Where are we on understanding and treating ME/CFS today?

Hi, all.

I've written the following in order to try to see the "big picture" concerning ME/CFS, in order to focus efforts going forward. These are my own views at present. I of course may be wrong, and I have probably left out some important things. I would appreciate comments. I have taken the liberty of using the royal "we."


My goal with respect to ME/CFS is for everyone who has it to be able to completely recover as soon as possible. I realize that this is a difficult goal to attain, but I believe its the goal we need to have.

So how do we work toward achieving this goal? I believe that we first have to develop an understanding of this disorder, and that this understanding will serve as the basis for developing effective treatment.

What aspects to we need to understand? I would say that we need to understand the etiologies (root causes), the pathogenesis (development of the disease process), the fundamental pathophysiology (whats the core mechanism of whats wrong with the way the body is working in this disorder) as well as additional contributions to the pathophysiology due to features that accumulate during the illness after the initial onset, and the symptoms, explained on the basis of the pathophysiology.

What do we need to treat? Based on experience up to now, I would say that we need to treat the fundamental pathophysiology, but we also need to treat the etiologies and the additional features that have accumulated. I have learned this the hard way.

Again, based on experience up to now, I would say that the fundamental pathophysiology is the same in nearly all cases of ME/CFS, and it involves a chronic vicious circle mechanism that includes depletion of glutathione, a functional deficiency of vitamin B12, a partial block of methionine synthase (which links the methylation cycle with the folate metabolism), and loss of folates from the cells. Essentially everything else in ME/CFS (other than direct effects of pathogens or initial toxins) stems from this vicious circle. This is elaborated in the Swedish seminar here: http://iaomt.media.fnf.nu/2/skovde_2011_me_kroniskt_trotthetssyndrom/$%7Bweburl%7D

I believe that the etiologies, on the other hand, differ from one case to another. For the sporadic cases of ME/CFS (as differentiated from the cluster or epidemic cases), there is an inherited genetic predisposition that is not yet well defined, but likely consists of a collection of polymorphisms, the specific ones again differing from one case to another.

The coexistence of an inherited genetic predisposition and some combination of a variety of physical, chemical, biological and/or psychological/emotional stressors is the etiology of ME/CFS, in my opinion. This variety of stressors has in common the characteristic that they all place demands on glutathione, and if they are sufficiently severe and long lasting in a person who has the genetic predisposition, it appears that they will produce a large enough depletion of glutathione to set up the chronic vicious circle mechanism that I believe is the core of the pathophysiology of ME/CFS.

What are the additional features that can accumulate during the illness? I believe that they are toxins and infections by various pathogens. They accumulate because two of the bodys major defense systems, i.e. the immune system and the detoxication system, are rendered dysfunctional by the chronic vicious circle mechanism in the pathophysiology of ME/CFS.

Where are we now in terms of treatment of the aspects that must be treated to bring about recovery? I would say that we have a basic understanding of the methylation treatment necessary to overcome the partial methylation cycle block in the pathophysiology, and it has been possible to accomplish this in a majority of PWMEs who have used this treatment. The essential part of the treatment is a combination of a high-dosage of Vitamin B12 (of the order of 2 milligrams per day) given sublingually or by injection, and one or more active (chemically reduced) folates at approximately the RDA for folate (400 to 800 micrograms per day). These two support the methionine synthase reaction, which appears to be partially blocked in ME/CFS. Successful treatment usually also includes other supportive nutrients.

However, there are still many who either experience no response from this treatment, or who experience such severe exacerbation of symptoms from it that they are not able to continue it. We need to identify the reasons for these in each case, and treat them effectively.

In addition, we have found that in most cases, even though this treatment overcomes the vicious circle mechanism and usually brings significant symptomatic improvement, it is not the complete answer for producing total recovery. There are many who experience improvement in their methylation cycle, folates and glutathione from this treatment, based on repeated lab testing, but their ratio of reduced to oxidized glutathione does not return completely to normal, suggesting that oxidative stress continues to be present. I think this is due to the presence of the original etiologies and/or the additional features that have accumulated.

