.  

As I've explained in another blog post, I do not feel it is appropriate for me to be dispensing medical advice as a layperson.  But I am still interested in seeing the exploration of the vascular connection to MS, and happy to share that the research continues. 

Jeff is now 15 years out from his MS diagnosis, and has shown no further MS disease progression.  His most recent MRI from last June shows continued healing of old lesions and completely healthy, normal gray matter.  And he's still composing, conducting, traveling, teaching, biking, jogging, living.  As his new GP recently commented, he's an incredibly healthy 59 year old man.  The fact that he has had MS for 15 years astonishes her.  Me too.

Here's a short research wrap up:

1. A group of Japanese neurologists examined the level of endothelial dysfunction exhibited by people with MS and found a correlation between lower flow mediated dilation (FMD), endothelial dysfunction, and MS progression.  FMD is lowered when we do not have enough endogenous nitric oxide.

Twenty-seven patients with MS and 24 healthy controls were enrolled. FMD was significantly lower in MS subjects than in control subjects (6.0 ± 0.6 vs. 8.6 ± 0.7, p = 0.006); furthermore, BHI was similarly lower in MS than in controls, but insignificant. Remarkably, FMD was significantly lower in secondary progressive MS subjects than in relapse-remitting MS subjects (3.7 ± 1.3 vs. 6.7 ± 0.7, p = 0.045). In addition, FMD was inversely correlated with the disability score as per the expanded disability status scale (R2 = 0.170, p = 0.033) and modified Rankin scale (R2 = 0.187, p = 0.027).

https://www.msard-journal.com/article/S2211-0348(21)00402-8/fulltext#%20

2. Russian neurologists are looking at how homocysteine decreases endothelial health, and contributes to MS progression. 

The effect of homocysteine on endothelial dysfunction was shown in vitro. It was reported that homocysteine (500 µM) decreases the viability and induces the apoptosis of human vascular endothelial cells. Increases in reactive oxygen species in endothelial cells treated with homocysteine were also found [70]. Increasing concentrations of reactive oxygen species in endothelial cells homocysteine may induce vascular inflammation [19,28]. 

https://www.mdpi.com/2076-3425/10/9/637/htm

I first wrote about the danger of elevated homocysteine levels as part of the Endothelial Health Program

Anemia/low vit. B12 creates high levels of homocysteine in the blood (a sulfur containing amino acid) which damages the endothelium A strict vegetarian diet that excludes all meat, fish, dairy and eggs, or an unbalanced diet of processed foods could create low vit. B12 levels and damage the endothelium (10)

https://ccsviinms.blogspot.com/2016/04/the-endothelial-health-program-8-years.html

3. Our friends from the ISNVD, Dr. Mark Haacke and Dr. Yulin Ge, continue to look at the MS brain, to study the vasculature.  This group is noting a new venous vascular sign in lesions, which they are calling multiple vessel sign (MVS).  Using a new contrast agent called Ferumoxytol, the researchers were able to see enhanced images of MS lesions, and noticed many more small vessel abnormalities.  Rindfleisch's discovery of the dilated blood vessel, the central vein sign, continues to be explored.

 The total number of lesions with vascularity on pre- and post-contrast data were 287 and 488, respectively. The lesions with abnormal vascular behavior were broken up into following categories: small lesions appearing only at the vessel boundary; dilated vessels within the lesions; and developmental venous angiomas. These vessel abnormalities observed within lesions increased from 55 on pre-contrast data to 153 on post-contrast data. Finally, across all the patients, the periventricular lesional vessel density was significantly higher (p < 0.05) than that of the periventricular NAWM.

https://pubmed.ncbi.nlm.nih.gov/33338965/

4. And finally, here is a fabulously thorough review from the ISNVD 2020 meeting, published in 2021.  This paper can serve as a primer for any medical researcher interested in learning more about the vascular connection to MS.  It's all here.  

https://www.frontiersin.org/articles/10.3389/fneur.2021.561458/full

stay well,

Joan

Guardians of the Brain

A recent paper in Nature explains how the brain's newly discovered immune system protects our gray matter.  https://www.nature.com/articles/d41586-022-01502-8

For those who have followed this blog over the past 15 years, you might remember my posts on the ground breaking work of Dr. Michal Schwartz.  It is thanks to her pushing back against the status quo and the work of her student, Dr. Jony Kipnis, that we now understand the importance of immune cells in the brain.  Neuroimmunology is a growing field, and has changed all we thought we knew about the central nervous system.

In 2002, Dr. Schwartz published a new paradigm for MS treatment with her then-student, Dr. Jony Kipnis.  They were concerned that MS treatments which suppressed or ablated the brain's immune cells would eventually be harmful to the brain.  Even though inflammation might be tamped down in the short term, the brain would atrophy, or lose volume, without its protective immune system.  She suggested modulating immune cells, and boosting the brain's immune response, rather than getting rid of it, which made sense to me.  https://pubmed.ncbi.nlm.nih.gov/12374425/

Jeff recently had a new MRI.  It's been 15 years since his MS diagnosis, and we are thankful to report that his gray matter is "normal and healthy" with no loss.  He has no new white matter lesions and he's still biking, hiking, jogging and working.  We are very thankful for his mild course in this disease, and thankful he was treated for stenotic jugular veins and dural sinus.  He was fortunate to be able to stay active and adapt a new lifestyle. 

