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    Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of and finding treatments for complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.

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

Xandoff

Michael
Messages
302
Location
Northern Vermont
Rich,

Thank you for your generous contributions to our forums. From an orthomolecular point of view, do you see any relationship between a ME CFS patient (me) whose symptoms started with chronic neck pain. The dorsal root ganglia is a focus for me because my spine feels like it is on fire for the last 8-9 years.

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.

In November 2010 my lab results indicating that on top of being XMRV positive (sept 2010) I tested positive for HHV-6 ( 3.45), Chlamydia Pneumoniae AB IGM (>1:256), Cytomegalovirus AB IGG CMV IgG (3.1), anemia (on going) High C-Reactive Protein, Vitamin D defiency (29), (in spite of taking 3,000 I.U. a day!) Low DHEA Sulfate (15.0), Mycoplasma Pneumoniae IGG AB (104) Low Testosterone (258) on going, and it suggestive of a past Epstein Barr Virus infection.

I went off valcyte after 14 months in 2012. It did help. I am waiting for Nagalase levels to come back from Belgium. Like others who post here I am of the walking dead making way through life. I went off all pain meds in Dec 2011. The pain is in my spine and my muscles. Any insight you might be able to shed would be appreciated.

I have a sister who had 4th stage Lymphoma at 19 who just passed (54) and a sister with Chrohns that had started Epstein Barr when she was 16.

Again thank you for your dedication and Posts!.
 

Dufresne

almost there...
Messages
1,039
Location
Laurentians, Quebec
Hi Rich,

I was at my MD's office today having a fairly good conversation about ME/CFS when he urged me to request "the CFS paper" from his secretary on my way out. So I did and it turned out to be a copy of your Townsend article. Thought you might like to know your ideas are getting around. Keep it up!
 

Seven7

Seven
Messages
3,444
Location
USA
Rich,

Thank you for your generous contributions to our forums. From an orthomolecular point of view, do you see any relationship between a ME CFS patient (me) whose symptoms started with chronic neck pain. The dorsal root ganglia is a focus for me because my spine feels like it is on fire for the last 8-9 years.
.

Xandoff: I have been wondering what that is about. My spine is burning not stopped. this started like 4 months ago, started in the head but now is mainly in spine. My onset was gradual, I didn't develop the burning or neck pain until year 5 of been sick. I do remember having a (cereal rice crispy) sound in the neck at the beginning but never hurt before. I am positive hh6v, coaxakie and Parvo.
I always attributed the burning to neuropathy pain (i get tingling, numbness, cramps in legs).

7
 

Don Quichotte

Don Quichotte
Messages
97
A poor answer to a good question is at least a step toward really understanding things.

So true, It is also important to keep on asking question and not be content with a partial answer.


We are all blind people describing the elephant, we all describe the bit we feel and so it sounds different from different sources. Of course there is no guarantee we are all studying the same elephant either.

Well, at least you all agree that the elephant is truly there. And that's a big step forward.

Speaking of elephants:

"Horton hears a who" is very wise philosophy and understanding of human nature disguised as a children's story.

I highly recommend to anyone who has not read it/saw it yet.

http://www.myspace.com/video/sneetches/horton-hears-a-who/5302394
 

richvank

Senior Member
Messages
2,732
Hi Rich,

I was at my MD's office today having a fairly good conversation about ME/CFS when he urged me to request "the CFS paper" from his secretary on my way out. So I did and it turned out to be a copy of your Townsend article. Thought you might like to know your ideas are getting around. Keep it up!

Thanks, Dufresne. I would appreciate it if you would PM me with the name of your MD. I'm trying to accumulate names of physicians who are interested in this. Thanks.

Rich
 

richvank

Senior Member
Messages
2,732
Rich,

I can feel the difference on B12 (love it) but my Dr asked me to stopped because it was b12 levels were too high (3,000). So how does one break the block if b12 keep increasing when supplementing? or does it mean I have no block??

Currently taking: coq10 200mg twice a day, Vit C 2,000/d, Fish Oil 4,000 /day, Imunovir + equillibrant.

Viral reactivation: ParvoVirus, Coaksakie, Roseola.
b cells results: 21 Range: 8-18 High
NK CD3-CD56+ results:1.27 Range: 5-16 Low
CD5+ results:67 Range: 68-82 Low
CD5+CD19+ results:0.78 Range: 1-9 Low
CD8+CD95+ results:1.46 ..

Thank you,
7

I used from fatigue to fantastic powder, has all Bs in it. But problem started when I tried to do the simplified protocol, I started the methylfolate and folic acid or one of the other bottles when I was asked to stop. How does one raise glutathione levels without using B vitamins????


Hi, 7.

I suspect that when you were supplementing B12 together with the fatigue to fantastic powder, your body probably was not able to convert the folic acid in the powder to methylfolate rapidly enough. It's better to use methylfolate with the B12. A high serum B12 level suggests that you do have a functional block in B12. What happens with a functional block is that the cells are not able to use B12 properly, so they export it back to the blood bound to haptocorrin. The liver cells are the only ones that can import this, and the residence time in the blood is about a week. So when a serum B12 measurement is made, it is dominated by this fraction of B12, which is not available to cells of the body other than the liver cells. It would be better to do a urine methylmalonate test to see if there is a functional (rather than an absolute) B12 deficiency. The serum B12 test is useful for detecting an absolute B12 deficiency (as can be caused by pernicious anemia or a transcobalamin deficiency or gut surgery or celiac or Crohn's disease), but it is not useful for detecting a functional B12 deficiency, which is what is found in ME/CFS.

You may have to start at lower than the suggested dosages when you combine B12 (such as sublingual hydroxocobalamin) and oral methylfolate, because when the methylation cycle rate increases, symptoms can be exacerbated at first.

If you want to know the status of the methylation cycle, the folate metabolism, and glutathione, I suggest that you ask your physician to order the methylation pathways panel. Contact information and an interpretive guide are pasted below.

Correcting a partial methylation cycle block, folates depletion, and glutathione depletion, if they are present, will help the operation of the immune system. You many still need to do antiviral treatment directly, though, because once the viral infections are able to get entrenched, the immune system can have difficulty dealing with them.

Best regards,

Rich

Methylation Pathways Panel

This panel will indicate whether a person has a partial methylation cycle block and/or glutathione depletion. I recommend that this panel be run before deciding whether to consider treatment for lifting the methylation cycle block. I am not associated with the lab that offers this panel.

