• David S. Bell, MD & Lyndonville, NY, 1985.
• Overview: Medical literature on CFS ...
• Conclusions: the immune response in ME/CFS.
• Criteria: the new pediatric diagnostic.

• Book: Neuro-Immune Fatigue, - 2007-08-22
• Book: Chronic Fatigue Syndrome & Fibromyalgia.
• Clonazepam (for) the “wired and frazzled”, Notes.
• Despair, Periods of .. progressive cognitive difficulties.
• Dorsal root ganglionitis: A personal history.
• Epinephrine and ..Propranolol.
• e-Book: Faces of CFS:, free - August, 2000.
• e-Book: Neuro-Immune Fatigue & Cellular Hypoxia.
• Enzyme: 2’-5’ A Synthetase and Rnase L.
• Frustration .. Acceptance .., Personal example.
• Group, Lyndonville Research, for kids.

• HHV-5 & ME/CFS: background, overview, ...
• Intnl Assoc for (CFS): Jan 7 thru 12, 2007
• Q&A, prions, sexual transmission ...
• Medicare, research, possibilities: Patient concerns.
• Mitochondrial diseases: Clinical Notes.
• Mitochondria, What are ?

• Newsletter Archive.
• Newsletter, Lyndonville, 2007-06-11.
• Newsletter, Lyndonville - 2008-02-23
  --- the 4th Japanese Fatigue Society Meetings.
• Newsletter, Lyndonville - 2009-07-23
  ---- Clinic changes/sale; Plans.
• Newsletter, Lyndonville - 2009-10-15
  ---- XMRV, and, The Whittemore-Peterson Institute

• Old-Timer’s Section .. the old joke about CFS.
• Overwhelmed .. generous sponsor.
• Oxidative phosphorylation: Literature Review.
• Propranolol's effect on POTS ... epinephrine.
• REFERENCES and XMRV.
• Success, John: The success of the human spirit.
• Teacher in the Lights, Guest Editorial.

• Testing: VO2 and anaerobic threshold.
• Test Relevancies.
• Test, Two-day Exercise: Review
• Test, 2 Day Exercise : note from a Patient.
• XMRV, an infectious gammaretrovirus.
• XMRV, as "The Puppet-master Virus".

Newsletter Archive, Lyndonville News - David S Bell
http://www.davidsbell.com/DSBNewsletters.htm

2008-06-26 Newsletter
http://www.davidsbell.com/lynnewsv4n1.htm

Web page version:
http://www.davidsbell.com/LynNewsV5N3.htm

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http://www.davidsbell.com/PrintLynNewsV5N3.htm

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2008-06-15 Newsletter
http://www.davidsbell.com/PrintLynNewsV5N3.htm

David S. Bell, MD graduated from Harvard College in 1967 with an AB degree in English literature followed by Boston University with an MD degree in 1971. Post doctoral training in pediatrics was completed in 1976 with subspecialty training in Pediatric Behavior and Developmental Disorders. In 1978 he began work at the University of Rochester but soon began a private practice in the town of Lyndonville, New York.

In 1985 nearly 220 persons became ill with an illness subsequently called chronic fatigue syndrome in the communities surrounding Lyndonville, New York. This illness cluster began a study of the illness which continues today. Dr. Bell is the author or co-author of numerous scientific papers on CFS, and, in 2003 was named Chairman of the Advisory Committee for Chronic Fatigue Syndrome of the Department of Health and Human Services. Publications include A Disease of A Thousand Names, (1988) and The Doctor’s Guide to Chronic Fatigue Syndrome, (1990). A comprehensive review of CFS is currently being written and is hoped to be published in 2005.

Dr. Bell currently practices general medicine in Lyndonville, New York with his wife Nancy, a family nurse practitioner. Roughly half of the patients seen in the practice suffer from chronic fatigue syndrome, fibromyalgia, orthostatic intolerance, and/or myalgic encephalomyelitis.

The medical literature on chronic fatigue syndrome and fibromyalgia has exploded in recent years, but in the process it has become bulky and difficult to follow. Meanwhile, the decreased public attention paid to CFS/FM/ME has led patients to feel abandoned and isolated, particularly since most medical providers are not familiar with the newer developments. Some patients may feel that there is even a worsening of the medical climate with increased disdain and neglect for their illness. It is my hope that the near future will bring dramatic changes to this climate. This newsletter is an attempt to increase awareness of CFS and FM through information that is based upon current medical literature.