I no longer share my opinions or advice on MS treatments on the internet, as I felt it was not my place as a lay person to give medical advice.  But I will continue to share the science.  

Please follow the ISNVD for further publications and research on the vascular connection to diseases of neurodegeneration.   https://isnvd.org

As the venous dural sinus in the place where the brain's immune system connects to the vasculature, neuroimmunologists will be exploring this further. 

stay well!   

Joan

MAGNIMS consensus recommendation: Measure brain and spinal atrophy in MS

Readers of this blog have already learned about the importance of monitoring their gray matter.  Volume loss, or the shrinking of tissue, is also referred to as atrophy and neurodegeneration.  I explain this process in more depth here: link  The MRI measurement of atrophy has been proven to be more indicative of MS progression, when compared to white matter lesions.  (The fact that we still use a seventy year old mouse model to measure white matter lesions for MS drug efficacy boggles the mind.)  This paper advises that MS specialists look at other MRI markers to understand how treatments might be impacting loss of tissue and MS progression.

A consortium of international MS experts published this review earlier in the year, right before COVID, and I missed it.  It was not sponsored by any specific drug company.  The MAGNIMS study group (Magnetic Resonance in Imaging in MS) was comprised of MS experts from seven countries.  I highly recommend discussing this research with your doctor, to make sure you understand how your own gray matter is doing.  

link to MAGNIMS study in Nature

The authors discuss lifestyle factors which impact brain volume. I like to call these factors "the things we can change."   There are things we can do today to maintain our gray matter.  The heart brain connection is real, and vascular health impacts our brains.

Many lifestyle factors, including physical activity124, influence estimates of brain volume. A higher level of alcohol intake has been associated with a higher rate of brain atrophy over a 6-year period115 and with a specific pattern of regional involvement of the white matter and grey matter125. A similar effect has been described for cigarette smoking and substance abuse (for example, marijuana use)115,126. Many systemic conditions, such as diabetes, chronic kidney disease, hypertension, obesity and vascular conditions can also accelerate brain atrophy115,127,128.

Please notice the mention of vascular conditions.   All of this is new.

I've written about how Jeff's gray matter atrophy was reversed thanks to vascular and lifestyle intervention.  This post is from 2018 Celebration!   Jeff's good health continues in 2020, and he is still hiking, biking, composing, and active.  He's also down to his high school track star weight (178!) and has built up muscle tone.  He remains my inspiration.  Our goal, God willing, is to stay healthy and active, and live to see the end of this pandemic.  We work on managing the things we can change--by eating whole foods, moving every day, getting sunshine, staying connected to family, praying, meditating, making music, laughing, helping others, and letting go of the factors beyond our control.  I've mentioned the serenity prayer before.  link Written in the trying 1930s by Reinhold Niebuhr, American theologian, it is a reminder to take each day at a time, especially as we face difficult times. 

Here is to getting through this- with renewed health-- physically, emotionally, spiritually.

with love from smokey California,

Joan

Endothelial Health goes mainstream...

.... and you can stream a new documentary to learn more.

Thanks to my son and daughter in law for the head's up on the documentary, THE GAME CHANGERS    https://gamechangersmovie.com

Presented by James Cameron, Arnold Schwarzenegger, and Jackie Chan  — a revolutionary new film about optimum health and strength.  You can view it now on Netflix.

My family told me I needed to watch it, because it was documenting what I have been harping on for years.  My son saw me change his Dad's diet and lifestyle, and has heard me discussing this topic for over twelve years.   Mainly, the importance of endothelial health, and how eating plants full of anti-oxidants and phytonutrients increases nitric oxide availability, helps endothelial cells, and increases blood flow to all of our body, most importantly our brains.   

Nutrition is a very large componant of my program, which also includes physical activity, good sleep, sunshine, meditation, probiotics, minerals, smoking cessation, and laughter.   Each and every one of these measures is known to increase nitric oxide, which relaxes our blood vessels and increases blood flow.  This is how we can combat the hypoperfusion, or slowed and restricted cerebral bloodflow, seen in MS, Alzheimer's, dementia and Parkinson's.  These are things we can do for ourselves.  

link to the program

This new movie is focused on elite athletes who utilize plant-based diets to achieve optimum strength and endurance.  And while I do not specifically advocate a vegan lifestyle in The Endothelial Health Program,   I suggest that people with MS favor whole foods and plants, to increase nitric oxide. (There are conflicting views on animal protein within the field of experts, and I DO NOT go into the weeds on this topic.)  My approach has always been to look at positive environmental measures people with MS can take to feel better.   And eating more plants will help accomplish that goal.

In the film, Dr. James Vogel, co-chair of the NFL subcommittee on Cardiovascular Health, discusses the importance of eating plants to increase available nitric oxide and increase blood flow.  He even speaks of the endothelium, and uses the image shown below. (YES!)

Truly, The Endothelial Program works.  Jeff remains on it.   He's still jogging, biking, writing music, traveling, living life, with no MS progression, no new lesions, and a reversal of his gray matter atrophy.  His most recent MRI shows continued healing of his brain, now 13 years since his diagnosis.

With the help of our vegan son and daughter in law, we have learned how to incorporate even more plants into our diet, boosting nitric oxide and reducing inflammatory foods.   Like jackfruit (google it!), legumes, tempeh, and lots more greens.

