Leonard, your posts are always amazing!
I have nasopharynx issues too. I also have vascular malformations in my brain. And finally, I have constipation problems since I was a kid that I solved with Lactobacillus Planctarum 299v (and gastroenteritis when I was 20 yo).
Anyway, it could be anything... Epsilon toxin? EBV? The combination?
Some weeks ago I looked for CRABs prices and they rose more than 250% in the last decade. In the biggest crisis since 1929 they are rising prices... Coincidence? Or is there a cure next on the corner?
Thank you very much,
S. Titi
Theoretical Immunology
Re: A new concept and treatment options for MS
Research proposal
Title:
To study the efficacy of treatment of chronic progressive MS with a combination of Methotrexate and Rituximab
Abstract:
The likely pathogenic mechanisms of MS provide a sound rationale for investigating the efficacy of a combination of chemotherapeutics. One mechanism is the lack of adequate epi-genetic viral control by intra-cellular mechanisms. Another mechanism is an excessive load of EBV infected and immortalized B-cells that cross react with transgenic cells and release superoxide causing huge oxidative stress. An effective treatment of progressive MS must address both problem areas at the same time.
Methotrexate enters and exits cells and activates intracellular events that stimulate adenosine production, regulating immune mediators resulting in a favourable situation with potent anti-inflammatory properties. Rituximab is a medication that works on the second pathogenic mechanism, kills B-cells by binding to CD20 receptors and thus depletes the B-cells. For MS, both intravenous (iv) and intrathecal (IT) administration should be applied.
While there has been varying evidence of efficacy for each of these compounds when tried in isolation and intravenous only, this trial will examine the efficacy of the combination of Methotrexate and Rituximab iv and IT for slowing the progression of MS.
Background:
The microcosm is so complicated that the research approach is to find out empirically whether the combination of agents works.
Declared mechanisms of action (by FDA and EMA) of medications are often no more than a best educated guess where the mechanism of action of one particular agent that is proposed sometimes varies considerably for different diseases (e.g. see working mechanism of Methotrexate for lupus and for rheuma arthritis where several mechanisms are proposed).
This research proposal proposes a clinical trial with a combination of two medications simultaneously. This treatment has been successfully applied for rheumatic arthritis, an autoimmune disease that has common roots with MS, and is a mainstay in its treatment.
Methotrexate and rituximab have been used and tested in MS as single agent therapies. They may temporarily halt a rapidly progressive downhill course and therefore are only a temporarily solution at best. The application of methotrexate in combination with rituximab has never been tested extensively for MS.
This study from 1995 about Methotrexate for progressive MS by reliable and highly regarded researchers is interesting. Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive MS. Significantly less progression of impairment as measured by validated tests of upper-extremity function was observed in the methotrexate treatment group in the absence of clinically significant toxicity.
http://www.uptodate.com/contents/treatm ... bstract/24
While Methotrexate is a folate antagonist, patients need administration thereof.
Methotrexate is on the list of the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.
This study on Rituximab for PPMS patients showed that time to confirmed disability was significantly delayed by rituximab. It concluded that despite the frequent mild/moderate adverse events related to the drug, rituximab appears overall safe for up to 2 years of therapy.
http://www.ncbi.nlm.nih.gov/pubmed/23843952
Rituximab is approved by the FDA as an anti-EBV treatment.
The treatment of MS by Rituximab may have largely failed sofar because only intra venous administration barely penetrates the cns.
The following article on Rituximab delivered intrathecally is interesting and may come close to a real cure for MS. http://www.ncbi.nlm.nih.gov/pubmed/25745637
It was hypothesized that rituximab therapy in patients with progressive forms of MS could disrupt ectopic lymphoid follicles in the meninges and thus slow progression of the disease.
http://www.thisisms.com/forum/rituxan-rituximab-f39/
Safety:
A thorough risk-benefit analysis of (combined) chemo therapy for MS, as has been called for by some recent papers, has never been done and is urgently needed.
As the above study on Methotrexate shows, the study was done without any clinically siginficant toxicity.
Rituximab was found to be relatively safe in people with progressive MS with most side effects relating to infusion reactions and an increase in infections.
Since 1995, Rituximab was administred over 700,000 times which provides an indiation that it must be inherently safe.
There is less concern with the JC + status because evidence shows there's a 1 in 100 risk of PML in Tysabri patients after 2 years and 1 in 25,000 with Rituxan. Canadian experience shows that JC virus positive patients who were on Tysabri and were moved to Rituxan are all are doing fine.
Studies indicate that there may be strong long term advantages drawn for the treatment with Methotrexate: less heart failure, less stroke, less risk of naso pharyngeal cancer.
[Statistics. Refs.]
I wish to be treated with Methotrexate and Rituximab but I keep running into the big fat wall of the medical system.
Notwithstanding, I believe to be on an information level where I can properly assess the possible rewards against the risks.
And that I have a right - the full right - to be treated as requested.
Title:
To study the efficacy of treatment of chronic progressive MS with a combination of Methotrexate and Rituximab
Abstract:
The likely pathogenic mechanisms of MS provide a sound rationale for investigating the efficacy of a combination of chemotherapeutics. One mechanism is the lack of adequate epi-genetic viral control by intra-cellular mechanisms. Another mechanism is an excessive load of EBV infected and immortalized B-cells that cross react with transgenic cells and release superoxide causing huge oxidative stress. An effective treatment of progressive MS must address both problem areas at the same time.
Methotrexate enters and exits cells and activates intracellular events that stimulate adenosine production, regulating immune mediators resulting in a favourable situation with potent anti-inflammatory properties. Rituximab is a medication that works on the second pathogenic mechanism, kills B-cells by binding to CD20 receptors and thus depletes the B-cells. For MS, both intravenous (iv) and intrathecal (IT) administration should be applied.
While there has been varying evidence of efficacy for each of these compounds when tried in isolation and intravenous only, this trial will examine the efficacy of the combination of Methotrexate and Rituximab iv and IT for slowing the progression of MS.
Background:
The microcosm is so complicated that the research approach is to find out empirically whether the combination of agents works.
Declared mechanisms of action (by FDA and EMA) of medications are often no more than a best educated guess where the mechanism of action of one particular agent that is proposed sometimes varies considerably for different diseases (e.g. see working mechanism of Methotrexate for lupus and for rheuma arthritis where several mechanisms are proposed).
This research proposal proposes a clinical trial with a combination of two medications simultaneously. This treatment has been successfully applied for rheumatic arthritis, an autoimmune disease that has common roots with MS, and is a mainstay in its treatment.
Methotrexate and rituximab have been used and tested in MS as single agent therapies. They may temporarily halt a rapidly progressive downhill course and therefore are only a temporarily solution at best. The application of methotrexate in combination with rituximab has never been tested extensively for MS.
This study from 1995 about Methotrexate for progressive MS by reliable and highly regarded researchers is interesting. Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive MS. Significantly less progression of impairment as measured by validated tests of upper-extremity function was observed in the methotrexate treatment group in the absence of clinically significant toxicity.
http://www.uptodate.com/contents/treatm ... bstract/24
While Methotrexate is a folate antagonist, patients need administration thereof.
Methotrexate is on the list of the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.
This study on Rituximab for PPMS patients showed that time to confirmed disability was significantly delayed by rituximab. It concluded that despite the frequent mild/moderate adverse events related to the drug, rituximab appears overall safe for up to 2 years of therapy.
http://www.ncbi.nlm.nih.gov/pubmed/23843952
Rituximab is approved by the FDA as an anti-EBV treatment.
The treatment of MS by Rituximab may have largely failed sofar because only intra venous administration barely penetrates the cns.
The following article on Rituximab delivered intrathecally is interesting and may come close to a real cure for MS. http://www.ncbi.nlm.nih.gov/pubmed/25745637
It was hypothesized that rituximab therapy in patients with progressive forms of MS could disrupt ectopic lymphoid follicles in the meninges and thus slow progression of the disease.
http://www.thisisms.com/forum/rituxan-rituximab-f39/
Safety:
A thorough risk-benefit analysis of (combined) chemo therapy for MS, as has been called for by some recent papers, has never been done and is urgently needed.
As the above study on Methotrexate shows, the study was done without any clinically siginficant toxicity.
Rituximab was found to be relatively safe in people with progressive MS with most side effects relating to infusion reactions and an increase in infections.
Since 1995, Rituximab was administred over 700,000 times which provides an indiation that it must be inherently safe.
There is less concern with the JC + status because evidence shows there's a 1 in 100 risk of PML in Tysabri patients after 2 years and 1 in 25,000 with Rituxan. Canadian experience shows that JC virus positive patients who were on Tysabri and were moved to Rituxan are all are doing fine.
Studies indicate that there may be strong long term advantages drawn for the treatment with Methotrexate: less heart failure, less stroke, less risk of naso pharyngeal cancer.
[Statistics. Refs.]
I wish to be treated with Methotrexate and Rituximab but I keep running into the big fat wall of the medical system.
Notwithstanding, I believe to be on an information level where I can properly assess the possible rewards against the risks.
And that I have a right - the full right - to be treated as requested.
Last edited by Leonard on Fri Oct 09, 2015 1:16 am, edited 11 times in total.
Re: A new concept and treatment options for MS
Recently, a new MRI of my head was made, the first since 2008. It had hardly changed. I suspect that the liberation from CCSVI has been a factor. After liberation in 2010 the 'noise' came down in both ears and in the centre of the head, mainly during the night. Clearly, if the situation of veins that were blocked for 95 % would have continued, further damage would have been done, no doubt. Yet, the progression has not stopped but continues, slowly but steadily.
I suspect that a significant part of the progression is not caused in the brains but in the periphery. That goes as far down as the connection of the nerves to the muscle cells. If I connect a muscle stimulator to my legs, the weaker right leg gives a clearly lower response than the left leg, an indication that the muscle sensitivity of the right is lower than that of the left. I presume post herpetic neuralgia (PHN) or a similar concept will not be far away. The VZV virus may be the important contributing factor. Some recent paper (I need to look for it) explains the role of Neuro Muscular Electric Stimulation (NMES) as Terry Wahls has used as a novel therapy against VZV.
I suspect that a significant part of the progression is not caused in the brains but in the periphery. That goes as far down as the connection of the nerves to the muscle cells. If I connect a muscle stimulator to my legs, the weaker right leg gives a clearly lower response than the left leg, an indication that the muscle sensitivity of the right is lower than that of the left. I presume post herpetic neuralgia (PHN) or a similar concept will not be far away. The VZV virus may be the important contributing factor. Some recent paper (I need to look for it) explains the role of Neuro Muscular Electric Stimulation (NMES) as Terry Wahls has used as a novel therapy against VZV.
Last edited by Leonard on Fri Jul 03, 2015 3:16 am, edited 1 time in total.
Re: A new concept and treatment options for MS
If there is anyone who knows about the treatment of MS with Methotrexate and / or Rituximab (Rituxan) in the US or Canada or the rest of the world, please let me know or send me a pm.
Thank you!
Thank you!