The panel requires an order from a physician or a chiropractor. The best way to order the panel is by fax, on a clinicians letterhead.


Available from:

Health Diagnostics and Research Institute
540 Bordentown Avenue, Suite 2300
South Amboy, NJ 08879
USA
Phone: (732) 721-1234
Fax: (732) 525-3288

Email: lab@vitdiag.com

Lab Director: Elizabeth Valentine, M.D.

Dr. Tapan Audhya, Ph.D., is willing to help clinicians with interpretation of the panel by phone, or you can use the interpretive guide below:


March 25, 2012


Interpretation of Results of the Methylation Pathways Panel

by
Richard A. Van Konynenburg, Ph.D.
Independent Researcher
(richvank@aol.com)


Disclaimer: The Methylation Pathways Panel is offered by the European Laboratory of Nutrients in the Netherlands and the Health Diagnostics and Research Institute in New Jersey, USA. I am not affiliated with these laboratories, but have been a user of this panel, and have written these suggestions at the request of Tapan Audhya, Ph.D., Director of Research for the Health Diagnostics lab, for the benefit of physicians who may not be familiar with this panel. My suggestions for the interpretation of results of the panel are based on my study of the biochemistry involved, on my own experience with interpreting panel results as part of the analysis of a fairly large number of cases of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) over the past four years, and on discussion of some of the issues with Dr. Audhya. I am a researcher, not a licensed physician. Treatment decisions based on the results of applying this panel and its interpretation to individual cases are the responsibility of the treating physician.

Application: In addition to being useful in analyzing cases of ME/CFS, this panel can also be usefully applied to cases of autism and other disorders that involve abnormalities in glutathione, methylation and the folate metabolism.

The panel includes measurement of two forms of glutathione (reduced and oxidized), S-adenosylmethionine (SAMe), S-adenosylhomocysteine (SAH), adenosine, and seven folate derivatives.

According to Dr. Audhya (personal communication), the reference ranges shown on the lab reports for each of these metabolites were derived from measurements on at least 120 healthy male and female volunteer medical students from ages 20 to 40, non-smoking, and with no known chronic diseases. The reference ranges extend to plus and minus two standard deviations from the mean of these measurements.

Glutathione (reduced): This is a measurement of the concentration of the
chemically reduced (active) form of glutathione (abbreviated GSH) in the blood
plasma. The reference range is 3.8 to 5.5 micromoles per liter.

Glutathione plays many important roles in the biochemistry of the body, including serving as the basis of the antioxidant enzyme system, participating in the detoxication system, and supporting the cell-mediated immune response, all of which exhibit deficits in CFS. The level of GSH in the plasma is likely to be more reflective of tissue intracellular glutathione status than the more commonly and more easily measured red blood cell or (essentially equivalent) whole blood glutathione level, which is about three orders of magnitude greater, because red blood cells are normally net producers of glutathione. Also, knowledge of the level of the reduced form, as distinguished from total (reduced plus oxidized) glutathione, which is more commonly measured, is more diagnostic of the status of glutathione function.

In order to be able to approximate the in vivo level of reduced glutathione when blood samples must be shipped to a lab, it is necessary to include special enzyme inhibitors in the sample vials, and these are included in the test kit supplied by these two laboratories.

Most people with chronic fatigue syndrome (PWCs), but not all, are found to have values of GSH that are below the reference range*. This means that they are suffering from glutathione depletion. As they undergo treatment to lift the partial methylation cycle block, this value usually rises into the normal range over a period of a few months. I believe that this is very important, because
glutathione normally participates in the intracellular metabolism of vitamin B12, and if it is low, a functional deficiency of vitamin B12 results, and insufficient methylcobalamin is produced to support methionine synthase in the methylation cycle. In my view, this is the mechanism that causes the onset of ME/CFS. This functional deficiency is not detected in a conventional serum B12 test, but will produce elevated methylmalonate in a urine organic acids test. In my opinion, many of the abnormalities and symptoms in ME/CFS can be traced directly to glutathione depletion.

Anecdotal evidence suggests that PWCs who do not have glutathione depletion do have abnormalities in the function of one or more of the enzymes that make use of glutathione, i.e. the glutathione peroxidases and/or glutathione transferases. This may be due to genetic polymorphisms or DNA adducts on the genes that code for these enzymes, or in the case of some of the glutathione peroxidases, to a low selenium status.

Glutathione (oxidized): This is a measurement of the concentration
of the oxidized form of glutathione (abbreviated GSSG) in the blood
plasma. The reference range is 0.16 to 0.50 micromoles per liter.

Normally, oxidized glutathione in the cells is recycled back to reduced glutathione by glutathione reductase, an enzyme that requires vitamin B2 and NADPH. If this reaction is overwhelmed by oxidative stress, the cells export excess GSSG to the plasma. In some (but not all) PWCs, GSSG is elevated above the normal
range, and this represents oxidative stress. It is more common in CFS to see this level in the high-normal range. This value may increase slightly under initial treatment of a partial methylation cycle block.*

Ratio of Glutatione (reduced) to Glutathione (oxidized): This is not shown explicitly on the panel results, but can be calculated from them. It is a measure of the redox potential in the plasma, and reflects the state of the antioxidant system in the cells. The normal mean value is 14. PWCs often have a value slightly more than half this amount, indicating a state of glutathione depletion and oxidative stress. This ratio has been found to increase during treatment of a partial methylation cycle block, but other types of treatment may be necessary to bring it to normal.*

S-adenosymethionine (RBC): This is a measure of the concentration of S-adenosylmethionine (SAMe) in the red blood cells. The reference range is 221 to 256 micromoles per deciliter.

SAMe is produced in the methylation cycle and is the main supplier of methyl (CH3) groups for a large number of methylation reactions in the body, including the methylation of DNA and the biosynthesis of creatine, carnitine, phosphatidylcholine, coenzyme Q10, melatonin and epinephrine. This measurement is made in the red blood cells because the level there reflects an average over a longer time and is less vulnerable to fluctuations than is the plasma level of SAMe.

Most PWCs have values below the reference range, and treatment raises the value.* A low value for SAMe represents a low methylation capacity, and
in CFS, it usually appears to result from an inhibition or partial block of the enzyme methionine synthase in the methylation cycle. Many of the abnormalities in CFS can be tied to lack of sufficient methylation capacity.