With regard to treating the etiologies and the additional features that accumulate during the illness, I would say that we have had success in some cases, but in many other cases these have not been successfully identified or have not been successfully treated. More work is needed to identify them and to develop treatment for them.

What are some possible reasons why a PWME would experience no response from the methylation treatment? One obvious possibility might be that the person does not have the vicious circle mechanism described above. Though this mechanism appears to be fundamental to the pathophysiology of ME/CFS, there may be some people who have similar symptoms but do not have this vicious circle. This is one of the main reasons it is helpful to run the methylation pathways panel (I refer here to the biochemical panel, not the genomic panel with a similar name.)

I suspect that another possibility is deficiency in one or more of the essential nutrients for the methylation cycle and related pathways. There are several vitamins, minerals and essential amino acids needed to support this part of the metabolism, and many PWMEs have been found to be deficient in some of them. Those who have hemopyrrollactamuria (HPU) are a subset of this group. Again, testing is available to determine whether there are deficiencies. This includes direct determination of the levels of the nutrients in the blood, measurements of certain enzyme activities that are specific to particular nutrients, and inferring deficiencies from metabolic tests (such as urine organic acids and amino acids in the urine), hair mineral tests, and essential element tests in the urine. The interpretation of hair testing is not simple or straightforward and requires considerable understanding and experience. Testing for HPU is also available.

Another possibility is high body burdens of one or more toxic metals, such as mercury, that are capable of blocking enzymes in this part of the metabolism. Testing is available to look for these in urine, blood, feces and hair, and chelation may be needed if the levels of the toxic metals are high.

Now, what about those who find this treatment to be intolerable? There are several categories of this. One that is very common is an increase in excitotoxicity when the treatment is started. This involves symptoms such insomnia, anxiety, nervousness, a wired feeling and hypersensitivity of the senses. This is likely due to an initial further decrease in glutathione in the astrocyte cells of the brain, as a result of conversion of more of the homocysteine to methionine, so that less is available for supporting glutathione synthesis. Sometimes lowering the dosages at first, especially of Vitamin B12 and the folates, and increasing them slowly over time, is effective. There is also a variety of substances that may help to calm down the excitotoxicity, including GABA, theanine, magnesium, taurine, grape seed extract, pycnogenol, progesterone cream, and Valerian root.

Another negative reaction, which is sometimes described as a toxic feeling, is probably due to mobilization of toxins by the improved sulfur metabolism, together with the time lag between mobilization and excretion. If the digestive system is not operating well, it may not be able to excrete toxins in the stool very well. If there is low stomach acid, intestinal bacterial dysbiosis, malabsorption, and/or leaky gut syndrome, these may need to be diagnosed with comprehensive stool testing and treated before the methylation protocol can be used. If there is at least one bowel movement per day, the use of various binders may help. These include activated charcoal or modified citrus pectin, which will help to usher toxins from the gut into the stools. Lemon juice (taking care to use a drinking straw and to flush the teeth with water afterward) can help to increase the excretion of some toxins into the urine.

Another issue here can be the presence of upregulating polymorphisms in the CBS (cystathionine beta synthase) enzyme. This can often be detected in the methylation pathways panel results, or a polymorphisms panel (such as the one offered by Dr. Amy Yasko) can be run. Some PWMEs who have these polymorphisms can tolerate methylation treatment without dealing with them specifically. Others may need to take measures such as those recommended by Dr. Yasko to treat these before they can do the methylation treatment.

Another negative reaction can be caused by development of potassium deficiency. This occurs because as the folates rise in the cells, the cells are able to divide and reproduce more rapidly. Since potassium is the most abundant positive ion inside all cells, this produces a demand for potassium, which is generally low in PWMEs to start with. Symptoms associated with low potassium include heart palpitations and muscle spasms. The blood serum potassium level can be measured with a standard comprehensive blood metabolic panel. Supplementing with potassium supplements or foods high in potassium may help with this.

