Jugular Veins are Important

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

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

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

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

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

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

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

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

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

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

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

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


This is not going away.
jugular veins are important,

Joan



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

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

HSCT-- Facts behind the Headlines

Whenever there is a news story on autologous hematopoietic stem cell transplants (HSCT), I hear about it.  Perhaps this also happens to you, MS patients and caregivers?  Well-meaning friends, family, and acquaintances forward you links to glowing miracle cure stories.  And I reply with sincere thanks--and also inform them that Jeff's doing really well, with no MS disability, inflammation, new lesions or disease progression, now 9 years past his diagnosis with MS.  So, HSCT is really not for him.  Believe me--I know how fortunate we are to be able to report that!

Here's the latest miracle cure HSCT story out of Sheffield Teaching Hospital in the UK, which was picked up on British television and the press.  It's received a lot of coverage after the BBC aired a report:
http://www.bbc.com/news/health-35065905


For those who have had MS awhile now, these repeated stories on HSCT are heartening, but at the same time discouraging.  Because HSCT is certainly not for everyone, and many can't even consider this treatment.  It is good to know that some people are getting relief from MS and recovering their abilities.  It's also very important to understand that these stories are anecdotal.  They are heart warming, for sure, I'm not trying to be a downer.  But there is a dark side to this "cure narrative" I'd like to explore:  the premise that a "faulty immune system" in MS which needs to be ablated and completely removed is keeping us from understanding true disease progression.  

The general public, press, and politicians get a false sense of progress when they read these news stories.  They think, "well, at least we've got multiple sclerosis cured"....when nothing could be farther from the truth.  And new and recently diagnosed MS patients, who have yet to have gone through a decade of these kinds of stories, may mistakenly believe this is a cure.

HSCT was developed for pediatric cancer, and has been a blessing for the children and their families who have seem mortality rates decrease and life expectancy increase.  In this instance, carpet bombing the body and killing off cancer cells and then rebuilding the immune system with harvested and purified stem cells has saved lives. http://emedicine.medscape.com/article/989518-overview

In MS, HSCT use was first promoted by Dr. Richard Burt in the 1990s and has been used to treat thousands with MS.  However, there have been no randomized, double-blind placebo controlled trials, so even after all this time, results are still not considered "gold standard."  In fact, some of the results may be placebo.  The stronger or more invasive the proposed treatment, the more powerful the placebo effect.   https://www.psychologytoday.com/blog/sideways-view/201502/the-placebo-effect

Here are the facts:

1.  HSCT is only appropriate for those with highly inflammatory relapsing remitting MS, who have not responded to other drug therapies, and who have new lesions and relapses within the past year.  Trial participants cannot have had MS for longer than 10 years and cannot be too disabled.  This is a very small and specific group of people with MS.
A systematic literature search identified a higher efficacy of aHSCT in younger, less disabled MS patients with inflammatory activity, similar to the findings from Hamburg.
http://www.ncbi.nlm.nih.gov/pubmed/25956824

2.  HSCT uses chemotherapy to wipe out the existing immune system.  Many researchers urge caution regarding this approach, because chemotherapy--on its own-- is known to have many deadly side effects, causing up to 5% mortality in some trials.  Chemotherapy also causes demyelination and brain atrophy.  I've written extensively on the long term neurological effects of chemotherapy here:  http://ccsviinms.blogspot.com/2014/03/chemotherapy-causes-brain-atrophy.html

3.  Long-term success rates show that MS disability is not halted.  HSCT is not a cure.  It may be a very helpful treatment for some with highly inflammatory MS, however the disease continues to progress in most patients.  And autoreactive T cells to myelin targets return.

Our data parallel results from some of the clinical phase I/II studies showing continued clinical disease progression in multiple sclerosis patients with high expanded disability system scores despite autologous stem cell transplantation.http://www.ncbi.nlm.nih.gov/pubmed/17293360

Demyelinating and inflammatory activities of MS persisted after allo-HSCT in all of the patients with MS. Active and chronic active MS lesions exhibited significantly higher numbers of CD3+ T cells and CD8+ cytotoxic T cells and significantly higher scores of CD68+ microglia/macrophages than did chronic inactive lesions or normal-appearing white matter.http://www.ncbi.nlm.nih.gov/pubmed/20558390

Re-emergence as well as in vivo expansion of autoreactive T cells to multiple myelin targets was evident in all patients studied. The reconstituted myelin-specific T cells exhibited the same Th1 and Th2 responses as preablation myelin-reactive T cells. In contrast, the post-therapy T-cell repertoire exhibited a significantly diminished capacity for Th17 responses.http://www.ncbi.nlm.nih.gov/pubmed/23463494

And now, the big question.  Why do autoreactive T cells return even after they've been blasted to kingdom come and replaced with a new immune system?  Why does MS continue to progress?