Re: A new concept and treatment options for MS
I believe that progression is caused by pressure or csf blockage in the spine. At first I thought that Terry Wahls NMES stimulation worked principally on the blood circulation through the brain, but now I believe it works as much on relaxing back muscles, relieving pressure on the spine and stimulating cerebro-spinal fluid. The FONAR cine upright MRI (only one in Europe may be London?) would reveal cervical obstruction of CSF fluid (for example). Brief upper back and back massages down to the lumbars while standing help me keep the fluids circulating. If a visit to an Osteopath helps, that might give you a clue to the functional aspect of the progression. I think you are too preoccupied with the biochemistry when the problem is functional. Anyway, a simple massage may help and I can't see how it would hurt. Regards, VestaLeonard wrote:Recently, a new MRI of my head was made, the first since 2008. It had hardly changed. I suspect that the liberation from CCSVI has been a factor. After liberation in 2010 the 'noise' came down in both ears and in the centre of the head, mainly during the night. Clearly, if the situation of veins that were blocked for 95 % would have continued, further damage would have been done, no doubt. Yet, the progression has not stopped but continues, slowly but steadily.
I suspect that a significant part of the progression is not caused in the brains but in the periphery. That goes as far down as the connection of the nerves to the muscle cells. If I connect a muscle stimulator to my legs, the weaker right leg gives a clearly lower response than the left leg, an indication that the muscle sensitivity of the right is lower than that of the left. I presume post herpetic neuralgia (PHN) or a similar concept will not be far away. The VZV virus may be the important contributing factor. Some recent paper (I need to look for it) explains the role of Neuro Muscular Electric Stimulation (NMES) as Terry Wahls has used as a novel therapy against VZV.
Re: A new concept and treatment options for MS
I think I got it!
It is not unlikely that the different mechanisms underlying MS (loss of epi-genetic control with herpes/ VZV leading to inflammation and; EBV infected B-cells leading to oxidative stress and mitochondrial jamming) assail the body in different places. The effect on our mobility and the associated nerve conduction is the result of a degrading serial pathway from brains to muscles and sensors.
Please take a very close look at this MS progression chart. Just look at the chart, never mind the text. I took the chart because it is the best I could find for now. http://multiple-sclerosis-research.blog ... ected.html
I do not think the chart is fully accurate. Others figures I could find are not accurate either. All figures have been drawn without a broader and consistent concept of MS in mind. What is the case?
I think you should think of MS as the serial connection and hence impaired conduction of nerves that are affected by two different mechanisms that cause an effect on different parts of the body: the inflammation mainly in the brains, shown on MRI as specific lesions of the white matter due to herpes/VZV virus infection in combination with epsilon toxin and; the progression causing in particular muscle/nerve weakness due to B-cells and oxidative stress and mitochondrial/ion pump failure.
[degrading legs with a spared arm function may also point to problems in the spinal cord running down to the legs.
this may be important when intrathecal rituximab administration is considered, see posting further down Sep 15]
Now you best look at the figure on the bottom of the chart. And then replace in your mind the straight horizontal lines by straight upward sloping lines. And then have a precise look at the connection points after each exacerbation. The new lines will start at a higher point than the extrapolation of the previous straight line. This is explained by the remaining damage of the exacerbation in the form of reduced nerve conduction. But it would be highly unlikely if the progressive mechanism would hit at exactly these same places and cells.
People normally follow logical laws; our mind works linear and it has greatest difficulty to deal with non-linear models or complex elements along a disease process. But linearity does not apply in medicine, and most certainly not in the case of MS. There are very many factors, a large variety of influences, different underlying mechanisms, feed-forwards and feed-backs that lead to MS. If you apply only causal thinking, you won’t be able to nail down the disease.
This article on the mitochondrial involvement in the etiology of MS is interesting. It makes an interesting observation about the working mechanism of mitoxantrone. Quote … Inhibitors of proteins that allow oxidative stress to damage the mitochondria, such as intravenous mitoxantrone, might delay the progression of MS … unquote. http://multiplesclerosisnewstoday.com/2 ... ogression/
This interview with Terry Wahls reveals more of her journey towards recovery. I must have read her book “Minding my mitochondria” at least three times but the book does not elaborate on her use of MS medication. I think that it cannot be excluded here that her use of “several cycles of mitoxantrone” did make a real difference. http://www.drfranklipman.com/a-conversa ... -wahls-md/ Interestingly, the careful reader will note that the scope of the interview goes way beyond MS and links the food chain with autoimmune disease in general.
In any event, I think we currently see a total impasse in the medical sector. I have had many positive and encouraging remarks on my thesis and its broader context (in bold blue texts in postings above and previous pages), from professionals from across the medical world, at all levels and from various disciplines, doctors, researchers, chairmen, etc. But the sector is slow or reluctant to pick up the ideas and take the matter forward, perhaps it is more pre-occupied with itself than with the patient.
I am sure that with good medical editor, we can do a groundbreaking article that would change the face of MS forever. If you know someone, please let me know or send me a pm.
It is not unlikely that the different mechanisms underlying MS (loss of epi-genetic control with herpes/ VZV leading to inflammation and; EBV infected B-cells leading to oxidative stress and mitochondrial jamming) assail the body in different places. The effect on our mobility and the associated nerve conduction is the result of a degrading serial pathway from brains to muscles and sensors.
Please take a very close look at this MS progression chart. Just look at the chart, never mind the text. I took the chart because it is the best I could find for now. http://multiple-sclerosis-research.blog ... ected.html
I do not think the chart is fully accurate. Others figures I could find are not accurate either. All figures have been drawn without a broader and consistent concept of MS in mind. What is the case?
I think you should think of MS as the serial connection and hence impaired conduction of nerves that are affected by two different mechanisms that cause an effect on different parts of the body: the inflammation mainly in the brains, shown on MRI as specific lesions of the white matter due to herpes/VZV virus infection in combination with epsilon toxin and; the progression causing in particular muscle/nerve weakness due to B-cells and oxidative stress and mitochondrial/ion pump failure.
[degrading legs with a spared arm function may also point to problems in the spinal cord running down to the legs.
this may be important when intrathecal rituximab administration is considered, see posting further down Sep 15]
Now you best look at the figure on the bottom of the chart. And then replace in your mind the straight horizontal lines by straight upward sloping lines. And then have a precise look at the connection points after each exacerbation. The new lines will start at a higher point than the extrapolation of the previous straight line. This is explained by the remaining damage of the exacerbation in the form of reduced nerve conduction. But it would be highly unlikely if the progressive mechanism would hit at exactly these same places and cells.
People normally follow logical laws; our mind works linear and it has greatest difficulty to deal with non-linear models or complex elements along a disease process. But linearity does not apply in medicine, and most certainly not in the case of MS. There are very many factors, a large variety of influences, different underlying mechanisms, feed-forwards and feed-backs that lead to MS. If you apply only causal thinking, you won’t be able to nail down the disease.
This article on the mitochondrial involvement in the etiology of MS is interesting. It makes an interesting observation about the working mechanism of mitoxantrone. Quote … Inhibitors of proteins that allow oxidative stress to damage the mitochondria, such as intravenous mitoxantrone, might delay the progression of MS … unquote. http://multiplesclerosisnewstoday.com/2 ... ogression/
This interview with Terry Wahls reveals more of her journey towards recovery. I must have read her book “Minding my mitochondria” at least three times but the book does not elaborate on her use of MS medication. I think that it cannot be excluded here that her use of “several cycles of mitoxantrone” did make a real difference. http://www.drfranklipman.com/a-conversa ... -wahls-md/ Interestingly, the careful reader will note that the scope of the interview goes way beyond MS and links the food chain with autoimmune disease in general.
In any event, I think we currently see a total impasse in the medical sector. I have had many positive and encouraging remarks on my thesis and its broader context (in bold blue texts in postings above and previous pages), from professionals from across the medical world, at all levels and from various disciplines, doctors, researchers, chairmen, etc. But the sector is slow or reluctant to pick up the ideas and take the matter forward, perhaps it is more pre-occupied with itself than with the patient.
I am sure that with good medical editor, we can do a groundbreaking article that would change the face of MS forever. If you know someone, please let me know or send me a pm.
Last edited by Leonard on Tue Sep 15, 2015 12:20 pm, edited 1 time in total.
Re: A new concept and treatment options for MS
Hi Leo,
The article you referenced on mitochondria refers to MitoQ or ubiquinone. I understand why you want to use medication to control oxidative reactions in faulty mitochrondria but couldn't restoring mitochondrial respiration with Q10 and acetyl-L-Carnitine be just as valid?
Regards
The article you referenced on mitochondria refers to MitoQ or ubiquinone. I understand why you want to use medication to control oxidative reactions in faulty mitochrondria but couldn't restoring mitochondrial respiration with Q10 and acetyl-L-Carnitine be just as valid?
Regards
Revised thesis
MULTIPLE SCLEROSIS (MS) UNRAVELLED
General
Chronic disease begins in the mitochondria. Mitochondria dysfunction and early death are common pathways in all those illnesses.
24 million people in the US have an autoimmune diagnosis, but another 50 million do not feel well and have autoantibodies but do not yet have enough antibodies to make a diagnosis. So, that means about 75 million have autoimmune problems. That’s extremely significant, and it is a sign that our lifestyles have led us down a very dangerous path. Even more disturbing, more and more children are being diagnosed with an autoimmune problem as children.
The current scourge of autoimmune diseases and new insights in its etiology directly connect human health with the food chain (e.g. high fat, high sugar “Western” diet, distorted Ω3-Ω6 fat balance, engrainisation and 'hardened' wheat, lack of phytonutritients and induced antioxidants). A paradigm change is needed.
But there is always general skepticism about anything new, especially when it seems to have a ‘holistic’ aspect. Where, in our modern economy, significant systemic problems are pervasive that hamper a course toward profoundly changing the paradigm.
http://www.drfranklipman.com/a-conversa ... -wahls-md/
http://multiplesclerosisnewstoday.com/2 ... ogression/
MS pathology
In MS, symptoms have always been treated; protocols were designed to suppress or modulate the immune system. But the real causes have never been treated; MS needs a protocol that treats causes. A thorough in-depth understanding of the disease mechanisms will be necessary for that.
People normally follow logical laws; our minds works linear and have greatest difficulty to deal with non-linear models or complex elements along a disease process. But linearity does not apply in medicine, and most certainly not in the case of MS. There are very many facets, a large variety of influences, different underlying mechanisms, feed-forwards and feed-backs, convolved vicious loops that lead to MS. If you apply only causal thinking, you won’t be able to unravel and nail down the disease.
MS is a subtle highly complex non-linear disease process that goes down as deep into our microcosm as the genetic rearrangement of DNA fragments at the micro-cellular level. What is first and what follows, what is coupled and how, is not always obvious. This explains the erratic course of the disease, and the large variety of symptoms and disease progression seen in MS patients.
In this same context, the dogmatic believe of immune suppression is just wrong; the reaction of the immune system to for instance cortisol is much more intricate then a simple straight-forward reaction. It is probably more appropriate to talk about creating conducive micro-cellular conditions where cytokine and chemokine release drop down and then the immune system calms down.
The viral connection to MS
Evidence was found of endogenous retrovirus gene activation in MS. Endogenous retroviruses are viruses captured by the human genome. Endogenous retroviral genes are scattered among the human genome; some are more recent than others. So far they have not been very well characterised or implicated in human diseases.
The viral tolerance theory postulates that during periods that people are immune compromised (can be the fetal period, the period of the newborn and immune deficient periods), the virus can incorporate some of its genes in the DNA of permissible cells.