Now, what about the etiologies and additional features that accumulate during the illness?
There is a wide variety of possibilities. First, there is ongoing psychological or emotional stress. This may be difficult to avoid because of life circumstances, but it is important to lower this to achieve full recovery, because this will continue to place demands on the HPA axis to secrete cortisol and on the sympathetic nervous system to secrete norepinephrine and epinephrine, which will produce oxidative stress and hence, continuing demands on glutathione.

Ongoing exposure to toxins and especially biotoxins (for those who are susceptible), must be eliminated, and as mentioned above, it may be necessary to do chelation or FIR sauna treatments to lower the levels of toxins.

There is a variety of pathogens that can serve as etiologies or that can accumulate during the illness. Some of them have ways of hiding from the immune system and thus will need to be dealt with specifically and directly. These may include Lyme disease and its coinfections, intestinal bacterial dysbiosis (as mentioned above) and yeast infection, a variety of viral infections, including enteroviral infections (and possibly retroviral infections), intracellular bacterial infections including mycoplasma, chlamydia and rickettsia, infections involving root canals and cavitations where teeth have been removed, sinus infections, including fungal as well as MARCONS (multiple antibiotic resistant coagulase negative Staphyloccus). Dealing with these infections is perhaps the most difficult aspect of treating ME/CFS. Some PWMEs have histories of many infections during the early part of their lives, before the onset of ME/CFS, suggesting possible genetic deficiencies in their immune systems. Testing for some of them (such as Lyme disease and retroviruses) is not very clearcut at present. Treatments for some of them are not always very effective. This is an area that needs a lot more work.

This is the status as I see it today. I would appreciate hearing your thoughts.

Best regards,

Rich

HI Rich,
This seems like a comprehensive review of the MCB hypothesis for CFS, although I would not say it is at this time a comprehensive perspective for all the other CFS theories. Although maybe in time methylation cycle problems and resulting localized glutathione problems will be seen as one of the major pathologies. I would like to think CFS will be so simple to solve as getting toxins out and restoring proper metabolism for methylation and detox.

Having been through several treatment approaches for this theory I can say that in my case and several others I am involved with this approach seems to reflect one part of the CFS complex, but I have never been able to progress beyond a 10-20% functional improvement from treatments you suggest above (in other words, going from 10% to maybe 30% functional), and I have tried most of them at some point.

Some other issues seem to be involved with CFS, perhaps they all do contribute to maintaining the oxidative stress precondition, but clearly we don't know at this time. A more complete picture I think might address some of the specific genetic problems encountered in research, vascular blood volume problems and immune problems that are identified, and most importantly the infections you mentioned. These are all difficult infections for anyone to manage, more so if a person has defective immune responses. And worst of all if the patient has developed auto-immune responses.

Thank you Rich. This is one huge puzzle. So many things to address. Thank you so much for helping and being there for us.

Thanks rich for all your time and effort - trying to bring it all together is very helpful indeed - especially with your knowledge.

Thank you for your work, Rich. Whatever the etiology and pathology of CFS/ME is, I believe it's vitally important to get these fundamental biological processes (methylation cycle) working. I don't believe there can be recovery without restoring these.

A very helpful summary of your views, Rich. You only mention the HPA axis in terms of cortisol though - I suspect the role of this may be rather more complex, given that so many of us have complicated autonomic dysfunctions.

Also, you mention hair mineral analysis as a tool. There's been quite a bit of discussion on here about this recently - I'm willing to consider it may be a valid technique but most of the scientific papers I've read suggest it isn't. I'd be interested to see any references you may have which show that it is valid and reliable.

Jenny

As always thanks rich for your brilliant work.

I'm convinced richvank's theory will prove to be correct in the long run. The only remaining difficulty lies in identifying the original etiologies that put stress on our glutathione to begin with. This can vary from person to person and can be a combination of multiple glutathione stressors. Also, having a broken immune system and detoxification system for years will invariably cause "additional features" to appear along the road making lifting the vicious cycle that much harder.

