Measuring MS

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Measuring MS

Postby 1eye » Tue Jan 12, 2016 6:13 pm

http://www.smw.ch/content/smw-2013-13887/

In this document, referred to by Ms. Beal, also called "cheerleader", in at least two posts here (see http://www.thisisms.com/forum/chronic-cerebrospinal-venous-insufficiency-ccsvi-f40/topic27228.html#p238800 ), there is clear evidence for the existence of a set of measurable rates of change in various brain structures in MS, some of which are unique to the MS phenotype.

These measurements give us a clinical non-destructive way of distinguishing these variants of the disease. Various statements have been made about the lack of efficacy of DMDs on the progressive forms of these phenotypes. There may actually be efficacy, especially if atrophy is measured.

If the primary measurable effect of multiple sclerosis is brain atrophy, and if it is measurable using an ordinary ruler, why is it not a standard practise to measure it?

It cannot be true that atrophy is of no consequence. Even if it can be shown that there is no statistical relationship between atrophy and some other currently fashionable clinical measures, surely atrophy itself is the primary undesireable , measurable consequence of the disease. Other details are of less consequence, including broken neurons. The more a brain shrinks, the less possible it is to retrain it.

As an MS patient, there are two related pieces of information that are vital to me.

Across all the MRIs I have had done,
1. What is the current state of my various affected brain structures?
2. What is my rate of atrophy in these affected brain structures?

In addition, the effects of various Disease Modifying therapies on the mathematical derivative, or acceleration of these various rates of atrophy is of extreme interest to MS patients, so they can assess which of these therapies can best slow it down. The required measures can be arrived at using three or more brain MRIs. Each MRI has one data point for the size of each affected atrophic structure. The more MRIs, the more detailed and certain the resulting assessments will be, of atrophy, and of treatment success.
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'MS' is over - if you want it
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I am not a doctor. Do not take anything I say as medical advice.
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Re: Measuring MS

Postby DrGeoff » Wed Jan 13, 2016 7:33 am

http://www.smw.ch/content/smw-2013-13887/

Well, what a can of worms this has opened - but I doubt if the right people will look at the worms and go away for a rethink.

Measuring brain atrophy (whether en masse, or by specific lobes or areas) seems so easy, one has to wonder why no-one else has thought of it.
The answer is probably a matter of vested interests. I have in mind, the people who may pay for a treatment. It matters little whether these are an insurance company, or a state medical system. Each will have their own pet test, and the supplier of treatment, therapy, or medication, will seek to address precisely that test so that their product will continue to be paid for.
Any good test should meet a number of criteria, including that of repeatability, and consistency, and validity. Even the EDSS should give the same result if two different clinicians make an assessment (and there are times when it is fashionable to deride the EDSS). Or, consider the "Timed 25 foot walk". I will be taking this in a few week to see if I continue to get funding for the Functional Electronic Stimulator (FES) that minimises the effect of my Drop foot. I will be tested with my FES turned on, or turned off. Will I deliberately influence the test result? Since the tester is from the FES supplier, will he/she care?
So, a simple measurement that only requires a ruler has a lot to commend it.
Some years (about 20) back I was responsible for a study that tested the accuracy with which the computer models of armored vehicles scaled over distance on a simulator display, and compared these to judgements of their distance made by members of the military. The primary instrument used was a transparent ruler. The results were not popular in some quarters (big money in simulators, and in the computer models that they used).
So, if a simple measurement of brain atrophy is a good measure of MS severity, and if repeated measurements are a good measure of disease progression, and if - as the Swiss study shows - this leads to a direct comparison of the effectiveness of the various DMTs, guess what will happen? Now guess the response from the company that produces the least effective DMT.
Of course, this could be used to compare other things, if used over several years. Diets for example, CCSVI treatment versus DMTs, and there are a lot more.
And the downside? Someone will need to pay for annual MRI scans!
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Re: Measuring MS

Postby ElliotB » Wed Jan 13, 2016 8:10 am

Just wondering if anyone knows whether brain atrophy and level of disability correspond to each other?
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Re: Measuring MS

Postby DrGeoff » Wed Jan 13, 2016 12:13 pm

The paper cited by cheer did suggest this.
The correlations are not overwhelming, but that could be down to a problem with the measures of disability that were referenced.
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Re: Measuring MS

Postby 1eye » Wed Jan 13, 2016 12:29 pm

http://www.smw.ch/content/smw-2013-13887/


Well, what a can of worms this has opened - but I doubt if the right people will look at the worms and go away for a rethink.


