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
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
