Death knells and coffins...

Death knell for CCSVI!---Another nail in the coffin---
Goodbye to all that; a short history of CCSVI---
CCSVI debunked!---The end for CCSVI

If all you read were the headlines, you might think that CCSVI was nothing more than a scourge, a fantasy, a vampiric spector that science has, thankfully, stabbed through the heart and removed forever.
It's over. Move along, people.  Nothing to see here.

But there is much more going on.

This week, a paper published in a neurological journal showed
"severe extracranial venous anomalies that signficantly impaired normal outflow from the brain" occur in some people with MS.
The full paper, in a provisional pdf, can be viewed here for free:
http://www.biomedcentral.com/content/pdf/1471-2377-13-151.pdf

These scientists do not think CCSVI is over.  They're still finding it.

Jeff and I know all about these extracranial venous anomalies that significantly impair the flow of blood from the brain to the heart.

Four and a half years ago, Jeff and I saw that very same problem happening in his body.  We were astounded at the MRV images on the computer screen in his doctor's office, which showed slowed collateral circulation and two malformed, stenotic jugular veins.

I put up an image from his magnetic resonance venography on an MS Forum.

And in doing so, poked a hornet's nest.

You can see in this MRV picture on the left from Stanford, Jeff had no jugular flow on the left side (right on pic), and reduced flow on the right.  This is evidenced by the collateral veins that are lit up like Satan's curly fries.  This is not normal.
What you should see are straight and open jugular veins, that look like drinking straws.  Like the picture on the right.  Can you see the difference???  Well, our doctor saw the difference, and we decided to treat Jeff's venous malformation.



In fact, both of the images were taken at Stanford University, by one of the premiere vascular specialists in the world.  He and his radiology team would later publish a paper on what healthy normal venous MRV looked like, compared to people with MS.  He believes that the kind of collateral circulation and pulsatility found in pwMS could well be damaging to the brain.  Here is one of his papers on this.
http://www.ajnr.org/content/33/8/1615.abstract


When Jeff's jugular veins were opened up, the collaterals went away, his cerebral blood flowed through his jugular veins in a timely manner, no more pulsatility.  And Jeff's brain has healed.  No MS progression.  His gray matter looks normal on MRI.

It's hard not to wonder what would have happened if I had simply taken the research to Stanford, where Jeff was treated, and then gone home to live out our days.  But I was part of an online MS forum, and we'd been sharing information between pwMS and caregivers.  In fact, that was how I first read Dr. Zamboni's published papers.

Maybe the research would have progressed more readily without patient involvement.  Maybe the scientific community would have been more accepting of Dr. Zamboni's research, without the media and patient spotlight.

But I doubt it.
And anyway, there's no going back.
I'm sorry for the way neurologists have used patient advocacy to prevail against the science.... but I'm also not sorry.  Because I got my energetic, brilliant husband back.  And he no longer has heat intolerence, sleep apnea, or crippling fatigue.  No MS progression.  He's still working more than full days, jogging, biking and living.

CCSVI exists.  It impairs blood flow from the brain.  It may not affect everyone with MS, and it may be present in normal people.  It's showing up in other neurological diseases.  There is great debate as to how it should be treated.  Jeff's doctor used stents, others have replaced veins, ballooned, used cutting balloons--others believe lifestyle and exercise may be enough, or antibiotics might help.  There is no agreement on the best course of treatment, and that has created confusion and controversy.

It's also clouded the fact that there are newly discovered and very obvious venous problems related to neurological disease.  

CCSVI exists.
How it is best treated will be debated, but this exploration is not even close to being over.
Joan

Sleep and the Brain

New research from the University of Rochester, published today, reconfirms the importance of sleep for brain health.

Their results, published in Science, show that during sleep a plumbing system called the glymphatic system may open, letting fluid flow rapidly through the brain. Dr. Nedergaard's lab recently discovered the glymphatic system helps control the flow of cerebrospinal fluid (CSF), a clear liquid surrounding the brain and spinal cord."It's as if Dr. Nedergaard and her colleagues have uncovered a network of hidden caves and these exciting results highlight the potential importance of the network in normal brain function," said Roderick Corriveau, Ph.D., a program director at NINDS.

A few years ago, I first wrote about REM sleep and brain oxygenation. After venoplasty and restoration of jugular, rather than collateral venous flow,  my husband Jeff had a return of dreaming and restful sleep.  Now that his jugular veins had been repaired, they were the major route of venous return for his brain while he slept, and the changes for him were immense and immediate.  After coming home from his procedure at Stanford, he no longer had night time spasms or fits of apnea, when he would literally wake up, gasping for air.  He now slept through the night, and woke refreshed.  He could now recount his very vivid dreams to me.   This was all new for him.