Even if common sense tells me that I've had the same amalgams and used the same deodorant without problem for years before getting sick so I must be fine with them. It is entirely possible that mercury and aluminum are now permitted to accumulate now that glutathione depletion has hampered my detoxification. The same could be said about a formerly dormant EBV infection taking advantage of a now hampered immune system.

The tipping point for glutathione depletion must have existed since we evolved but it appears the modern world is creating additional glutathione stressors and pushing more individuals over the tipping point into the stable but unhealthy glutathione depleted state known as M.E..

Hi Rich, thank you so much for your hard work and time. Your theory makes a lot of sense to me, although i dont really understand how it links in with other theories e.g mito dysfunction, (sorry i had a whole list to go here but the brains seized up again!) Whicxh brings me to my other point. How does this theory link in with abnormalities shown on SPECT scans and known to be a part of the picture of M.E as a neurological disease? in the light of your thoughts, what do you make of the findings from autopsies in the UK showing dorsal root ganglionitis and its contribution to the death of these severely ill patients?

What about the generaly poor nutritional status seen in PWME such as low COQ10, low carnitine etc - id ont really understand how this fits in, can you explain please?
Many many thanks, Justy

P.S i have still not tried the full SMP, but have had some improvement with 300mcg a day sub cut injection of MB12.

Hi rich,

As always I appreciate your thoughts on me/cfs. If I read this correctly, are you saying that anything that can go wrong could be the cause of or co-existing factors in me/cfs ? If so, I'll buy into this.

One thing that I haven't seen discussed in this illness is the possibility of permanent damage to our organs. Imho, our only hope for reversing this damage is a healthy diet like dr wahls.

Tc .. X

Hi, Kurt.

Thanks for your response. I'm sorry that the various treatments haven't done you more good than they have.
Yes, I wrote this from the point of view that the methylation cycle partial block is the core of the pathophysiology, because I believe that it is. I realize that there are other hypotheses, and I hope as time goes on we will be able to figure out how they fit together. I agree that the other aspects you mentioned are important, and not well understood at this point.

Best regards,

Rich

Hi, Madie.

I'm happy to hear about your recent progress! Thanks for reviewing what is working for you.

Theory is one thing, and treatment is another. Providing support for several aspects at once, as in Dr. T.'s SHINE program, though I don't agree with him on everything, can certainly help.

Best regards,

Rich

Hi, Sally, Enid and Adreno.

Thank you for the encouragement. I appreciate the input all of you provide. I learn a lot from you.

Best regards,

Rich

Hi, Jenny.

Thanks for your comments. I agree that the HPA axis dysfunction is more complex than the low and dysregulated cortisol. I think that abnormalities in acetylcholine, norepinephrine and epinephrine, as well as aldosterone and the interactions with the other steroid hormones play roles, too. In my view, the part of the metabolism that is affected in ME/CFS is so fundamental that when it is disrupted, there is a cascade of problems that occur, and even listing them all is a challenge, let alone figuring out how the whole cause and effect tree is constructed.

Hair analysis is something I hope to learn more about. It is definitely not straightforward.

Best regards,

Rich

Thanks, fla. It sounds like we are on the same wavelength.

Best regards,

Rich

Hi, justy.

Thanks for your comments. I'm glad to hear that the methyl B12 is helping you some.

You've raised a lot of good issues, and each one is a major topic in itself. I will try to respond briefly to each one of them, but you can find more detail in the video or slides from the seminar I presented in Sweden, in which I elaborated the basic hypothesis in terms of its connections to various features of ME/CFS. The video and slides (below the video) can be found here:

http://iaomt.media.fnf.nu/2/skovde_2011_me_kroniskt_trotthetssyndrom/$%7Bweburl%7D

(I heard today from a contact in Sweden that so far about 700 people have watched the whole seminar, and a total of 3,261 different people have watched a total of 2,670 hours. I very much appreciate what the people of the IAOMT group in Sweden have done in posting this seminar.)