Careful here: there are ears in some very high places who will not like to hear that they are wrong.

Measuring brain atrophy (whether en masse, or by specific lobes or areas) seems so easy, one has to wonder why no-one else has thought of it.

The obvious answer is that they have.
The answer is probably a matter of vested interests. I have in mind, the people who may pay for a treatment. It matters little whether these are an insurance company, or a state medical system. Each will have their own pet test, and the supplier of treatment, therapy, or medication, will seek to address precisely that test so that their product will continue to be paid for.

If enough people think MS patients should not have to pay for it, they won’t have to. Many will pay for it anyway, in the meantime.
Any good test should meet a number of criteria, including that of repeatability, and consistency, and validity. Even the EDSS should give the same result if two different clinicians make an assessment (and there are times when it is fashionable to deride the EDSS).

Or, consider the "Timed 25 foot walk". I will be taking this in a few week to see if I continue to get funding for the Functional Electronic Stimulator (FES) that minimizes the effect of my Drop foot. I will be tested with my FES turned on, or turned off. Will I deliberately influence the test result? Since the tester is from the FES supplier, will he/she care?

So, a simple measurement that only requires a ruler has a lot to commend it.

Some years (about 20) back I was responsible for a study that tested the accuracy with which the computer models of armored vehicles scaled over distance on a simulator display, and compared these to judgements of their distance made by members of the military. The primary instrument used was a transparent ruler.

The results were not popular in some quarters (big money in simulators, and in the computer models that they used).

So, if a simple measurement of brain atrophy is a good measure of MS severity, and if repeated measurements are a good measure of disease progression, and if - as the Swiss study shows - this leads to a direct comparison of the effectiveness of the various DMTs, guess what will happen? Now guess the response from the company that produces the least effective DMT.

Of course, this could be used to compare other things, if used over several years. Diets for example, CCSVI treatment versus DMTs, and there are a lot more.

In comparing DMTs, one test seems to be the only one I need. Other tests each validate and compare a DMTs effect on usually one symptom per test. Atrophy causes more than one problem.

I am collecting timed 25-foot walk results of all the tests of me. I may not be able to get some of them, because the vendor probably destroyed them after they found no efficacy.

I have been on an involuntary wash-out period, off all DMTs for some years.
And the downside? Someone will need to pay for annual MRI scans!

I will be surprised if that’s the best you can do. Many are free to pay for these tests and evaluate DMDs in relation to each other on their own. Thank gods for the people on the high side of the poverty gap.

Speaking of FES devices, I wonder why nobody tests Sativex and similar drugs, or as-currently-assessed DMD treatments, for net positive effects on single symptoms like foot-drop, or cognitive function. Need for FES could potentially be less, regardless of insurance.

However it is reasonable to test things like biotin for their effects, if any, on foot-drop, atrophy, and whatever else. It’s a pretty binary symptom, but may improve, if rate of atrophy improves.




Just wondering if anyone knows whether brain atrophy and level of disability correspond to each other?
cheer will likely resolve this, but I think yes. Delta rate of atrophy should also be measured.
"Try - Just A Little Bit Harder" - Janis Joplin
CCSVI procedure Albany Aug 2010
'MS' is over - if you want it
Patients sans/without patience

I am not a doctor. Do not take anything I say as medical advice.
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Re: Measuring MS

Postby cheerleader » Wed Jan 13, 2016 12:52 pm

Thanks for linking this info on the big boy board, 1eye :)

I began looking at biomarkers for MS progression when Jeff was diagnosed in 2007, after his neuro mentioned that white matter lesions weren't the best correlate for disease progression. I wondered what was?

Over the years, I've followed Dr. Zamboni's research (obviously, as my husband Jeff was the first North American treated for CCSVI) but also the BNAC team in Buffalo, since I met Dr. Zivadinov at the very first CCSVI conference in 2009 in Bologna. BNAC gets funding to image the brain and help pharma understand if/how their drugs are working. And the focus from white matter lesions to gray matter atrophy, specifically the thalamus, began to get more attention in Buffalo.
Almost all of BNAC's pharma funded research is now looking at thalamic atrophy in MS.

