REAL breakthroughs in MS research

It's been a busy month for MS research.  I wanted to give a brief overview of the new publications coming out in vascular journals, linking CCSVI and MS to slowed cerebral blood flow, changes in cerebrospinal fluid flow and coagulation factors.

As much as neurologists and immunologists continue to claim this exploration is dead, finito, over---there are still dozens of publications in press or being published which elucidate the vascular connection of CCSVI to neurological disease.  This exploration is far from over, as more and more international investigators join in the exploration.


1.  The International Society for Neurovascular Disease (ISNVD)--a multi-disciplinary group of researchers, has published their position statement on recommendations for multimodal noninvasive and invasive screening for detection of extracranial venous abnormalities indicative of CCSVI.

The full text is available here:
http://www.jvir.org/article/S1051-0443(14)00746-5/fulltext

This position paper is extremely important, because it addresses the variablity of findings made by other researchers examining impaired venous flow in people with MS---and gives the first ever standardized imaging and evaluation recommendations.  It is written by some of the leading venous and imaging experts in the world.

The ISNVD recommends the use of a multimodal noninvasive and invasive imaging approach to optimally identify extracranial venous structural/morphologic and hemodynamic/functional abnormalities indicative of CCSVI. Creation of more quantitative imaging criteria are needed for further characterization of these venous abnormalities. Screening and monitoring of these venous abnormalities with the use of a combined noninvasive and invasive imaging approach should help establish the actual incidences and prevalence of extracranial venous abnormalities indicative of CCSVI in various populations. In addition, a multimodal imaging approach will address whether these abnormalities can cause significant hemodynamic consequences for intracranial venous drainage. The proposed noninvasive and invasive imaging protocols represent a first step toward establishing and validating the criteria for detection and monitoring of extracranial venous abnormalities indicative of CCSVI in open-label or double-blinded randomized controlled studies. The ISNVD recognizes that the rapidly evolving science and growing interest in this field will facilitate a refinement of these protocols in the near future.

2.  Another international collaborative effort looks at cerebrospinal fluid (CSF) dynamics in MS, using phase contrast MRI.  At the helm of this research is internationally recognized imaging expert, Dr. E. Mark Haacke.

This research separated pwMS into two groups, those with stenotic internal jugular veins (ST), and those without stenotic IJVs (NST) Changes in outflow was noted in those with stenotic veins.

The delay between the beginning of beginning of systole and the CSF outflow was higher in ST compared to NST MS. Less IJV flow was observed in ST vs NST MS. None of the measures was different between the different MS phenotypes. These results suggest that alterations of IJV morphology affect both IJV flow and CSF flow timing but not CSF flow amplitude
http://benthamscience.com/journal/abstracts.php?journalID=cnr&articleID=124278

3.  Tying into this impairment of CSF outflow dynamics, another recent publication found that the third ventricle in the brains of those with CCSVI was much larger than in healthy controls on MRI.   The third ventricle is one of four ventricles in the brain, and is filled with cerebrospinal fluid (CSF).  In normal brains it is a narrow cavity and CSF flows freely through in a timely manner.  In those with hydrocephalus or normal pressure hydrocephalus, this ventricle expands.  
http://ccsviinms.blogspot.com/2012/11/normal-pressure-hydrocephalus-once.html

This buildup of fluid can damage the brain.  And the third ventricle is enlarged in those with CCSVI, indicating a lack of timely venous flow is impacting CSF flow.

In the MS–CCSVI group, the third ventricle diameter was 6.2±1.7 mm (from a minimum of 2.5 mm to a maximum of 9.2 mm, with a median of 6.3 mm, and a mode of 6.0 mm). Our data showed that 29 patients (88%) had an increase in third ventricle diameter, whereas only four patients (12%) had physiological size (less than 4 mm) comparable to all healthy control group subjects (27.28%). These results show that the increase in the third ventricle diameter could represent a criterion of positivity of neurological disease in patients with CCSVI.
http://www.dovepress.com/increased-size-of-third-ventricle-in-patients-with-multiple-sclerosis--peer-reviewed-article-JVD

4.  Finally, a group of vascular researchers look at how successful endovascular treatment of CCSVI changes the blood.  The fact that MS is related to higher levels of fibrin, ET1 and other markers of hypercoagulation and endothelial dysfunction has already been firmly established.
http://ccsviinms.blogspot.com/2014/03/blood-matters.html 
http://ccsviinms.blogspot.com/2012/11/whats-blood-got-to-do-with-it-nov.html

This group wanted to see if these blood markers changed, once normal venous flow was established.  They were.  In fact, lower coagulation activation status was associated with a better clinical outcome.  Another connection to the blood and endothelium.

