New Disease Model for MS

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New Disease Model for MS

Postby Direct-MS » Thu Feb 03, 2011 9:02 pm

A New Disease Model for MS

Ashton Embry, January, 2011

A disease model is a hypothesis for what causes a disease and how it progresses. A model is developed using all the available empirical data which have accumulated for the disease and combining that with theoretical knowledge gained from studying many diseases. The key aspects of a viable model are that it explains all important observations, is theoretically reasonable and is as simple as possible.

One of the major contributions of a good model is that it allows new understanding of the disease process and points the way to potentially effective treatments. Given a model’s influence on the research effort and proposed/employed treatments for a given disease, it is important to reappraise the model as new data become available. Such reappraisal can take the form of either a minor modification of the model or possibly a complete overhaul, depending on how well or badly the new data fit with the existing model.

Over the last 160 years, many disease models have been proposed for MS but none have led to development of an effective treatment. This suggests we are still awaiting the development of a reasonably realistic model which incorporates the key factors that are causing and driving MS.

Over the past 50 years, two models have received the lion’s share of attention and research funding - the infection model and the autoimmune model. The infection model proposes that MS is caused by either a bacterial or viral infection in the central nervous system. However, the continued failure to identify a causative infectious agent, despite many detailed studies, has downgraded this model such that it now receives little support.

Currently, the preferred disease model for MS is that it is a cell-mediated, autoimmune disease. This model has the immune system becoming sensitized to parts of myelin due to both genetic susceptibility and a viral infection such as Epstein-Barr (EBV). It is also proposed that a defect in immune regulation is needed to promote the initiation and continuation of autoimmunity and vitamin D deficiency is one of the favoured causes of such decreased immune regulation. Over time, repeated autoimmune attacks on myelin eventually cause clinical symptoms and MS is diagnosed, usually in early adulthood.

This model has been preferred because over the years it has done the best job of explaining the available data for MS, including many diverse, epidemiological, genetic and immunological studies. Also, an experimental animal model, called experimental autoimmune encephalitis (EAE), reproduces many features of MS and thus adds further support to the autoimmune disease model. Using the autoimmune model as a foundation, developed therapies have focused on suppressing or modulating various parts of the immune system.

Over the past 20 years, dissatisfaction with the autoimmune model has grown as new observations, which cannot be easily explained by the model, have accumulated. Some of the important data which have raised doubts about the autoimmune model include:
1) Current immune-based therapies have little, if any, effect on disease progression.
2) Neurodegeneration appears to be an important part of MS throughout disease development, becoming dominant in the latter stages.
3) Detailed pathological studies of newly developed lesions have demonstrated that myelin disintegration precedes the invasion of the immune system indicating immune action is secondary.
4) MS lesions are venocentric and often are associated with iron deposits
5) Immune activity sometimes occurs associated with the optic nerve where no myelin is present.
6) No autoimmune activity occurs in the peripheral nervous system where myelin is also present.

These observations have not led to any serious reappraisal of the autoimmune model mainly because no one has been able to provide a better model which would explain these data as well as all the other data which seem to support the autoimmune model.

Little over a year ago, the important observation that most people with MS have impaired venous drainage from the brain (CCSVI) became widely known. Notably, this finding was not compatible with the autoimmune model, especially given the finding that the venous malformations responsible for CCSVI preceded the MS disease process. These new data, which have now been solidly confirmed by venography on thousands of MS patients, have led to the development of an entirely new model for MS.

In this CCSVI model, extra-cranial, venous blockages cause altered blood flow in the brain which in turn results in myelin breakdown in various ways including oxygen deprivation (hypoperfusion). It is also hypothesized that the altered flow leads to iron deposition in the walls of veins, consequent breakdown of the blood-brain barrier, the introduction of noxious elements into the CNS, and consequent neurodegeneration. Immune involvement is seen as part of the clean up process by a normal immune system.