This web site is not a commercial venture to make money.
No products will be sold here, and I will not endorse any products. We are not soliciting patients for our medical practice, and would discourage persons from coming. I currently follow many hundreds of patients with CFS/FM, and if I ever find a simple cure for them I will publish it away in the Lyndonville News. But CFS/FM/ME is a complex and difficult illness, and I would not advise people to hold their breath for the simple cure. It will take time and steady progress.

I am convinced that chronic fatigue syndrome and fibromyalgia are treatable illnesses that can be managed successfully. I believe that the medical profession will rise to the task of addressing this illness properly. I also feel that there will be treatments in the future that will completely reverse the symptoms. I hope that the Lyndonville News will be of value to the community of those interested in CFS/FM/ME.

Faces of CFS:, free e-book
http://www.davidsbell.com/Faces_of_CFS.pdf
229 pages in .pdf, narrow page width easy read
August 15, 2000
Autobiography of a doctor treating a local CFS-ME outbreak.

... a bit of a summary of the conference of the International Association for Chronic Fatigue Syndrome (IACFS) held January 7 thru 12, hosted by P.A.N.D.O.R.A.

One presentation was the Miami erythropoietin trial. Good news and bad.
First, 70% of ME/CFS patients have a low red blood cell volume. This was an NIH funded trial and solidifies the finding for use in the laboratory evaluation.

The bad news is that treatment, while it brought the RBC volume up to normal, it did not help the symptoms very much. Some help to the orthostatic symptoms, but not fatigue. The meaning of this for me is what we have been leaning toward. The low blood volume contributes to orthostasis and treatment of that is helpful, but is not the prime target. ...

Some persons clearly have persistence of virus in their brain, particularly Epstein-Barr virus and human herpes virus-6, and treating those viruses with the right drug may be very (very, very) helpful. There is a new project starting in California that intends to find out just how many persons with ME/CFS have this virus.

But here’s the problem (there is always a problem).
Our local lab, and most others are hopeless when it comes to measuring for these viruses accurately. They are so bad it is not even worth doing. The good labs require cash for the testing, and it is unlikely that your insurance will cover the test at all. You would be able to deduct the cost of the test from your taxes at the end of the year, but the money has to go with the sample.

This makes finding out who should be treated with the antivirals virtually impossible. Go figure, you spend $7,000 a year for medical insurance but can’t get the tests that are likely to be of help.

Lots of discussion of cellular hypoxia.
This is the issue of oxygen being delivered to the cells of the heart, brain, skeletal muscles and other organs, but the process of turning the oxygen into energy is derailed. Mitochondrial, metabolic, cellular, glutathione, nitric oxide…. we don’t even know what to call this area yet. ...

The doctor-to-doctor session had a lively discussion of saline infusions, replacement of androgen and estrogen, sleep medications, environmental testing and other management issues. Very interesting, and practical. ...

The issue, of course, has been the need for patients to “prove” their disability to social security and private disability companies in order to receive benefits. In the old days, health care providers could write a letter saying that their patient was disabled but this no longer matters. Many health care providers have not spent years of research in CFS, and, while they know their patients, do not know how to prove the disability. Medical insurance companies will not pay for unusual laboratory testing such as the 2’5’A, and RNase L assays. Disability Companies disregard the results anyway because of complex arguments. This test-retest exercise test has potential for circumventing the whole debate. ...

Q&A Page

There is no doubt that inoculations can set off the process.
These shots are designed to stimulate the immune system in a way that can prevent a future infection with something like a strain of the flu virus. Therefore it is just like getting that particular flu virus strain and thus can set off the process. The vaccine that I have seen causing the greatest problem is the Hepatitis B. Maybe that is a coincidence, ...

... Because it has been ignored for so long, we really do not know if there is an increased incidence of this illness. If there is, I like the idea of a two hit process. It would go like this. Hit #1 would be silent, either with an infectious agent, a new agent, or a toxin. By itself it does not do anything but sets the stage for hit #2 which would be the standard infection. Because of the silent first hit, the second hit causes ME/CFS.

I have never systematically looked for lifetime vegans with ME/CFS.
You question is really about the possibility that the illness may be a prion disease. To my knowledge no one has looked at this in any detail. I would be interested to hear from any reader who has any information about this. The known prion diseases are neurologic illnesses that are fatal. It may be that there are variations not yet understood that are not fatal.