S-adenosylhomocysteine (RBC): This is a measure of the
concentration of S-adenosylhomocysteine (SAH) in the red blood cells. The reference range is 38.0 to 49.0 micromoles per deciliter.

SAH is the product of the many methyltransferase reactions that utilize SAMe as a source of methyl groups. In CFS, its value ranges from below the reference range to above the reference range. Values appear to converge toward the reference range with treatment.

Sum of SAM and SAH: When the sum of SAM and SAH is below about 268
micromoles per deciliter, it appears to suggest the presence of
upregulating polymorphisms in the cystathionine beta synthase (CBS)
enzyme, though this may not be true in every case. For those considering following the Yasko treatment program, this may be useful information.

Ratio of SAM to SAH: A ratio less than about 4.5 represents low
methylation capacity. Both the concentration of SAM and the ratio of
concentrations of SAM to SAH are important in determining the
methylation capacity, because they affect the rates of the methyltransferase reactions.

Adenosine: This is a measure of the concentration of adenosine in the
blood plasma. The reference range is 16.8 to 21.4 x 10(-8) molar.

Adenosine is a product of the reaction that converts SAH to homocysteine. It is also exported to the plasma when mitochondria develop a low energy charge, so that ATP drops down to ADP, AMP, and eventually, adenosine. Adenosine in the plasma is normally broken down to inosine by the enzyme adenosine deaminase.

In some PWCs adenosine is found to be high, in some it is low, and in some it is in the reference range. I don't yet understand what controls the adenosine level in these patients, and I suspect that there is more than one factor involved. In most PWCs who started with abnormal values, the adenosine level appears to be moving into the reference range with methylation cycle treatment, but more data are needed.

5-CH3-THF: This is a measure of the concentration of 5L-methyl
tetrahydrofolate in the blood plasma. The reference range is 8.4 to 72.6 nanomoles per liter.

This form of folate is present in natural foods, and is normally the most abundant form of folate in the blood plasma. It is the form that serves as a reactant for the enzyme methionine synthase, and is thus the important form for the methylation cycle. It is also the only form of folate that normally can enter the brain. Its only known reactions are the methionine synthase reaction and reaction with the oxidant peroxynitrite.

When there is a partial block in methionine synthase, the other forms of folate continue to be converted to 5L-CH3-THF by the so-called methyl trap mechanism. Some of the 5L-CH3-THF is broken down by reaction with peroxynitrite, which results from the condition of oxidative stress that is usually concomitant with glutathione depletion.

Many PWCs have a low value of 5L-CH3-THF, consistent with a partial block in the methylation cycle. Most methylation treatment protocols include supplementation with 5L-CH3-THF, which is sold over-the-counter as Metafolin, FolaPro, or MethylMate B (trademarks), as well as the newer Quatrefolic (trademark) and in the prescription medical foods supplied by PamLab, including Deplin, CerefolinNAC and Metanx. There are some others on the market that include both racemic forms (5L and 5R) of this folate.

When methylation treatment is used, the level of 5-CH3-THF rises in nearly every PWC. If the concentration of 5-CH3-THF is within the reference range, but either SAM or the ratio of SAM to SAH is below the reference values, it suggests that there is a partial methylation cycle block and that it is caused by inavailability of sufficient bioactive B12, rather than inavailability of sufficient folate. A urine organic acids panel will show elevated methylmalonate if there is a functional deficiency of B12. I have seen this combination frequently, and I think it demonstrates that the functional deficiency of B12 is the immediate root cause of most cases of partial methylation cycle block. Usually glutathione is low in these cases, which is consistent with such a functional deficiency. As the activity of the methylation cycle becomes more normal, the demand for 5-CH3-THF will likely increase, so including it in the treatment protocol, even if not initially low, will likely be beneficial.

10-Formyl-THF: This is a measure of the concentration of 10-formyl
tetrahydrofolate in the blood plasma. The reference range is 1.5 to 8.2 nanomoles per liter.

This form of folate is involved in reactions to form purines, which form part of RNA and DNA as well as ATP. It is usually on the low side in PWCs, likely as a result of the methyl trap mechanism mentioned above. This deficiency is likely the reason for some elevation of mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) often seen in PWCs. This deficit may also impact replacement of cells lining the gut, as well as white blood cells.

Rarely, 10-formyl-THF is found to be much higher than the normal reference range. If this is found, the patient should be examined for cancer, since cancer cells upregulate this form of folate in order to make purines more rapidly to support their rapid cell division.

5-Formyl-THF: This is a measure of the concentration of 5-formyl
tetrahydrofolate (also called folinic acid) in the blood plasma. The reference range is 1.2 to 11.7 nanomoles per liter.

This form is not used directly as a substrate in one-carbon transfer reactions, but it can be converted into other forms of folate, and may serve as a buffer form of folate. Most but not all PWCs have a value on the low side. It is one of the
supplements in some methylation protocols. It can be converted to 5L-CH3-THF in the body by a series of three reactions, one of which requires NADPH, and it may also help to supply other forms of folate to the cells until the methionine synthase reaction comes up to more normal activity.

THF: This is a measure of the concentration of tetrahydrofolate in
the blood plasma. The reference range is 0.6 to 6.8 nanomoles per liter.

This is the fundamental chemically reduced form of folate from which several other reduced folate forms are synthesized, and thus serves as the hub of the folate metabolism. THF is also a product of the methionine synthase reaction, and participates in the reaction that converts formiminoglutamate (figlu) into glutamate in the metabolism of histidine. If figlu is found to be elevated in a urine organic acids panel, it usually indicates that THF is low. In PWCs it is lower than the mean normal value of 3.7 nanomoles per liter in most but not all PWCs.

Folic acid: This is a measure of the concentration of folic acid in
the blood plasma. The reference range is 8.9 to 24.6 nanomoles per liter.

Folic acid is a synthetic form of folate, not found in nature. It is added to food grains in the U.S. and some other countries in order to lower the incidence of neural tube birth defects, including spina bifida. It is the oxidized form of folate, and therefore has a long shelf life and is the most common commercial folate supplement. It is normally converted into THF by two sequential reactions catalyzed by dihydrofolate reductase (DHFR), using NADPH as the reductant. However, some people are not able to carry out this reaction well for genetic reasons, and PWCs may be depleted in NADPH, so folic acid is not the best supplemental form of folate for these people.