The incorporated viral genes (transgenes) are tolerant to the body where no immune memory against these transgenes has established. In MS, in particular the oligodendrocyte precursor cells (OPCs) in locally affected tissue will be infected but also the bone marrow, more in general stem cells that divide. People with transgenes in their body are healthy but predisposed to develop a disease.
It is suspected that retroviruses are activated in the brains of MS patients; we know there is endogenous retroviral activation in MS brains. It is suspected that they are activated by something else, some sort of mutation or genetic rearrangement that goes on.
Probably, demonation is simply a response to so called - or what the body believes to be - foreign gene expression and potentially protein expression. Bacterial cell molecules and transportable proteins like ε-toxin produced by bad Clostridium bacteria in a leaky gut trigger intra-cellular events.
Whatever the exciting event is, endogenous retroviral gene expression which is then sensed itself in the proper Major Histocompatibility Complex (MHC) background leads to demonation. MS is in fact a retroviral disease, not an exogenous retroviral disease as HIV, but an endogenous retroviral disease within a bared immune response. This brings together the viral concept of MS and folds in the concept that MS is an autoimmune disease.
A direct link between brain and immune system
The recent discovery of the Brain Lymphatic System causes a revolution in the thinking about the immunity of the brain. The vessels discovered are actual, real lymph vessels with enclosing vessel walls. These vessels line the meningeal layer and drain alongside cerebral veins. The mouse and human brains both contain actual vessels--and as inferred, probably all mammalian brains have lymph vessels in the meningeal layer.
The interaction between the CSF, blood, lymphatic and immune system in the brain is complex. The lymph cleansing system discovered does not involve vessels inside cerebral brain tissue. It is a free-flowing wash of CSF and lymph fluid, facilitated by glial cells (thus the "glymphatic" name) and sleep. However, the theory is that these newly discovered vessels are used for drainage of this interstitial cleansing fluid. This theory needs further research.
Dr. Schwartz has been publishing for 15 years on the fact that those circulating T reg cells are there for a purpose: to facilitate cognition, neuroplasticity and healing in the brain.
http://www.pagepressjournals.org/index. ... /view/5360
http://www.macleans.ca/society/science/ ... the-brain/
http://www.nature.com/nature/journal/v5 ... 14432.html
https://cosmosmagazine.com/life-science ... your-brain
http://www.medpagetoday.com/Blogs/Cohen ... g330925d0r
Two different mechanisms underly MS
The MS timeline shows a double peak in the graph of age of onset where a first peak appears around the age of mid 20’s and a second peak in the early 40’s. Of course we know about RR and the progressive phase, but this fact provides an indication for a two stage process with different underlying mechanisms.
In the RR phase, the herpes virus spreads including herpes simplex, Varicella Zoster (VZV) and Epstein-Barr (EBV) in meningeal follicles, the lymphatic system and stem cells including OPCs and bone marrow.
In periods of low immunity, the cell machinery including vitamin D receptors may get blocked. The mitochondria are insufficiently fed, the ion pump can not maintain its equilibrium and one gets an acute relapse. The immune system corrects the cells that are in crisis. One possible mechanism is through intra-cellular viral control by interferon γ (IFNγ) by T cells (arrival of CD4+ T lymphocytes, CD8+ cytotoxic T cells produce IFNγ). IFN’s are a group of proteins known primarily for their role in inhibiting viral infections. As cells recover, remittance is seen of MS symptoms. In particular VZV which is an “inflammatory virus” is suspect at this stage.
A well functioning intestine with sufficient production of IFN’s is essential. A distorted gut microbiota caused by a “Western” diet with high fat and sugar may interfere with the production of IFNγ and may skew us towards getting sick.
As of mid age, another phenomenon kicks in. The EBV virus has spread so far that increasingly B-cells get infected with a lack of sufficient T-cell control function to contain an unbridled B-cell replication. At this point the progressive mechanism is underway.
EBV infected and immortalized B-cells cross-react with transgenic cells (common epitodes) and at the same time cause a huge oxidative stress on the mitochondria with insufficient protective cellular feeding and antioxidant mechanisms (astrocyte, Nijland).
Mitochondria will fail one by one up to the point where the cell cannot maintain the equilibrium of the ion pump to perform normal motor operation. This occurs first because the ion pump needs most energy, in fact more than the muscle cells. At this point, cells may not have died but become ‘electrically’ dormant. The neurological path is weakened. At this stage, any new problems with receptor blocking will now result in more severe symptoms and if one has not already been diagnosed during the RR phase, one gets diagnosed at this stage.
MS is thus a loss of epi-genetic control with herpes/VZV in combination with ε-toxin leading to genetic rearrangement, mitochondrial dysfunction and cellular inflammation and; EBV infected or immortalized B-cells leading to huge oxidative stress and mitochondrial jamming. Or in other words, MS is caused by a lack of cell-mediated immunity and a deficient humoral immunity (B-cells).
Both mechanisms may assail the body in different places including both the brains with white matter lesions in the first phase as well as weakening muscles and their nervous connection including in the spinal column in the second phase. The effect on our mobility is then the result of a degrading serial pathway from brains to muscle cells and sensors.
http://www.bio.davidson.edu/courses/imm ... gamma.html
MS and cell mediated immunity
The co-evolution of the herpes virus and cellular immunity – a process that has taken one Billion years to evolve – explains a very deeply intertwined relationship. This process is facilitated with a central role for the gut in our immunity including that of the brains. Our “Western” diet causes an effect on IFNγ and IL17 production which in turn causes an effect on cell-mediated immunity with T-cell (IFNγ) mediation. During periods of low immunity, periodic reactivation from latent viral reservoirs results in viral subclinical shedding and the associated inflammation with continued neurological and developmental issues.
When a representative model of the human gut eco-system was established in mice, switching from low-fat, plant polysaccharide-rich diet to a high fat, high sugar “Western” diet shifted the structure of the microbiota of these “humanized” mice in a single day and changed the metabolic pathways in the micro biome and its gene expression.
http://stm.sciencemag.org/content/1/6/6ra14
Germ free mice induced for EAE produced lower levels of proinflammatory cytokines, IFNγ and IL17 in both the intestine and the spinal cord and displayed reciprocal increase of CD4 T cells.
http://www.pnas.org/content/108/Supplem ... nsion.html
Some microbe families from the gut microbiota however promote the inflammatory cascade in the CNS. The strongest here being the unculturable Clostridium family of which the Segmented Filamentous Bacteria is the most active and have a key role in the coordinated maturation of gut helper T cell responses.
http://www.ncbi.nlm.nih.gov/pubmed/19833089
This observation coincides with the recent finding on ε-toxin: Clostridium perfringens Epsilon Toxin Causes Selective Death of Mature Oligodendrocytes and Central Nervous System Demyelination. It would thus occur that cell mutation is incited by both a lack of IFN γ combined with a toxic microcellular environment.
http://mbio.asm.org/content/6/3/e02513-14
It has been suggested for decades that micro organisms contribute to the pathogenesis of MS and that there is a link with the lymphatic system. The article from 2007 already noted "Data is reviewed which shows that the CSF and extra-cellular fluid circulation is bi-directionally linked to the lymphatic drainage channels of the nasopharyngeal mucosa. While this provides a facility by which the CNS may mount immunological responses to antigenic challenges from within, it is also a route by which products of nasopharyngeal infection may drain into the CNS and be processed by the immune cells of the meninges and Virchow-Robin perivascular spaces.”
http://www.unboundmedicine.com/medline/ ... _Sclerosis_
Genetic rearrangement of transgenic cells
In MS, we see many patients with a leaky gut. Bad gut bacteria produce the ε-toxin that leak into the circulation and apparently home in on cells that are virus infected. These are typically the OPCs because they help divide the viral genes.
Why do ε-toxin home in on OPCs? In fact, they may home in on all cells but in OPCs the "fertile" ground is found to do the genetic rearrangement. Which then shows up as white matter lesions.
It is postulated that ε-toxin, but perhaps other bacterial cell molecules and transportable proteins as well e.g. from the naso pharynx and/or from the gut, trigger transgene herpes/VZV/EBV primed cells to activate intra-cellular events e.g. through sharing segments of DNA. This would lead to the release of pro-inflammatory lipid mediators, enzymatic activities and modified cell signaling events.
Also mycotoxins such as black mold (stachybotrys) may trigger MS. The environment of Scotland and Seattle are extremely similar in many ways: they are on almost the same latitude, they are both maritime climates with average temperatures between 40's-60's Fahrenheit with 100% humidity. Both places rarely get strong heat or clear strong sun or enough UV rays to dry out moldy houses, cars, etc and dry out or kill spores in the air, nor does either place get much of a hard freeze to arrest mold growth and dry out air. With the advent of air conditioning, places that are normally very dry and sunny like Kuwait, are seeing an explosion in MS.
In other words, 'synergetic effects' of virus and bacterial and myco-toxins working together that Buhner talks about in his book Healing Lyme disease coinfections cause havoc in the cell’s genetic arrangement, shedding cytokines and chemokines and leading to inflammation. With the note that cells have between 1500 and 3000 working mitochondria, this will result in a gradual decline of cellular function.
http://mbio.asm.org/content/6/3/e02513-14
http://www.amazon.com/Healing-Lyme-Dise ... me+disease
Disruption of humoral immune control by EBV
The second mechanism that occurs as of mid-age but that is probably underway much longer is a different mechanism all together. EBV infected B-cells cause immune subversion and disease progression. With the virtual non-existence of MS in EBV seronegative people (still 5 - 10 % of population), epidemiological analysis would seem to confirm a strong relationship of EBV with MS.
Universal EBV seropositivity, high EBV antibody levels and alterations in EBV-specific CD8+ T-cell immunity are commonly observed and likely to be an important contributing factor to MS rather than the result of MS.
Disruption of the highly evolved balance (after one Billion years of co-evolution) between the EBV lytic and latent life cycles and host immune control results in a range of EBV-associated diseases involving B-cells, epithelial cells, T-cells, natural killer (NK) cells and muscle cells.
Here a weak epigenetic control of the virus may contribute to a spreading of the disease in meningeal follicles. Staphylococcal immune complexes and myelinolytic toxin in early acute MS lesions connects the matter to EBV proliferation from the pharyngeal cells.
http://www.msard-journal.com/article/S2 ... 9/abstract
This is only a precursor to the real problem, that is a subversion of the immune response by EBV infection of the B-cells. An EBV protein inactivates monocyte signaling resulting in a subverted and ineffective immune response with EBV residing in the B cell and immortalizing it as well as T-lymphocyte imbalances.
The high load of EBV infected autoreactive T- and B-cells will pass the Central Nervous System (CNS) and cross-react with the transgenes in the OPCs. Due to this cross-reaction, many OPCs will die which leads to a diminishing number of OPCs, of dendrocytes and a reduced myelination of neurons. During this cross-reaction, many mediators will be released by the infiltrating T-cells. This will increase angiogenesis and cause hyperproliferation of surrounding tissue cells in the CNS which in turn causes the pathological lesions (sclerotic plaques) typical for MS.