The question is whether ME/CFS can be transmitted sexually.
The question cannot be answered because we do not know the specific agent that has initiated ME/CFS in a specific individual. It is likely that some known sexually transmitted illnesses can initiate ME/CFS. (Remember, the illness is more often a post-infectious phenomenon rather than due to a specific infection) However ME/CFS clearly may occur in persons who have never had sexual exposure. One “outbreak” many years ago occurred in a convent.

... Take the separation of CFS from fibromyalgia (FM) for example.
In the early eighties they were considered two distinct illnesses. FM was seen by the rheumatologists and CFS was seen by the infectious disease specialists. But when the studies started coming in, the Epstein-Barr virus titers did not help to separate them into different groups, nor did the immunology, nor even the symptom pattern as it all crossed the lines. Now it seems that both the pain of FM and the exhaustion of CFS are due to the autonomic nervous system. One of the reasons that the work of Dr. Spence and colleagues is so valuable is that they may have come across a clear physiologic difference between FM and CFS.

2007-03-06 Newsletter
http://www.davidsbell.com/lynnewsv4n1.htm
International Association for Chronic Fatigue Syndrome (IACFS)
http://elog.rttr3.com/

Well, it is another new year. Happy new year everyone, and I hope that your holidays were enjoyable. This issue of the Lyndonville News is a bit of a summary of the conference of the International Association for Chronic Fatigue Syndrome (IACFS) held January 7 thru 12, hosted by P.A.N.D.O.R.A. More detailed and balanced summaries will be in the IACFS newsletter. ...

Conference Reports – overview

The conference was perhaps the best ever. As before, there were two parts, a patient-oriented part and a scientific part. Both were superb. For those patients who were there, they will probably have a difficult next month trying to recover and process what they experienced, but it should turn out to be worth it in the long run.

The science is getting better and better.
... Miami erythropoietin trial.
Good news and bad. First, 70% of ME/CFS patients have a low red blood cell volume. This was an NIH funded trial and solidifies the finding for use in the laboratory evaluation. The bad news is that treatment, while it brought the RBC volume up to normal, it did not help the symptoms very much. Some help to the orthostatic symptoms, but not fatigue. The meaning of this for me is what we have been leaning toward. The low blood volume contributes to orthostasis and treatment of that is helpful, but is not the prime target.

Some persons clearly have persistence of virus in their brain, particularly Epstein-Barr virus and human herpes virus-6, and treating those viruses with the right drug may be very (very, very) helpful. There is a new project starting in California that intends to find out just how many persons with ME/CFS have this virus. But here’s the problem (there is always a problem). Our local lab, and most others are hopeless when it comes to measuring for these viruses accurately. They are so bad it is not even worth doing.

The good labs require cash for the testing, and it is unlikely that your insurance will cover the test at all. You would be able to deduct the cost of the test from your taxes at the end of the year, but the money has to go with the sample. This makes finding out who should be treated with the antivirals virtually impossible. Go figure, you spend $7,000 a year for medical insurance but can’t get the tests that are likely to be of help.

Lots of discussion of cellular hypoxia.
This is the issue of oxygen being delivered to the cells of the heart, brain, skeletal muscles and other organs, but the process of turning the oxygen into energy is derailed. Mitochondrial, metabolic, cellular, glutathione, nitric oxide... we don’t even know what to call this area yet. A complicated subject, and one that I would like to explore in greater detail in the office, but again, the testing requires cash up front for the laboratory tests. This is still quite new, and treatment aspects may not be ready for prime time.

Dr. Paul Cheney gave a superb lecture on “Functional Hypoxia” as the keynote speaker of the patient banquet, but it may have been a little over the heads of the worn out, CFS-drained patient brains trying to eat dinner. It is my hope to attempt to translate this talk at some time in the near future.

Lots of very good talks on measuring different
neuro metabolites and metabolic break down products in both ME/CFS and fibromyalgia. Tests of genes in the spinal fluid, lactate in the brain, holes in the heart, spectroscopic blips on serum samples. Good science which adds to our understanding, but not ready to become a simple test. Hang in there for another two to thirty years.

New pediatric diagnostic criteria. Very exciting.
We now have an instrument that will be able to diagnose ME/CFS in children and adolescents. The instrument will be posted on the IACFS web site, and we will have it freely available in our office. Right now we are collecting data from all over the world. Next step is to publish in a good pediatric journal and make these criteria official. This is a very good science-based advance in the ability to correctly diagnose children and adolescents with ME/CFS (see Advocacy section).