Could it be that the underlying cause of the activation of these t cells is not a faulty immune system---but rather a continuing process of neurodegeneration?

The kind of neurodegenerative process we see happening in the gray matter structures of the MS brain?  The type of neurodegeneration that shows continued atrophy of the thalamus in all people with MS---from CIS to PPMS?  http://ccsviinms.blogspot.com/2016/01/thalamic-atrophy-and-ms-progression.html

A major pathological complication of auto-HSCT may be the effects reported on brain volume.  Rapid loss of brain volume has been measured a few months after treatment [50]. Auto-HSCT has seemingly detrimental effects on the integrity of the brain tissue that leads to rapid loss of about 1.92 % of brain volume.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715306/

There is a huge difference between finding MS treatments which give patients relief from their symptoms and reduction in disability for a year or two-----and understanding the underlying disease mechanism which allows for continued MS progression.  Temporarily tamping down inflammation is not the same as halting MS disease progression.  

Keep getting the correct info out there.  Push for researchers and policy makers to examine the underlying cause of MS disease progression.  

That's the only way forward,

Joan

This is about the use of bone marrow stem cells to to replace the immune system and is the most extreme form of "induction therapy" aimed at rebooting the immune system. This study has been reported by us and it is clear that the majority of people are not leaping out of their wheel chairs. This is just the type of poor reporting that the media specialise in ...media hype

http://multiple-sclerosis-research.blogspot.com/2015/03/miracle-stem-cells.html

PICTURE CREDIT:  TOM SCOTT---Journalism Warning Labels

Thalamic Atrophy and MS progression

EDIT:  New research
February 2018  Annals of Neurology, confirms prior research.  Gray matter matters in MS.
"Deep gray matter volume loss drives disability worsening in multiple sclerosis"http://onlinelibrary.wiley.com/doi/10.1002/ana.25145/full

Why does MS progress?  What allows the disease to erode physical and mental abilities?  This is the big question for researchers and patients alike.  In the 1940s, it was assumed that the visible scars upon autopsy, the white matter lesions showing demyelination, were the cause of MS progression.  And the EAE mouse model of MS was created. MS was an autoimmune disease in which the myelin sheath was destroyed.  link

As MRI technology developed, the efficacy of disease modifying MS drug treatments was determined by the lack of new white matter lesions.   White matter lesions were considered the "bio marker" of MS disease progression.  And a twenty billion dollar a year business was created.  The narrative goes something like this:  MS is an autoimmune disease.  The immune system target is myelin.  The immune system is destroying myelin and must be stopped!  White matter lesions cause disability.  This was the finely crafted explanation of MS treatment, which continues today.

But it's not completely true.

We've known for quite a while that MS is not truly an autoimmune disease---any more than stroke is an autoimmune disease.   The immune system does the same thing when there is a break in the blood brain barrier in stroke and there is a similar antigenic response to myelin.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162361/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4173797/
http://www.ncbi.nlm.nih.gov/pubmed/26105701

In MS,  myelin destruction appears to be secondary to death of neurons
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0066117
http://www.direct-ms.org/sites/default/files/BruckInflamDegen2.pdf
http://www.ncbi.nlm.nih.gov/pubmed/19420101

and the main correlate to disease progression is loss of gray matter, not white matter lesions.
http://pubs.rsna.org/doi/full/10.1148/radiol.10100326
http://www.neurology.org/cgi/content/meeting_abstract/80/1_MeetingAbstracts/P06.118
http://www.ncbi.nlm.nih.gov/pubmed/18570297
http://www.ncbi.nlm.nih.gov/pubmed/21586487
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4471328/
http://www.ncbi.nlm.nih.gov/pubmed/24819917
https://www.researchgate.net/profile/Alberto_Cifelli/publication/11062115_Thalamic_neurodegeneration_in_multiple_sclerosis/links/09e41508e990886c9c000000.pdf

That's why someone with MS, like my husband Jeff, could present with over 20 white matter lesions, a dozen enhancing, and still be able to jog and bike, with a <1 EDSS.   It's also why progression in MS continues after the immune system stops "attacking" myelin during the RRMS phase.   People with progressive MS may no longer have new white matter lesions, but the disease certainly doesn't stop.   It's also why people with primary progressive MS don't have many white matter lesions.

As Dr. Philip James says, "Scars are a sign of healing."  Multiple Sclerosis means many scars, and these scars are a sign of an immune system attempting to repair the damage done during the break in the blood brain barrier.  And stopping demyelination does not stop MS progression.

Immunomudulating MS drugs may affect white matter lesions, but they do not prevent gray matter atrophy.