My hope for all of us, as we begin a new decade, is that we can take care of ourselves, our families, our communities, and discover that there are many things we can do to improve our own health and the health of our planet.

Be well,

Joan 

China continues to lead the research

New research from neurosurgeons in Beijing looks at how the veins impact brain health.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6932895/

As most of you know by now, the arterial side, or blood flow delivery, receives all of the research.  We have scans for the carotid arteries which are routinely given for stroke and cognitive dysfunction in aging populations.  But this new resarch looked specifically at how jugular venous stenosis impacted cerebral perfusion, or the amount of blood flow exiting the brain.

It has seemed obvious to most of us that consideration of venous health must be determined in diseases of neurodegeneration.  Sadly, this is not so in western neurology.  North American and European neurology remains content to ignore venous health.

Hypoperfusion, or slowed blood flow, remains a constant finding in people with multiple sclerosis.
http://www.ajnr.org/content/early/2018/01/11/ajnr.A5504
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416892/


In this new research, Chinese neurologists studied those with cerebral venous stenosis (CVS) as well as patients with arterial stenosis (CAS) and those who had both arterial and venous stenosis (CAVS)

From the publication:

Cerebral venous stenosis (CVS) mainly results from extracranial venostenosis (internal jugular vein stenosis, IJVS) and intracranial venostenosis (cerebral venous sinus stenosis, CVSS) [4–7]. Previous publications have described its typical clinical manifestations such as headache, noise, visual impair, sleep disorder and dysphrenia [4, 8]. It can be confirmed by magnetic resonance venography (MRV), computed tomography venography (CTV) and digital subtraction venography (DSV) generally, however, the presentations of brain tissue and perfusion-metabolism status are not fully known. Furthermore, since covered by CAS, some venous stenosis may be misdiagnosed. As for these patients, only treating on arterial stenosis is far from adequate, in contrast, restoring the patency of venous outflow is the key to relieve the refractory neurological symptoms. The aim of this study is to describe the clinical characteristics and imaging findings in CAS, CVS and CAVS, in attempt to further aid the differentiation of these disorders in the clinical settings.

Cerebral arterial stenosis (CAS) plays an important role in chronic cerebral circulation insufficiency (CCCI) [1–3]. Persistent reduced cerebral blood volume and flow cause ischemia and hypoxia in the brain tissue, leading to various brain dysfunctions [1]. Chronic cerebrospinal venous insufficiency (CCSVI) has also been confirmed to contribute to neurological deficits and impose a significant impact on cerebral arterial circulation to some extent [4–9]. In theory, CCSVI plays a causative role in pathogenesis of CCCI as well. Venous outflow disturbance may raise the pressure in arterio-venous anastomoses and affect the blood flow (CBF) and volume (CBV) in the arterial system subsequently [4–6]. Advanced neuroimaging can confirm vasculopathic diagnoses, but clinicians often neglect to further explore the disorders as they related to venous vasculopathy. This leaves many patients with rather severe venous stenosis-related ailment untreated and in a great deal of suffering.

And what did they find?

Neurological impairments including sleep disturbance, hearing disorder, visual disorder, headache, tinnitus, tinnitus cerebri, dry or puffy eyes, neck discomfort, dizziness, anxiety or depression and nausea or vomiting were commonly seen in CVS and CAVS group. The incidences of subjective memory decline were almost same among three groups.

It is now eleven years since Jeff was treated for his severe jugular venous stenosis.  His previous symptoms of headache, fatigue, heat intolerence, dizziness, sleep disturbance, and sleep apnea have remained resolved.  He is able to jog, work, engage in outdoor activities, travel, live life.  He has had no further white matter lesions, and his gray matter atrophy has reversed.  His brain continues to heal, as many lesions have shrunk or disappeared.  For this, we are thankful.

I am also thankful that the ISNVD continues to study venous stenosis and MS diagnoses.  I am thankful for the Chinese researchers who are helping their patients, and looking at how treating venous stenosis heals the brain. 
Here are a few of their publications on treating jugular venous stenosis, and outcomes.
https://journals.sagepub.com/doi/10.1177/0300060519860678
http://www.ijcem.com/files/ijcem0042381.pdf
https://onlinelibrary.wiley.com/doi/full/10.1111/cns.12859

I am not hopeful for North American and European research, however, as the MS drug companies are forecast to be a $40 billion dollar industry by 2026.   link

Stay well, keep moving, get UV rays, eat whole foods, engage in community, remain positive and keep your eyes on the horizon.

Joan

Here are some of the images from the Chinese publication



Here is my husband's MRV from Stanford 5/09, prior to his stenting treatment to open his jugular veins.  Notice the curly collateral veins running alongside the pinched jugulars.  This is what venous stenosis looks like.  He did not have an MRV after treatment, but he did have his cerebral blood flow transit time measured and his hypoperfusion was reversed.

The way forward

We've all learned a great deal about how to live well in advocating for better MS treatments.
One important lesson I've witnessed is that healing is not about making money.  We will never heal disease if we put dollars before people.

Doing the same thing over and over again and expecting different results is the definition of insanity.
Our world is insane.  We sense this, and we know things must change.  But we become overwhelmed by the immensity of the situation.