When I attended the first CCSVI conference in Bologna in 2009, I heard Dr. Salvi talk about the restoration of REM sleep and dreaming in Italian patients that had been treated for CCSVI.  It was the first intimation that something vital was happening to Jeff's brain while he was in deep sleep.  Here is my post on this topic, with research on oxygenation of the brain during sleep--
http://ccsviinms.blogspot.com/2010/09/to-sleep-perchance-to-oxygenate.html#more

Earlier this year, a new study from the University of Wisconsin showed us why sleep is essential for remyelination of the brain and synthesis of oligodendrocyte precursor cells.

They found that during sleep, hundreds of transcripts that govern the synthesis of cells called oligodendrocyte precursor cells (OPCs) are up-regulated during sleep, while genes involved in cell death, cell stress response and cell differentiation are up-regulated during wake. An assay of living cells confirmed that OPC proliferation doubles during sleep, especially during rapid eye movement phase (REM sleep) associated with dreaming.
http://www.med.wisc.edu/news-events/sleep-produces-cells-that-grow-and-repair-nerve-cell-insulation-/41696
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And today, a new study from the University of Rochester helps us understand the different functions the brain performs during sleep and wake, and why sleep is essential.  
http://www.eurekalert.org/pub_releases/2013-10/nion-bmf101713.php

In findings that give fresh meaning to the old adage that a good night's sleep clears the mind, a new study shows that a recently discovered system that flushes waste from the brain is primarily active during sleep. This revelation could transform scientists' understanding of the biological purpose of sleep and point to new ways to treat neurological disorders.

The University of Rochester researchers have been studying how the brain cleans waste during sleep, and they have named this process the "glymphatic system", because it combines the lymph process of cleansing and glial cells.  This system is like "a plumbing system that piggybacks on the brain's blood vessels and pumps cerebral spinal fluid (CSF) through the brain's tissue, flushing waste back into the circulatory system where it eventually makes its way to the general blood circulation system and, ultimately, the liver."

Time for the BIG picture. When we lie down, our cerebral circulation changes.  This is, due in large part, to the fact that gravity allows the jugular venous system to become the main outflow.  The collateral venous system, which is activated when we are upright, gives way to the larger jugular veins.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1665206/

In normal people-- who do not have jugular venous malformations, or CCSVI-- this allows for effective flow while supine.  Why is this important?  Because it appears that this flow is essential for removal of waste from the brain.  Here's more from the U of R--

Venous Hemodynamics

Understanding venous hemodynamics is of the utmost importance when studying CCSVI.
"CCSVI is not about architecture, it's about flow."
Dr. Paolo Zamboni said this to me when we first met at his international CCSVI conference in Bologna, Italy in September 2009.
He explained that it was not enough to scan the veins, or use MRV technology, or just look for stenosis.  It was essential to understand hemodynamics.

Which is why the knowledge of scientists like Clive Beggs is so important.  As an engineer and Professor of Medical Technology, Professor Beggs has insight into the physics of blood flow.

Highly Recommended Reading----


Venous hemodynamics in neurological disorders: an analytical review with hydrodynamic analysis  
Clive B Beggs
Venous abnormalities contribute to the pathophysiology of several neurological conditions. This paper reviews the literature regarding venous abnormalities in multiple sclerosis (MS), leukoaraiosis, and normal-pressure hydrocephalus (NPH). The review is supplemented with hydrodynamic analysis to assess the effects on cerebrospinal fluid (CSF) dynamics and cerebral blood flow (CBF) of venous hypertension in general, and chronic cerebrospinal venous insufficiency (CCSVI) in particular.

CCSVI-like venous anomalies seem unlikely to account for reduced CBF in patients with MS, thus other mechanisms must be at work, which increase the hydraulic resistance of the cerebral vascular bed in MS. Similarly, hydrodynamic changes appear to be responsible for reduced CBF in leukoaraiosis. The hydrodynamic properties of the periventricular veins make these vessels particularly vulnerable to ischemia and plaque formation.

Despite conflicting studies, there is increasing evidence that CCSVI is a real physiological phenomenon, and that it is in some way associated with MS. The evidence from CSF-related studies in patients with MS, and the hydrodynamic analysis presented here, suggests that CCSVI causes venous hypertension in the dural sinuses. However, the role that CCSVI might play in the pathophysiology of MS remains unclear, and more work is urgently needed to understand the clinical relevance of this condition.

http://www.biomedcentral.com/1741-7015/11/142

The FDA and Multiple Sclerosis treatments

Who gets to advise the FDA on multiple sclerosis drugs and treatments?

There have been several new MS drugs brought to market in the five years since CCSVI research was first discussed in medical journals.  We have to wonder whether the process of hastening these new drugs to market was aided by the influence of phamaceutical companies.

In the news today, e-mails are released that show pharmaceutical companies pay to attend FDA advisory meetings and submit their own recommendations on drugs to be marketed,   http://www.washingtonpost.com/business/economy/pharmaceutical-firms-paid-to-attend-meetings-of-panel-that-advises-fda-e-mails-show/2013/10/06/a02a2548-2b80-11e3-b139-029811dbb57f_story.html?hpid=z1

I thought it might be a good idea to see what information is available to the public regarding who is recommending MS treatments to the FDA, and how they do this.