The doctor-to-doctor session had a lively discussion of saline infusions, replacement of androgen and estrogen, sleep medications, environmental testing and other management issues. Very interesting, and practical.

History

In this conference, Staci Stevens, Dr. Mark Van Ness, Dr. Chrisopher Snell, Peg Ciccolella, and their group presented their test-retest exercise paper summarizing the results in six patients. I am including this summary in the history section of the newsletter because I believe that it is history in the making. It is the first time a clear proof of physical impairment has ever been presented to circumvent the controversy. For this reason I would like to describe it in a little more detail.

Peak oxygen consumption, percentage of predicted heart rate, and oxygen consumption at anaerobic threshold were measured on two consecutive days in 6 CFS patients and 6 sedentary control subjects and compared to accepted normal data. As expected, data for CFS patients and control subjects were not significantly different for the first day exercise test, consistent with previously published studies.

However, on the day 2 exercise test, CFS patients had significantly lower VO2 peak, and at anaerobic threshold. VO2 peak: controls 28.9 +/-8.0 ml/kg/min vs CFS: 20.5 +/- 1.8 ml/kg/min; Anaerobic threshold: controls: 18.0 +/- 5.2 ml/kg/min and CFS patients: 11.0 +/- 3.4 ml/kg/min.

Normal persons should have less than 8% variability in test-retest within 24 hours, and the sedentary controls demonstrated this low variability. However the drop on peak VO2 and anaerobic threshold was substantial, in the range of 38%. These changes in day 2 exercise testing suggest a significant and verifiable physical abnormality in CFS patients, essentially verifying the symptom of post-exertional malaise.

The issue, of course, has been the need for patients to “prove” their disability to social security and private disability companies in order to receive benefits. In the old days, health care providers could write a letter saying that their patient was disabled but this no longer matters. Many health care providers have not spent years of research in CFS, and, while they know their patients, do not know how to prove the disability. Medical insurance companies will not pay for unusual laboratory testing such as the 2’5’A, and RNase L assays. Disability Companies disregard the results anyway because of complex arguments. This test-retest exercise test has potential for circumventing the whole debate.

First the test is 100% objective.
It does not rely of patients complaints, what disability insurance companies call “moans and groans”. Effort can be assessed and CFS subjects can be shown to give adequate effort. The results are showing a marked drop in the anaerobic threshold. This is the level that cells convert from oxygen metabolism to anaerobic (no oxygen) metabolism. Normal, lazy, and crazy persons cannot affect their anaerobic threshold. But persons with ME/CFS have a demonstrable defect, probably in the area of energy generation in the mitochondria of individual cells.

There will be more of this over the next few years, as it could help define subgroups, and may point to severity and prognosis. In my opinion, disability companies have cancelled disability payments for thousands of persons who they claim are only “faking” disability. I know one disabled mother who lived in the back of a Chevrolet. Now we can prove that the disability of ME/CFS is very real.

A note of caution. The test on the second day makes people feel quite ill. We will be attempting some methods of making the recovery more comfortable for patients with severe illness.

Advocacy

It is my hope that some energy will be spent on testing and encouraging the new pediatric diagnostic criteria. To this end I would be willing to speak at gatherings of school nurses or school physicians, such as an annual state educational meeting. One way to reach pediatricians is through practical application of these criteria in children or adolescents who are having difficulty attending school.

If you have a child or adolescent in this position, you might be able to help arrange an educational meeting via the school nurse at your school. If I could not do such a lecture, I can communicate to the other members of our committee that developed the criteria. If there are proposals to do such a lecture, please call Debbie at 585-765-2060.

At any rate, I am working toward retirement and plan to cut down soon. I would like to write like mad and get all this out of my system. And spend more time with my feet up on the back porch of the farm. I would like to do more newsletters. I would like to give more talks about the mechanisms of the illness. Hopes and dreams. I do hope the chapter makes some sense.

Neuro-Immune Fatigue and Cellular Hypoxia
file:///C:/A-5-Health/CD-Health-General/CFS-Me/
Book-Hypoxia-DavidBell-2007-06.htm

Unfortunately for me, the body seems to love cascades.
Moreover, we do not understand the specific waterfall steps of the immune system cascade perfectly. Add to that, each step can go in different directions – the immune system talks to the nervous system, and the nervous system regulates the endocrine system, and so on. But the cascade creates a redundancy or safety net which makes it less disastrous if something goes wrong.

