update 28 July 2014
I would like to recap based on our learnings.
MS has many aetiologies. The picture is not black and white. MS is multifacetted with considerable variation among patients (the NO / OHNOO cycle interacts with distinct tissues to produce varying patterns of symptoms and signs) http://www.allergyresearchgroup.com/Exp ... sp-35.html . Variation may also be seen in pattern/degree of ccsvi, immune system handling of EBV and gradations of ADMA generation by the kidney/renal system.
Our system for health care (and the thinking inside it) is locked up in a grid, no one has the power and democratic legitimacy needed to take control. The pattern of thinking by most medical experts is too linear / singular rather than lateral / heterogeneous. We need to break out of the situation: http://en.wikipedia.org/wiki/Paul_Feyerabend Everybody wants a magic bullet but for MS that does not work. Doctors should have a veterinarian look at things. As regards the therapy, it is the sum of all the things you do that makes a difference and it will take time to be effective.
In MS, the energy metabolism is disrupted with reduced absorption of essential nutrients. But most studies on MS get lost in the complexity at the back of the mechanism, a mechanism that does not even have to be fully understood. At the front we find the high EBV load, the vicious NO / OHNOO cycle, oxidative stress, peroxinitrite that jams the cells etc. The approach should focus on the front, not on the back! Virology and biochemistry are primary; neurology and endocrinology are secondary.
Ccsvi links the drainage of the dural nerve system, the dural sinuses, and meningeal inflammation. It provides a possible explanation for meningeal inflammation and subpial cortical lesions exclusively observed in MS patients. Environmental factors such as exposure to heavy metals (even of previous generations) and related genetic factors of veins may play their role here (Boston document, Texas study). Still apart from the whole amalgam discussion, PwMS also seem to have a worse than average dental health which may find its explanation here as well.
Quite a bit of research implicates EBV is central in the development of MS. One ingenious study looked at blood samples collected from 3 million US military personnel at their time of enlistment, and their subsequent development of MS. Those who had high anti-bodies to EBV at the time of enlistment, that is those who had a chronic viral infection, even up to 5 years before the onset of MS, had a 20-30 times higher risk of getting the disease than those with low antibody levels.
Researchers in Houston, Texas have speculated that some of the effects of interferons in MS might be due to their anti-viral properties (in fact as much as their effects on the immune system).
In susceptible people, or it is probably better to say people that have a certain predisposition, that is those with the 'right' genetic make-up, and the right sort of environmental triggers e.g. lack of sunshine, fish oil, infection with EBV may trigger the onset of the disease later in life. The kidney/renal system producing ADMA is a highly suspect factor predisposing people.
The mechanisms causing disability progression and the lesions are only loosely coupled: the EBV envelop protein vs EBV infected B cells inducing peroxynitrite nitrating the lipids. Studies also confirm that disability progression and lesions are not 1:1 correlated.
Autoimmunity is explained by chronic high concentration EBV immune complexes cross-coupling with epitodes of EBV remnants in transgenetic cells. About 8% of cells in our body is transgenetic, after about 120 million years of evolution.
In MS disability progression, because the effects of poor health of dendrocytes and a lack of energy come together, they appear one and the same process. But I think underlying are in fact two different processes: the EBV envelop protein causing the replenishment of new dendrocytes to stall vs peroxynitrite disabling glyceraldehyde-3-phosphate and ADP/ATP conversion causing mitochondrial energy / the pump to fail. In casu, I see my own disability progress but at the same time to migrate more and more towards an energy failure. And although there is a common causal factor, they are different processes. An explanation for the big temperature effects seen in Pw MS -who inevitably run more on the borderline- should probably be sought in this corner as well.
The count of mitochondria in our cells is important too. If you have more mitochondria and active membranes, you are less susceptible for developing MS, I think because it just takes longer for the system to get jammed. The number is proprotionate to the vitamin D level in the circulation of the mother from say the 2nd to the 6th month of pregnancy and of the adolecent during the main phase of cellular growth. Where the vitamin D level is influenced by cholesterol and sunlight. That is why I think that our modern low fat diet that may be good for mid-aged and elderly people and helps protect against heart disease etc is not necessarily good for young mothers and children.
Women are reported to produce more nitric oxide than men, possibly explaining the gender bias seen in MS. A similar gender bias is seen in autoimmune diseases characterized by excessive peroxynitrite (i.e. CFS, lupus, rheumatoid arthritis).
Nitric oxide is known to stimulate the nociceptors that initiate the perception of pain. I am sure nitric oxide is sky high in MS patients explaining pain in the limbs.