Low values suggest folic acid deficiency in the current diet. High values, especially in the presence of low values for THF, may be associated with inability to convert folic acid into reduced folate readily, such as because of a genetic polymorphism in the DHFR enzyme. They may also be due to high supplementation of folic acid.

Folinic acid (WB): This is a measure of the concentration of folinic acid in the whole blood. The reference range is 9.0 to 35.5 nanomoles per liter.

See comments on 5-formyl-THF above. Whole blood folinic acid usually tracks with the plasma 5-formyl-THF concentration. They are the same substance.

Folic acid (RBC): This is a measure of the concentration of folic acid in the red blood cells. The reference range is 400 to 1500 nanomoles per liter.

The red blood cells import folic acid when they are initially being formed, but during most of their lifetime, they do not normally import, export, or use it. They simply serve as reservoirs for it, giving it up when they are broken down.

Many PWCs have low values of this parameter. This can be caused by a low folic acid status in the diet over the previous few months, since the population of RBCs at any time has ages ranging from zero to about four months. However, in CFS it can also be caused by oxidative damage to the cell membranes, which allows folic acid to leak out of the cells. Dr. Audhya reports that treatment with omega-3 fatty acids has been found to raise this value over time in one cohort.

If anyone finds errors in the above suggestions, I would appreciate being notified at richvank@aol.com.

* Nathan, N., and Van Konynenburg, R.A., Treatment Study of Methylation Cycle Support in Patients with Chronic Fatigue Syndrome and Fibromyalgia, poster paper, 9th International IACFS/ME Conference, Reno, Nevada, March 12-15, 2009. (http://www.mecfs-vic.org.au/sites/w...Article-2009VanKonynenburg-TrtMethylStudy.pdf)
 

richvank

Senior Member
Messages
2,732
Hi, Xandoff and 7.

You both report positive tests for several viruses. You both report what sounds like inflammation in the spine (burning pain). We know from autopsies on M.E. patients that there is dorsal root inflammation in the spine. This all seems to fit together. Sounds to me like viral infection in the spine.

In the GD-MCB hypothesis that I have been working with since early 2007, the vicious circle mechanism that I suggest is at the core of the pathophysiology of ME/CFS has many deleterious effects on the body, one of which is to cause dysfunction of the immune system, and particularly the cell-mediated immune response, which is most necessary for combating viral infections and intracellular bacterial infections (including Chlamydia and mycoplasma). Part of this is the shift to the Th2 immune response, at the expense of the Th1 response. I think that it is necessary to lift the partial methylation cycle block and restore the folates and glutathione by a methylation treatment, and it may also be necessary to treat the infections directly. However, I don't think the immune system will be restored and be able to take over the job of combating and holding down the infections unless the methylation problem is corrected.

Best regards,

Rich
 

Seven7

Seven
Messages
3,444
Location
USA
Rich,

Thank you so much!!! I will bring it to Dr Rey so she can order me the tests! Very interesting that they are CFS specialist but ordered the Blood tests not the urine?!?

Here is their contact if you want to collect the name too.

Dr Irma Rey.
info@cfsclinic.com
305.595.4300
305.598.4155 fax


7
 

richvank

Senior Member
Messages
2,732
Rich,

Thank you so much!!! I will bring it to Dr Rey so she can order me the tests! Very interesting that they are CFS specialist but ordered the Blood tests not the urine?!?

Here is their contact if you want to collect the name too.

Dr Irma Rey.
info@cfsclinic.com
305.595.4300
305.598.4155 fax


7


Hi, 7.

I wish you success with that! I have not met Dr. Rey, but I should tell you that I have known Dr. Klimas for several years, and have tried to interest her in my hypothesis and suggested treatment for the past 5 years. Unfortunately, I don't think I've been successful in doing that yet. My most recent attempt was at the Ottawa IACFS/ME conference last September. Dr. Klimas was kind enough to hand me the mike and let me speak briefly, and she let me know that she knew what I was going to say, because she had heard it many times before, but again, I don't think she became a convert! :)-) I think I did win some other converts there, though, so maybe over time these things will become more accepted.

I understand that she does use high-dose B12, but I don't think she has been willing to add methylfolate so far. I think the hurdle is that there is no published randomized, double-blind, placebo-controlled clinical trial supporting this hypothesis and treatment. Physicians have to be careful about using treatments that are not supported by this type of documentation, because they work in a very controlled environment, having to satisfy the state medical licensing boards, the FDA, the insurance companies, and their colleagues in the medical profession who maintain the "standard of care." They need the support of their colleagues in case they have to face malpractice lawsuits. In addition, physicians are trained rather strictly in medical school to use prescription drugs, and they tend to stick to their early training. So I think I have some understanding of the barriers they face, and I don't blame them for being cautious, when they could lose their livelihood by alienating the powers that be.

There are some M.D.'s who become "integrative" or "alternative" or "functional" or "holistic" though, and try to incorporate the best of what works, whether it's a patented drug or not. Some state medical boards are more forgiving about this than others, and some of these docs have had to move to a different state to be able to continue to practice. In California, where I live, the state business and professions code actually includes provision for unlicensed alternative health care providers, and the state medical board doesn't seem to be as hard on the integrative docs as in some other states.

With regard to the urine methylmalonic acid test, it is offered by LabCorp as test no. 716365 and by Quest Diagnostics as test no. 16508. So it's available from the commercial labs that the physicians commonly use, but many of them don't understand the functional B12 deficiency or look for it. I should also note that in ME/CFS, if there is a deficiency in B6, B2, or biotin, which there often is, it can interfere with the methylmalonic acid test so that the results may not come out high enough to show the functional B12 deficiency. I prefer using a complete urine organic acids panel, such as the Genova Diagnostics Metabolic Analysis Profile, the Metametrix Organix profile, or the Great Plains Lab OAT, because these panels will show these deficiencies.

I'll be interested to hear what kind of a response you get from Dr. Rey.

Best regards,

Rich
 

Don Quichotte

Don Quichotte
Messages
97
Hi Rich,

I apologize for the time it took me to answer your post. I wanted to think more about it, and also was juggling with other things.

Well, I'm human, and I'm sure I have an ego, too, but I do try to focus on the objective.

That's what I meant.