The health of our own selves, our neighbors and our world depends on our awakening to this need for change.  We cannot sit by and be passive, or wait for some politician or celebrity to fix this.  There are no caped crusaders coming.  For those who are believers, we know that our creator asks us to take care of others, and to love our neighbors as ourselves.  We are all going to have to care.  If you've read this far, chances are you also care.  So, consider the rest of this post a bit of encouragement to keep going.

In the past twelve years, since Jeff was first diagnosed with MS, I've seen very little movement in the understanding of MS etiology, or what causes MS.  We've seen over 10 new pharmaceutical treatments come on to the market, with varying degrees of success in addressing only one type of MS, relapsing remitting.  All of these drugs are based on the unproven theory of an errant immune system which needs to be beaten down, modified, or ablated.  But not one drug has addressed the underlying loss of gray matter integrity, or neurodegeneration--- which is behind MS disease progression.  Understanding the vascular connection to MS has been underfunded, and in the case of CCSVI, only funded to be debunked.  This is because it is difficult to monetize a new, cardiovascularly focused lifestyle.  There is not one pill to heal the endothelium, or increase the brain's perfusion and lymphatic drainage.

Even with all of the negative influences of social media: the bickering, the false narratives, the hacking and use by foreign agents to create chaos---even with all of this darkness, there has been the light of connection.  People have found help for their most pressing concerns.  We've seen people care enough to share good information on wellness and lifestyle modifications, as well as the vascular treatment modalities, and this has changed lives.

Ordinary people have shown up, created the conferences, gone to the meetings, walked alongside others.  Some even made movies, wrote books, funded research,  found doctors, walked the walk and showed others an "alternative" way to treat MS.   And because of all of these efforts, those newly diagnosed with MS are doing better.  When Jeff and I meet newly diagnosed people these days, they ALL know about and implement healthy diet plans, optimize vitamin D levels and sunshine exposure, exercise, meditate, and employ good sleep habits.  They believe they can change their lifestyles and affect their health.  And they do.  We might forget, but this focus on lifestyle modification is new!  link

Here's a wonderful upcoming conference on alternative MS treatments in BC, Canada this October 19th, hosted by the Canadian Neurovascular Health Society
https://www.cnhs.ca/copy-of-2018-neurovascular-health-c

Beyond the pharmaceutical world, we've watched other wealthy and powerful corporations put their bottom line above human life.  From the fossil fuel industry, to the rise in private prisons, the industrial-military complex, the gun manufacturers, and industrial food producers.  These industries create products which are not benign.  They make money harming our bodies, our water, land and air.  They have changed our planet, perhaps irrevocably.  They make money exploiting our fears.

In my lifetime, the world's population has doubled---from 3.5 billion to over 7 billion humans.  And there will be more people coming.  Projections are for 10 billion humans on earth by 2050.  Considering a human beings' value in terms of money-making potential-- as a creator or consumer---will no longer suffice.  Dividing people into groups of good/bad, legal/illegal, white/brown, Christian/Muslim/Jew/non-believer will not work.  There will be more and more climate change refugees, as people will be forced to leave their drought stricken homelands in search of water, food, life.  Building higher walls, creating harsher penalties will not stop the flow of humans seeking survival.  They are us.

We will have to ask ourselves, how can we create a world which will sustain life, and not focus on depleting our resources for financial gain.  How can we be leaders in the change?  How can we share and care for our neighbors as ourselves?

"We need knowledge of how to share."  I highly recommend you watch this short, inspiring video.
Link to Vandana Shiva discussing the Way Forward


Encouraging YOU to find the way forward.
Joan

What happened?

It's been awhile since my last blog entry.  It's not for lack of published research on the vascular connection to MS, as there are new studies showing slowed (hypo) perfusion in the MS brain link a breakdown of the blood brain barrier preceding lesion formation link and further evidence of the importance of cardiovascular health in maintaining brain volume for pwMS.  link

The hiatus was simply because Jeff and I have been busy. We've been traveling, performing, giving masterclasses, celebrating our son getting married and receiving his master's degree, and enjoying living.  Jeff remains active and continues to jog, hike and bike.  He has been very busy with composing commissions, including a song cycle for the St. Louis Symphony, a symphony for the New West Symphony, and new chamber and dance works.  Some new scoring projects to look out for in 2019 are the documentary "The Biggest Little Farm" and a new series for ABC called "Grand Hotel."   Trust me, we know we're blessed.  When Jeff was first diagnosed with MS in 2007, his prognosis was pretty dire.  We do not take his health, or our lives today, for granted.

I wanted to write this post to share a very important paper I first read several years ago.  It was written in 1988--over 30 years ago!   I believe it can help us answer the question as to what happened to CCSVI?  

The entire paper is here: Malcom Nicolson and Cathleen McLaughlin :Social constructionism and medical sociology: a study of the vascular theory of multiple sclerosis

The authors are responding to a critique of their work, which stated that societal hierarchies really didn't influence medical research, and needn't be considered.  The writers disagreed with this critique, and in this paper they show how medical research and treatment are developed with a societal bias.  This bias depends on who claims ownership of a particular disease and what their specialty is.  A researcher's area of knowledge and expertise decide how a disease is viewed and treated.

From the paper:

Scientists cannot therefore devise scientific theories solely in the light of their direct immediate experience of phenomena. They base new knowledge upon the relevant data and upon their pre- existing beliefs and theories. We understand the unknown in the light of what we already know - which, of course, in tum has its roots in training and in prior socialisation. Different observers, therefore, produce radically different cognitive worlds because modes of observation, and the points from which observation takes place, differ.