The assessment of brain volume changes on serial magnetic resonance imaging (MRI) scans can provide an objective measure of the neurodegenerative component of multiple sclerosis (MS) pathology. Results from placebo-controlled and crossover clinical trials indicate that immunomodulating (e.g. recombinant interferon-beta [IFNbeta]-1a [Rebif] and IFNbeta-1b [Betaferon] and glatiramer acetate [Copaxone]) and immunosuppressive (e.g. cladribine and alemtuzumab) treatments for relapsing-remitting (RR) and secondary progressive MS lack substantial efficacy in preventing the development of brain atrophy, despite the marked effects of these treatments on clinical and MRI outcomes of disease activity.

link

The striking differences in EDSS development at one year follow-up, combined with the high subcortical atrophy rates in EDA patients compared to controls, support the use of NEDA as an outcome measure in MS. The high subcortical atrophy rates in the EDA patients, combined with the high proportion of patients treated with first line DMTs in this patient group, underlines the need for treatment strategies targeting GM atrophy in early RRMS, especially in patients with evidence of disease activity.
link

The thalamus might be, thus, an ideal region of interest to test the effectiveness of new neuroprotective MS drugs. Especially, we will address underlying pathological mechanisms operant during thalamus degeneration in MS, such as trans-neuronal or Wallerian degeneration. Furthermore, we aim at giving an overview about different paraclinical methods used to estimate the extent of thalamic pathology in MS patients, and we discuss their limitations. Finally, thalamus involvement in different MS animal models will be described, and their relevance for the design of preclinical trials elaborated.
link

As you can see, MS drug companies know gray matter atrophy is a real problem in disease progression, which is why they are paying researchers to look at thalamic atrophy in MS, and see how their newest drugs are doing in maintaining gray matter.   Check out BNAC's recent grants----Teva, Biogen and Novartis all want to know if their drugs are stopping gray matter atrophy.  This is not coincidence.   http://www.bnac.net/?page_id=359
Dr. Zivadinov has been publishing on thalamic atrophy and MS progression for a few years now.
http://www.buffalo.edu/news/releases/2013/03/028.html
http://www.ncbi.nlm.nih.gov/pubmed/23613615

So, what's the thalamus?  Where is it, and what does it do?
Your thalamus is a vital brain structure, which resides deep within the brain as gray matter--called "gray" because of its color.  Gray matter is neurons and glial cells. and lacking the white matter color created by myelin.  The thalamus is responsible for relaying information to the rest of your brain.  It receives sensory input: the auditory, visual, smell and touch messages, and directs those messages to the rest of the brain.  If the thalamus is damaged or loses neurons (what we call "atrophy),  vision problems, sleep problems, balance and walking problems would result.  Just like what we see with MS progression.

The walls of the third ventricle are formed by the thalamus, so when there is shrinking and a loss of gray matter--the third ventricle expands and gets wider, as it fills with more cerebrospinal fluid.  Your brain, like all nature, abhors a vacuum.  CSF fills in the gaps.

Here are some MRI examples of how the thalamus shrinks, and the third ventricle (the black area in the center/top of the brain) expands--  from left to right--normal brain, RRMS, and right is progressive MS

Want to find out how your own brain is doing?  Ask the MRI techs to look at your gray matter.  Specifically your thalamus and width of the third ventricle.  They can go back and compare your past MRIs, too.  That's how we found out that Jeff's gray matter atrophy had reversed, and his gray matter now looks normal, nine years since MS diagnosis and almost 7 years since treatment for CCSVI.  The width of his third ventricle is completely normal.  No sign of any gray matter loss.

Here's more on MRI technology and measuring the thalamus.  Note that the researchers mention how "ventricular enlargement" can give an indication of gray matter loss.
Thus, there is a huge need of a methodology suitable to be applied in daily clinical practice in order to estimate GM atrophy in a convenient and comprehensive way. Given the thalamus is the brain structure found to be more consistently implied in MS both in terms of extent of atrophy and in terms of prognostic value, we propose a solution based in this structure. In particular, we propose to compare the extent of thalamus atrophy with the extent of unspecific, global brain atrophy, represented by ventricular enlargement.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4144089/


The notion that clinically relevant MS pathology is restricted to focal WM lesions has been overwhelmingly negated by an expanding body of neuropathologic data implicating significant cortical myelin, neuro-axonal, and synaptic loss2–5,9,19 in both early and late stages of the disease. Pathology afflicting the deep GM structures, in particular the thalamus, is frequently observed in MS, but less well studied.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589190/

I would suggest that understanding how CSF, (g)lymph and blood are all drained through the deep gray matter structures of the brain via the venous sinus and paravenous pathways is vitally important.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699410/

Maintaining gray matter should be the target for all MS treatments.

Last November, we learned that Vitamin D levels are correlated to gray matter health in MS.
link

Here are all my blog posts on maintaining gray matter.  I've been writing about this for awhile, and am truly shocked that this topic is not being discussed by MS specialists, who are still hyperfocused on white matter lesions.
link

Hope this helps you understand your own brain, and gives you some questions to ask the MRI techs and your neurologist.
Keep learning---it will maintain those neurons, and keep your gray matter going strong!
Joan