Coagulation activation and endothelial dysfunction parameters were shown to be reduced at 1 month and stable up to 12-month follow-up, and they were furthermore associated with a good clinical outcome. Endovascular procedures performed by a qualified staff are well tolerated; they can be associated with other currently adopted treatments. Correlations between inflammation, coagulation activation and neurodegenerative disorders are here supported by the observed variations in plasma levels of markers of coagulation activation and endothelial dysfunction.
http://journals.lww.com/bloodcoagulation/pages/articleviewer.aspx?mobile=0&year=2014&issue=10000&article=00012&type=Abstract&desktopMode=true

There is much movement in the study of how impaired venous return affects the brain for those with CCSVI/MS, and how treating this impairment improves clinical outcomes.  I live with anecdotal proof.  Jeff is now almost six years past his endovascular treatment and repair of malformed jugular veins and dural sinus.  He is jogging, traveling the world, working more than full-time, with a reversal of gray matter atrophy.  His third ventricle looks normal on MRI, he has had no further MS progression.  His coagulation numbers went from severe hypercoagulation, to normal.

There is a connection.  We will not let this research slip through the cracks.
stay tuned,
Joan

ECTRIMS 2014--$20 Billion reasons

If you ever want to understand why there is no research into the cause, or "disease etiology" of MS, all you need to know is contained in this story from the business news in Boston.

The are $20 billion reasons why research has abandoned ship.


More than 8,000 people are expected to attend MSBoston2014, opening Wednesday at the John Hynes Convention Center. The event, considered the premier international MS gathering this year, is hosted jointly by the American and European Committees for Treatment and Research in Multiple Sclerosis, which alternate meetings between Europe and North America (ECTRIMS)

“Things have gotten dramatically better,” said Lori Espino, president of the Greater New England Chapter of the National Multiple Sclerosis Society. “There are so many options out there for patients, and they slow the progression of the disease. It’s all about creating hope for people.”

Worldwide sales of MS drugs totaled more than $16 billion last year and are projected to top $20 billion within the next two to three years, with MS pills accounting for about half of the sales, said Eric Schmidt, biotech analyst at investment bank Cowen & Co. in New York.

“MS is one of our core areas,” said EMD Serono’s chief medical officer Thorsten Eickenhorst. “We have research activities ongoing and products in our clinical pipeline.”

https://www.bostonglobe.com/business/2014/09/09/for-multiple-sclerosis-sufferers-anxious-hope/yfTyQW4JkmsNDRQEdIxi5N/story.html 

Dear ECTRIMS participants----

Many of us have already abandoned the Good Ship Lollypop (sponsored by Biogen!), and have decided to find our own answers, outside of the theory of EAE/autoimmunity which has never been proven. According to independent university and governmental agency research--your treatments may modulate immune response, but they don't stop MS disease progression. 

http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?productid=1833&pageaction=displayproduct
 http://www.sciencedaily.com/releases/2012/07/120717162736.htm  

Here is neurologist Dr. George Ebers discussing long term outcomes with MS medications.  None of the drugs are proven to alter progression.  He would say that you are not telling the truth to people with MS.
https://www.youtube.com/watch?v=OqY-_K1fYJY

That is why we are charting our own course.  We are looking at the evidence given to us by stroke, vascular and imaging experts, like members of the ISNVD--those who are finding connections to cerebral blood flow, perfusion, gray matter atrophy, and neuronal loss.  
http://www.isnvd.org

We are listening to doctors who actually have MS--like Dr. Terry Wahls and Dr. George Jelinek--groups who are funding real research and have found solutions in nutrition, lifestyle modification, exercise and UV therapy.  We are finding relief in dealing with slowed venous return; through venoplasty, chiropractic care and endothelial health.
http://ccsviinms.blogspot.com/2014/04/unproven-treatments-for-ms.html

You can have the high seas of "anxious hope" and 20 billion dollar sales----we prefer to walk, with our feet firmly planted in reality.  We're hoping to find others to join us.