And of course, with every step something can go wrong.
In the blood clotting cascade, if one enzyme or protein is missing the result is hemophilia A. With another error it is delta granule storage disease; another is Von Willebrand’s disease. They may look similar from the symptoms – a cut does not stop bleeding – but the mechanism that has gone wrong in the cascade is different in each illness. In ME/CFS there is a problem, or there are problems, with the immune activation cascade. The end result of this problem or these problems is the symptom complex of ME/CFS. ...

In the first chapter of this section we discussed the evidence pointing to certain infections causing ME/CFS. The next question is how do these infections cause the prolonged symptoms, and for some, the flu that never ends. The answer to this question involves the immune mechanism set off by the infection, and specifically the abnormal immune mechanism that allows for persistence of symptoms even after the obvious infection has gone away. ..

In the second chapter we discussed the non-infectious causes of ME/CFS, and that there is a variation in these pathways from the cascade initiated by a standard infection. Yet many of the same cytokines are involved, and ultimately that all these cascades (which result in ME/CFS) come to a common point.

The confusion regarding ME/CFS and the one thousand or so other illnesses loosely contained under this umbrella term is that both sides are correct. ME/CFS is caused by an infection, and is caused by neurological insults other than direct or obvious infection. Perhaps in the future we will be able to classify all one thousand subtypes more accurately, but for now ME/CFS will have to do. It appears that this common point where the cascades merge is in the area of cellular metabolism, more specifically the inability of converting oxygen into energy, or cellular hypoxia. In this chapter we will be looking primarily at the immune mechanism (or abnormal immune mechanism) following an infectious insult; we will be ignoring the ME/CFS caused by toxic exposure, brain injury, heavy metal poisoning, cigatura poisoning, and the like as it is likely that the cascade will be different.

In the early days of ME/CFS research in the US, emphasis rested upon looking at the Epstein-Barr virus as the cause to the immune activation that seemed to be the hallmark of the illness. The name Chronic Fatigue Immune Dysfunction Syndrome (CFIDS) dates from this time and remains accurate as a name for some types of this illness. However, most patients assumed that this meant that patients with ME/CFS had an “under-active” immune illness response, an immune deficiency. The dominant aspect is just the opposite, an over-active immune state. ME/CFS is a condition where the immune system is spinning its tires in the sand, getting really tired and going nowhere.

There are some immune deficiencies in ME/CFS, which some scientist/clinicians like Dr. Nancy Klimas and Dr. Roberto Petarca have been studying for years. The natural killer cells are off both in number and function, and some cellular immune responses are delayed. The arguments raging in the literature about the usefulness of these studies relate to which particular subgroups are being studied. The immune deficiencies may be the critical issue if they turn out to cause persistent infection and the resulting immune over-reaction. For now, let us turn our attention to the cytokine cascade activated by the initiating infection. ...

The production of these cytokines, (specifically interferon, IL-1, IL-6, and TNF) is known to cause the symptoms of illness, often called “acute sickness behavior.” This term does not imply that there is anything artificial or psychological about the behavior, it is as real as limping behavior in a person with a broken leg. These effects of cytokines were discovered during trials where the cytokines were given to healthy volunteers who then developed fever and other symptoms.

In ME/CFS something goes wrong.
The infection may be an ordinary “garden variety” virus, an enterovirus, or the Epstein-Barr virus of mononucleosis. But in a person with the genetic vulnerability the process does not shut down and the flu-like sensation persists for months, years, sometimes for the rest of his or her life. It is this abnormal mechanism that is the center of attention in ME/CFS.

The symptoms caused by cytokines differ from “end organ” symptoms. For example, weakness is a common symptom in ME/CFS, but muscle testing with electrodes does not indicate muscle fiber disease. Characteristically, the sensation of profound weakness is experienced by those persons given cytokine injections despite normal muscles.

Confusion and problems with memory and attention are symptoms caused by cytokines and in experimental subjects, when the cytokine wears off these cognitive symptoms resolve without damage to brain cells (presumably). It is precisely because these symptoms are not caused by diseases of muscle or joint that medical providers have ignored them. If you go to the doctor with a cough caused by the flu you are patted on the head and ignored, unless you cough up gobs of lung tissue. Then it is taken a little more seriously. ...