Subversion of the immune response by EBV
Primary lytic replication of EBV in pharyngeal mocusal epithelium precedes long-lived latent infection of resting memory B-cells. During primary infection, EBV infects autoreactive naïve B-cells in the tonsil, driving them to enter germinal centres where they proliferate intensely and differentiate into latently infected autoreactive memory B cells (Step 1), which then exit from the tonsil and circulate in the blood (Step 2).
http://www.nature.com/nsmb/journal/v19/ ... b.2367.pdf
http://www.nature.com/cti/journal/v3/n1 ... 1425a.html
The number of EBV-infected B cells is normally controlled by EBV-specific cytotoxic CD8+ T cells, which kill proliferating and lytically infected B cells, but not if there is a defect in the defense mechanism.
One concept postulates the EBV secretes lytic-cycle early protein BARF1 which is a binding protein for the hematopoietic cytokine hCSF-1, evading and subverting key host signaling pathways. BARF1 also inhibits the secretion of antiviral IFN-α. This impedes the primary response via CD8+ cytotoxic T-cells and natural killer cells to clear EBV-infected cells, in line with T-cell mediated adaptive immunity against EBV.
Another concept suggests EBV is masked by a protein p47phox which is required to make superoxide to prevent recurrent infections. Here, the idea is that these transformed B cells are not perceived as foreign and thus not as a serious infection by the immune system.
Surviving EBV-infected autoreactive memory B cells enter the CNS where they take up residence and produce oligoclonal IgG and pathogenic autoantibodies, which attack myelin and other components of the CNS (Step 3).
Autoreactive T cells that have been activated in peripheral lymphoid organs by common systemic infections circulate in the blood and enter the CNS where they are reactivated by EBV-infected autoreactive B cells presenting CNS peptides (Cp) bound to major histocompatibility complex (MHC) molecules (Step 4). These EBV-infected B cells provide costimulatory survival signals (B7) to the CD28 receptor on the autoreactive T cells and thereby inhibit the activation-induced T-cell apoptosis, which normally occurs when autoreactive T cells enter the CNS and interact with non-professional antigen-presenting cells such as astrocytes and microglia, which do not express B7 costimulatory molecules (Step 5).
After the autoreactive T cells have been reactivated by EBV-infected autoreactive B cells, they produce chemokines and cytokines such as interleukin-2 (IL2), IFNγ and tumour necrosis factor (TNFβ) and orchestrate an autoimmune attack on the CNS with resultant oligodendrocyte and myelin destruction (Step 6).
A further concept is described by David Hudnal in his chapter Epstein-Barr Virus: Pathogenesis and Host Immune Response. Following initial exposure to infectious saliva, EBV likely undergoes a brief period of lytic replication in oral and nasal epithelium. Subsequent infection of naïve B cells within subjacent tonsillar lymphoid tissues leads to a brief “pre-latent” period of lytic and latent gene expression prior to epigenetic repression of viral genes. This brief pre-latent period is marked by limited expression of a small set of lytic genes with regulatory function, excluding lytic genes essential for DNA replication and virion assembly. It is likely that by promoting cell growth and inhibiting apoptosis, pre-latent lytic gene products, including BART miRNA, viral BCL-2 homologs, and BZLF1, contribute to the early survival of EBV-infected B cells.
Following epigenetic repression of the full complement of lytic genes and a subset of latent gene promoters, rapid growth of latent-infected B cells is induced by expression of the full growth-promoting complement of latency genes, i.e., the latency III program. Expression of the full complement of lytic and latent antigens by infected epithelial cells and B cells triggers a vigorous humoral and cellular immune response that leads to suppression of viral replication.
Latent-infected B cells persist by switching from the highly immunogenic latency III program to the less immunogenic latency II program, with virus gene expression restricted to three proteins, EBNA-1, LMP-1, and LMP-2A. EBNA-1 maintains the viral genome, while LMP-1 and LMP-2A maintain cell growth while preventing apoptosis. The absence of EBNA-2-mediated transactivation allows for latency II B cells to adopt a germinal center B-cell phenotype and, in so doing, survive germinal center and/or extrafollicular proliferation and maturation into EBV-infected memory B cells. EBV-infected memory B cells persist by switching from the latency II program to the latency 0 program, with near- complete absence of viral gene expression, with only intermittent LMP-2a expression.
The biochemical reaction hypothesis – the fatigue explained
Besides a cross-reaction with transgenic OPCs, the autoreactive B-cells have substantial super-oxygen generating capability (the mechanism to prevent recurrent infections). The superoxide reacts with the nitric oxide (NO) in the finest capillaries and produces excess peroxynitrite which is by far the worst free radical.
Although the peroxynitrite may inhibit viral replication, it disables glyceraldehyde 3 phosphate which impacts the sodium/potassium pump and cell viability. Over time the vitality of the cell declines as ATP levels decline and the loss of some AMP leads to a fall in Adenosine (endogenous inhibitor of arachidonic acid) and a loss of purine from Adenosine loss.
Ultimately energy levels decline and uric acid levels fall. The loss of Adenosine and cellular IFNγ will lower the ability to control inflammation and indeed the suppression of the transfer of EBV from latently infected cells to other cells. And the endothelium inflammates leading to an endothelial dysfunction.
As regards the anti-inflammatory properties of Adonesine (the A in ATP), Adenosine is a purine. The last step in the metabolism of purines is Uric acid. As Uric acid is low in MS, it is likely the recycling is faulty. Probably cells convert 2 ADP into 1 ATP and 1 AMP. The AMP washes out of the cell and the ATP is spent to become ADP and then combines with another ADP to become ATP and AMP again but the purine gets gradually lost to the cell until it is unviable. Uric acid also is a scavenger of peroxynitrite so the cycle worsens over time.
Oxidative stress has been strongly implicated in both the inflammatory and neurodegenerative pathological mechanisms in MS. In response to oxidative stress, cells increase and activate their cellular antioxidant mechanisms. Glutathione (GSH) is the major antioxidant in the brain, and as such plays a pivotal role in the detoxification of reactive oxidants. Previous research has shown that GSH homeostasis is altered in MS.
http://www.ncbi.nlm.nih.gov/pubmed/24842957
The huge oxidative stress jams mitochondria of the cells, causes effects on the mitochondrial electron transport chain and ion pump inactivation, inhibits ADP to ATP conversion and depletes energy in the form of ATP leading to mitochondrial energy failure.
As the pumps already run on their edge where a number of mitochondria in the cell have failed, the equilibrium can not be easily maintained. When cell gates close with increasing temperature (either from the outside or fever induced; cooler weather or high air pressure have the reverse effect), the conduction of the nerve path runs down. Here the ion pumps are the most important energy consumers that require the biggest amount of cellular energy.
http://www.amazon.com/Sinatra-Solution- ... en+sinatra
As the number of active gates/mitochondria per cell decreases, we see an increasingly big temperature effect in patients with MS and a loss of muscle strength and sensitivity in the periphery. As cells shrink in size because gates/mitochondria successively fail, it causes whole brain atrophy.
Hence, the typical fatigue, weakening of muscles and whole-brain atrophy observed in MS patients is partly caused by the EBV infected B cells but with a completely different underlying mechanism than the demyelinating plaques in the brains. And the typical MS motor dysfunction will be caused by a combination of factors.
(Short term) stressors initiate cases of multisystem illnesses by stimulating nitric oxide synthase (NOS) activity and consequently produce increased levels of NO and its oxidant product peroxynitrite. The immune system will be triggered by the biochemical cycle mechanism with NF-кB a first responder to the harmful cellular stimuli. The increased NF-кB activity will lead to increased iNOS activity by stimulating through the inflammatory cytokines the activity of the iNOS gene itself.
NO synthase is influenced by sex hormones, is higher in women which explains the gender bias in autoimmunity.
At some point the HPA axis may also get affected with consequences for cortisol production and with that gut functioning resulting in yet another vicious cycle.
http://www.amazon.com/Explaining-Unexpl ... artin+pall
Beyond MS - towards to a new paradigm for autoimmunity
In our current system, we see a very large number of overlapping autoimmune diseases with different names. Every expression of a neurological set of symptoms got its own name, based on several types of observations. And we see various signs and symptoms that are overlapping.
But in fact, a bigger common scheme is underlying. A scheme that encompasses the wide variety of observations, their patterns of case initiation, their chronic nature and many of their shared and unique symptoms and signs of the chronic phase of the disease. A scheme that explains many unexplained observations and the multiple similarities of these illnesses by a simple conceptual framework.
Traditional major disease paradigms should be complemented by a new model based on the health of the mitochondria, a new virological consciousness and a biochemical cycle mechanism.
ANNEX I: Specific features of MS explained in this context
The case of identical twins
If identical twins get separated at young age but before adolescence, the person that moves further South has less risk to develop MS at a later date. That person will have more sun exposure and therefore a higher vitamin D level in the circulation during adolescence when the body goes through a main phase of cellular growth. When the cells are formed, they take vitamin D directly from the circulation where the vitamin D level determines the number of mitochondria per cell (1500-3000; the heart up to 5000, Sinatra). And when the cells have more mitochondria, they will be more resilient. Extending that line of thinking, all players of the national Canadian ice hockey team – a physically very demanding sports - were born in February. The foetus went through the main phase of cellular growth during the end of Summer early Autumn when the vitamin D level in the circulation of their mother must have peaked.
The double peak in the graph of age of onset
This provides an indication for a two stage process with different underlying mechanisms. In particular the Varicella Zoster virus (VZV) which is an inflammatory virus is suspect in the RR phase. As of mid age, the EBV virus has spread so far that B-cells get infected with a lack of sufficient T-cell function to contain an unbridled B-cell replication. At this point the progressive mechanism is already well underway.
The extinction of new cases above the age of 60
An typical feature of the MS is the extinction of the disease above 60 years of age, with no new cases reported after 60. Immunosenescence results in a natural decline in humoral immunity above 60 caused by a reduction in the population of antibody producing B-cells. Where apparently the immune system unable to get under control - after millions of years of coevolution with the virus – switches back one gear or changes to avoid further damage is done.
Chronic Cerebro Spinal Venous Insufficiency (CCSVI)
CCSVI or blocked internal jugular veins may be a factor here causing hypoperfusion, lower AMP and Adonesine, and with that a reduced control of infection by cellular immunity, e.g. infection and proliferation of EBV from the nasopharynx. Evidence accumulates of vein irregulaties and the incidence of MS in the vicinity of the heavy metal industry (Boston and Texas studies).
CCSVI may be a factor here again because the pharynx/tonsil drain through the Internal Jugular Veins where hypoperfusion may result in low pharynx/tonsil immunity with subsequent spreading of infection into the CNS.
The pharynx and tonsils
An interesting feature is that in childhood, the tonsil is relatively large compared to the nasopharinx. Possibly, here we may find an explanation why EBV infection of young children gives a different (less viral load) but stronger (age) protective immune response than in late-infected adolescents or adults. [Hudnall speculates on the link to pharyngual epithelium and the tonsil in his chapter on Epstein-Barr Virus: Pathogenesis and Host Immune Response]
In Rheuma Arthritis, a disease with common roots to MS, there is a suspicion that the pharynx/tonsils are a causal factor. Patients who get their tonsils removed (from Waldeyer's tonsillar ring with a key role in our immunity) show a clear and lasting improvement.
EBV universal positivity
With the negative argument, that is the virtual non-existence of MS in EBV seronegative people (still 5 - 10 % of population), epidemiological analysis would seem to confirm a strong relationship of EBV with MS.