The group that looks at evidence for the MS community and advises on drug approval is the 

"Peripheral and Central Nervous System Drugs Advisory Committee"

There are many reports prepared by pharmaceutical companies to be submitted to this group, which are available for public disclosure without redaction on the FDA.gov site.

Here is one for Fingolimod, now marketed as Gilenya-- prepared by Novartis- and submitted to the advisory committee for their June 10th, 2010 meeting.

The authors are free-lance biotechnicians who specialize in "bringing pharmaceuticals to market."

http://www.fda.gov/downloads/Advisory%20Committees/CommitteesMeetingMaterials/Drugs/Peripheraland%20CentralNervousSystemDrugsAdvisoryCommittee/UCM214675.pdf

The FDA advisory committee decided that day to approve Fingolimod/Gilenya and made the announcement to the press.  They were giddy with the fact that this drug was the first FDA approved oral medication for people with MS.

http://www.medscape.com/viewarticle/723361

What is important to note is that by the time 2012 came around, the FDA had to issue a formal warning on Gilenya, due to several deaths and cardiac events reported after the drug was marketed to pwMS.  These cardiac deaths and side-effects were not flagged by the FDA, or Novartis---but reported by a non profit watchdog group, the Institute for Safe Medication Practices.

http://www.ismp.org

Recently, the Institute for Safe Medication Practices, a nonprofit watchdog group, has urged the FDA to put more restrictions on the use of Gilenya. The group reviewed the number of side effects of the drug reported to the FDA MedWatch program in the second quarter of 2011, and it concluded that "the FDA and manufacturer should consider substantial restrictions on its use and enhanced monitoring."

Here is the strongly worded comment from the ISMP--

It was a significant gamble for the FDA to allow unrestricted marketing of powerful but novel immunosuppressant drug before determining the optimal dose and learning more about its long term risks.  Only about 300 people were exposed to fingolimod for a period of two years prior to approval.

http://www.ismp.org/QuarterWatch/pdfs/2011Q2.pdf

Moving forward

For the many people with MS who were first treated for CCSVI in 2009 and 2010, It is more than insulting to be told that your benefits are “short-lived” or “not measurable” or “placebo.”  Especially when there is documentation that contradicts this claim.

As many of you know, my husband Jeff had difficulty walking at his diagnosis in 2007, but six years later, he is downhill skiing and mountain biking.  Yes, MS is a variable and relapsing-remitting disease, but I would like to propose something.

Jeff has had many tangible and quantifiable benefits from venoplasty. 

1. His cerebral blood flow and venous return were measurably increased. 

2 His gray matter atrophy reversed, and his gray matter now looks “normal” on MRI.  This includes his third ventricle width, thalamus and brain stem.

3. He has had no further white matter lesions, nor has he had another MS relapse.

4. He has EDSS improvement from 1.5 to .5

5. As a 50 year old man who was told he would progress quickly, due to the number of enhancing lesions he had at presentation, these quantifiable measurements, (which would be heralded as great victories for Tysabri or Rituxan, had he taken these drugs) matter.

And we are keeping Jeff’s medical records and his disease process is being followed, now 4.5 years past venoplasty.

Kathleen Lynch made a wonderful suggestion at the NCS conference---I had been asked by an audience member how I believed we could continue to move this research forward, and not let it be tossed into the trash bin-- as the MS Societies, MS specialists and pharmaceutical companies are currently recommending.

Kathleen stood up and suggested that patients needed to keep their medical records and documentation as a scientific proof of their disease process.

If you have documented proof of improvement in EDSS or on MRI, or disease cessation, I encourage you to document this,  and keep all of your records on file.  I think we may want to make a concerted, international effort, to begin a data registry--which includes this documentation.  And we will need to make a formal presentation of this evidence to the MS Societies and scientific councils who are in charge of research funding.  I would like them to meet Jeff, see his MRI and assess him.

At the NCS Sherbrooke conference, which was not attended by any of the invited MS Societies or MS specialists, Sean Sethi from MR Innovations presented many clear MRV examples of the difference between stenotic jugular veins in people with MS and the open and flowing images of normal jugular veins.  The visuals were striking.

http://www.sciencedirect.com/science/article/pii/S0730725X13002117

His comment was that he wants this evidence to “be the hammer that takes the nail out of the CCSVI coffin.”

It is far too early for any organization to be proclaiming CCSVI research as over.

How can any group which purports to be looking after people with multiple sclerosis deny the very clear evidence of venous abnormalities in MS, and the documented improvements in many who have been treated to repair these malformations? 

To not pursue this research, to dismiss those who have MRI evidence of disease cessation and healing of brain tissue, is purely evil, and should not be tolerated.

For those who have this evidence, now is the time to get your files in order.  This goes beyond YouTube videos and anecdotal reporting.  This will be scientifically valid proof.

And we have it.

Joan