A published example of a cytokine storm occurred in healthy volunteers given an experimental drug (Sunthralingam, 2006). The drug was an antibody whose function was to stimulate T cells, which, it turns out, it did too well. The subjects were healthy volunteers and the drug caused a cytokine cascade involving many different cytokines, including tumor necrosis factor alpha, gamma interferon and several interleukins.

The healthy volunteers all became very ill and had to be admitted to an intensive care unit. The importance of this disastrous trial was to show the progression of a cytokine storm precipitated by a specific monoclonal antibody in previously healthy persons. In medical school I used to volunteer for these kinds of trials because I was broke.

There are many different cytokine cascades.
Variations in ME/CFS may relate to variations in individual cascades, which are just now beginning to be studied. But the essential point has been established. Cytokine cascades cause symptoms and illness. ...

Enzyme: 2’-5’ A Synthetase and Rnase L

This is the next step in the process that was started by Suhadolnik and his group around 1995 and continues actively at the present time. An enzyme called 2’-5’A Synthetase is normally stimulated by the cytokine interferon to make Rnase L, an enzyme that can “chew up” viral RNA. Therefore it is part of the normal anti-viral defense system. In ME/CFS there is a glitch present with an abnormal protein present (the 37kDa fragment) in those most severely affected by the illness.

There are three ways that an abnormality in this system may cause problems in ME/CFS. First it allows for the continuous stimulation and production of interferon which, as we will see, could be a major player in the symptoms of the illness. Secondly, it may permit the persistence of the initiating infection. And thirdly, an excess of Rnase L can cause other difficulties down the road, because its actions are not limited to viral RNA. It may be chewing up good RNA as well. In a follow-up study it was noted that 72% of patients had an excess of the abnormal protein in ME/CFS while only 1% of the normal population had it. ..

... a word about medications that increase serotonin, commonly known as “antidepressants.” It is known that blockade of at least one serotonin receptor will reduce several cytokines including tumor necrosis factor, and some of the interleukins. Reduction in pain for some persons with ME/CFS may be a side effect of these medications, and not due to the “antidepressant” effects. ...

Conclusions: the immune response in ME/CFS

There are several conclusions from the studies concerning the immune response in ME/CFS.

1) Persons with ME/CFS have persistent immune activation as if there were a persistent infection going on. More technically, there is an abnormal shift of the immune response to Th2 instead of the normal balance between Th1 and Th2.

2) There is a persistence of cytokine secretion that is likely responsible for the persistence of ME/CFS symptoms.

3) The symptoms of ME/CFS can be temporarily reproduced by injections of cytokines such as interferon and interleukins.

4) ME/CFS can be caused by treating a patient with Hepatitis C with interferon.

Question and Answer

.. The periods of despair that persons with this illness experience are beyond description. I apologize for the article of cerebral atrophy and progressive cognitive difficulties, but unfortunately they are true findings for some with the illness. ... Is there any hope? Absolutely yes. And it is not a false hope. I remain convinced that the problems with this illness are reversible, and someday we will find them.

.. It seems to strike out of nowhere.
I have a number of professional athletes as patients and they were in the peak of health when they got sick. But where does a strep throat come from? Before we understood about germs we considered “evil humors” as the cause. Someday we will understand exactly the genetic predispositions, the triggering factors and the reasons the illness is sustained. ...

Clinical Notes – Frustration

The other day I saw a patient in the office who was in desperate circumstances because of ME/CFS. She was alone as her husband decided there was more fun elsewhere. The social security appeal has been pending for a couple of years after the initial denial. A neighbor will buy a few groceries every once in a while. The simple activities of daily living are not simple at all: a shower is a difficult task, requiring a chair. She has no primary care.

Meanwhile in the office I get notes from specialists saying that some counseling might be of value, and that she should start an exercise program with daily walking. A consultant recently said to me, “After all, exercise is the only known cure for chronic fatigue syndrome.”

Persons with ME/CFS are known to have abnormal MRI scans of the brain, and because of the sometimes severe cognitive symptoms an MRI is an important test. But to get an MRI, the medical provider must go through the pre-authorization process: discussion with a low level employee to justify the test. The employee probably gets an incentive to deny the tests. We live in an era of health care rationing by nuisance. Because the hurdles are such a nuisance for the provider they say “to hell with it.” As for the patient with ME/CFS, the insurance companies say, “To hell with them.” If they only knew…

But before we get so depressed we all go and jump off a bridge, there is a bright side. Sometimes the fight against all odds makes a person stronger. It can do something to the soul, whatever that is.