Gender bias
NO synthase is influenced by sex hormones, is higher in women which explains the gender bias in autoimmunity and MS.
Blood pressure
There are a couple of threads in the CCSVI forum pronouncing low blood pressure as a common symptom in MS patients. http://www.thisisms.com/forum/general-d ... c9665.html
This could be a sign of a high NO synthase relaxing the vessels but at the same time elevating the oxidative stress.
Low saturated fat diet – Swank
Saturated fats block the anti-viral properties of ApoA1. ApoA1 has anti-sense RNA which may explain its anti-viral properties.
oxLDL is surpressed by Simvastatin (or Metformin) which explains its effect on whole brain atrophy and disability progression.
http://www.thelancet.com/journals/lance ... 4/abstract
Gut flora transplantation
Patients recovered from MS after a gut flora transplantation / Borody.
HIV patients
HIV patients recovered from MS after they started with anti-viral therapy.
Strong temperature effect
Gradually, as the MS progresses and increasingly mitochondria fail and cells become electrically dormant, rising temperature and closing cellular gates (a natural protective mechanism) will have more profound effect on patients with MS.
Periods of immune deficiency
Patients with MS may experience periods of immune deficiency. One sign of such period is dry eyes.
The role of Vitamin D
Vitamin D has many roles in the built of the cells. After adolescence, Vitamin D blocks EBNA and with that the proliferation of the EBV.
http://www.abstractstosubmit.com/ectrim ... /0_917.pdf
Besides the links mentioned in the thesis above, literally hundreds of other links to the medical literature can be found on this thread.
General
Chronic disease begins in the mitochondria. Mitochondria dysfunction and early death are common pathways in all those illnesses.
24 million people in the US have an autoimmune diagnosis, but another 50 million do not feel well and have autoantibodies but do not yet have enough antibodies to make a diagnosis. So, that means about 75 million have autoimmune problems. That’s extremely significant, and it is a sign that our lifestyles have led us down a very dangerous path. Even more disturbing, more and more children are being diagnosed with an autoimmune problem as children.
The current scourge of autoimmune diseases and new insights in its etiology directly connect human health with the food chain (e.g. high fat, high sugar “Western” diet, distorted Ω3-Ω6 fat balance, engrainisation and 'hardened' wheat, lack of phytonutritients and induced antioxidants). A paradigm change is needed.
But there is always general skepticism about anything new, especially when it seems to have a ‘holistic’ aspect. Where, in our modern economy, significant systemic problems are pervasive that hamper a course toward profoundly changing the paradigm.
http://www.drfranklipman.com/a-conversa ... -wahls-md/
http://multiplesclerosisnewstoday.com/2 ... ogression/
MS pathology
In MS, symptoms have always been treated; protocols were designed to suppress or modulate the immune system. But the real causes have never been treated; MS needs a protocol that treats causes. A thorough in-depth understanding of the disease mechanisms will be necessary for that.
People normally follow logical laws; our minds works linear and have greatest difficulty to deal with non-linear models or complex elements along a disease process. But linearity does not apply in medicine, and most certainly not in the case of MS. There are very many facets, a large variety of influences, different underlying mechanisms, feed-forwards and feed-backs, convolved vicious loops that lead to MS. If you apply only causal thinking, you won’t be able to unravel and nail down the disease.
MS is a subtle highly complex non-linear disease process that goes down as deep into our microcosm as the genetic rearrangement of DNA fragments at the micro-cellular level. What is first and what follows, what is coupled and how, is not always obvious. This explains the erratic course of the disease, and the large variety of symptoms and disease progression seen in MS patients.
In this same context, the dogmatic believe of immune suppression is just wrong; the reaction of the immune system to for instance cortisol is much more intricate then a simple straight-forward reaction. It is probably more appropriate to talk about creating conducive micro-cellular conditions where cytokine and chemokine release drop down and then the immune system calms down.
The viral connection to MS
Evidence was found of endogenous retrovirus gene activation in MS. Endogenous retroviruses are viruses captured by the human genome. Endogenous retroviral genes are scattered among the human genome; some are more recent than others. So far they have not been very well characterised or implicated in human diseases.
The viral tolerance theory postulates that during periods that people are immune compromised (can be the fetal period, the period of the newborn and immune deficient periods), the virus can incorporate some of its genes in the DNA of permissible cells.
The incorporated viral genes (transgenes) are tolerant to the body where no immune memory against these transgenes has established. In MS, in particular the oligodendrocyte precursor cells (OPCs) in locally affected tissue will be infected but also the bone marrow, more in general stem cells that divide. People with transgenes in their body are healthy but predisposed to develop a disease.
It is suspected that retroviruses are activated in the brains of MS patients; we know there is endogenous retroviral activation in MS brains. It is suspected that they are activated by something else, some sort of mutation or genetic rearrangement that goes on.
Probably, demonation is simply a response to so called - or what the body believes to be - foreign gene expression and potentially protein expression. Bacterial cell molecules and transportable proteins like ε-toxin produced by bad Clostridium bacteria in a leaky gut trigger intra-cellular events.
Whatever the exciting event is, endogenous retroviral gene expression which is then sensed itself in the proper Major Histocompatibility Complex (MHC) background leads to demonation. MS is in fact a retroviral disease, not an exogenous retroviral disease as HIV, but an endogenous retroviral disease within a bared immune response. This brings together the viral concept of MS and folds in the concept that MS is an autoimmune disease.
A direct link between brain and immune system
The recent discovery of the Brain Lymphatic System causes a revolution in the thinking about the immunity of the brain. The vessels discovered are actual, real lymph vessels with enclosing vessel walls. These vessels line the meningeal layer and drain alongside cerebral veins. The mouse and human brains both contain actual vessels--and as inferred, probably all mammalian brains have lymph vessels in the meningeal layer.
The interaction between the CSF, blood, lymphatic and immune system in the brain is complex. The lymph cleansing system discovered does not involve vessels inside cerebral brain tissue. It is a free-flowing wash of CSF and lymph fluid, facilitated by glial cells (thus the "glymphatic" name) and sleep. However, the theory is that these newly discovered vessels are used for drainage of this interstitial cleansing fluid. This theory needs further research.
Dr. Schwartz has been publishing for 15 years on the fact that those circulating T reg cells are there for a purpose: to facilitate cognition, neuroplasticity and healing in the brain.
http://www.pagepressjournals.org/index. ... /view/5360
http://www.macleans.ca/society/science/ ... the-brain/
http://www.nature.com/nature/journal/v5 ... 14432.html
https://cosmosmagazine.com/life-science ... your-brain
http://www.medpagetoday.com/Blogs/Cohen ... g330925d0r
Two different mechanisms underly MS
The MS timeline shows a double peak in the graph of age of onset where a first peak appears around the age of mid 20’s and a second peak in the early 40’s. Of course we know about RR and the progressive phase, but this fact provides an indication for a two stage process with different underlying mechanisms.
In the RR phase, the herpes virus spreads including herpes simplex, Varicella Zoster (VZV) and Epstein-Barr (EBV) in meningeal follicles, the lymphatic system and stem cells including OPCs and bone marrow.
In periods of low immunity, the cell machinery including vitamin D receptors may get blocked. The mitochondria are insufficiently fed, the ion pump can not maintain its equilibrium and one gets an acute relapse. The immune system corrects the cells that are in crisis. One possible mechanism is through intra-cellular viral control by interferon γ (IFNγ) by T cells (arrival of CD4+ T lymphocytes, CD8+ cytotoxic T cells produce IFNγ). IFN’s are a group of proteins known primarily for their role in inhibiting viral infections. As cells recover, remittance is seen of MS symptoms. In particular VZV which is an “inflammatory virus” is suspect at this stage.
A well functioning intestine with sufficient production of IFN’s is essential. A distorted gut microbiota caused by a “Western” diet with high fat and sugar may interfere with the production of IFNγ and may skew us towards getting sick.
As of mid age, another phenomenon kicks in. The EBV virus has spread so far that increasingly B-cells get infected with a lack of sufficient T-cell control function to contain an unbridled B-cell replication. At this point the progressive mechanism is underway.
EBV infected and immortalized B-cells cross-react with transgenic cells (common epitodes) and at the same time cause a huge oxidative stress on the mitochondria with insufficient protective cellular feeding and antioxidant mechanisms (astrocyte, Nijland).
Mitochondria will fail one by one up to the point where the cell cannot maintain the equilibrium of the ion pump to perform normal motor operation. This occurs first because the ion pump needs most energy, in fact more than the muscle cells. At this point, cells may not have died but become ‘electrically’ dormant. The neurological path is weakened. At this stage, any new problems with receptor blocking will now result in more severe symptoms and if one has not already been diagnosed during the RR phase, one gets diagnosed at this stage.
MS is thus a loss of epi-genetic control with herpes/VZV in combination with ε-toxin leading to genetic rearrangement, mitochondrial dysfunction and cellular inflammation and; EBV infected or immortalized B-cells leading to huge oxidative stress and mitochondrial jamming. Or in other words, MS is caused by a lack of cell-mediated immunity and a deficient humoral immunity (B-cells).
Both mechanisms may assail the body in different places including both the brains with white matter lesions in the first phase as well as weakening muscles and their nervous connection including in the spinal column in the second phase. The effect on our mobility is then the result of a degrading serial pathway from brains to muscle cells and sensors.
http://www.bio.davidson.edu/courses/imm ... gamma.html
MS and cell mediated immunity
The co-evolution of the herpes virus and cellular immunity – a process that has taken one Billion years to evolve – explains a very deeply intertwined relationship. This process is facilitated with a central role for the gut in our immunity including that of the brains. Our “Western” diet causes an effect on IFNγ and IL17 production which in turn causes an effect on cell-mediated immunity with T-cell (IFNγ) mediation. During periods of low immunity, periodic reactivation from latent viral reservoirs results in viral subclinical shedding and the associated inflammation with continued neurological and developmental issues.
When a representative model of the human gut eco-system was established in mice, switching from low-fat, plant polysaccharide-rich diet to a high fat, high sugar “Western” diet shifted the structure of the microbiota of these “humanized” mice in a single day and changed the metabolic pathways in the micro biome and its gene expression.
http://stm.sciencemag.org/content/1/6/6ra14
Germ free mice induced for EAE produced lower levels of proinflammatory cytokines, IFNγ and IL17 in both the intestine and the spinal cord and displayed reciprocal increase of CD4 T cells.
http://www.pnas.org/content/108/Supplem ... nsion.html
Some microbe families from the gut microbiota however promote the inflammatory cascade in the CNS. The strongest here being the unculturable Clostridium family of which the Segmented Filamentous Bacteria is the most active and have a key role in the coordinated maturation of gut helper T cell responses.
http://www.ncbi.nlm.nih.gov/pubmed/19833089
This observation coincides with the recent finding on ε-toxin: Clostridium perfringens Epsilon Toxin Causes Selective Death of Mature Oligodendrocytes and Central Nervous System Demyelination. It would thus occur that cell mutation is incited by both a lack of IFN γ combined with a toxic microcellular environment.
http://mbio.asm.org/content/6/3/e02513-14
It has been suggested for decades that micro organisms contribute to the pathogenesis of MS and that there is a link with the lymphatic system. The article from 2007 already noted "Data is reviewed which shows that the CSF and extra-cellular fluid circulation is bi-directionally linked to the lymphatic drainage channels of the nasopharyngeal mucosa. While this provides a facility by which the CNS may mount immunological responses to antigenic challenges from within, it is also a route by which products of nasopharyngeal infection may drain into the CNS and be processed by the immune cells of the meninges and Virchow-Robin perivascular spaces.”
http://www.unboundmedicine.com/medline/ ... _Sclerosis_
Genetic rearrangement of transgenic cells
In MS, we see many patients with a leaky gut. Bad gut bacteria produce the ε-toxin that leak into the circulation and apparently home in on cells that are virus infected. These are typically the OPCs because they help divide the viral genes.