And the authors use multiple sclerosis as their empirical case study---by outlining how the neuron-centric neurologists had ignored and even deliberately buried the evidence of the vascular system's impact on brain health, in order to focus on their own immunological view of the disease and their  pharmaceutical immune modulating treatments.

This is from the abstract:

A recent debate surrounding the pathogenesis of multiple sclerosis is analysed in terms of the skills, interests and backgrounds of the medical personnel involved. It is noted that the proponents of the vascular theory possess developed expertises in interpreting disease in structural, vascular terms, whereas their opponents' skills lie in immunology or neurology. Different observers have produced different conceptions of the disease because modes of observation, and the points from which observation takes place, differ. It is also noted that the debate over the causation and treatment of MS has occurred between a large and powerful social group and a weak and marginal one. The effects of this power inequality on the production and assessment of knowledge about MS are investigated.

The vascular links to MS have long been known, since Rindfleisch first saw the central vein sign through a microscope in 1863.  CCSVI was not the first vascular treatment to be "debunked" by neurologists using badly designed and obviously biased studies.

As the paper states many times, vascular specialists are not as powerful as neurologists, and rarely are able to respond to these dismissals or badly replicated stabs at their research.  They are paid less, receive less funding for their research, are less respected.  We've seen them disparaged as "plumbers."  Neurologists comment that this is because blood vessels are not as complex as the brain.  And yet, ironically, it is a lowly central vein sign which is 100% accurate in diagnosing MS lesions.
The Central Vein Sign 

Before Dr. Zamboni was ever called a quack, Dr. Tracy Putnam, the founding neurologist of the National MS Society, was maligned for using a newly discovered blood thinner, dicoumarin, to treat his MS patients.  Neurologists were quick to point out that the blood thinner did not help all people with MS, and Putnam's work was therefore invalid.  All of his prior work, his blocking venous return in dogs and creating MS lesions, his understanding of the venous system, was rejected in toto.   Because the new and exciting science of immunology was gaining traction and research funding.  link

After that, Dr. Roy Swank received the "quack" treatment in the 1960s, for suggesting a cardiovascularly healthy low fat diet and exercise could help MS patients.  Even though Swank showed improvements in the vast majority of MS patients who remained on his program, neurologists tossed his research in the trash, mocking him and claiming his studies were not valid.  link

Dr. Franz Schelling, an Austrian physician published a complete review of prior vascular MS research, and asked important questions as to why the jugular foramen opening and venous returns in skulls of people with MS were vastly different from normal skulls.  He research took place at the University of Innsbruck in the 1970s, and his original paper would be published, and is frequently cited by vascular and anatomical researchers, but not neurologists. ( link   link  link )

He then studied cerebral lesions and found a mechanical connection between venous reflux and lesion presentation in the brain and spine.   Dr Franz Schelling produced a Poster Presentation - The Discovery of the Venous Origin of Cerebral Multiple Sclerosis - at the Second European Congress of Nuclear Magnetic Resonance (NMR) in Medicine and Biology.  He was there to encourage other researchers to look at what he had discovered in people with MS  link to poster

Highly recommended and thorough research, which was tossed in the bin with nary a response or curious inquiry from neurologists, and a tragic portrayal of quackery, once again.
link to Schelling's research

The paper on Social Constructivism focuses on another doctor who was similarly dismissed.  Dr. Philip James had the same exact treatment of his hyperbaric oxygen MS studies in the 70s and 80s.  First, he was labeled a quack, then neurologists attempted to copy his studies, changed his protocol and (no surprise!) couldn't replicate his results.  Again, research tossed into the garbage.  This pattern of debunking vascular studies has a long, sordid history.

As the accounts of new experiments and fresh clinical trials are published, each side is able to place its own interpretation upon the results. The early hyperbaric oxygen trials were badly organised and poorly controlled. The results were thus easy to dismiss, particularly since multiple sclerosis is often marked by spontaneous remission, regardless of medical intervention. 

What is most important to take away from all of this is that each of these older "debunked" treatments----HBOT, diet, exercise, blood thinners (such as aspirin) are now scientifically recognized as helpful to people with MS, because of their affect on cerebral blood flow.   And people with MS often utilize some or all of these treatments, without realizing their connection to vascular MS research.  Are these treatments cures?  For some, they can stop MS disease progression. But MS is a wildly variable disease, and these treatments do not work for all.  Does that fact invalidate the research?  I don't think so.  But I'm not a neurologist.

I had hoped people would recognize that venoplasty was not being called a "cure" for MS.  It was simply another treatment--like exercise, diet, lifestyle, meditation, sleep, etc-- which could potentially improve cerebral blood flow, heal the endothelial layer of blood vessels, maintain gray matter and slow MS disease progression.  No surprise,  neurologists went ahead with ill-conceived and flawed studies, in order to debunk Dr. Zamboni and shut it all down.   Better to kill the theory and debunk the messenger,  than attempt to understand the connection.

Even after all of this unnecessary drama, it makes me happy to see people wth MS sharing their knowledge and encouraging each other on social media.  People with MS are healthier today because of this collective knowledge.  I still have hope that the ISNVD will further define the connection between the larger veins, cerebral perfusion and MS, and how to treat CCSVI.  ISNVD website   And maybe someday, neurologists will admit that the engorged central vein-- first seen with a microscope in 1863 and now part of an MRI MS diagnosis-- is important to understand, even if it's only a lowly blood vessel.

