7T MRI shows MS vascular connection

High powered MRI is allowing us to see the vascular connection to MS.  A recently published study used 7T MRI to compare the lesions of people with MS and those with Neuromyelitis Optica (NMO).  link

21 patients with MS and 21 patients with NMO were imaged.  There was one important difference between the two groups.  Only the patients with MS showed signs of "iron laden lesions" which contained a central vein.  None of the people with NMO showed this.

NMO is a truly autoimmune disease, in which immune cells attack the optic nerve and spine.   In contrast to MS,  NMO has a known antigen, called Aquaporin 4.  In NMO, the immune cells attack this antigen and cause demyelination.  However, there has never been a specific antigen discovered for MS.  In fact, MS lesions are very different from NMO lesions, as high powered MRI is showing us that inside MS lesions, there is a central vein which is allowing blood products, like iron, into brain tissue.

Here is how the researchers describe the difference:

Distinguishing MS from NMO lesions. 
Axial T2-weighted image from a representative patient with MS demonstrating a hyperintense lesion (black arrow) traversed by an ill-defined central venule adjacent to the inferior horn of the lateral ventricles. The lesion appears hypointense on a corresponding T1-weighted MPRAGE image. The lesion shows a hypointense peripheral rim and an iso- to hypointense central core traversed by a well-defined venule on GRE-T2*-weighted image. This lesion is hyperintense on QSM. Hypointense signal intensity within the lesion on GRE-T2*-weighted image and hyperintensity on QSM suggest iron accumulation (upper row). An axial T2-weighted image from a representative NMO lesion reveals 2 round hyperintense lesions (white arrows) in the subcortical WM region. The lesions appear hypointense on T1-weighted and hyperintense on GRE-T2*-weighted images. However, these lesions are isointense and therefore inconspicuous on QSM (lower row). The scale bar is for the QSM image with units of parts per billion.

Looking at the images, we can see the arrows pointing to the MS and NMO lesions.  All the images (on the top for MS and bottom for NMO) are of the same area of brain tissue.   It is the GRE-T2 image which clearly shows the MS lesion has a very small, yet well-defined vein (venule) going through the center.  The NMO lesion does not.  The QSM image shows that around this vein, in the MS patient, there is iron.  The researchers do not say that this is from blood leaking into tissue.  But this is the very obvious inference.  Blood, or heme, contains iron.  Microbleeds into brain tissue have been documented in MS. link   And here, once again, we have more proof.

For those of us who know our history, we remember that Rindfleisch saw the EXACT SAME THING through his microscope in 1863.

If one looks carefully at freshly altered parts of the white matter ...one perceives already with the naked eye a red point or line in the middle of each individual focus,.. the lumen of a small vessel engorged with blood...All this leads us to search for the primary cause of the disease in an alteration of individual vessels and their ramifications; All vessels running inside the foci, but also those which traverse the immediately surrounding but still intact parenchyma are in a state characteristic of chronic inflammation. 

Rindfleisch E. - "Histologisches detail zu der grauen degeneration von gehirn und ruckenmark". Archives of Pathological Anatomy and Physiology. 1863;26:474–483.

link

CW Adams published on damaged cerebral veins and the deposition of iron from blood in MS brains in 1988.
Yet, even after all the historical evidence, when Dr. Zamboni published on the link between venous disease, iron deposition into tissue, inflammation and MS lesions in his "Big Idea" paper in 2008---he was resoundingly ignored (or worse, mocked) by MS researchers. Here's the history of this research into the central vein sign, iron deposition and MS lesions-- link

Once again, we see the evidence of the vascular connection, in clear, high-powered MRI images. Iron deposited into brain tissue, creating inflammatory lesions, all around a small, central vein.

At a certain point, you simply have to say---
WAKE UP!

My family reached that point almost a decade ago, and because of this, my husband remains healthy. The evidence continues. There is a vascular connection to MS.
Whether or not MS specialists and immunologists will ever acknowledge this fact and help patients is moot. It is up to all of us to educate, inform, encourage, and move the research forward.


Be well,
Joan

The Central Vein Sign and New Research

September 20, 2013

It was 150 years ago, in 1863, when Eduard von Rindfleisch first peered through his microscope at an MS lesion and noted a vein inside the cerebral MS lesion.

If one looks carefully at freshly altered parts of the white matter ...one perceives already with the naked eye a red point or line in the middle of each individual focus,.. the lumen of a small vessel engorged with blood...All this leads us to search for the primary cause of the disease in an alteration of individual vessels and their ramifications; All vessels running inside the foci, but also those which traverse the immediately surrounding but still intact parenchyma are in a state characteristic of chronic inflammation. 