Why do ε-toxin home in on OPCs? In fact, they may home in on all cells but in OPCs the "fertile" ground is found to do the genetic rearrangement. Which then shows up as white matter lesions.
It is postulated that ε-toxin, but perhaps other bacterial cell molecules and transportable proteins as well e.g. from the naso pharynx and/or from the gut, trigger transgene herpes/VZV/EBV primed cells to activate intra-cellular events e.g. through sharing segments of DNA. This would lead to the release of pro-inflammatory lipid mediators, enzymatic activities and modified cell signaling events.
Also mycotoxins such as black mold (stachybotrys) may trigger MS. The environment of Scotland and Seattle are extremely similar in many ways: they are on almost the same latitude, they are both maritime climates with average temperatures between 40's-60's Fahrenheit with 100% humidity. Both places rarely get strong heat or clear strong sun or enough UV rays to dry out moldy houses, cars, etc and dry out or kill spores in the air, nor does either place get much of a hard freeze to arrest mold growth and dry out air. With the advent of air conditioning, places that are normally very dry and sunny like Kuwait, are seeing an explosion in MS.
In other words, 'synergetic effects' of virus and bacterial and myco-toxins working together that Buhner talks about in his book Healing Lyme disease coinfections cause havoc in the cell’s genetic arrangement, shedding cytokines and chemokines and leading to inflammation. With the note that cells have between 1500 and 3000 working mitochondria, this will result in a gradual decline of cellular function.
http://mbio.asm.org/content/6/3/e02513-14
http://www.amazon.com/Healing-Lyme-Dise ... me+disease
Disruption of humoral immune control by EBV
The second mechanism that occurs as of mid-age but that is probably underway much longer is a different mechanism all together. EBV infected B-cells cause immune subversion and disease progression. With the virtual non-existence of MS in EBV seronegative people (still 5 - 10 % of population), epidemiological analysis would seem to confirm a strong relationship of EBV with MS.
Universal EBV seropositivity, high EBV antibody levels and alterations in EBV-specific CD8+ T-cell immunity are commonly observed and likely to be an important contributing factor to MS rather than the result of MS.
Disruption of the highly evolved balance (after one Billion years of co-evolution) between the EBV lytic and latent life cycles and host immune control results in a range of EBV-associated diseases involving B-cells, epithelial cells, T-cells, natural killer (NK) cells and muscle cells.
Here a weak epigenetic control of the virus may contribute to a spreading of the disease in meningeal follicles. Staphylococcal immune complexes and myelinolytic toxin in early acute MS lesions connects the matter to EBV proliferation from the pharyngeal cells.
http://www.msard-journal.com/article/S2 ... 9/abstract
This is only a precursor to the real problem, that is a subversion of the immune response by EBV infection of the B-cells. An EBV protein inactivates monocyte signaling resulting in a subverted and ineffective immune response with EBV residing in the B cell and immortalizing it as well as T-lymphocyte imbalances.
The high load of EBV infected autoreactive T- and B-cells will pass the Central Nervous System (CNS) and cross-react with the transgenes in the OPCs. Due to this cross-reaction, many OPCs will die which leads to a diminishing number of OPCs, of dendrocytes and a reduced myelination of neurons. During this cross-reaction, many mediators will be released by the infiltrating T-cells. This will increase angiogenesis and cause hyperproliferation of surrounding tissue cells in the CNS which in turn causes the pathological lesions (sclerotic plaques) typical for MS.
Subversion of the immune response by EBV
Primary lytic replication of EBV in pharyngeal mocusal epithelium precedes long-lived latent infection of resting memory B-cells. During primary infection, EBV infects autoreactive naïve B-cells in the tonsil, driving them to enter germinal centres where they proliferate intensely and differentiate into latently infected autoreactive memory B cells (Step 1), which then exit from the tonsil and circulate in the blood (Step 2).
http://www.nature.com/nsmb/journal/v19/ ... b.2367.pdf
http://www.nature.com/cti/journal/v3/n1 ... 1425a.html
The number of EBV-infected B cells is normally controlled by EBV-specific cytotoxic CD8+ T cells, which kill proliferating and lytically infected B cells, but not if there is a defect in the defense mechanism.
One concept postulates the EBV secretes lytic-cycle early protein BARF1 which is a binding protein for the hematopoietic cytokine hCSF-1, evading and subverting key host signaling pathways. BARF1 also inhibits the secretion of antiviral IFN-α. This impedes the primary response via CD8+ cytotoxic T-cells and natural killer cells to clear EBV-infected cells, in line with T-cell mediated adaptive immunity against EBV.
Another concept suggests EBV is masked by a protein p47phox which is required to make superoxide to prevent recurrent infections. Here, the idea is that these transformed B cells are not perceived as foreign and thus not as a serious infection by the immune system.
Surviving EBV-infected autoreactive memory B cells enter the CNS where they take up residence and produce oligoclonal IgG and pathogenic autoantibodies, which attack myelin and other components of the CNS (Step 3).
Autoreactive T cells that have been activated in peripheral lymphoid organs by common systemic infections circulate in the blood and enter the CNS where they are reactivated by EBV-infected autoreactive B cells presenting CNS peptides (Cp) bound to major histocompatibility complex (MHC) molecules (Step 4). These EBV-infected B cells provide costimulatory survival signals (B7) to the CD28 receptor on the autoreactive T cells and thereby inhibit the activation-induced T-cell apoptosis, which normally occurs when autoreactive T cells enter the CNS and interact with non-professional antigen-presenting cells such as astrocytes and microglia, which do not express B7 costimulatory molecules (Step 5).
After the autoreactive T cells have been reactivated by EBV-infected autoreactive B cells, they produce chemokines and cytokines such as interleukin-2 (IL2), IFNγ and tumour necrosis factor (TNFβ) and orchestrate an autoimmune attack on the CNS with resultant oligodendrocyte and myelin destruction (Step 6).
A further concept is described by David Hudnal in his chapter Epstein-Barr Virus: Pathogenesis and Host Immune Response. Following initial exposure to infectious saliva, EBV likely undergoes a brief period of lytic replication in oral and nasal epithelium. Subsequent infection of naïve B cells within subjacent tonsillar lymphoid tissues leads to a brief “pre-latent” period of lytic and latent gene expression prior to epigenetic repression of viral genes. This brief pre-latent period is marked by limited expression of a small set of lytic genes with regulatory function, excluding lytic genes essential for DNA replication and virion assembly. It is likely that by promoting cell growth and inhibiting apoptosis, pre-latent lytic gene products, including BART miRNA, viral BCL-2 homologs, and BZLF1, contribute to the early survival of EBV-infected B cells.
Following epigenetic repression of the full complement of lytic genes and a subset of latent gene promoters, rapid growth of latent-infected B cells is induced by expression of the full growth-promoting complement of latency genes, i.e., the latency III program. Expression of the full complement of lytic and latent antigens by infected epithelial cells and B cells triggers a vigorous humoral and cellular immune response that leads to suppression of viral replication.
Latent-infected B cells persist by switching from the highly immunogenic latency III program to the less immunogenic latency II program, with virus gene expression restricted to three proteins, EBNA-1, LMP-1, and LMP-2A. EBNA-1 maintains the viral genome, while LMP-1 and LMP-2A maintain cell growth while preventing apoptosis. The absence of EBNA-2-mediated transactivation allows for latency II B cells to adopt a germinal center B-cell phenotype and, in so doing, survive germinal center and/or extrafollicular proliferation and maturation into EBV-infected memory B cells. EBV-infected memory B cells persist by switching from the latency II program to the latency 0 program, with near- complete absence of viral gene expression, with only intermittent LMP-2a expression.
The biochemical reaction hypothesis – the fatigue explained
Besides a cross-reaction with transgenic OPCs, the autoreactive B-cells have substantial super-oxygen generating capability (the mechanism to prevent recurrent infections). The superoxide reacts with the nitric oxide (NO) in the finest capillaries and produces excess peroxynitrite which is by far the worst free radical.
Although the peroxynitrite may inhibit viral replication, it disables glyceraldehyde 3 phosphate which impacts the sodium/potassium pump and cell viability. Over time the vitality of the cell declines as ATP levels decline and the loss of some AMP leads to a fall in Adenosine (endogenous inhibitor of arachidonic acid) and a loss of purine from Adenosine loss.
Ultimately energy levels decline and uric acid levels fall. The loss of Adenosine and cellular IFNγ will lower the ability to control inflammation and indeed the suppression of the transfer of EBV from latently infected cells to other cells. And the endothelium inflammates leading to an endothelial dysfunction.
As regards the anti-inflammatory properties of Adonesine (the A in ATP), Adenosine is a purine. The last step in the metabolism of purines is Uric acid. As Uric acid is low in MS, it is likely the recycling is faulty. Probably cells convert 2 ADP into 1 ATP and 1 AMP. The AMP washes out of the cell and the ATP is spent to become ADP and then combines with another ADP to become ATP and AMP again but the purine gets gradually lost to the cell until it is unviable. Uric acid also is a scavenger of peroxynitrite so the cycle worsens over time.
Oxidative stress has been strongly implicated in both the inflammatory and neurodegenerative pathological mechanisms in MS. In response to oxidative stress, cells increase and activate their cellular antioxidant mechanisms. Glutathione (GSH) is the major antioxidant in the brain, and as such plays a pivotal role in the detoxification of reactive oxidants. Previous research has shown that GSH homeostasis is altered in MS.
http://www.ncbi.nlm.nih.gov/pubmed/24842957
The huge oxidative stress jams mitochondria of the cells, causes effects on the mitochondrial electron transport chain and ion pump inactivation, inhibits ADP to ATP conversion and depletes energy in the form of ATP leading to mitochondrial energy failure.
As the pumps already run on their edge where a number of mitochondria in the cell have failed, the equilibrium can not be easily maintained. When cell gates close with increasing temperature (either from the outside or fever induced; cooler weather or high air pressure have the reverse effect), the conduction of the nerve path runs down. Here the ion pumps are the most important energy consumers that require the biggest amount of cellular energy.
http://www.amazon.com/Sinatra-Solution- ... en+sinatra
As the number of active gates/mitochondria per cell decreases, we see an increasingly big temperature effect in patients with MS and a loss of muscle strength and sensitivity in the periphery. As cells shrink in size because gates/mitochondria successively fail, it causes whole brain atrophy.
Hence, the typical fatigue, weakening of muscles and whole-brain atrophy observed in MS patients is partly caused by the EBV infected B cells but with a completely different underlying mechanism than the demyelinating plaques in the brains. And the typical MS motor dysfunction will be caused by a combination of factors.