As to placebo: there is nothing wrong (in my opinion) with an effective placebo effect. In fact, it would be great if we could treat everyone with an inert/safe agent instead of interfering with complex biological systems we really know very little about.

The problem with this in diseases like CFS is that many physicians equate "placebo" with an unreal effect (which in my opinion is not true) and therefore response to "placebo" is seen as proof of the un-realness of the illness.
I have seen serious management errors done in patients whose pain responded to placebo.
For some physicians response to placebo= no real disease and something faulty in the patient.
Many physicians (wrongly) believe that they would never respond to placebo. They also do not realize that response to placebo is a sign of physical and mental health and the body's ability to heal itself with relatively minor help.

The same problem is true for the tests you are using. As those are not yet accepted as diagnostic tests that correlate with the clinical illness, and in fact may be seen in many different conditions, correcting them with various supplements is not proof for anything.

Diagnostic tests in general are surrogate markers of a disease, and therefore have a given sensitivity (=how many patients with the disease will have a positive test) and specificity (=how many patients that do not have the disease will have a positive test). The tests you use have never been validated regarding their sensitivity nor specificity and therefore can't be used to diagnose the illness nor monitor the response to treatment.

Right. Note, though, that all three of these examples involved interaction of glutathione with chemotherapy agents.

The third example is not related to cancer but to replication of HCV.

Also, take into account that Methotrexate (an inhibitor of DHFR) is being used successfully for many years in the treatment of various autoimmune disease.
Leukovorin (folinic acid) is being used as rescue, when high doses of MTX are given.

This is why it is important to understand the pathophisiology of the illness, before intervening. (not that we always do that, and not that we don't make serious mistakes because we "stick" patients in the wrong "box" or fail to recognize specific polymorphisms or traits that make them have a paradoxical response to a certain commonly used pharmacological agent, and therefore cause more harm than good in our treatment).

So, I personally think, that in order to find effective (hopefully curative) treatment for CFS, we have to:

1. clearly define the clinical picture, and possibly stratify into different groups. ( I am not sure that CFS is one disease, I think it is more a "waste-basket" diagnosis for various diseases that lead to significant fatigability and physicians can't explain by their current understanding and knowledge/ diagnostic tests).

2. Search for an objective surrogate marker (this can be a physiological, biochemical, genetic or serological test), with a good sensitivity and specificity. (at least 80%) in each of those sub-groups. This is not essential, as take into account that there are well-recognized clinically diagnosed diseases (such as Parkinson's) for which no such test is available. Most diseases were initially described clinically and only later was a surrogate marker found.

3. Do small scale non-randomized studies (such as the one you did) while measuring those parameters (as well as subjective questionaires) before and after treatment.

4. Choose those interventions that seem most effective and do larger scale studies. When you have good parameters to follow you don't always need placebo, mostly if you are using non-pharmacological agents.

See this study for instance:

http://www.ncbi.nlm.nih.gov/pubmed/17064768

The disadvantage of physicians is that they have too many pre-conceptions based on what they have learned (some of which may be wrong) and their own experience. We know what is wrong with this patient and how it should be managed because we have seen 800 like him before. The fact that this specific patient has a rare polymorphism or variant of the illness we know so well, is hard for us to comprehend in a busy clinic day.

99/100 patients with low CO2 blood levels will have hyperventilation as the cause of this. There are numerous reasons for hyperventilation- sepsis, liver disease, anxiety etc. So, in the vast majority of the patients a clinician sees over his life-time, this will indeed be the reason. But, not in all!

In fact, clinicians are so narrow-minded regarding this, that I have seen a paper in which exercise testing was done in patients with mitochondrial myopathy showing markedly lower CO2 levels at peak exercise than would be expected. The interpretation of the authors was that they had a hyperventilatory response. As their minute venilation exceeded their metabolic needs.

But, when you look carefully at the results you see that their peak ventilation was 75% of that of normal subjects, so clearly not an hyperventilatory response. The authors of this paper had such fixed conceptions regarding the cause of low CO2 that they mixed cause and effect. They did not understand that the reason for the decreased ability to exercise was the inability of the muscles to utilize O2 delivered to them. The major source of blood CO2 is from muscles, so if the muscles produce less CO2 during exercise, you will have less blood CO2.
The breathing ability was also decreased (as the respiratory muscle had the same dysfunction) but the levels of CO2 produced were so low, that even with this diminished breathing capacity the patients had no CO2 retention.
Their dyspnea was not the result of central effect on the brain of high CO2 levels (as would happen in most cases) but the result of the inability of their muscles to perform the work of breathing.

You have the advantage of not being confused by such misconceptions. And therefore can much more easily see the (lack of) the emperor's clothes.

That is why I think your work is important.

Best,
 

Don Quichotte

Don Quichotte
Messages
97
The gluthathione depletion may have been "worth it" when my body was fighting the sledgehammer virus 26 years ago, but I am sceptical that it still is today.

You may be correct and may belong to those patients who will have a beneficial effect with this treatment.
 

richvank

Senior Member
Messages
2,732
Hi Rich,

***Hi, Don.

I apologize for the time it took me to answer your post. I wanted to think more about it, and also was juggling with other things.

***No problem. Me, too!

As to placebo: there is nothing wrong (in my opinion) with an effective placebo effect. In fact, it would be great if we could treat everyone with an inert/safe agent instead of interfering with complex biological systems we really know very little about.

The problem with this in diseases like CFS is that many physicians equate "placebo" with an unreal effect (which in my opinion is not true) and therefore response to "placebo" is seen as proof of the un-realness of the illness.
I have seen serious management errors done in patients whose pain responded to placebo.
For some physicians response to placebo= no real disease and something faulty in the patient.
Many physicians (wrongly) believe that they would never respond to placebo. They also do not realize that response to placebo is a sign of physical and mental health and the body's ability to heal itself with relatively minor help.

***I agree. The whole idea is to help people to recover their health, and the mind has a lot to do with how the body responds.
As a scientist, though, I would really like to understand how it all works, and I feel more confident in the possibility of being able to sort out the biochemistry than the workings of the mind, maybe sort of like the guy looking for the lost coin where there is more light! :)-) But I don't discount the value of an optimistic mind, and I think it's very important to encourage people and to help them to have hope.

The same problem is true for the tests you are using. As those are not yet accepted as diagnostic tests that correlate with the clinical illness, and in fact may be seen in many different conditions, correcting them with various supplements is not proof for anything.