Rindfleisch E. - "Histologisches detail zu der grauen degeneration von gehirn und ruckenmark". Archives of Pathological Anatomy and Physiology. 1863;26:474–483.

We've known for over a century that MS lesions are perivenous, meaning lesions form around a vein.  There is a vein in the center of almost every cerebral MS lesion, and this makes the MS lesion unique.

So, it was interesting to see THREE brand new papers on this topic in 2013, coming from neurological research. 

Here's one from July 2013, published in "Frontiers of Neurology"--suggesting that these central veins and perivenous lesions, which are now very clear on 7Tesla MRI, might be helpful in making an MS diagnosis.

Venocentric Lesions: an MRI marker in MS?

In the past decade, numerous studies have explored a promising biomarker for MS: MRI-detectable veins within lesions. This biomarker is well established as detectable at 3 and 7T and efforts should be made to identify/optimize clinically practical methods for its evaluation. Prospective studies have shown that the presence of venocentric lesions at an early but ambiguous clinical presentation is highly predictive of future MS diagnosis. Work remains to be done to confirm or exclude lesions of common MS mimics as venocentric. Common imaging practice and lesion-rating paradigms should be adopted by scientists working in this field.

http://www.frontiersin.org/Multiple_Sclerosis_and_Neuroimmunology/10.3389/fneur.2013.00098/full

Here's another paper entitled "The Central Vein Sign: is there a place for susceptibility weighted imaging in possible multiple sclerosis." (Readers of this page know that CCSVI investigator, Dr. Mark Haacke, is the inventor of SWI.  He has noted these central veins and iron deposition in the MS brain for almost a decade now, and linked their presence to CCSVI.)

Susceptibility weighted imaging (SWI) may have the potential to depict the perivenous extent of white matter lesions (WMLs) in multiple sclerosis (MS). We aimed to assess the discriminatory value of the "central vein sign" (CVS).

The "central vein sign" was predominantly seen in MS lesions. The "central vein sign" helps discriminate between MS and non-MS lesions.

http://www.ncbi.nlm.nih.gov/pubmed/23436147

Here's yet another study published in the Journal of Neuroimmunology in May 2013 which notes the central veins visible in MS lesion.

Of the 29 patients enrolled and scanned using 7-T MRI, so far 22 have received a clinical diagnosis. All 13 patients whose condition was eventually diagnosed as MS had central veins visible in the majority of brain lesions at baseline. All 9 patients whose condition was eventually not diagnosed as MS had central veins visible in a minority of lesions.

In our study, T2*-weighted 7-T MRI had 100% positive and negative predictive value for the diagnosis of MS. Clinical application of this technique could improve existing diagnostic algorithms

.

http://www.ncbi.nlm.nih.gov/pubmed/23529352

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These papers are no surprise--researchers have been noting these veins inside MS lesions for over a century.  But what continues to shock me is that researchers aren't asking WHY?

2013--The 150th anniversary of MS as a vascular disease

December 31, 2012 at 9:33am

What's old is new.

2013 is the 150th anniversary of Eduard Rindfleisch's publication describing MS as a vascular disease.  

Rindfleisch, a German pathologist, studied post-mortem brain samples from people with MS.  He noted that inside all of the lesions he could clearly see an enlarged blood vessel.  He believed the inflammatory response seen in the MS brain was created by hypereremia, or engorgement, due to blocked blood flow.

It's now 2013.  150 years is a long time.  Too long.

Here is what Rindfleisch noticed in the MS brain in 1863.

If one looks carefully at freshly altered parts of the white matter ...one perceives already with the naked eye a red point or line in the middle of each individual focus,.. the lumen of a small vessel engorged with blood...All this leads us to search for the primary cause of the disease in an alteration of individual vessels and their ramifications; All vessels running inside the foci, but also those which traverse the immediately surrounding but still intact parenchyma are in a state characteristic of chronic inflammation. 

Rindfleisch E. - "Histologisches detail zu der grauen degeneration von gehirn und ruckenmark". Archives of Pathological Anatomy and Physiology. 1863;26:474–483.

http://www.ms-gateway.ie/understanding-ms/research/eduard-rindfleisch-1836-1908-107.htm

Unbelievably, in 2012 researchers begin to look at the cerebral veins of people with MS while they are alive, using MRI venograms.  And they notice what Rindfleisch saw---engorged penetrating veins in active, or newly-formed lesions.  