1. Mitochondrial dysfunction--caused by depletion of glutathione, which allows oxidative stress, in turn causing partial blocks in the Krebs cycle and the respiratory chain and damage to the phospholipid membranes, and which also allows the buildup of toxins that block enzymes in the mitochondria and serve as adducts on the DNA. The mito dysfunction is also caused by the partial methylation cycle block, which lowers the rate of production of creatine, carnitine, phosphatidylcholine, and coenzyme Q10, all of which are needed by the mitochondria.

2. SPECT scans--abnormalities caused in part directly by glutathione depletion, which affects the oxidation state of the technetium isotope that is used, and thus affects its distribution in the brain. Abnormalities also caused by variations in blood perfusion in the brain, which could be caused by vasculitis, owing to the immune dysfunction, or by lowered blood flow to the brain as a whole, caused by low total blood volume, diastolic dysfunction of the heart, and HPA axis dysfunction, all of which stem from the basic vicious circle mechanism. The low blood volume is caused by central diabetes insipidus, in turn caused by low glutathione in the hypothalamus/pituitary. The diastolic dysfunction is caused by mito dysfunction in the heart muscle cells (see above for causes of that). The HPA axis dysfunction is also caused by glutathione depletion in the hypothalamus/pituitary.

3. Dorsal root ganglionitis--Due to infections as a result of the immune dysfunction that in turn results from the vicious circle mechanism. Glutathione depletion inhibits the cell-mediated immunity, and the disruption of lowered levels due to the HPA axis dysfunction allows inflammation to increase.

4. Low nutritional status--I've discussed Co Q10 and carnitine above. They require methylation for their synthesis. The partial block in the methylation cycle lowers their rates of production. Other nutritional deficiencies result from dysfunction of the digestive system, again resulting from the vicious circle mechanism, and also abnormalities in the use of fuels for the mitochondria, due to the glutathione depletion placing a partial block early in the Krebs cycle.

I realize that this is pretty compressed. I was able to take more time in the seminar, because they gave me more than 3 hours, so if you would like more details, I suggest checking out the video and/or slides.

Best regards, and thanks again.

Rich

Sounds good, methylation has helped me so much, I do think though more research has to go into the Th1/Th2 (and Th17) responses for immune imbalances and its causes, no matter whether it comes before glutathione depletion or after (chicken nf the egg). I also think there might be more key supplements that need to come more into the fore-front, one being Taurine for example. I just have started my research on it (here is a blog of someone who had low Taurine levels which wan't the main focus though: http://pochoams.blogspot.com/2007/12/immunology-and-treatment-of-cfs-under.html) but it looks very promising as an essential supplement for it that I have started using. I always did well with denergy drinks containing Taurine, but often other ingredients prevented me from drinking more or the gut refused to cooperate, but there are pills that contain Taurine only - worth an addition IMO.

Hi, xchoc.

Thanks for your post. I guess that is sort of what I am saying, if I understand you correctly.

I agree that a healthy diet is very important.

I don't know to what degree there is permanent damage. I am concerned about the mitochondria in general. New mitochondria are made by binary division of older mitochondria, and the mitochondrial DNA must come from them. Oxidative stress over a long time may damage the mitochondrial DNA to the point that it is difficult to make vigorous new mitochondria. I think this emphasizes the importance of getting the glutathione levels back up sooner rather than later, to shut down the oxidative stress. I think it also shows the importance of not overdoing when the mitochondrial are dysfunctional, because they are less able to protect themselves against DNA damage while glutathione is low, and exercise will raise the oxidative stress.

Best regards,

Rich

One more thing, these guys are biased obviously , but this is an impressive list of studies of where Taurine can help (incl. oxidative stress):
http://www.jbiomedsci.com/supplements/17/S1

Hi, mellster.

Thanks for your input. I'm glad that methylation treatment has helped you.

I agree that a better understanding of the immune system dysfunction in ME/CFS is needed.

I also agree that taurine can be helpful, at least for some PWMEs. For those who have one or more upregulating SNPs in the CBS enzyme, however, adding taurine may not be a good idea, because they may already have more than normal. I hope it helps you.

Best regards,

Rich