I can hope,

Joan

Hope in China-- a new clinical trial

Over the past couple of years, I have been following a group of Chinese researchers from the Beijing Institute for Brain Disorders.   This group is using stents to repair slowed jugular venous flow, reduce collateral veins, improve intracranial hypertension and cerebral perfusion in a variety of patients.

My interest in this area comes from the fact that my husband was treated this same way in 2009.  His benefits from jugular stenting continue, as he has had no new white matter lesions.  He sleeps soundly, dreams, and wakes refreshed.  He had a huge reduction in headache.  His visual loss has ceased.  His fatigue has been reduced.  His gray matter atrophy has been reversed.  He has had no MS progression in eleven years.
Here is the publication on his treatment at Stanford
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4164629/

The Beijing Institute for Brain Disorders was founded in 2012, in the hopes of using new technologies to prevent and repair neurological disorders.  The group of neurosurgeons have published  that jugular venous stenting is a safe and effective procedure, which is helping a variety of patients with neurological disorders.

They have seen intracranial hypertension, headache, visual disturbances, and tinnitus improved in 15 patients who had stents implanted in their jugular veins.
https://www.ncbi.nlm.nih.gov/pubmed/29114973

Because of their preliminary study, this group is now undertaking a randomized clinical trial in Beijng with 60 participants, utilizing stents in jugular veins of patients with jugular vein stenosis.  link to clinical trial

Here is what they will be looking at over the course of one year.  (Please notice how the secondary outcome measures are similar to measures used in Multiple Sclerosis clinical trials--and similar to my own husband's benefits from treatment.)

            ++++++++++++++++++++++++++++++++++++++++++
Primary Outcome Measures  
Correction of internal jugular vein stenosis (IJVS) and abnormal collateral veins 
[Time Frame: baseline, 1, 6 and 12 months ]
The status of internal jugular vein blood flow and collateral veins will be evaluated by imaging modalities, mainly including: Jugular Vein Doppler Ultrasound, Magnetic Resonance Venography (MRV), Computed Tomography Venography (CTV) and Digital Subtraction Angiography (DSA)

Secondary Outcome Measures  :
The evaluation of cerebral spinal fluid (CSF) pressure 
[Time Frame: baseline, immediately post-stenting, within 1 month ]
CSF pressure will be assessed by lumbar puncture

The evaluation of headache 
[Time Frame: baseline, within 1, 6 and 12 months ]
The intensity of headache will be assessed with the Headache Impact Test-6 (HIT-6  The evaluation of tinnitus [ Time Frame: baseline, within 1, 6 and 12 months ]
The severity of tinnitus will be assessed by the Tinnitus Handicap Inventory Questionnaire (THIQ)

The evaluation of the severity of papilledema and other ophthalmological conditions 
[ Time Frame: baseline, within 1, 6 and 12 months ]
The severity of papilledema will be assessed based on Frisén papilledema grade (FPG) criteria; the assessment of other ophthalmological conditions including visual acuity, visual field, and fundus etc. will be based on visual acuity chart, visual fields picture, and optical coherence tomography (OCT) etc.

Changes in cerebral white matter (WM) 
[ Time Frame: baseline, within 12 months ]
The characteristics of WM will be evaluated by Magnetic Resonance Imaging (MRI).

The evaluation of cognitive function [ Time Frame: baseline, within 12 months ]
Cognitive function will be assessed with the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA) and/or the Modified Telephone Interview for Cognitive Status (TICS-M).

The evaluation of mental status [ Time Frame: baseline, within 12 months ]
Mental status will be assessed with the Hospital Anxiety and Depression Scale (HADS). The HADS score ranges between 0 and 21 for either anxiety or depression. A cut-off point of 8/21 is indicated for anxiety or depression.

The evaluation of sleeping status [ Time Frame: baseline, within 12 months ]
Sleeping status will be assessed with the Pittsburgh Sleep Quality Index (PSQI) and/or the Athens Insomnia Scale (AIS). The PSQI score provides an overall score ranging from 0 to 21, where a cut-off score of ≤5 denotes a healthier sleep quality. The AIS score provides an overall score ranging from 0 to 24, where a cut-off score of <6 denotes a healthier sleep quality.

The extent of disability or dependence in the daily activities 
[ Time Frame: baseline, within 12 months ]
The extent of disability will be assessed by the modified Rankin Scale (mRS). (Score 0-no symptoms; score 1-no significant disability; score 2-slight disability; score 3-moderate disability; score 4-moderately severe disability; score 5-severe disability; score 6-dead.)

                             +++++++++++++++++++++++++++++++++++++++++
Finally, here is a brand new published review from this same group, 
"Understanding jugular venous outflow disturbance."
link

I have read the full paper, and am confidant that this research group knows what they are doing, what they are looking for, and what the stakes are.  By removing Multiple Sclerosis from the equation, they will be able to proceed, without the interference of pharmaceutical interest--which has daunted the study of CCSVI.

Thanks to the Beijing Institute for Brain Disorders for taking on this very important study.

Joan

The brain contains 400 miles of blood vessels....