***I agree. We have to watch to see if the person's response corresponds to the lab test improvements. And we really need to use objective tests for things like fatigue, cognition, pain, and sleep, rather than subjective ratings on a visual analog scale.

Diagnostic tests in general are surrogate markers of a disease, and therefore have a given sensitivity (=how many patients with the disease will have a positive test) and specificity (=how many patients that do not have the disease will have a positive test). The tests you use have never been validated regarding their sensitivity nor specificity and therefore can't be used to diagnose the illness nor monitor the response to treatment.

***I know that's true for the orthodox medical community at large, and I think I understand why. However, having seen probably more than 200 of the results from the methylation pathways panel myself, and having seen sequential test results for several people over time, I am forming my own opinion about at least the sensitivity of this panel, but I know that more formal testing with rigorous controls will be needed to even attempt to convince the medical community. But we have to start from where we are, and we are building up an informal experience base. There are quite a few physicians (integrative physicians) who are using this panel now. I know this because I hear it from a representative of the lab, and also because some of the physicians send the results to me for advice on interpretation. I don't have much information about selectivity, though, because the people who pay to have this test run usually have a pretty strong suspicion that they have ME/CFS,and most have been diagnosed already. So the sensitivity looks pretty good, in my opinion, but the selectivity is another matter, and I don't know much about that. I do know that the panel is used in autism, also, but in my opinion regressive autism and ME/CFS have mostly the same biochemical abnormalities. But I agree that there is much more that we need to do in this area.

The third example is not related to cancer but to replication of HCV.

***Right, but as I understood it, it did involve response to a drug treatment, in that case arsenic trioxide. It's clear that glutathione can interfere with some drug treatments, because it has a major role in removing toxins from the body, and the body views xenobiotic drugs as toxins. It's less clear to me that glutathione is a bad actor in a body that is not under treatment with drugs.

Also, take into account that Methotrexate (an inhibitor of DHFR) is being used successfully for many years in the treatment of various autoimmune disease.
Leukovorin (folinic acid) is being used as rescue, when high doses of MTX are given.

***Right. I, myself, was treated with 5-fluorouracil and leucovorin for colorectal cancer. And I also took lots of antioxidants, including NAC, which presumably supported my glutathione level during this treatment.

This is why it is important to understand the pathophisiology of the illness, before intervening. (not that we always do that, and not that we don't make serious mistakes because we "stick" patients in the wrong "box" or fail to recognize specific polymorphisms or traits that make them have a paradoxical response to a certain commonly used pharmacological agent, and therefore cause more harm than good in our treatment).

***I agree. That has been my main effort in ME/CFS, and one of the main goals of our informal treatment study was to shed light on the pathophysiology. The other one, of course, was to try to help some of Dr. Nathan's ME/CFS patients.

So, I personally think, that in order to find effective (hopefully curative) treatment for CFS, we have to:

1. clearly define the clinical picture, and possibly stratify into different groups. ( I am not sure that CFS is one disease, I think it is more a "waste-basket" diagnosis for various diseases that lead to significant fatigability and physicians can't explain by their current understanding and knowledge/ diagnostic tests).

***I agree about defining the clinical picture better. I think the case definitions have gotten better as successive ones have been developed, especially the two Canadian-led efforts.
As far as stratification or subgrouping goes, this has been a goal for some researchers for quite a while, at least since the Madison, Wisconsin conference in 2004. However, I don't think any of them know how to do it in a way that will be meaningful for promoting progress. Some have tried to do it by symptoms, but I don't think that has led to any real gains in understanding. It has also been attempted using gene expression, and again, I don't think that has helped much.

***My own opinion, based on my experience, is that there are different etiologies, with a common pathogenesis and pathophysiology. If you interview a few patients and consider their histories, I think you will have to come to the view that there are different etiologies. If you run the methylation pathways panel, I think the commonality in the results you will find points to a common pathophysiology. So I would classify myself as both a "splitter" and a "lumper" now.

***But I would agree that there are physicians who use ME/CFS as a wastebasket diagnosis. Dr. Byron Hyde in Canada has made a big point of this. He does a comprehensive diagnostic procedure with lots of tests (which many people cannot afford), and he identifies a variety of undiagnosed disorders in people who have been diagnosed with ME/CFS by other physicians. Of course, it isn't easy to diagnose some of these complex cases, and when a physician is allocated only a few minutes per patient by our current system of managed care, how can we expect him or her to do a perfect job of diagnosis? I spend many hours studying some cases. That's not something that is practical for a physician who has to function in the system we have.

2. Search for an objective surrogate marker (this can be a physiological, biochemical, genetic or serological test), with a good sensitivity and specificity. (at least 80%) in each of those sub-groups. This is not essential, as take into account that there are well-recognized clinically diagnosed diseases (such as Parkinson's) for which no such test is available. Most diseases were initially described clinically and only later was a surrogate marker found.

***A fairly reliable marker would certainly be a big help. A lot of effort is going into trying to find one that would fit into the current diagnostic paradigm in a cost-effective way. I agree that the methylation pathways panel has not been well-studied for sensitivity and selectivity, but if a patient meets that new international ME criteria and has a partial methylation cycle block, folate depletion and glutathione depletion on this panel, I would say that they are a "real one." Of course, I realize that my opinion about this is just that until and unless it is adequately tested and shown to be valid.

3. Do small scale non-randomized studies (such as the one you did) while measuring those parameters (as well as subjective questionaires) before and after treatment.

***Right.

4. Choose those interventions that seem most effective and do larger scale studies.

***Right.

When you have good parameters to follow you don't always need placebo, mostly if you are using non-pharmacological agents.

***I agree, but I have really reached a stone wall about this with quite a few of the "orthodox" physicians in the ME/CFS world. They have been thoroughly indoctrinated about "evidence-based medicine" by the FDA, backed up by Big Pharma, and without a placebo-controlled study, they basically tell me to "Have a nice day!"

See this study for instance:

http://www.ncbi.nlm.nih.gov/pubmed/17064768

***That looks like an interesting little study. Too bad the results didn't come out a little better, but it looks as though Co Q-10 does help some of these patients. I don't see any follow-up to this pilot study 5 years ago. It would probably be hard to get funding for a larger study, since Co Q-10 is not a patentable drug.

