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 ia an MRI examples of how the thalamus shrinks, and the third ventricle (the black area in the center/top of the brain) expands-- 

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

 

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

Normal Pressure Hydrocephalus---the once "controversial" discovery of Dr. Salomon Hakim

November 25, 2012 at 1:59pm

Those of us interested in moving CCSVI diagnosis and treatment forward can always learn from history.

In the 1960s, a neurosurgeon in Bogota, Columbia made the controversial claim that he could reverse neurodegeneration by surgically diverting an excess of cerebrospinal fluid (CSF) by placing a shunt in his patients.

Professor Salomon Hakim first published his thesis in 1964 and then published 6 case reports of "normal pressure hydrocephalus" in The New England Journal of Medicine and the Journal of the Neurological Sciences in 1965. Hakim rose to the forefront of academic medicine as he described a newfound ability to reverse symptoms of “neurodegeneration” that had long been considered irreversible.

link

It is important to understand that today, 60 years after Hakim's discovery, treating normal pressure hydrocephalus is an accepted practice, even though diagnosing NPH is an inexact science.  There were never any double blinded clinical trials for this surgery.  Hakim claimed he could reverse gait impairment, cognitive problems and urinary incontinence by diverting CSF flow.  And the proof was in his patients' recovery.  No one cries "placebo effect!" after a patient recovers mobility, cognition or bladder control once treated for NPH.

Here is a first hand account of the changes in brain function and recovery, written by a woman treated for NPH.  Her story was published in the New York Times.

link

I first learned about NPH from Dr. Elliot Frohman in Bologna, Italy--at the first CCSVI conference in September 2009.  It was Dr. Frohman, an MS specialist and neurologist, who commented that CCSVI treatment reminded him of the success he had seen after treating his patients for NPH. Here is what Dr. Frohman said about venoplasty for CCSVI.  I wrote it down in my notes, because his comment literally stunned me.

 I have seen this happen in “normal pressure hydrocephalus- (NPH) Where there is a loss of gait, cognitive and bladder issues and the lesions disappear because the expanded ventricle swallows the lesion. I have shunted the brains of NPH patients, and they showed remarkable improvements. Again, the enlargement of the third ventricle precedes the changes.

So, what's NPH?  And what might it have to do with CCSVI?

The brain and spinal cord are surrounded by a clear fluid called cerebrospinal fluid (CSF). This fluid is produced and stored in cavities in the brain called ventricles. It circulates around the brain, moving from ventricle to ventricle. The purposes of the fluid are to cushion and protect the brain and spinal cord, to supply them with nutrients, and to remove some of their waste products. Any excess fluid drains away from the brain and is absorbed by other tissues.

Hydrocephalus (literally water on the brain) is a condition in which there is too much CSF in the ventricles. This occurs when the natural system for draining and absorbing extra CSF does not work right. The ventricles enlarge to accommodate the extra fluid and then press on different parts of the brain, causing a number of different symptoms. Hydrocephalus has many different causes. Some people are born with the condition, while others develop it during their lives.

Normal pressure hydrocephalus (NPH) is a type of hydrocephalus that occurs in adults, usually older adults. NPH is different than other types of hydrocephalus in that it develops slowly over time. The drainage of CSF is blocked gradually, and the excess fluid builds up slowly. The slow enlargement of the ventricles means that the fluid pressure in the brain may not be as high as in other types of hydrocephalus. However, the enlarged ventricles still press on the brain and can cause symptoms. (The term "normal pressure" is somewhat misleading.)

And cerebrospinal fluid is affected by venous return.  Open jugular veins are essential for CSF clearance.  link

The less blood flowing through the brain back to the heart, the more CSF can build up and reabsorption is hindered.  For those who want to learn more about this connection, I highly suggest reading Dr. Michael Flanagan's book and blog, The Downside of Upright Posture.

Venoplasty for CCSVI changes cerebrospinal fluid flow rates.  

The reseachers at BNAC noted that even 12 months after venoplasty, the patients treated for CCSVI had a faster rate of CSF flow going through their brains.  

link

My husband had a profound relief of fatigue, cognitive fog, heat intolerance, spasms and sleep apnea after being treated for CCSVI in May 2009. These improvements still continue, now 3 and a half years later.  His third ventricle is now normal on MRI, he has no gray matter atrophy.  

Dr. Frohman and his neurological community would have you believe that Jeff's benefits from CCSVI venoplasty are placebo, while the patients they have treated for NPH benefits are real.  Why this cognitive dissonance?  

Only more research, publications like the BNAC paper on cerebrospinal fluid changes after venoplasty, and more pressure from patients and caregivers will provide answers.

Joan