This blog post has the links to research, and a link which explains the use of measuring the width of the third ventricle and the thalamus as biomarkers for MS progression. As we all know, disability is not simply a measure of 25 timed walk or EDSS, as cognitive issues can be just as detrimental as physical ones.
http://ccsviinms.blogspot.com/2016/01/t ... ssion.html

The correlation of thalamic atrophy also makes sense in terms of understanding progressive MS---as loss of gray matter is found to continue during the progressive phase of MS. Indeed, gray matter atrophy is the only biomarker that begins with CIS, and ends at the final stages...

Fire away with questions, thoughts, debate, contrary research---but make sure to first check out the blog post, and see if your question is answered there. Will save time/energy here.
http://ccsviinms.blogspot.com/2016/01/t ... ssion.html

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http://ccsviinms.blogspot.com
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Re: Measuring MS

Postby 1eye » Wed Jan 13, 2016 5:17 pm

The 3rd ventricle is enlarged, which could be caused by surrounding atrophy. It, the thalamus and corpus callosum, are all affected by atrophy, and are all quite centrally located. Could there be a drainage problem? I would hate to see one of these areas ignored in favour of others.
"Try - Just A Little Bit Harder" - Janis Joplin
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'MS' is over - if you want it
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Re: Measuring MS

Postby cheerleader » Wed Jan 13, 2016 6:58 pm

1eye wrote:The 3rd ventricle is enlarged, which could be caused by surrounding atrophy. It, the thalamus and corpus callosum, are all affected by atrophy, and are all quite centrally located. Could there be a drainage problem? I would hate to see one of these areas ignored in favour of others.


Certainly could be a drainage issue, as well, 1eye. That's what we see in normal pressure hydrocephalus (NPH) in the elderly...you know all about the CSF shunts employed to address this problem. In NPH the ventricular horns are enlarged as well.

But these MS MRI techs are talking about using thalamic atrophy in combination with third ventricle widening in terms of being the best biomarker for MS progression. I think their calculations make sense--it's very specific. Check out the whole paper.
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/
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Re: Measuring MS

Postby 1eye » Wed Jan 13, 2016 7:54 pm

This is the first time I've read anywhere that third ventricle enlargement is not caused by internal pressure, but by external atrophy.

It would be potentially misleading for global atrophy to be assumed to be numerically connected to atrophy of individual organs, or in a similar fashion to enlargement of the third ventricle without categorical proof that internal pressure has nothing to do with it, and that atrophy rate is the same as enlargement rate.

The brain has a lot of very complex structures, and these may all have unique rates of atrophy. Attempts to find a clinical measure of atrophy that is universally applicable to every organ are likely doomed. There may be some mathematical relation between organs' atrophy rates, but equally well, there may not.

An MRI contains plenty of such measurable quantities for each organ, and two MRIs provide rates over time for each. Three MRIs provide deltas for each, and these can be directly caused by treatment or progression. These deltas may be more useful than any other measure of progression.

Don't forget the corpus callosum. Mine can be accurately tracked since 1996, and it was already atrophic in 1997,
"Try - Just A Little Bit Harder" - Janis Joplin
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'MS' is over - if you want it
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Re: Measuring MS

Postby 1eye » Thu Jan 14, 2016 1:19 pm

Atrophy has direction (up, down, big, little) and magnitude. It's therefore something of a vector. This vector is influenced by age, stress, infection, etc.

Atrophy can also be influenced by treatment or progression. Atrophy's changes over time are correlated, either to treatment or progression of the disease itself. The delta form is a fairly direct measurement. It answers the question of whether direction has changed. Magnitudes of changes, or snapshot measurements are measured with a space-graduated MRI.