Fifteen years ago I had a patient just like the one mentioned above.
She was sick and scared, and alone, and depressed. But over ten years she became a different person. She decided that life was better without her worthless husband. She lived on peanut butter for a couple of years but eventually got social security so that her most basic needs were met – she had a roof over her head and food on the table.

She learned to accept the limitations of her illness, and, most importantly, that the illness was not her fault. She learned to manage her time so that within each day she had one to two hours of activity where she could get something done. And she became grateful for those two hours. She lived patience for the remainder of the day. She even learned meditation and yoga to clear her cluttered mind. Anger and resentment melted away. She recently said to me the only people who understand the story of Job in the Bible are those persons who have lived it.

It has been fifteen years and I would not wish her illness on anyone, not even the medical skeptics who ridicule persons with this illness. But, despite the odds, this person has become happy in a way that I have not seen happen to my able bodied patients. There are truths hidden in the religious teachings of the world, but she is one of the few who has come to learn them. ..

2007-08-22 - Neuro-Immune Fatigue, book
Well, the book is finished. And it carries the awkward title of Cellular Hypoxia in Neuro-Immune Fatigue. Don’t panic. While this is a somewhat intimidating title, I hope that by reading it, persons interested in FM/CFS/ME will get a picture of where the science is leading in the past few years. It may seem like a jump, but we are all a little beyond the standard description of symptoms.

It is not a book for rookies and has little introductory material, meaning that it should not be given to aunt Tille who needs to learn about CFS. It is a small book, only 120 pages, but I hope that by leaving out tons of scientific detail, the concepts about what takes place inside the cell may become clear. It describes a theory that fibromyalgia and ME/CFS are parts of a spectrum of illnesses, called here Neuro-Immune Fatigue, and that the common end pathway of these illnesses is a dysregulation of cellular metabolism leading to the inability of the cell’s mitochondria to utilize oxygen.

Lost already? I have tried in this book to make these concepts as reader friendly as possible. And the material is not new. Drs Martin Pall and Paul Cheney and others have been talking about this for years. I do think that the whole confusing conglomeration of ME, CFS, chemical sensitivities, fibromyalgia, orthostatic intolerance, chronic Lyme disease is ready to be understood with the science we have today. If no one should ever buy this book, I will be content. I really wrote it to sort out my own thinking on the subject. And in the process I hope this will be useful to others. My life’s dream will be fulfilled if it helps scientists and clinicians make the next step in what I perceive to be the direction the research is heading. For those of you who are interested, in past issues of the Lyndonville News a few first drafts of chapters were presented.
(Available free at :
http://www.davidsbell.com/DSBNewsletters.htm

So, if you really want to buy this book, send me a check for $25 to
1276 Waterport Road, Waterport, NY 14571,
and I will mail you a copy within a day or so.
The science is now coming in fast and furious, and at the very least this short book will serve as an introduction to the complex new science of cellular energetics. For those of you who purchase the book, I would be eager to hear your comments and suggestions at lynnews@davidsbell.com

On The Farm

A number of you wrote with surprise or dismay about my coming retirement, where I would be able to gaze out the back porch to the fields of hay being baled now as we talk. I appreciate the warm thoughts that are expressed, but I do not think it is time for alarm. I plan to close my regular practice, but hopefully continue to see patients with ME/CFS, and even explore new treatments. But it is time to write. I don’t know whether it will be good writing, nor do I know if it will be effective. It is also time to dive into the mechanisms of cellular energy production. I am interested in any thoughts as to how to distribute the information. Here are a few ideas of projects.

I am beginning work on a very short book entitled Chronic Fatigue Syndrome and Fibromyalgia: A Short Treatment Guide for the Primary Care Provider. This book is short (around 50 pages) and reader friendly, designed to be given to a primary care provider respectfully by a patient with ME/CFS or fibromyalgia in order to communicate in a simple and direct way some of the treatment approaches that experienced clinicians have put in place for some years now. The approaches will not be just my own, I hope to discuss and interview many of the foremost clinicians for their ideas on such subjects. I hope to have it written in six months or so. Another book that I hope to write is a re-write of the Doctor’s Guide to Chronic Fatigue Syndrome. I can’t believe that that book is twenty years old.

