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

 

History, Hysteria and Hope

May 24, 2013

  

In the last two years, the paradigm for treating MS has changed.  Vitamin D supplementation is routinely recommended.  A healthy diet and exercise are encouraged.  Stress reduction and lifestyle changes, like smoking cessation, are encouraged.  

We are seeing a subtle shift in the understanding of MS as a purely autoimmune disease which cannot be modified, to an inflammatory disease which can be addressed with lifestyle changes encouraging cardiovascular health.

This is new.  

We also now understand that the changes which happen to the brain early in the MS disease process create pain, depression and fatigue.  These are not imagined symptoms.  They are real, and linked to atrophy of the hippocampus and thalamus.

Here is some more background about how MS has been viewed and treated throughout history.

You will see, the shift in how neurology considers MS is still evolving.

We're getting there.

The history of MS research is full of assumptions that were once held as fact by neurologists, but were later proven untrue.  It's important to review how multiple sclerosis patients have been described over the course of history, in order to understand the current mindset of neurology.  I hope this opens some eyes.   

Each of these three points were once believed to be factual.  We now know they were wrong, dead wrong. 
But the repercussions of these inaccurate beliefs linger today.

1. MS is related to the patient's psychological condition.

The very beginnings of MS research were dominated by French neurologist Charcot's fascination with hysteria and personality disorders as related to neurological disease.

Hysteria, from the ancient Greek word for uterus, was a nervous illness long associated exclusively with women. Symptoms differed from patient to patient and from one historical period to another, but they always involved both the body and the mind. Some characteristic symptoms included shortness of breath, heaviness in the abdomen, muscular spasms and fainting. Anxiety, irritability and embarrassing or unusual behaviour were also noted.

Hysteria received intense attention during the late 1800s. The French neurologist Jean-Martin Charcot proposed hysteria was an inherited nerve disease, similar to multiple sclerosis...Charcot investigated hysteria using hypnosis. In lectures he invoked characteristic symptoms in male and female hysterics by applying pressure to specific spots on the hypnotised patient’s body. Critics argued these performances testified to Charcot’s powerful influence over his patients, not the nature of hysteria.

http://www.sciencemuseum.org.uk/broughttolife/techniques/hysteria.aspx

This subtle message, which began as an understanding of MS as a disease involving the psyche,  was that MS was somehow initiated by a personality or nervous disorder which could be controlled by the neurologist.  This subtext continued on into the 20th century.  Here is research from the 1950s.

"The personality characteristics associated with multiple sclerosis as revealed by the MMPI profiles are presented and discussed. The personality characteristics revealed are: a reaction of depression, preoccupation and concern about bodily functions, feelings of hopelessness and insecurity, as well as tendencies toward indecisiveness, narrowness of interests, and introversion. Difficulty in accepting the disease, and its progressive limitations, as well as ambivalence and insecurity concerning the future, are often reflected in relatively poor emotional control and social adjustment."

http://psycnet.apa.org/journals/ccp/15/3/253/

2. MS does not cause fatigue.  

In the 20th century it was believed that fatigue was not a symptom of MS.  It was believed that fatigue was what caused MS.

Patients were told to stop exercising and to rest in order to avoid relapses.  The underlying message, again, was that there was a personality type that developed MS--neurotic, stressful, type A personality--hysterics. The message was that if patients could just rest, take it easy, not worry;  they could avoid relapses and disease progression.  This has been proven untrue.  Many different people develop MS: from athletes to academics, from mothers to rock stars, from children to middle aged adults.   And stress and rest are not part of the equation in contracting the disease.  And fatigue is often the presenting symptom before an official MS diagnosis as we learned this week.  And those who are able to exercise do better with symptom management.

3. MS does not cause pain

 When most people think of multiple sclerosis, they think of a disease that causes symptoms of weakness and motor problems -- not pain.

"About 10 or 20 years ago, there was a saying that MS causes all kinds of trouble but doesn't cause pain, which really isn't true," says Francois Bethoux, MD, director of rehabilitation services at the Mellen Center for Multiple Sclerosis Treatment and Research at The Cleveland Clinic.

http://www.medicinenet.com/script/main/art.asp?articlekey=52405

As many with MS can tell you---they feel pain.  Their pain is real, and it is caused by their MS.  Even though patients have been describing their pain to their doctors for over a hundred years, it is only in the last 10 years that this has been taken seriously.

__________________________________________________________

I believe that the distance between the multiple sclerosis patient and the neurologist was allowed to persist through the historical characterization of the MS patient as hysteric, emotionally labile, neurotic or mentally unbalanced.  These false depictions were created by a group of doctors who were threatened by their own personal lack of understanding of the disease and inability to change its course.    It was too difficult to confront the ravages of MS and not be able to cure the disease.  It was easier to portray the patient as defective and the source of their malady.   This provided a comfortable distance between doctor and patient.

Neurology so distanced itself from the patient, that THEY DIDN'T EVEN BELIEVE THE MS PATIENT WAS IN ACTUAL PAIN.  It took over one hundred years for neurologists to admit that there might be pain, or fatigue, or depression caused by multiple sclerosis.  This is absurd.

Since the advent of MRI technology, doctors have concrete evidence of the degredation of gray matter, atrophy of the hippocampus, and demyelination in areas of the brain responsible for emotion, pain and cognition.  All of these changes to the brain are linked to depression, pain and fatigue.  
http://ccsviinms.blogspot.com/2010/07/study-on-brain-changes-in-ms-and.html

These changes to the brain occur early in MS.  Researchers can see the slowed blood flow and hypoperfusion.  They can study fMRI images. 7Tesla imaging (Ge, et al) has allowed researchers to see the microscopic vascular changes that happen to the veins in the MS brain. 
http://ccsviinms.blogspot.com/2009/12/hypoperfusion-decreased-blood-flow-in.html

The physical changes to the brain are caused by a disease process.  They are not psychological or imagined.   The disease comes first, and the brain damage follows.

If there are any young neurologists reading this, I implore you, bridge the gap between patient and doctor.

Look at your patients as family members, friends, siblings, loved ones, human beings. 

Study their MRI images, work with vascular doctors and look at their cerebral blood flow, specifically, the venous return.  Don't be afraid of collaboration between disciplines.  For this is the future of medicine.

Talk to your patients, but most importantly, listen to them.  When they tell you they are in pain, or exhausted or depressed--believe them.  Try to help them.  And try to learn WHY this is happening.

It's time to say goodbye to the era of Charcot and hysteria.  It's time for science.

Joan

Charcot demonstrating hypnosis on an "hysterical" Salpêtrière patient, "Blanche" 

A painting by Pierre Brouillet