The disadvantage of physicians is that they have too many pre-conceptions based on what they have learned (some of which may be wrong) and their own experience. We know what is wrong with this patient and how it should be managed because we have seen 800 like him before. The fact that this specific patient has a rare polymorphism or variant of the illness we know so well, is hard for us to comprehend in a busy clinic day.

***That's certainly understandable. A general physician has to deal with everything from soup to nuts coming into the clinic, with only a small amount of time for each one. Memorizing patterns from experience is a way to cope. The zebras end up in the internet groups! :)-)

99/100 patients with low CO2 blood levels will have hyperventilation as the cause of this. There are numerous reasons for hyperventilation- sepsis, liver disease, anxiety etc. So, in the vast majority of the patients a clinician sees over his life-time, this will indeed be the reason. But, not in all!

***Right.

In fact, clinicians are so narrow-minded regarding this, that I have seen a paper in which exercise testing was done in patients with mitochondrial myopathy showing markedly lower CO2 levels at peak exercise than would be expected. The interpretation of the authors was that they had a hyperventilatory response. As their minute venilation exceeded their metabolic needs.

But, when you look carefully at the results you see that their peak ventilation was 75% of that of normal subjects, so clearly not an hyperventilatory response. The authors of this paper had such fixed conceptions regarding the cause of low CO2 that they mixed cause and effect. They did not understand that the reason for the decreased ability to exercise was the inability of the muscles to utilize O2 delivered to them. The major source of blood CO2 is from muscles, so if the muscles produce less CO2 during exercise, you will have less blood CO2.
The breathing ability was also decreased (as the respiratory muscle had the same dysfunction) but the levels of CO2 produced were so low, that even with this diminished breathing capacity the patients had no CO2 retention.
Their dyspnea was not the result of central effect on the brain of high CO2 levels (as would happen in most cases) but the result of the inability of their muscles to perform the work of breathing.

***I think that M.D. training necessarily involves a lot of memorization. Analytical thinking may receive less emphasis. An interview with Burt Berkson is interesting in this regard:

http://www.honestmedicine.com/2009/...k-and-our-medical-system-the-interview-t.html

You have the advantage of not being confused by such misconceptions. And therefore can much more easily see the (lack of) the emperor's clothes.

That is why I think your work is important.

***I appreciate your seeing it this way! Some others of my friends in the medical profession (I won't mention names) like to remind me that I also have some disadvantages! :)-) I do think both perspectives have some validity. I very much appreciate the interactions I continue to have with physicians, who have "hands and eyes-on" experience with a wide variety of disorders and diseases, which I don't have. But I agree that sometimes I can give things a "fresh look." My background is in engineering and the applied physical sciences. Things are done somewhat differently in those fields from what appears to go in in the biomedical field. Interacting with clinicians does tend to keep me from going too far off on a tangent, though.

Best,

***Thanks, and best to you, too.

***Rich
 

Gavman

Senior Member
Messages
316
Location
Sydney
The disadvantage of physicians is that they have too many pre-conceptions based on what they have learned (some of which may be wrong) and their own experience. We know what is wrong with this patient and how it should be managed because we have seen 800 like him before. The fact that this specific patient has a rare polymorphism or variant of the illness we know so well, is hard for us to comprehend in a busy clinic day.

Very much yes. I've seen naturopaths who swear going off dairy/sugar will fix everything with the liver. Or give kidney remedies for CFS, which seem to exacerbate the symptoms. It might work for plenty of people but not for everyone.

Placebo is such a scientists way of poo-pooing other peoples frame of reference.
 

Don Quichotte

Don Quichotte
Messages
97
After much thought I have reached the conclusion that the answer to the question- "where are we in treating and understanding ME/CFS today?" is about where we were in understanding leukemia and other malignant blood diseases in the 19th century.
It seems to me that the much better tools we have today can't lead to a leap in the understanding of this disease and we probably have to go through similar steps (albeit, I hope much faster).

I have tried to briefly summarize the history and current knowledge, so that you will understand what I mean.


[U]Insights from leukemia and other malignant blood diseases. [/U]

The term "leukemia" means "white blood" in greek. This condition was first described by Rudolf Virchow in the 19th century. This name was given because the patient's blood was much whiter than that of a normal person.
This illness was always fatal within days, weeks, months or years leading to acute or more insidious weakness, anemia, bleeding fever and eventually death. Neither its course or pathgenesis was understood, nor effective ways for treatments.

This as opposed to an illness with a similar course, but without such findings in the blood which was called "pernicious anemia"

In 1920, by serendipity (and an erroneous assumption) whipple showed that large amounts of liver ingestion could cure pernicious anemia in some patients. He decided to try this treatment based on improvement of anemia in dogs that were bled to simulate blood loss. It was only much later that it was found that the improvement in the dogs was due to iron and had nothing to do with the substance that cured pernicious anemia-vitamin B12.

Patients that did not respond to ingestion of the liver substance did respond to intramuscular injections of liver extract. Another physician showed that if he gave patients raw meat he himself partially ingested it could improve their illness, thus proving the existence of "intrinsic factor" in the gastric fluid-essential for the proper ingestion of B12 and missing in some patients.

It was only at a later stage that antibodies against this IF were discovered.
So, pernicious anemia, a fatal disease with severe hematological and systemic manifestations, was the result of nutritional and immunological factors. It could easily be treated by supplying this missing nutritional substance, without the need to take care of the underlying autoimmune cause. The vast majority of the patients have a dramatic response to vitamin B12 replacement with full or near full recovery from their illness even after many years.

Leukemia, on the other hand was found to respond to arsenic, and also in children to an anti-folate.

It was at a much later stage that different forms of leukemia were recognized based on the morphological appearance of the malignant cells under the microscope and then on various proteins they expressed on their cell surface.

Whereas one form of leukemia responds very well to inhibition of folate (an essential vitamin), another form responds to high doses of vitamin A.

Our understanding of leukemia and our ability to give effective treatments is rapidly growing with genetic studies and a deeper understanding of the underlying pathophysiology. But, we still rely on the clinical and morphological picture in order to diagnose the illness initially.

One type of leukemia (chronic myeloid leukemia) can be treated (and possibly even cured) by a medication based on this understanding. This specific leukemia is the result of one single gene translocation. Blocking this protein by an ingenious artificial molecule (called glivec) leads to complete disappearance of the malignant cells.