According one article, a low-fat diet inhibits replication of the virus and thus helps to keep the virus/B-cell count down. A sustained low-fat diet (for half a year or more) will improve the gut flora (from personal experience my gut flora and control stabilised - unexpectedly) which suggests a better working of the immune system (>90% of the immune system is in the gut; the name Natasha Campbell comes to mind) and with that a better virus 'control' (Swank). Besides diet, in general the immune system weakens with age where an already weak immune function will get weaker faster.
The cycle seems self-reinforcing: EBV infection gives ever weaker immune protection which aggravates EBV infection. Strengthening the immune function would seem central to any therapy.
I find the theory Beyond Avonex and Valtrex by Scott on regimens-f22/topic24019.html beautiful thinking and highly plausible as it connects all the things that I see in my own family. It is fully complementary to and reinforces the overall concept below. I cannot be naïve anymore and simply accept that this is all coincidence. It is just too good to be dismissed. I encourage you all to read Scott's theory.
Perverse drivers in the medical system and fear of stepping outside accepted practice hamper the exploration of new ideas. Fortunately, the collective cognition on the Internet leads to new concepts beyond old thinking in traditional quarters. Together with prof. Peter Finke http://www.perlentaucher.de/buch/peter- ... ience.html , we can only hope that this citizen science that now thrives on social fora may find "ways out of the impasse of reality".
A new concept and treatment options for MS II
update 29 April 2014
MS has multiple aetiologies
CCSVI (probably in part a birth defect) positively correlates with MS (1)
and is a factor that contributes to an early compromise of the BBB
Venous reflux/hypoperfusion combined with weakening immune system (see also point 3. below):
- promotes local inflammatory processes (2)
- reactivates HERV-W (Herpes, VZV, EBV) in cerebral meninges (as in cartilage of joint as in RA)
With broken BBB:
- Phase 1: Herpes simplex/VZV or Cpn blocks receptors --> inflammation --> RR (time constant days to weeks)
The virus may be latent for many years and reactivate only sporadically after so many years. In the beginning, for me reactiviation repeated only every 8 or 9 years, always in the Spring when the immune system is low.
- Phase 2: HERV Herpes/VZV/EBV --> injury of cell types i.e. dendrocytes --> progressive (time constant months to years)
VZV causes micro vasculopathy http://download.springer.com/static/pdf ... 7&ext=.pdf
B-cells release toxic substance that cause death of differentiated oligodendrocytes http://www.ncbi.nlm.nih.gov/pubmed/22458983
EBV envelop protein inhibits OPC differentiation; http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2672075/
EBV promotes the proliferation of Peroxynitrite that is by far the worst free radical, poisoning the system in several ways e.g. causing mitochondrial failure, nitrating fat tissue giving rise to inflammation (lesions in combination with fats?) etc... see also Part III below and regimens-f22/topic24019.html
The problem of demyelination -which is the real problem in MS, studies have clearly shown this- may well be a bit more than the envelop protein e.g. be intermingled in some way with virus, fats, B-cell immune complexes, peroxinitrite and ADP/ATP. But for now and for the overall concept that does not seem so important.
Graph of age of onset of MS has double peak --> different mechanisms underlie Ph1 and Ph2;
Ph2 is age dependent, not on RR severity
(1) CCSVI = Venous insufficiency of Internal Jugular Veins in the neck, draining the Cerebro Spinal
(2) Local inflammatory processes combined with inflammation induced high levels of nitric oxide cause narrowing of cerebral veins and autonomous nervous system dysfunction
Uncontrolled EBV infection reactivates in ectopic B-cell follicles in cerebral meninges --> chronically active EBV
Infection of autoreactive B-cells
Elevated EBV anti-bodies (already years before the first MS symptoms begin)
Cross-coupling of immune complexes with epitodes of remnant virus parts (in transgenic cells) explains the action against the "self"
- is secondary process (The MSRV-Env protein has also pro-inflammatory properties which translate into the production of different cytokines)
- EBV is chronic; immune complexes not effective against EBV; fat metabolism involved in EBV replication
Note: Chronically active EBV presents
- coronary artery aneurysm (uncle, farther's cousin)
- nasopharyngeal carcinoma (grand farther)
- Meniere (farther)
- mitochondrial energy failure? (brother)
- MS (me, with very high readings of Herpes simplex and EBV immune)
3. Weakening immune system
Immune system gets ever weaker <-- mitochondria get weaker
(poor quality of food e.g. high carb, lack of phytonutrients, stress, lack of sunshine/vit D/fat, environment, vaccinations, HERV/EBV)
Immune system is producing useless /non-working antibodies against EBV
B-lymphocytes unbridled multiplication
Hypo gamma globulin (shortage IgG3)
Immune system forgets about the rest
Chronic infection, for example:
- leaky gut --> Ɛ toxin
- Cpn infection (in RR)
- even toenails fungus which has crossed here several times
- Rheuma Arthritis
- Autonomic dysfunction smooth muscle layer
(my own titre was very high, eating own muscles, is this the regulatory system attempting to relax smooth muscle of cerebral veins?)