They conclude that the cerebral veins in people with MS are not normal----149 years after Rindfleisch said this.

http://www.ncbi.nlm.nih.gov/pubmed/22968782

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Here is a timeline which outlines the history of the study of MS as a vascular disease.

http://www.ccsvi.org/index.php/the-basics/history-and-timeline

When you read this timeline, notice how the researchers asserting the vascular connection used actual autopsied brain tissue from people with MS.  These are not manufactured mouse models of MS. Notice how many times the words perivenous, veins, blood and fibrinogen are mentioned, thoughout the decades of research.  

An inflammatory process is activated whenever there is a break in the blood brain barrier in humans.  The idea that MS is created by a rogue immune system-- crossing the blood brain barrier and attacking myelin-- is STILL only a theory.  The break in the blood brain barrier precedes demyelination in MS.  Why does this happen?

Dr. Zamboni showed how extracranial venous malformations could lead to cerebral hypoperfusion. A process that would lead to a hypoperfusion/reperfusion injury to the brain. 

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

A process that would explain what Rindfleisch noted 150 years ago and researchers see today.  And despite what some neurologists are claiming, Dr. Zamboni's theory has not been disproven by their research.  Because they are not looking at collateral circulation, hypoperfusion and mean transit time.

When MS specialists claim that "we've investigated the vascular connection to MS, and there's nothing there" they are usually referring to Dr. Tracy Putnam's research and trials of newly discovered blood thinners in people with MS.  This happened in the 1940s, when Dr. Putnam was modeling MS lesions by blocking the venous sinus of dogs.  Dr. Putnam was just beginning to understand the implications of blocked venous flow on the brain, when Thomas Rivers created the EAE model of MS. People wanted a cure for MS, and looked to the creators of the polio vaccine for the answers.  Vascular research was abandoned.  For those interested in more of this history, here is the story of TJ Putnam.

http://ccsviinms.blogspot.com/2012/06/dr.html

The following paper was published by researchers at the Royal Free Hospital of Medicine in London. It is available online, in toto, for free.  The reason it is important is that researchers examined actual autopsied brains from people with acute MS, and studied the lesions on an immunohistochemical level.  This paper was published in 1994.

Immunohistochemical study of vascular injury in acute multiple sclerosis.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC501826/?page=1

AIMS--To examine the vascular changes occurring in three archival cases of acute multiple sclerosis, and to provide immunohistochemical evidence of early endothelial cell activation and vascular occlusion in this condition.

METHODS--Central nervous system tissues from three cases of acute active multiple sclerosis and six non-inflammatory controls were stained using the following methods: haematoxylin and eosin, Luxol fast blue, cresyl violet, Bielschowsky's silver, and reticulin. Tissues were also immunostained with specific antibodies against collagen type IV, factor XIIIa, class II antigens, glial fibrillary acidic protein, and fibrinogen.  

RESULTS--Early vascular endothelial cell activation which may progress to vasculitis and vascular occlusion including class II antigen expression and fibrin deposition were identified. The vascular changes were seen prior to cerebral parenchymal reaction and demyelination, and were not seen in control cerebral tissues.

CONCLUSION--It is proposed that vascular endothelial cell activation may be an early and pivotal event in the evolution of multiple sclerosis, and that demyelination may have an ischaemic basis in this condition. The vascular endothelium may contain an early element in the evolution of multiple sclerosis.

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Why is there so much reticence by MS researchers to truly collaborate wih vascular doctors, to understand Dr. Zamboni's discovery of truncular venous malformations in the extracranial veins of pwMS?

Cleveland Clinic/Case Western studied post mortem jugular veins from pwMS and found the presence of a novel venous valve that had not been described in anatomy textbooks.  Just as Dr. Zamboni said, pwMS have truncular venous malformations.  Yet there has been no more investigation into this phenomena.  Why not?  

It is now four years since the first group of patients and caregivers began discussing Dr. Zamboni's research on This is MS.  And so far, only BNAC has collaborated with Dr. Zamboni to study his doppler protocol.  Millions of MS Society dollars are spent on a variety of diagnostics--without looking at the deep cerebral veins, with utilization of valsalva manuever, without consulting phlebologists on the nature of truncular venous malformations.  All of the wasted time and money, in an attempt to quell vascular research, and assert the dominance of immunomodulating drugs.  

Let's celebrate 2013 as the 150th anniversary of Rindfleisch's observation.

We call for collaboration.   It's time.

Happy New Year!!

Joan

The venous connection to MS- a timeline

January 3, 2010 at 6:09pm

To those doctors who insist the venous connection to MS is an unproven theory, I offer a timeline of doctors who might beg to differ.