A year after Jeff was diagnosed with Multiple Sclerosis, I wrote several university researchers regarding MS as a vascular disease of endothelial dysfunction.  One of these researchers was at my alma mater, the University of Rochester.  I had first read about his work in our alumni newsletters, and later on pub med. link

Berislav Zlokovic was initially inspired to understand the blood brain barrier's role in neurodegeneration after losing a dear friend to ALS.

"The vascular system is crucial to health -- it's how oxygen and other nutrients are delivered to cells, and how toxins are removed," said Zlokovic, who is professor of Neurosurgery and Neurology and director of the Center for Neurodegenerative and Vascular Brain Disorders. "Any damage to the vascular system is a serious threat to the organism. It's clear now that the vascular system is certainly involved in the development of ALS."

Zlokovic first began doing research on the disease in 2004, when a former classmate from medical school who had been diagnosed with ALS and was looking for new treatments contacted him. By the time his friend died two years later, Zlokovic was well underway in studies investigating the possible role of the vascular system. link

He has been one of the premiere researchers looking at how the vasculature is implicated in the breakdown of tight junctions in all diseases of neurodegeneration.  I wrote to him about Dr. Swank's prior research on capillary fragility, and how I thought it made sense when observing the petechial bleeding on my husband's legs, his enhancing MS lesions on MRI, and the possibilty that the cause of both was systemic endothelial dysfunction.
(Swank RL. Subcutaneous hemorrhages in multiple sclerosis. Neurology. 1958; 8: 497-498.)

Dr. Zlokovic did not reply to my intial inquiry, but we did eventually connect after his presentation at the ISNVD as the keynote speaker, 2011 in Bologna.  He soon left the U of R for the University of Southern California's Keck School of Medicine.

I was thrilled to see that his lab has recently received $25 million in grants to study how leaky blood vessels in the brain contribute to Alzheimer's Disease.  link

Berislav Zlokovic, MD, PhD, a pioneer of the theory that fixing the brain’s leaky blood vessels will prevent Alzheimer’s disease, has received four grants totaling up to $24.9 million over five years.

The funding allows Zlokovic, director of the Zilkha Neurogenetic Institute, to attack from different fronts the blood-brain barrier, a gatekeeper that prevents toxic substances from entering the brain.

“The brain contains 400 miles of blood vessels that can stretch from Los Angeles to San Francisco,” said Zlokovic, chair and professor of physiology and biophysics at the Keck School of Medicine of USC. “If there is a leak along this vascular tube and the pothole is, for example, near the hippocampus — the center of learning and memory — that can contribute to the development of dementia and Alzheimer’s disease. We can delay the onset or slow the progression of Alzheimer’s if we are able to fix leaky capillaries when they first start, some 10 to 15 years before Alzheimer’s symptoms even surface.”

But at the same time, I'm deeply saddened by the realization that we are still in this same place----sixty years after Dr. Swank first noted leaky capillaries and petechial rashes in people with MS and successfully treated this issue in many patients with diet and exercise. link   Thirty years after Dr. Franz Schelling discovered the venous connection to MS and inspired Dr. Paolo Zamboni to look at jugular reflux in people with MS.  link  It sometimes feels like an endless cycle of discovery and amnesia, as researchers uncover, and then willfully bury or forget the vascular connection to diseases of neurodegeneration.

“The blood-brain barrier’s leaks allow many blood-derived toxic products, cells and pathogens to enter the brain and directly damage brain circuits involved in memory and learning,” Zlokovic said. “Additionally, bad proteins that normally are ejected from the brain, such as beta-amyloid, have to struggle against the flow of traffic. This situation can eventually lead to ‘a second hit’: Beta-amyloids and tau tangles remain in the brain and cause damage that become evident years later.”

The research will determine the structure of the perivascular space, how cerebral brain fluid reacts to changes in brain equilibrium and blood-brain barrier leakage. The ultimate goal is to identify therapeutic targets for the treatment of small vessel disease of the brain, which may contribute to cognitive impairment.

I honestly hope Dr. Zlokovic and his team find new therapeutic targets.  They sure have a bunch of money to do so.  However, researchers might do well to also look at mechanistic issues behind these leaky blood vessels.  Venous hypertension and CCSVI were contributing to the breakdown of my husband's blood brain barrier.   Venoplasty to repair his jugular veins resulted in disease reversal for him--with no new lesions and a reversal of gray matter atrophy.   The spots on his legs, and the spots in his brain were connected.  Diet and exercise have continued this virtuous cycle of healthy cerebral perfusion, shear stress, and endothelial cell health. 

Don't wait for this ongoing research loop to end with some new blockbuster drug.  There are things you can do today, to help heal your endothelial cells and limit the breakdown of capillaries.
Promise.   link


Joan

UBC CCSVI Clinical Trial

I want to say upfront, I am not hopeful regarding the results of the University of British Columbia (UBC) CCSVI trial.  The preliminary results may be most dramatically revealed at the Society of Interventional Radiologist conference on March 8th in the Marquis Ballroom of the Marriot in Washington DC.  I have a pretty strong hunch they will be negative and will not show any benefit in venoplasty for CCSVI.  

I wish I could be more upbeat and say that this trial will give CCSVI venoplasty intervention a fair shot, but I've been concerned about bias and an ill-conceived trial since the beginning.  Anne Kingston wrote the best article on this topic back in 2012--
"Finally, CCSVI Clinical Trials.  So Why is Everyone So Pissed Off?"  link

Here is what I thought about Traboulsee's 2014 CCSVI imaging study- Scientific Misconduct?