Presently, a war of words is going on between the supporters of the conventional, autoimmune model and those that favour the upstart CCSVI model. Notably both sides use observations which are not compatible with their opponents’ model to argue against it. For example, the autoimmune model supporters use the common presence of a specific immune gene, immune dysregularities, and the requirement of an EBV infection, to discredit the CCSVI model. They also make the valid argument that some cases of CCSVI do not result in MS. The CCSVI model supporters use the established presence of venous blockages and altered blood flow, as well as the six points which had previous raised doubts about the autoimmune model, to disparage it.

Given a valid model has to incorporate all the important data, both the autoimmune and CCSVI models are not valid because they both fail to include critical data. Clearly, a new disease model for MS is required. It must honour the data which had formed the basis of the autoimmune model but must also include the key observations related to CCSVI. The key aspect of this model is that two independent conditions - CCSVI and immune dysregulation - must occur for MS to develop. Notably both of these pathologies depend on both genetic and environmental factors for their manifestation.

In this “two to tango” model, CCSVI gradually erodes the integrity of the blood-brain barrier which contributes to neurodegeneration and also allows the dysregulated immune system access to the CNS. This results in an abnormal immune reaction to disintegrating myelin and eventual permanent damage to the nerve axons themselves. The strength of both CCSVI and the immune dysregulation will vary greatly between individuals and hence very different presentations of MS would be expected. For example, those with lesser immune dysregulation may not experience an immune-related, relapsing and remitting phase and may be diagnosed with a progressive course driven mainly by CCSVI-related neurodegeneration.

Given this new, improved model, the best way to treat MS is to:
1) Upon diagnosis, be tested and treated for CCSVI
2) Use nutritional strategies to counter any immune dysregularity and to promote vascular health
3) Consider using an MS drug to help counter immune activity only if the actions of points one and two fail to halt disease progression.

We have to hope the scientists and clinicians who deal with MS will put aside their prejudices and allegiances to the drug companies and acknowledge the autoimmune model is no longer valid. Only then will they realize that their current research and treatment strategies for MS need to be completely rethought and changed.
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Postby MrSuccess » Thu Feb 03, 2011 11:51 pm

well done .... Sir ....... well done





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Postby frodo » Fri Feb 04, 2011 1:17 am

I would like to add that a model can never proved to be truth with no doubts (look for the flat earth society in internet), but they can be proved to be false.

The six critical points mentioned in the article clearly prove that the only-and-primary-autoimmune model is wrong.
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Postby sou » Fri Feb 04, 2011 4:27 am

Peripheral nervous sytem's myelin is quite different than that of the CNS. But, even we forget about 6, what answer can be given for the toughest 2, 3 and 5?
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Re: New Disease Model for MS

Postby scorpion » Fri Feb 04, 2011 5:44 am

Direct-MS wrote:A New Disease Model for MS

Ashton Embry, January, 2011

A disease model is a hypothesis for what causes a disease and how it progresses. A model is developed using all the available empirical data which have accumulated for the disease and combining that with theoretical knowledge gained from studying many diseases. The key aspects of a viable model are that it explains all important observations, is theoretically reasonable and is as simple as possible.

One of the major contributions of a good model is that it allows new understanding of the disease process and points the way to potentially effective treatments. Given a model’s influence on the research effort and proposed/employed treatments for a given disease, it is important to reappraise the model as new data become available. Such reappraisal can take the form of either a minor modification of the model or possibly a complete overhaul, depending on how well or badly the new data fit with the existing model.

Over the last 160 years, many disease models have been proposed for MS but none have led to development of an effective treatment. This suggests we are still awaiting the development of a reasonably realistic model which incorporates the key factors that are causing and driving MS.

Over the past 50 years, two models have received the lion’s share of attention and research funding - the infection model and the autoimmune model. The infection model proposes that MS is caused by either a bacterial or viral infection in the central nervous system. However, the continued failure to identify a causative infectious agent, despite many detailed studies, has downgraded this model such that it now receives little support.

Currently, the preferred disease model for MS is that it is a cell-mediated, autoimmune disease. This model has the immune system becoming sensitized to parts of myelin due to both genetic susceptibility and a viral infection such as Epstein-Barr (EBV). It is also proposed that a defect in immune regulation is needed to promote the initiation and continuation of autoimmunity and vitamin D deficiency is one of the favoured causes of such decreased immune regulation. Over time, repeated autoimmune attacks on myelin eventually cause clinical symptoms and MS is diagnosed, usually in early adulthood.