When any organ atrophies over time, regardless of atrophy elsewhere, it may have an effect on some separate function. But if it is found for instance, that all organs atrophy at the same rate, individual organ blood supply or drainage are less likely to present issues.
"Try - Just A Little Bit Harder" - Janis Joplin
CCSVI procedure Albany Aug 2010
'MS' is over - if you want it
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Re: Measuring MS

Postby cheerleader » Thu Jan 14, 2016 1:57 pm

Two researchers who are members of the ISNVD, Zivadinov and Minagar, collaborated on a paper.
It explains thalamic atrophy and MS and summarizes the research-
Thalamic pathology, similar to the cortical pathology, appears to be present in MS from very early on, including at the CIS stage and in pediatric MS. In the progressive phase of MS, which is poorly explained by focal inflammatory WM demyelination, cortical and subcortical GM pathology including neuronal and axonal degeneration are the likely substrates for accumulating cognitive and motor dysfunction that characterizes long-standing disease.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589190/

Dr. Minagar is going to be presenting on "MS as a vascular disease" at the ISNVD conference in April.
http://isnvd.org/sites/default/files/IS ... 1-2015.pdf
It is no coincidence that the researchers speaking out on thalamic atrophy and MS are also involved with the ISNVD and looking at MS as a vascular disease.
Why? http://ccsviinms.blogspot.com/2012/01/i ... -know.html
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Re: Measuring MS

Postby 1eye » Fri Jan 15, 2016 8:26 am

cortical and subcortical GM pathology including neuronal and axonal degeneration are the likely substrates for accumulating cognitive and motor dysfunction that characterizes long-standing disease


I think this narrows it down but I think there is much more going on, characterized by atrophy. Are circulation problems a primary driver of this disease?
"Try - Just A Little Bit Harder" - Janis Joplin
CCSVI procedure Albany Aug 2010
'MS' is over - if you want it
Patients sans/without patience

I am not a doctor. Do not take anything I say as medical advice.
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Re: Measuring MS

Postby ElliotB » Fri Jan 15, 2016 1:15 pm

"How To Stop Shrinking Your Brain And Improve Your Thought Process"

http://www.medicaldaily.com/knowledge-b ... ess-302450


Imagine, improved diet, exercise, supplements, and proper sleep can all help your brain - what a novel idea!
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Re: Measuring MS

Postby cheerleader » Sat Jan 16, 2016 10:23 am

ElliotB wrote:"How To Stop Shrinking Your Brain And Improve Your Thought Process"
http://www.medicaldaily.com/knowledge-b ... ess-302450 Imagine, improved diet, exercise, supplements, and proper sleep can all help your brain - what a novel idea!

Yup! Great link, Elliot. So much we can do to maintain gray matter.
Here was my list of what to do on "Gray Matters" Written and put on line in 2012: Links to research included!
https://www.facebook.com/notes/10151031434857211/

1. eat fish or take an omega 3 supplement
2. exercise. walk if you can, swim, practice seated yoga, dance, bike, move.
3. discover a new interest-- a foreign language, knitting, oil painting, floral arranging, cooking, juggling.
4. get vitamin D from sun and/or supplement
5. meditate
6. get plenty of good sleep, and take naps.
7. listen to music...even better, sing along or play an instrument.
8. read a book or join a book club
9. eat Indian food, or take a curcumin supplement. If curcumin is contraindicated for you, you can skip this one :)
10. hug often. A pet, a grandkid, a spouse, a tree, a friend--yourself :)


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Re: Measuring MS

Postby 1eye » Sat Jan 16, 2016 11:03 am

It seems we are restricted, constrained, to the "what to do until the fix arrives" type of advice, but that's as it should be, since we are not medical doctors, or published researchers...

Definitely these kinds of things help. It also keeps me from screaming. I am also quite accepting, knowing full well that what ails me may remain a mystery far longer than I expect to live. My 20-year contract to provide solar power to Ottawa Hydro is very unrealistically long, but my heirs can have it.

My friend with MS has a viral sore throat, but not to worry. Even though she is not diagnosed yet, the genome of the suspected virus is owned by Monsanto, so help is on the way. :wink:

The only thing wrong with this MedicalDaily site is that they propagate things with headlines like "Russian Doctor Caught On Surveillance Killing Half-Naked Patient With 1 Punch. Things with videos attached are hard to avoid... stress kills.
Last edited by 1eye on Wed Jan 20, 2016 12:23 pm, edited 1 time in total.
"Try - Just A Little Bit Harder" - Janis Joplin
CCSVI procedure Albany Aug 2010
'MS' is over - if you want it
Patients sans/without patience

I am not a doctor. Do not take anything I say as medical advice.
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