Fast forward to 2017.  Even though the UBC CCSVI study is still on-going, preliminary results have been fast-tracked for a release at a vascular conference in the US.  This research was submitted to the SIR conference after the deadline for submissions in September. This is from the SIR website, where the investigators are allowed to explain why their presentation deserves consideration.  

Please provide a justification below for this abstract's eligibility to be considered for late-breaking submission.

This will be the first presentation of a randomized, double blind clinical trial of jugular and azygos venoplasty in MS, including patient reported, clinical, and MRI outcomes. The presentation will include all data from the first 48 weeks in all patients after their first procedure only, comparing sham to venoplasty.

This is a multicenter trial with an independent trial coordinator. The database was locked December 23, 2016 and the authors were (and still are) blinded to the outcome. It is a trial of sufficient magnitude and scientific rigor that it deserves presentation at a major society meeting.
link  (search "Traboulsee" to see the submission)

Get that? The trial coordinators and authors claim to still be blinded to results. Seems odd, right? Why submit to SIR, a "major society meeting" without knowing the results? And why now? Why not wait until all the data has been collected and collated?

I believe the reason the UBC study was submitted to SIR, before completion and after the SIR deadline, is because Dr. Zamboni announced, at the Veith Conference in November 2016, that his Brave Dreams Trial had been completed and results would be published in mid-2017. link  

The UBC team submitted their abstract after Dr. Zamboni's announcement, as I believe they wanted to get out in front of the Brave Dreams published study results and put the final "nail in the coffin," ring the last "death knell", be the "last word" (or fill in any of the other hyperbolic titles for anti-CCSVI publications over the last five years.) I honestly think they want to kill this research and be done with it.

I have a hunch we will be reading a lot of negative CCSVI stories in the media in the next few days. Here's a first example from Vox:  
This is why you shouldn't believe that exciting new medical study

Joan, wait... (you say to me) this UBC study is gold-standard research! You sound like a conspiracy theorist. Science is science. Blinding and placebo controlled trials are what you have been asking for! This is exactly what the vascular connection to MS needs---independent study. That doesn't mean you get the results you want! Also, didn't you say you're done with all of this???

Yes, you're absolutely right.  And I am done, but felt it was important to go on record.  Here's my problem. This study does not look at blood flow before and after treatment.  They did not measure venous pressure--so how could they possibly know if stenosis had been treated?

The results of this study are not all objective.  Dr. Zamboni has stated that the Brave Dreams trial results are objective.  Objective results are numbers and stats and things that can be measured and tallied using unbiased machines.  Venous pressure is an objective measure.  Not questionaires from subjective humans compiled by even more subjective humans. 

There was no retreatment for restenosis in the UBC trial (a problem for 50% of patients) or suggested aftercare and lifestyle intervention.  Jeff had to be retreated at Stanford, as he developed intimal hyperplasia.  He also had aftercare treatment and drastically changed his lifestyle, diet and exercise program.  

Angioplasty for carotid artery stenosis has had placebo control trials, and you know what metric they used to measure success?  Size of stenosis and blood flow.  That's it.  Not a questionaire asking "how are you feeling?"  The researchers measured blood flow before and after and at monthly intervals up to a year.  They used ultrasound to see how carotid stenosis looked, if there was restenosis it was re-treated.   And most importantly, after treatment,  they put the study participants on an aftercare program, making sure they had blood thinning treatment and that they exercised and ate better.  Trial participants quit smoking or lost weight, if warranted.  Because without aftercare and lifestyle changes, restenosis can be immediate, and all gains from angioplasty are lost.  IRs know this.   link

Take my husband's reversal of gray matter atrophy on MRI.  No one can call that placebo!  He doesn't just feel better or have less brain fog.  His brain shows objective healing on MRI.   He has had no new lesions, and his old ones have shrunk. Another objective measurement from Jeff's venoplasty treatment was blood flow.  His jugular vein blood volume doubled after being stented.  Other research has shown that CSF flow increased after treatment for CCSVI.  link  These are all benefits which can be measured using medical equipment, and are not part of the UBC data.

I fear the UBC researchers are going to say any subjective benefit after treatment is placebo. That there are no objective benefits in those treated, because they have not measured blood flow, CSF flow and gray matter atrophy. They certainly didn't retreat restenosis. And Charcot will be laughing, once again, at how easily he is able to control the mind of the hysteric, labile, desperate MS patient. link

To recap my concerns:

1. Not objective results.  Too easy to claim "placebo"  No measurement of blood flow before/after

2. No treatment for restenosis (as in angioplasty trials)

3. No aftercare or lifestyle changes required (as in angioplasty trials)

4. Timing of release is suspicious
5. A history of bias and nay saying against CCSVI from trial lead investigator

Don't be discouraged. No matter what the UBC researchers claim, or how loudly they say it, it isn't over. Italy and Australia still have their trials. And we have other reseachers looking at the vascular connection. This research is not going away. Not with the ISNVD, not with The Gladstone Lab, The Kipnis Lab, the Nedergaard Lab and others--all committed to getting to the bottom of the vascular connection to diseases of neurodegeneration.

And I may be wrong!! Let's hope for that! Please let me be wrong!!!!
In the meantime, live your best, vascularly healthy life.
(Because I'm right about that part :-) )

Joan