This model has been preferred because over the years it has done the best job of explaining the available data for MS, including many diverse, epidemiological, genetic and immunological studies. Also, an experimental animal model, called experimental autoimmune encephalitis (EAE), reproduces many features of MS and thus adds further support to the autoimmune disease model. Using the autoimmune model as a foundation, developed therapies have focused on suppressing or modulating various parts of the immune system.

Over the past 20 years, dissatisfaction with the autoimmune model has grown as new observations, which cannot be easily explained by the model, have accumulated. Some of the important data which have raised doubts about the autoimmune model include:
1) Current immune-based therapies have little, if any, effect on disease progression.
2) Neurodegeneration appears to be an important part of MS throughout disease development, becoming dominant in the latter stages.
3) Detailed pathological studies of newly developed lesions have demonstrated that myelin disintegration precedes the invasion of the immune system indicating immune action is secondary.
4) MS lesions are venocentric and often are associated with iron deposits
5) Immune activity sometimes occurs associated with the optic nerve where no myelin is present.
6) No autoimmune activity occurs in the peripheral nervous system where myelin is also present.

These observations have not led to any serious reappraisal of the autoimmune model mainly because no one has been able to provide a better model which would explain these data as well as all the other data which seem to support the autoimmune model.

Little over a year ago, the important observation that most people with MS have impaired venous drainage from the brain (CCSVI) became widely known. Notably, this finding was not compatible with the autoimmune model, especially given the finding that the venous malformations responsible for CCSVI preceded the MS disease process. These new data, which have now been solidly confirmed by venography on thousands of MS patients, have led to the development of an entirely new model for MS.

In this CCSVI model, extra-cranial, venous blockages cause altered blood flow in the brain which in turn results in myelin breakdown in various ways including oxygen deprivation (hypoperfusion). It is also hypothesized that the altered flow leads to iron deposition in the walls of veins, consequent breakdown of the blood-brain barrier, the introduction of noxious elements into the CNS, and consequent neurodegeneration. Immune involvement is seen as part of the clean up process by a normal immune system.

Presently, a war of words is going on between the supporters of the conventional, autoimmune model and those that favour the upstart CCSVI model. Notably both sides use observations which are not compatible with their opponents’ model to argue against it. For example, the autoimmune model supporters use the common presence of a specific immune gene, immune dysregularities, and the requirement of an EBV infection, to discredit the CCSVI model. They also make the valid argument that some cases of CCSVI do not result in MS. The CCSVI model supporters use the established presence of venous blockages and altered blood flow, as well as the six points which had previous raised doubts about the autoimmune model, to disparage it.

Given a valid model has to incorporate all the important data, both the autoimmune and CCSVI models are not valid because they both fail to include critical data. Clearly, a new disease model for MS is required. It must honour the data which had formed the basis of the autoimmune model but must also include the key observations related to CCSVI. The key aspect of this model is that two independent conditions - CCSVI and immune dysregulation - must occur for MS to develop. Notably both of these pathologies depend on both genetic and environmental factors for their manifestation.

In this “two to tango” model, CCSVI gradually erodes the integrity of the blood-brain barrier which contributes to neurodegeneration and also allows the dysregulated immune system access to the CNS. This results in an abnormal immune reaction to disintegrating myelin and eventual permanent damage to the nerve axons themselves. The strength of both CCSVI and the immune dysregulation will vary greatly between individuals and hence very different presentations of MS would be expected. For example, those with lesser immune dysregulation may not experience an immune-related, relapsing and remitting phase and may be diagnosed with a progressive course driven mainly by CCSVI-related neurodegeneration.

Given this new, improved model, the best way to treat MS is to:
1) Upon diagnosis, be tested and treated for CCSVI
2) Use nutritional strategies to counter any immune dysregularity and to promote vascular health
3) Consider using an MS drug to help counter immune activity only if the actions of points one and two fail to halt disease progression.