In other types of leukemia genetic analysis enables us now to stratify patients according to risk groups and tailor treatment accordingly. We have more and more targeted treatments which effect a single protein thus (hopefully) being more effective and causing less harm to normal cells.

At the same time the discovery of treatment for various nutritional related anemias, led to a new entity- refractory anemia-an anemia that does not respond to known treatments.
This was later found to be a pre-leukemic state which could last for years, with some patients never developing full blown leukemia.
Because of the abnormalities seen in the morphology of the cells, without overt malignant changes it was termed-myelodysplasia of the bone marrow. (MDS). Abnormalities of iron metabolism as well as mitochondrial damage were found important in the pathogenesis.
Genetic studies later revealed that in fact many genetic leukemic abnormalities were present in the cells of patients with MDS.

Interestingly, some of those patients seem to respond to nutritional interventions, at least to some extent. This is not surprising, as they involve mitochondrial abnormalities with energy-metabolism impairment, interconnected with epigenetic changes due to impairment of essential methylation enzymes. (There is a complex reciprocal relation between mitochondrial function and methylation leading to epigenetic changes and possibly later mutations). Yet treatment which impairs methylation is effective in some patients.

. Another type of chronic leukemia was recently found to receive protection from the microenviroment (=surrounding normal cells) of the bone marrow due to their supply of glutathione to the malignant cells (who have an impaired redox state). So, although alteration of the redox state is probably important in the initial pathophysiology of the illness, it later becomes important in the increased vulnerability of the malignant cells to treatment involving oxidative stress. Possibly antioxidants in the early stages of the disease (or before its development) could be beneficial, but this could becomes deleterious at later stages.

Chronic fatigue syndrome (and possibly other neurological conditions) is now in the state that leukemia and pernicious anemia were in the 19th century. We only (vaguely) know the clinical presentation of this disease. Quite likely, like leukemia, it is a heterogenous disease and therefore what may work in one group of patients can be detrimental in another even if they superficially seem to have the same illness.

For obvious reasons, diseases of the blood are much easier to study than diseases that have neurological manifestations. That is why, I believe, so much more progress has been made in their understanding and treatment.
Yet, due to this progress and dramatic improvement in cure rates, we also better understand the complexity of biological systems and the inevitable limitations of our knowledge and understanding.

We still have patients who despite all our knowledge and understanding are refractory to all our treatments. We still have patients in which we can achieve a good response and even remission, but know that sooner or later their disease will relapse.
Even in the more treatable forms of leukemia with the highest cure rates we still have patients whose disease becomes resistant to our commonly used treatments.

We constantly find more pathways we can block, and more sophisticated treatment approaches, but with all this we always have those patients whose illness doesn't fit our paradigm, due to some not yet defined polymorphism which affects the way they metabolize pharmacological agents or a rare variant of the malignant cells.
Such known and unknown polymorphisms can also be advantageous in other patients.

We still have (occasional) patients with a less common presentation of pernicious anemia which we miss and therefore don't give easy to administer highly effective treatment.

Patients with leukemia are also "advised" (by those who strongly believe in the psychosocial approach) to have a "positive approach" and avoid stress as this will increase their chance of cure.
I can't argue that for some patients taking this approach gives them a sense of control and makes them feel better. (Although for other is may a source of stress in itself, feeling that they are responsible for their lack of response to treatment).
But, I am quite sure (from my experience) that a "positive approach" has very little effect on the course of their illness. I have seen patients with a very positive attitude die from their illness and also patients with a very negative attitude (to the extent that the staff would joke that they "scared away" their illness) do very well.

Providing emotional support in my opinion is accepting the myriad of human emotions that patients experience and not trying to "convince" them to change their personality or pattern of behavior to suit their physician's needs.
I do not see various forms of emotional support as medical treatment. I see it as part of a supportive human relationship.

The causes of leukemia are also poorly understood. It is most likely a combination of genetic predisposition, exposure to environmental factors (which are probably much more significant in our industrialized world) and bad luck of the occurrence of a specific deleterious random mutation.

I think we fail to appreciate the importance of randomness and serendipity both in the pathopysiology of diseases and in the research which leads to their understanding and treatment. This is true for diseases in general, as it is for understanding the specific disease of one patient.

That is why we many times have to "shoot in the dark" or make intelligent guesses based on limited data and a lot of thought process. That is why we need to relentlessly seek the truth, fight for what we think is true, but at the same time be always ready to accept that we may have been wrong in our assumptions and take a different route.
That is why medicine requires a dynamic and collaborative thought process.
That is why someone looking with fresh eyes and with no previous misconceptions can have better insights many times and lead us in a route we didn't consider taking before.

I think we also put too little emphasis on the self-healing (physically and emotionally) abilities.
Many of our pharmacological agents are two-sided swords. We intervene in various biological processes we overall know very little about. Giving too little may not be enough to control the disease. Giving too much may impair normal function to the extent that we destruct normal repair and healing.

Too much for one patient can be too little for another. So, this is really a very hard balance to find.
Hopefully we will eventually have the ability to give individualized patient and disease tailored treatment, but we are still a long way from reaching this goal.
 

ahimsa

ahimsa_pdx on twitter
Messages
1,921
Don Quichotte said:
Providing emotional support in my opinion is accepting the myriad of human emotions that patients experience and not trying to "convince" them to change their personality or pattern of behavior to suit their physician's needs.
I do not see various forms of emotional support as medical treatment. I see it as part of a supportive human relationship.

This is such a long and complicated thread that I have not been able to read (much less understand!) all the posts here.

However, I wanted to highlight this lovely quote from Don Quichotte. I wish that all people--not just doctors but also family, friends, co-workers, neighbors--could feel this level of empathy. Patients who are going through a serious chronic illness need support and kindness.

Thanks so much for posting this.
 

Allyson

Senior Member
Messages
1,684
Location
Australia, Melbourne
Thanks so much Rich for the thoughtful analysis, and others for insight ful replies.
my experience after many years suffering and about 2 years trying treatments:
Taurine did nothing for me
I treid hair analysis and they did not diagnose or even suggest ME as a cause fo my then fatigue
tho th supps they gave me - Mg sinc etc helped a bit
Creatine is like a wonder drug for me and i dont think it has been mentioned that I could see above
tho IM B12 may be finally working now too after several months on it
i don t think you mentioned OI and I notice position makes a BIG difference to my condition
ie after lying down several days i am fine.... but anytime vertical makes me crash.
Thanks again