1863 Rindfleisch

Dr. E. Rindfleisch noticed that, consistently in all the autopsy specimens of MS brains he viewed with his microscope, a vein engorged with blood was present at the centre of each lesion.

Rindfleisch wrote:

"If one looks carefully at freshly altered parts of the white matter ... one perceives already with the naked eye a red point or line in the middle of each individual focus,.. the lumen of a small vessel engorged with blood ... All this leads us to search for the primary cause of the disease in an alteration of individual vessels and their ramifications; All vessels running inside the foci, but also those which traverse the immediately surrounding but still intact parenchyma are in a state characteristic of chronic inflammation."

Rindfleisch E. - "Histologisches detail zu der grauen degeneration von gehirn und ruckenmark". Archives of Pathological Anatomy and Physiology. 1863;26:474–483.

1930s Putnam

Dr. T. J. Putnam researched lesions and noted that thrombosis of small veins could be the underlying mechanism of plaque formation-  He later created MS-like lesions in dogs by blocking their dural sinuses.

Putnam, T.J. (1937) Evidence of vascular occlusion in multiple sclerosis

1940s Dow and Berglund

Dr. Robert Dow and Dr. George Berglund continue on with Dr. Putnam's research and finding venous connections to MS lesions.

VASCULAR PATTERN OF LESIONS OF MULTIPLE SCLEROSIS Arch Neurol Psychiatry. 1942;47(1):1-18.

1950s  Zimmermann and Netsky

Dr. Zimmerman and Netsky carry on with Dow and Berglund's research, and note that the lesions are indeed venous in nature, but not caused by small thrombosis as Putnam surmised.

Zimmerman, H. M., Netsky, M. G.: The pathology of multiple sclerosis. Res. Publ. Ass. Nerv. Ment. Dis. New York 28, 271--312 (1950)

1960s Fog

Dr. Torben Fog, a Danish professor – noted that MS lesions are predominantly around the small veins. His subsequent study of 51 plaques from two cases of typical MS, making thin sections of the plaques and following their shape and course with direct drawings of each section, showed that most were prolongations of periventricular plaques, and that the plaques did follow the course of the venous system.

Fog Torben, The topography of plaques in multiple sclerosis, with special reference to cerebral plaques. Acta Neurol Scand, 41,Suppl. 15:1, 1965)

Fog T. On the vessel-plaque relations in the brain in multiple sclerosis. Acta Psychiat Neurol Scand. 1963; 39, suppl. 4:258

1980s Schelling

The story began in 1973, at the University of Innsbruck, when F. Alfons Schelling, M.D. began investigations into the causes and consequences of the enormous individual differences in the widths of the venous outlets of the human skull. The results of this study appeared, in 1978, in the official organ of the German-speaking Anatomical Societies, the "Anatomischer Anzeiger".

F.A. Schelling's 1981 discovery, at the Hospital for Nervous Diseases in Salzburg, of a striking widening of the main venous passageways through the skulls in victims of multiple sclerosis were to occupy the author's thoughts through the following decades of his quite diversified medical career. And in putting together, bit by bit, all the observations on the venous involvement in the emergence of the specific, and, in particular, cerebral lesions of multiple sclerosis, he was able to recognize their causes.

"Unequal propagation of central venous excess pressure into the different cerebral and spinal venous drainage systems is the rule rather than the exception. The intensity of the forces thus to be exerted on vulnerable cerebrospinal structures by the resulting pressure-gradients in the craniovertebral space is unknown. There is a need to consider the various conditions which may cause individual proneness to heavier reflux into particular cerebral as well as epi- and subdural spinal venous compartments. An attempt is made to indicate eventual consequences of excessive retrograde dilatation especially of internal cerebral veins. The importance of elucidating the neuropathological and clinical implications of undue reflux into the skull or spine is deduced from the probability of relations between localized backflow into the craniovertebral space and unexplicated cerebrospinal diseases. In this regard the features of multiple sclerosis are discussed."

Damaging venous reflux into the skull or spine: relevance to multiple sclerosis, Schelling F.

Here is Dr. Schelling's website for more information. His book (available for free on his site) outlines the history of the connection of MS to the venous system. Dr. Schelling is a brilliant, kind and generous man. When he came public with his research, he was dismissed, ridiculed and mocked. I am so happy that he is able to now witness Dr. Zamboni's technological corroboration of his findings. It was my pleasure and honor to meet him in Bologna, and to share his research with you.

link to Dr. Schelling's site