We have to hope the scientists and clinicians who deal with MS will put aside their prejudices and allegiances to the drug companies and acknowledge the autoimmune model is no longer valid. Only then will they realize that their current research and treatment strategies for MS need to be completely rethought and changed.


It is not dissatisfaction with the autoimmune model that has caused frustration Dr. Embry, BUT the pace of MS research that has caused people to grow frustrated. I am sure that people who have cancer, Parkinson's, and Alzheimer's also hope for quick and easy cures such as opening up a vein or eating the right foods but unfortunately these diseases are very complicated and human beings(MS researchers, doctors, neuros) just can not play "god" and perform miracles. Of course as people we want quick and easy answers/cures for anything that afflicts us but as you know that is not the fate of human kind although what the medical community has given us in the way of cures and symptomatic relief from SOME diseases in the last 100 years is astounding if you think about it. While your article is very pragmatic and well written you make assumptions that have not yet been verified through rigorous scientific testing. CCSVI and diet have NOT been proven to correlate with MS is any way and to say so it is misleading, no matter how how hopeful your article may sound, to make a connection between them.
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Postby sou » Fri Feb 04, 2011 5:49 am

Neither has autoimmunity proven to be the cause. Why should we support it, then? Isn't it misleading, too?

On the other hand, venous obstructions are facts that can be easily seen even by non-doctors. How about angry lymphocytes? And what is the antigen? 70 years of autoimmunity without an antigen? How can this be?
Shortest joke: "We may not be able to cure MS but we can manage its symptoms."
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Re: New Disease Model for MS

Postby CCSVIhusband » Fri Feb 04, 2011 6:05 am


It is not dissatisfaction with the autoimmune model that has caused frustration Dr. Embry, BUT the pace of MS research that has caused people to grow frustrated. I am sure that people who have cancer, Parkinson's, and Alzheimer's also hope for quick and easy cures such as opening up a vein or eating the right foods but unfortunately these diseases are very complicated and human beings(MS researchers, doctors, neuros) just can not play "god" and perform miracles. Of course as people we want quick and easy answers/cures for anything that afflicts us but as you know that is not the fate of human kind although what the medical community has given us in the way of cures and symptomatic relief from SOME diseases in the last 100 years is astounding if you think about it. While your article is very pragmatic and well written you make assumptions that have not yet been verified through rigorous scientific testing. CCSVI and diet have NOT been proven to correlate with MS is any way and to say so it is misleading, no matter how how hopeful your article may sound, to make a connection between them.


Or it could be that pace is slowed because researchers are barking up the wrong tree - and have been for 20 years, yet refuse to look at other theories (CCSVI).

The auto-immune model for MS is flagrantly flawed. PERIOD.

So what make work in the flawed model on lab rats ... doesn't translate to humans, because ... the model is flawed.


Let's see how these CCSVI mice do ... :)
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Re: New Disease Model for MS

Postby scorpion » Fri Feb 04, 2011 6:19 am

CCSVIhusband wrote:

It is not dissatisfaction with the autoimmune model that has caused frustration Dr. Embry, BUT the pace of MS research that has caused people to grow frustrated. I am sure that people who have cancer, Parkinson's, and Alzheimer's also hope for quick and easy cures such as opening up a vein or eating the right foods but unfortunately these diseases are very complicated and human beings(MS researchers, doctors, neuros) just can not play "god" and perform miracles. Of course as people we want quick and easy answers/cures for anything that afflicts us but as you know that is not the fate of human kind although what the medical community has given us in the way of cures and symptomatic relief from SOME diseases in the last 100 years is astounding if you think about it. While your article is very pragmatic and well written you make assumptions that have not yet been verified through rigorous scientific testing. CCSVI and diet have NOT been proven to correlate with MS is any way and to say so it is misleading, no matter how how hopeful your article may sound, to make a connection between them.


Or it could be that pace is slowed because researchers are barking up the wrong tree - and have been for 20 years, yet refuse to look at other theories (CCSVI).

The auto-immune model for MS is flagrantly flawed. PERIOD.