(Short term) stressors initiate cases of multisystem illnesses by stimulating nitric oxide synthase (NOS) activity and consequently produce increased levels of NO and its oxidant product peroxynitrite. The immune system will be triggered by the biochemical cycle mechanism with NF-кB a first responder to the harmful cellular stimuli. The increased NF-кB activity will lead to increased iNOS activity by stimulating through the inflammatory cytokines the activity of the iNOS gene itself.
NO synthase is influenced by sex hormones, is higher in women which explains the gender bias in autoimmunity.
At some point the HPA axis may also get affected with consequences for cortisol production and with that gut functioning resulting in yet another vicious cycle.
http://www.amazon.com/Explaining-Unexpl ... artin+pall
Beyond MS - towards to a new paradigm for autoimmunity
In our current system, we see a very large number of overlapping autoimmune diseases with different names. Every expression of a neurological set of symptoms got its own name, based on several types of observations. And we see various signs and symptoms that are overlapping.
But in fact, a bigger common scheme is underlying. A scheme that encompasses the wide variety of observations, their patterns of case initiation, their chronic nature and many of their shared and unique symptoms and signs of the chronic phase of the disease. A scheme that explains many unexplained observations and the multiple similarities of these illnesses by a simple conceptual framework.
Traditional major disease paradigms should be complemented by a new model based on the health of the mitochondria, a new virological consciousness and a biochemical cycle mechanism.
ANNEX I: Specific features of MS explained in this context
The case of identical twins
If identical twins get separated at young age but before adolescence, the person that moves further South has less risk to develop MS at a later date. That person will have more sun exposure and therefore a higher vitamin D level in the circulation during adolescence when the body goes through a main phase of cellular growth. When the cells are formed, they take vitamin D directly from the circulation where the vitamin D level determines the number of mitochondria per cell (1500-3000; the heart up to 5000, Sinatra). And when the cells have more mitochondria, they will be more resilient. Extending that line of thinking, all players of the national Canadian ice hockey team – a physically very demanding sports - were born in February. The foetus went through the main phase of cellular growth during the end of Summer early Autumn when the vitamin D level in the circulation of their mother must have peaked.
The double peak in the graph of age of onset
This provides an indication for a two stage process with different underlying mechanisms. In particular the Varicella Zoster virus (VZV) which is an inflammatory virus is suspect in the RR phase. As of mid age, the EBV virus has spread so far that B-cells get infected with a lack of sufficient T-cell function to contain an unbridled B-cell replication. At this point the progressive mechanism is already well underway.
The extinction of new cases above the age of 60
An typical feature of the MS is the extinction of the disease above 60 years of age, with no new cases reported after 60. Immunosenescence results in a natural decline in humoral immunity above 60 caused by a reduction in the population of antibody producing B-cells. Where apparently the immune system unable to get under control - after millions of years of coevolution with the virus – switches back one gear or changes to avoid further damage is done.
Chronic Cerebro Spinal Venous Insufficiency (CCSVI)
CCSVI or blocked internal jugular veins may be a factor here causing hypoperfusion, lower AMP and Adonesine, and with that a reduced control of infection by cellular immunity, e.g. infection and proliferation of EBV from the nasopharynx. Evidence accumulates of vein irregulaties and the incidence of MS in the vicinity of the heavy metal industry (Boston and Texas studies).
CCSVI may be a factor here again because the pharynx/tonsil drain through the Internal Jugular Veins where hypoperfusion may result in low pharynx/tonsil immunity with subsequent spreading of infection into the CNS.
The pharynx and tonsils
An interesting feature is that in childhood, the tonsil is relatively large compared to the nasopharinx. Possibly, here we may find an explanation why EBV infection of young children gives a different (less viral load) but stronger (age) protective immune response than in late-infected adolescents or adults. [Hudnall speculates on the link to pharyngual epithelium and the tonsil in his chapter on Epstein-Barr Virus: Pathogenesis and Host Immune Response]
In Rheuma Arthritis, a disease with common roots to MS, there is a suspicion that the pharynx/tonsils are a causal factor. Patients who get their tonsils removed (from Waldeyer's tonsillar ring with a key role in our immunity) show a clear and lasting improvement.
EBV universal positivity
With the negative argument, that is the virtual non-existence of MS in EBV seronegative people (still 5 - 10 % of population), epidemiological analysis would seem to confirm a strong relationship of EBV with MS.
Gender bias
NO synthase is influenced by sex hormones, is higher in women which explains the gender bias in autoimmunity and MS.
Blood pressure
There are a couple of threads in the CCSVI forum pronouncing low blood pressure as a common symptom in MS patients. http://www.thisisms.com/forum/general-d ... c9665.html
This could be a sign of a high NO synthase relaxing the vessels but at the same time elevating the oxidative stress.
Low saturated fat diet – Swank
Saturated fats block the anti-viral properties of ApoA1. ApoA1 has anti-sense RNA which may explain its anti-viral properties.
oxLDL is surpressed by Simvastatin (or Metformin) which explains its effect on whole brain atrophy and disability progression.
http://www.thelancet.com/journals/lance ... 4/abstract
Gut flora transplantation
Patients recovered from MS after a gut flora transplantation / Borody.
HIV patients
HIV patients recovered from MS after they started with anti-viral therapy.
Strong temperature effect
Gradually, as the MS progresses and increasingly mitochondria fail and cells become electrically dormant, rising temperature and closing cellular gates (a natural protective mechanism) will have more profound effect on patients with MS.
Periods of immune deficiency
Patients with MS may experience periods of immune deficiency. One sign of such period is dry eyes.
The role of Vitamin D
Vitamin D has many roles in the built of the cells. After adolescence, Vitamin D blocks EBNA and with that the proliferation of the EBV.
http://www.abstractstosubmit.com/ectrim ... /0_917.pdf
Besides the links mentioned in the thesis above, literally hundreds of other links to the medical literature can be found on this thread.
Last edited by Leonard on Fri Oct 09, 2015 12:54 pm, edited 11 times in total.
Re: A new concept and treatment options for MS
Hi Leo,
That is an outstanding piece of work. I hope everyone reads it.
Regards
That is an outstanding piece of work. I hope everyone reads it.
Regards
Re: A new concept and treatment options for MS
Hi Vesta,vesta wrote:I believe that progression is caused by pressure or csf blockage in the spine. At first I thought that Terry Wahls NMES stimulation worked principally on the blood circulation through the brain, but now I believe it works as much on relaxing back muscles, relieving pressure on the spine and stimulating cerebro-spinal fluid. The FONAR cine upright MRI (only one in Europe may be London?) would reveal cervical obstruction of CSF fluid (for example). Brief upper back and back massages down to the lumbars while standing help me keep the fluids circulating. If a visit to an Osteopath helps, that might give you a clue to the functional aspect of the progression. I think you are too preoccupied with the biochemistry when the problem is functional. Anyway, a simple massage may help and I can't see how it would hurt. Regards, VestaLeonard wrote:Recently, a new MRI of my head was made, the first since 2008. It had hardly changed. I suspect that the liberation from CCSVI has been a factor. After liberation in 2010 the 'noise' came down in both ears and in the centre of the head, mainly during the night. Clearly, if the situation of veins that were blocked for 95 % would have continued, further damage would have been done, no doubt. Yet, the progression has not stopped but continues, slowly but steadily.
I suspect that a significant part of the progression is not caused in the brains but in the periphery. That goes as far down as the connection of the nerves to the muscle cells. If I connect a muscle stimulator to my legs, the weaker right leg gives a clearly lower response than the left leg, an indication that the muscle sensitivity of the right is lower than that of the left. I presume post herpetic neuralgia (PHN) or a similar concept will not be far away. The VZV virus may be the important contributing factor. Some recent paper (I need to look for it) explains the role of Neuro Muscular Electric Stimulation (NMES) as Terry Wahls has used as a novel therapy against VZV.
You are right...spine problems are responsible fot a lot of neurological diseases. Though there are more 'players' in this game responsible for the symptoms...
Did you have an upright MRI yet?
rgds,
Robert
Re: A new concept and treatment options for MS
Hello Robert: No, I haven't had an upright MRI and unless it comes to <France, I probably won't. I didn't have a serious sports injury as you did and believe my progressed MS came from the body tension which developed during the RRMS stage. (See my site MS Cure Enigmas.net, Jan 21, 2015, "How RRMS Progresses to SPMS".) Late 2014 I unintentionally used myself as a guinea pig to illustrate just how spinal "injury" leads to mobility problems (Inclined Bed Warning, January 5, 2015) I slept on an inclined bed for about 10 days which compressed the lumbars and put so much pressure on the spine that I could barely walk. An Osteopathic treatment put things back in place, so afterwards I could walk as before, though I think I actually injured myself a bit. I get regular osteopathic treatments to keep the body structure regulated as much as possible. An Upright MRI might reveal childhood injuries but I guess I'm just tired and feel I can keep the progression Under control now that I understand the issues. Good luck in London in October, I'm really excited to learn the results and hope you can get some relief.Robnl wrote:Hi Vesta,vesta wrote:I believe that progression is caused by pressure or csf blockage in the spine. At first I thought that Terry Wahls NMES stimulation worked principally on the blood circulation through the brain, but now I believe it works as much on relaxing back muscles, relieving pressure on the spine and stimulating cerebro-spinal fluid. The FONAR cine upright MRI (only one in Europe may be London?) would reveal cervical obstruction of CSF fluid (for example). Brief upper back and back massages down to the lumbars while standing help me keep the fluids circulating. If a visit to an Osteopath helps, that might give you a clue to the functional aspect of the progression. I think you are too preoccupied with the biochemistry when the problem is functional. Anyway, a simple massage may help and I can't see how it would hurt. Regards, VestaLeonard wrote:Recently, a new MRI of my head was made, the first since 2008. It had hardly changed. I suspect that the liberation from CCSVI has been a factor. After liberation in 2010 the 'noise' came down in both ears and in the centre of the head, mainly during the night. Clearly, if the situation of veins that were blocked for 95 % would have continued, further damage would have been done, no doubt. Yet, the progression has not stopped but continues, slowly but steadily.
I suspect that a significant part of the progression is not caused in the brains but in the periphery. That goes as far down as the connection of the nerves to the muscle cells. If I connect a muscle stimulator to my legs, the weaker right leg gives a clearly lower response than the left leg, an indication that the muscle sensitivity of the right is lower than that of the left. I presume post herpetic neuralgia (PHN) or a similar concept will not be far away. The VZV virus may be the important contributing factor. Some recent paper (I need to look for it) explains the role of Neuro Muscular Electric Stimulation (NMES) as Terry Wahls has used as a novel therapy against VZV.
You are right...spine problems are responsible fot a lot of neurological diseases. Though there are more 'players' in this game responsible for the symptoms...
Did you have an upright MRI yet?
rgds,
Robert
Regards,
Vesta
Re: A new concept and treatment options for MS
The above thesis MS UNRAVELLED is not in the least thanks to you Scott and many others on this forum.Scott1 wrote:Hi Leo,
That is an outstanding piece of work. I hope everyone reads it.
Regards
Thank you all for that.
Microbial interactions with the immune system
For the researchers among us who want to read more about the role of the gut microbiota for our immune system, this symposium provides some 200 pages of interesting material:
https://colloque4.inra.fr/inra_rowett_2012
If you click on Post-congress materials, you can download the proceedings. This conference is part of a series of annual Inra Rowett symposia on gut microbiology.