4. Treatment options
Lots and lots of antioxidants and flavonoids (incl. supplements such as CoQ10) see the list on http://www.prohealth.com/library/showar ... ibid=17947
Neuro Muscular Electric Stimulation (NMES) general-discussion-f1/topic24974.html
for nutrients and NMES see also pg 14-17 of http://www.ms-uk.org/files/npwm_2009_0053.pdf
Hormonal and amino acid support as L-Arginine
Anti-viral as Valacyclovir (as long-term treatment option); in the short term, valacyclovir may cause a reactivation of the virus
Gamma globulin IgG3
Other issues for consideration:
Vitamin D gut/immune system support
Vit A to help restore gut function
Nutritional support / diet
Detoxification for strong mitochondria; strenghten B-cells, epithelium, meninges
Food rich in anti oxidants incl. polyphenols, acathpocyanids (bue black), lutein (red) and caretnoids (yellow orange)
CoQ10 (e.g. MitoQ effective form)
High quality food phyto nutritients
Oxygen in bed room (when at rest in supine position)
Low fat / Swank / FAS = EBV inhibit (Fatty Acid Synthase inhibitor, no palmitoylated proteins, no palmitic acid)
Promote brain perfusion
stimulate Chinese 'axis'; electrically stimulate vagus nerve (as in RA)
Adrenal – cortisol - gut
Anti viral (e.g. Zovirax/acyclovir or Valacyclovar or anti-HIV/HAART)?
Anti biotics – Cpn RR
Gamma globulin IgG3 to help normalise the immune system
A new concept and treatment options for MS III
I'm afraid the acyclovir is a long term treatment. I took 500g twice a day, every day, for a decade. The reason is the active life of single tablet is around 15 hours and you need to work on total cover. All it does is put a stop in the codan of the RNA of the EBV so when your B cells divide you can make an uninfected B cell instead of an EBV immortalized cell. The reason you want to limit the EBV proliferation is an EBV infected B cell gives off two molecules of oxygen (superoxide). Whilst we need superoxide to control pathogens we don't need an overproduction of it.
I think the reason why some people don't develop MS and we do tell us that EBV is not the whole story. The other part is the so called predisposition. My thinking is this condition is due to our kidney/renal system producing asymmetric dimethylarginine (ADMA) whereas healthy people produce the symmetrical form. ADMA is an endogenous inhibitor of all forms of Nitric Oxide synthase. The capacity to vasodilate is dependent on how much endothelial Nitric Oxide synthase we have to make Nitric Oxide. In people with MS there is a very high level of inducible Nitric Oxide synthase (iNOS) rather than endothelial (eNOS).
iNOS is made by the body in response to injury. The ADMA depletes eNOS and iNOS arises as a natural response. Why is this important? When superoxide and Nitric Oxide come into close proximity they spontaneously make Peroxynitrite which is, by far, the worst free radical. Peroxynitrite mucks up many functions as well as nitrating the lipids. The most important factor is the disabling of Glyceraldehyde-3-phosphate. If this doesn't function, ADP can't become ATP. We need ATP to drive the sodium-potassium pump in each cell. If that doesn't function we can't make energy.
EBV contributes superoxide toward the production of peroxynitrite, but if you have a renal malfunction that is producing ADMA leading to too much iNOS ,you are likely become compromised as an MS person when the peroxynitrite runs rampant.
The lack of energy is due to the collapse of the function of the pump as is the loss of mitochondrial vitality. The inability to vasodilate is due to the lack of Arginine. The lack of Arginine is due to a renal malfunction.
The renal problem may be as simple as late maturity of function or we may have a mutant form of Megalin. I often read posts about Vitamins D, B12 and A. They are all transported through the renal proximal tube by Megalin where some metabolizing occurs. Vitamin A is sorely lacking in the general conversation but it is very involved in gut health.