So what make work in the flawed model on lab rats ... doesn't translate to humans, because ... the model is flawed.


Let's see how these CCSVI mice do ... :)


I disagree with you. The problem is not that researcher s have not looked at other causes but instead the problem is when they have tested their alternative ideas they generally turn out to be a dead end.
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Postby CCSVIhusband » Fri Feb 04, 2011 6:48 am

"I have not failed 1,000 times. I have successfully discovered 1,000 ways to NOT make a light bulb." - Thomas Edison


It only takes 1 time to get it right, even after that many failures.

Because they've looked into the WRONG things for 20 years - does that mean CCSVI is automatically wrong? (to go with the other theories you mention) - like what, bee stings (please - sorry gullible people), goat serum (please, again, sorry gullible people) ... being newer to "MS" I can't speak to all of them ... but you don't follow CCSVI very closely (per your own words to Dr. Sclafani - yet you sure speak an awful lot against it).

It's the first explanation that has a history with MS along with it - (the original thoughts on 'MS' being veinous centric) - and now the technology now exists to allow it (veinous centric - CCSVI) to be detected, and treated that didn't in the 1800s.

Maybe if it had, we wouldn't have all these wasted dollars and years on injecting foreign substances into the brains of mice (is that what happened to you or my wife while sleeping? Someone put something in your brains to give them EAE ... errrrrrrrrrrrrr ... "MS", it's all the same right)? Gee, I wonder why those CRABS drugs don't work.

Like I said ... CCSVI mice ... coming soon.
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Postby CCSVIhusband » Fri Feb 04, 2011 6:50 am

Anyone watch Gray's Anatomy last night ... and their "placebo" controlled trial? - along with results of those who get "placebo".

And also the use of technology - twitter - in medicine?

Both were interesting commentaries. Even though it's a TV show (I know), it does have very highly regarded doctors on staff to edit and make sure there is integrity to their presentation of medicine.
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Postby Cece » Fri Feb 04, 2011 7:05 am

CCSVIhusband wrote:It's the first explanation that has a history with MS along with it - (the original thoughts on 'MS' being veinous centric) - and now the technology now exists to allow it (veinous centric - CCSVI) to be detected, and treated that didn't in the 1800s.

I agree with you completely.

The much disparaged bee-stingers, though - bee stings have an immediate effect of vasodilation, as well as probably an adrenaline boost - it probably worked, a little, for a subset of pwMS. It is however up there along with drinking worms on my list of MS therapies that I don't want to try.

Instead of gullible or desperate, maybe "highly motivated"....
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Postby 1eye » Fri Feb 04, 2011 7:25 am

results in myelin breakdown in various ways including oxygen deprivation (hypoperfusion)

and various pathologies due to glucose starvation, which may be related to other problems laid to autoimmunity.
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Postby 1eye » Fri Feb 04, 2011 7:28 am

drinking worms

Don't knock it till you've tried it.
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Postby Cece » Fri Feb 04, 2011 8:32 am

1eye wrote:
drinking worms

Don't knock it till you've tried it.

I don't mean to knock it, even if I can't see myself knocking one back anytime soon! It's got some logical underpinnings, I'm interested to see if the research pans out.
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Postby cheerleader » Fri Feb 04, 2011 8:38 am

Great write up. Thanks again, Dr. Embry. Marie Rhodes' new book lays out this paradigm with references to all of the research. It's not a new, or particularly desperate, idea. It's a scientific theory that finally explains the venocentricity of MS, the perivenous injury to the brain, and the atrophy of gray matter. The autoimmune theory, on it's own, doesn't have any means of addressing these facts. And that's a problem for all of the pwMS who continue to address their MS with immune modulating medications.

Cerebral blood flow is a new area of investigation, and as much as nay sayers would like to contend that "we've been through all of this vascular stuff before" and it's "been a dead end", --we simply have not had the technological means of studying blood flow in, blood flow out and comparing the levels in pwMS vs. normals until recently....and there are huge differences. Research coming. It's about time.

Here's more info on Marie's book-
http://ccsvibook.com/

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dx dual jugular vein stenosis (CCSVI) 4/09
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