Joan

MS "breakthrough" research--On/Off Switch!!!

I am sick and tired of reading news stories about some "new MS breakthrough" which uses the EAE mouse model of MS and describes MS as an autoimmune disease.  It is as though the immunology research community believes that if they just keep acting like they are busy discovering things (where they have been looking for 70 years and finding nothing about disease etiology) they can keep getting funding for their labs, and keep people with MS thinking there is momentum.

The latest in a sea of sameness is the Bristol University crap about an "on/off switch" for the immune response to MS.

Here's the full paper, published in Nature---for those who like to read published research, rather than press releases full of hyperbole and BS.

http://www.nature.com/ncomms/2014/140903/ncomms5741/full/ncomms5741.html

In reading the paper, we learn that this new "breakthrough" is remarkebly reminiscent of Copaxone treatment, in which killer T cells are said to be modulated to helpful T cells by means of exposing them to an antigen (in Copaxone's case, that's a mimic of the proteins found in myelin basic protein---glatiramer acetate.)  This particular "new breakthrough hope"  therapy is going after CD4+ T cells, using injected peptide epitopes, rather than intact antigens--which are said to be "more effective."

Again, all of the testing was done on the mouse model, EAE.  Not humans with MS.

As reviewed elsewhere23, 45, peptide epitopes targeting ​CD4+ T cells have distinct advantages over intact antigens, and yet the mechanism by which peptide therapy prevents and treats ongoing autoimmune and allergic diseases is poorly defined. Mucosal routes of administration have proven safe and effective in animal models of allergy and autoimmunity, but have not translated well to the clinic. Here we demonstrate that the s.c. route of administration is more effective than the i.n. route, with a 1,000-fold lower dose of antigen being effective for anergy induction when compared with previous studies17, 18. As noted17, the efficacy of tolerance induction and disease prevention depends on signal strength. In this study, all aspects of inflammatory T-cell function, including proliferation, inflammatory cytokine secretion and encephalitogenicity were suppressed, whereas the ability of cells to secrete ​IL-10 and suppress EAE increased in a dose-dependent manner. ​IL-10 clearly serves as a promising mediator of effective antigen-specific immunotherapy1, 12.

But muting or changing the inflammatory response of CD4 + T Cells isn't really explaining why they are there in the first place, or how come this exact same cellular response shows up in ischemic stroke, slowed cerebral blood flow and reperfusion injury in humans.

That's right!!  CD4+ T cells show up after stroke, ischemia, and reperfusion injury.  These cells are responding to slowed blood flow in the brain, or hypoperfusion.

Here are stroke and vascular researchers discussing CD4+ T cells and the immune reaction to stroke and vascular issues in published research.  Perhaps we should let them know that stroke or reperfusion injury is an autoimmune disease that can be turned on or off!

For instance, lymphocytes from stroke survivors show more activity against myelin than the lymphocytes from patients with multiple sclerosis. In addition, myelin-reactive T cells are found in higher numbers among patients with cerebrovascular disease. These data thus provide evidence that a cellular immune response to brain antigens occurs following stroke.
http://stroke.ahajournals.org/content/41/10_suppl_1/S75.full


These findings indicate that CD4⁺ and CD8⁺ T lymphocytes, but not B lymphocytes, contribute to the inflammatory and thrombogenic responses, brain injury, and neurological deficit associated with experimental stroke
http://circ.ahajournals.org/content/113/17/2105.long

These findings implicate a CD4+ subset of T lymphocytes as key mediators of early inflammatory responses after renal  ischemic reperfusion  injury. 

http://www.scielo.br/pdf/bjmbr/v40n4/6420.pdf


I have a novel suggestion for researchers---why not look at the connection of MS to stroke, the vascular endothelium, CCSVI and reperfusion injury?  Why not understand this cellular response in non "auto-immune" diseases?

Now that would be a REAL breakthrough,
Joan