For the layman among us who are interested in the role of the gut on who we are, this book provides a beautiful insight:
http://www.amazon.com/Gut-Inside-Story- ... ng+bowels
For me as semi-literate, this book put many things that I came across during my journey of discovery in a proper perspective.
https://colloque4.inra.fr/inra_rowett_2012
If you click on Post-congress materials, you can download the proceedings. This conference is part of a series of annual Inra Rowett symposia on gut microbiology.
For the layman among us who are interested in the role of the gut on who we are, this book provides a beautiful insight:
http://www.amazon.com/Gut-Inside-Story- ... ng+bowels
For me as semi-literate, this book put many things that I came across during my journey of discovery in a proper perspective.
Last edited by Leonard on Tue Sep 15, 2015 11:50 am, edited 3 times in total.
Are we close to a real cure for progressive MS?
Lately, there seems to be more pronounced attention to the role of B-cells in MS, in line with the above thesis on MS unravelled.
Of course, we know that above the age of 60 there are no new reported cases of MS. Immunosenescence results in a natural decline in humoral immunity above 60 caused by a reduction in the population of antibody producing B-cells. So apparently B cells are involved.
The March 2015 report of the Boston meeting of the Progressive MS Alliance also suggested an important role of the B-cells in MS. Other studies then are ongoing in several universities on the role of B-cells. Some were reported in the press like a study by the Erasmus University Rotterdam.
And of course we know about the immune subversion by EBV from the above thesis on MS unraveled. An extensive analysis of my blood showed a very high concentration of herpes simplex and EBV antibodies (about 20x their normal values). Together with high muscle titers (is related), these were the only scores from a long list of about 100 items that were outside their normal range.
The EBV trail in my family is another indication. My grandfather died in 1963 at the age of 68 from a nasal pharyngeal carcinoma (NPC), an uncle at the age of 70 from a coronary artery aneurysm, my brother has a mitochondrial energy failure and his son had Hodgkin (he is healthy now). All diseases are EBV related, there is robust scientific evidence for that. Although for the rest I see a big and healthy family and a happy family above all, this branch of the family has some difficulties with EBV. Together with the CCSVI which I undeniably had, I think we have come a long way towards explaining my own MS.
The combination of B-cells and EBV is the central theme of this blog: http://multiple-sclerosis-research.blog ... mumab.html
The blog asks some really good questions, I quote:
"I predict that the class of monoclonal antibodies that deplete B-cells (anti-CD20 and anti-CD19) will be the real game-changers in the field; they come with very high-efficacy and have a relatively good safety profile. There are, however, several unanswered questions around their use in MS. (1) How should they be used; as maintenance therapies or as induction therapies. A maintenance therapy requires the drug to be given continuously and indefinitely. In comparision, an induction therapy require a treatment period of say 2 years and then a watch and see approach with re-treatment given if MS disease activity reemerges. No prizes for guessing what class of drug Pharma want. The distinction between maintenance and induction is not trivial and affects pricing and reimbursement. In short it gives Pharma executives a big headache. (2) How safe is long-term B cell depletion? Can you survive without any circulating B cells for 30 or 40 years? I suspect you can as there are a large number of hereditary disorders, which affect B cells. We simply treat these patients with immunoglobulin or antibody replacement therapy. (3) Do anti-CD20s work in non-relapsing progressive MS? The Roche ocrelizumab PPMS trial will address this question. (4) How do B cell depleters work? Are they working via an anti-EBV mechanism? As you know EBV resides in B-cells and B-cell depleting agents are very good at suppressing EBV viral loads. In fact Rituximab, which is very effective in MS, is the only licensed anti-EBV drug on the market; it has a license for EBV-associated post-transplant lymphoproliferative disease. (5) Do other drugs and strategies that transiently deplete B cells working in the same way, for example mitoxantrone, cyclophosphamide, alemtuzumab, cladribine, bone marrow transplant, etc.? I love it when science results in more questions be asked than it answers; innovation feeds innovation."
Rituximab which depletes B cells is also mentioned as the only licensed anti-EBV treatment.
The treatment of MS by Rituximab may have largely failed sofar because only intra venous administration barely penetrates the cns.
The following article on Rituximab delivered intrathecally is interesting and may come close to a real cure for MS: http://www.ncbi.nlm.nih.gov/pubmed/25745637
Of course, we know that above the age of 60 there are no new reported cases of MS. Immunosenescence results in a natural decline in humoral immunity above 60 caused by a reduction in the population of antibody producing B-cells. So apparently B cells are involved.
The March 2015 report of the Boston meeting of the Progressive MS Alliance also suggested an important role of the B-cells in MS. Other studies then are ongoing in several universities on the role of B-cells. Some were reported in the press like a study by the Erasmus University Rotterdam.
And of course we know about the immune subversion by EBV from the above thesis on MS unraveled. An extensive analysis of my blood showed a very high concentration of herpes simplex and EBV antibodies (about 20x their normal values). Together with high muscle titers (is related), these were the only scores from a long list of about 100 items that were outside their normal range.
The EBV trail in my family is another indication. My grandfather died in 1963 at the age of 68 from a nasal pharyngeal carcinoma (NPC), an uncle at the age of 70 from a coronary artery aneurysm, my brother has a mitochondrial energy failure and his son had Hodgkin (he is healthy now). All diseases are EBV related, there is robust scientific evidence for that. Although for the rest I see a big and healthy family and a happy family above all, this branch of the family has some difficulties with EBV. Together with the CCSVI which I undeniably had, I think we have come a long way towards explaining my own MS.
The combination of B-cells and EBV is the central theme of this blog: http://multiple-sclerosis-research.blog ... mumab.html
The blog asks some really good questions, I quote:
"I predict that the class of monoclonal antibodies that deplete B-cells (anti-CD20 and anti-CD19) will be the real game-changers in the field; they come with very high-efficacy and have a relatively good safety profile. There are, however, several unanswered questions around their use in MS. (1) How should they be used; as maintenance therapies or as induction therapies. A maintenance therapy requires the drug to be given continuously and indefinitely. In comparision, an induction therapy require a treatment period of say 2 years and then a watch and see approach with re-treatment given if MS disease activity reemerges. No prizes for guessing what class of drug Pharma want. The distinction between maintenance and induction is not trivial and affects pricing and reimbursement. In short it gives Pharma executives a big headache. (2) How safe is long-term B cell depletion? Can you survive without any circulating B cells for 30 or 40 years? I suspect you can as there are a large number of hereditary disorders, which affect B cells. We simply treat these patients with immunoglobulin or antibody replacement therapy. (3) Do anti-CD20s work in non-relapsing progressive MS? The Roche ocrelizumab PPMS trial will address this question. (4) How do B cell depleters work? Are they working via an anti-EBV mechanism? As you know EBV resides in B-cells and B-cell depleting agents are very good at suppressing EBV viral loads. In fact Rituximab, which is very effective in MS, is the only licensed anti-EBV drug on the market; it has a license for EBV-associated post-transplant lymphoproliferative disease. (5) Do other drugs and strategies that transiently deplete B cells working in the same way, for example mitoxantrone, cyclophosphamide, alemtuzumab, cladribine, bone marrow transplant, etc.? I love it when science results in more questions be asked than it answers; innovation feeds innovation."
Rituximab which depletes B cells is also mentioned as the only licensed anti-EBV treatment.
The treatment of MS by Rituximab may have largely failed sofar because only intra venous administration barely penetrates the cns.
The following article on Rituximab delivered intrathecally is interesting and may come close to a real cure for MS: http://www.ncbi.nlm.nih.gov/pubmed/25745637
Last edited by Leonard on Tue Sep 15, 2015 12:13 pm, edited 2 times in total.
B-cells central to MS
http://www.progressivemsalliance.org/wp ... grants.pdf
quote
Title: Intrathecal monoclonal antibody therapy and cerebral microdialysis in progressive
multiple sclerosis
Summary: Small clusters of immune cells called B cells are commonly found within the brains of
people with progressive MS, which points to the presence of hidden and potentially damaging
immune activity. Rituximab is an agent that eliminates B cells. Trials using rituximab in progressive
MS so far have not been successful, possibly because rituximab is unable to access these particular
B cell clusters. This team is administering rituximab directly into the spinal fluid (intrathecally). In
an ongoing trial they have been treating people with progressive MS with this method, with some
success.
Title: A phase 1 open-label trial of intrathecal rituximab for progressive multiple sclerosis patients
with magnetic resonance imaging evidence of leptomeningeal enhancement
Summary: Multiple sclerosis involves an immune system attack on the brain and spinal cord. Within
the tissues covering the brain and spinal cord (meninges), abnormal clusters of immune B cells have
been described in progressive, and to a lesser extent, relapsing MS. These clusters are associated
with increased damage to the adjoining surface of the brain and may play a role in MS progression.
Rituximab is an agent that can eliminate B cells. This team proposes to use a special MRI technique
to identify these cell clusters in 12 people with secondary- or primary-progressive MS. In people who
have them, the team will then conduct a pilot test of rituximab delivered directly into the spinal fluid
(intrathecally), and will evaluate the safety and potential effectiveness of this method for reducing
the immune cell clusters.
https://clinicaltrials.gov/ct2/show/NCT01719159
Further information on the role of B-cells in MS:
http://www.healthline.com/health-news/m ... lls-081214
http://stm.sciencemag.org/content/6/248/248ra107
In a broad sense, the work programme of the Progressive MS Alliance aligns with the above thesis on MS UNRAVELLED.
Are we on the verge of a real breakthrough here?
quote
Title: Intrathecal monoclonal antibody therapy and cerebral microdialysis in progressive
multiple sclerosis
Summary: Small clusters of immune cells called B cells are commonly found within the brains of
people with progressive MS, which points to the presence of hidden and potentially damaging
immune activity. Rituximab is an agent that eliminates B cells. Trials using rituximab in progressive
MS so far have not been successful, possibly because rituximab is unable to access these particular
B cell clusters. This team is administering rituximab directly into the spinal fluid (intrathecally). In
an ongoing trial they have been treating people with progressive MS with this method, with some
success.
Title: A phase 1 open-label trial of intrathecal rituximab for progressive multiple sclerosis patients
with magnetic resonance imaging evidence of leptomeningeal enhancement
Summary: Multiple sclerosis involves an immune system attack on the brain and spinal cord. Within
the tissues covering the brain and spinal cord (meninges), abnormal clusters of immune B cells have
been described in progressive, and to a lesser extent, relapsing MS. These clusters are associated
with increased damage to the adjoining surface of the brain and may play a role in MS progression.
Rituximab is an agent that can eliminate B cells. This team proposes to use a special MRI technique
to identify these cell clusters in 12 people with secondary- or primary-progressive MS. In people who
have them, the team will then conduct a pilot test of rituximab delivered directly into the spinal fluid
(intrathecally), and will evaluate the safety and potential effectiveness of this method for reducing
the immune cell clusters.
https://clinicaltrials.gov/ct2/show/NCT01719159
Further information on the role of B-cells in MS:
http://www.healthline.com/health-news/m ... lls-081214
http://stm.sciencemag.org/content/6/248/248ra107
In a broad sense, the work programme of the Progressive MS Alliance aligns with the above thesis on MS UNRAVELLED.
Are we on the verge of a real breakthrough here?