I prefer to break the problem into two separate issues 1) a renal problem and 2) a viral infection that promotes the proliferation of Peroxynitrite that poisons the system. I posted a unfortunately long winded explanation called "Beyond Avonex and Valtrex" which goes into more detail with links to research.
see also regimens-f22/topic24019.html
The original first posting of 8 January 2011 starts here:
This is a copy of my posting on the thread on ccsvi:
It is hypothesised that multiple sclerosis (MS) is caused by an insufficient glucose level in the brain or parts of the brain.
Patients with MS are consuming more sugar than the average person, to get it elevated in our blood streams, to try and meet the unmet needs of the brain. And the result of greater sugar consumption is a greater prevalence of chronic yeast infections and symptoms as candida . Also the faster recovery of motor functions of MS patients on the intake of sugar/glucose, in particular in the beginning, would seem to suggest a glucose link. Furthermore, it is an explanation for the fast recovery of some patients post- ccsvi liberation and a post-liberation increase in dreams and REM sleep, since REM has high glucose demands.
The blood flow delivers oxygen and glucose to the very hungry brain as well as other nutrients, and takes away waste products. A lack of glucose puts the neurons in a dormant state; they become under-nourished. The consequence is demyelination and, if seriously under-nourished for a longer period of time, myelin and neuronal death. When this happens, the microglia jump on this and clean up the mess. Once they get out of the BBB, the T-cells jump on them and we start see the scars and the inflammation. That is when MS shows up.
Why are the cells under-nourished? There are at least two reasons: iron deposits on the vessel walls that inhibit the transport of glucose across the BBB and; insulin resistance that inhibits this same transport of glucose. The iron deposition may develop at a young age as a result of problems with the drainage, its origin is probably pre-congenital. The insulin resistance may develop at a later age. MS is probably a consequence of both, in a wide variety of cases among the population. One effect may be a more important for an early age onset and the other for a later age onset. The double peak in the age of onset of MS would indeed suggest the possibility of such underlying mechanism [there are two peaks on the age of onset graph at 25-30 and 40-45 http://newsgroups.derkeiler.com/Archive ... 01256.html ].
Stenoses in the veins draining the brain and spinal column (ccsvi, Zamboni) cause refluxes in the deep cerebral veins and will lead to iron deposition on the vessel walls (you can see this on 7T MRI) and this inhibits glucose transport through the affected parts of the BBB. Iron deposition is a normal phenomenon in organs and limbs in case of problems with the drainage that has been known for a long time. By opening up the blockages in the veins by angioplasty, the blood flow can restore to normal, and eventually as the iron is taken away the BBB function may restore to normal. The increased blood flow during pregnancy and stop of MS progression adds to the plausibility of the concept. The low fat/Swank diet and the use of blood thinners/anti-clotting (effect Copaxone?) may also help improve the blood flow with the same positive effects.
Some persons may already have a fairly weak glucose condition in their brain due to the low blood flow through the head and the iron depositions. At mid age then, the insulin resistance starts to develop and the glucose transport will be further weakened. The Vitamine D relationship, well known in MS, plays its role here.
As studies found, higher levels of Vitamine D (childhood and/or during pre-congenital phase) may delay the onset of MS a bit because of lower intra-cellular calcium levels where insulin resistance and problems with glucose transport will develop a bit later on. Conversely, lower levels of Vitamine D will elevate intra-cellular calcium levels where insulin resistance develops earlier on and thus impaired glucose transport across the BBB will develop earlier.
This may explain the differences found among MS patients and a control group that were screened for ccsvi: people who have stenoses and therefore a low blood flow but high Vitamine D will still provide enough glucose to their neurons and myeline, and therefore will not experience the MS symptoms, or at the very least not as quick as those with low Vitamine D. The prevalence of diabetes type 2 in MS patients would further suggest a link with the insulin resistance. It is also known that this insulin resistance develops long before the signs of diabetes become apparent and the diabetes type 2 is diagnosed, further adding to this part of the hypothesis.
Studies have also found that a low-glucose condition causes or at the very least it is likely to cause demyelination. The process of demyelination is already well underway before diabetes type 2 shows up.
Also it ties in with the effect of heat on glucose in the bloodstream (it fluctuates more wildly; diabetics have to account for this in the summer) and, if overheated, the brain will endure worse damage from this lack of glucose.
What lessons may we draw:
1. get the veins opened and restore the normal blood flow. This will increase the volume of blood, and improve the cerebral hypoxia side of the equation, and the cerebral hypoglycemia side. The iron deposits may be taken away (?)
2. if appropriate and confirmed, start taking (diabetes type 2?) medication early on to overcome insulin resistance and improve the glucose transport across the BBB. And also, get the blood sugar level back to normal.