Clonazepam (for) the “wired and frazzled”,
Clinical Notes

The clinical notes for this newsletter is kindly suggested by a reader who sent information to the website. It is extraordinary how much knowledge and information is available, and really needs to be collected and presented. It is because of this that I would like to re-organize the research group (see below).

For years I have said that clonazepam is perhaps the most useful medication in ME/CFS, and because of the notes of a reader, I now understand why. Clonazepam is a medication distantly in the anti-seizure and benzodiazepine class. I say distantly because it is different from Xanax™ or Valium™. Clonazepam has a long duration of action, and is more gentle. It has no euphoria and I have never seen anyone become addicted to it. In some patients and in the right dose it improves the symptoms of ME/CFS, particularly sleep and general malaise; for some, it increases energy and activity.

The effect in reducing fatigue has always been confusing, as it is a medication that should cause tiredness. Persons with ME/CFS should not be able to tolerate it. There are two broad categories of ME/CFS; one is the “heavy as a log” tiredness where it is easy to fall asleep, and persons drink coffee to stay awake. This type of CFS is milder, and relatively easy to treat. Clonazepam does not help in this type. The second type is the “wired and frazzled” where despite exhaustion, persons cannot sleep and they are unable to take any stimulants. Clonazepam can help in this type and it is not because of the simple explanation of anxiety. This type of ME/CFS is neuro-excitatory, and it may be that the benefit is related to effects of clonazepam on the sympathetic nervous system. My thanks to the kind reader who sent in the information and references.

Teacher in the Lights,
Guest Editorial, Jean Gargala

A flick of a light switch changed my life. Too dramatic?
Maybe.....but not from my perspective. I was officially diagnosed with Chronic Fatigue Syndrome in 1990 and have struggled with all the usual symptoms and all the typical problems that go along with trying to cope with any chronic illness. I've worked part-time since 1993 and have had many different supervisors: some supportive, some oblivious about my health, one downright mean. I experienced a fairly steady course with my symptoms and learned how to balance my life pretty well. I was able to do most things I wanted to if I moderated everything carefully.

Just about a year ago, the symptom that began torturing me on a daily basis was dizziness. It was an indescribable sensation that threatened to upset the carefully crafted balance of work vs. rest that enabled me to function in all the roles that are so important to me. After months of frustrating visits to various specialty doctors, I was able to get confirmation of what Dr. Bell had initially suspected: I was having daily migraine symptoms.

Early on, I had noticed fluorescent lights made the dizziness worse.
I became excruciatingly aware of how frequently we encounter fluorescent lights in our daily lives. My husband had to take over the household shopping, (one more thing he had to take on) since stores are lighted with fluorescent lights.

I work in a school, where there is an abundance of fluorescent lights.
I was determined to keep working. I took floor lamps into my office and kept the overhead lights off....what a relief. But much of my work is done in other areas of the school building. One day I casually mentioned to my principal that the fluorescent lights bother me. She immediately stood up, walked over, and turned off her office lights. She has an inside office with no windows letting in natural daylight, so we sat there talking in the dark. It brought instant relief for me!

(If you've never experienced the dizziness, nausea, and headache caused by migraine triggered by fluorescent lights, count your blessings!). Not only did I have the relief of not being under the fluorescent lights, but I also knew I didn't have to pretend to be feeling okay. I felt valued as an employee and respected as someone who has something to contribute even if I have a special need (for the lights off). Not only does my principal turn her office lights off, but she makes it a routine to adjust the lights in other rooms if I am present. It may not always be practical to have all lights off, but she makes sure they are adjusted as much as possible.

I have tried to articulate to my principal just how much her casually flicking that light switch has meant to me. She waves away my comments, saying, "it's nothing" or "don't mention it". What it means to me is this: a chance to keep working at a job that means a lot to me; I'm able to provide financial support to my family; I'm able to continue the important social contacts in my workplace; I'm able to have the intellectual stimulation of working; I'm able to feel like a productive member of society.

This isn't meant to be a criticism of anyone who has chosen to seek Disability benefits. Those benefits serve an important function for many people. I just wasn't ready to seek those benefits yet. Thanks to my principal making a simple accommodation - just a flick of a light switch - I can continue working, with all the many benefits that provides me.
Jean Gargala

2008-02-23 Newsletter
the 4th Japanese Fatigue Society Meetings
http://www.davidsbell.com/PrintLynNewsV5N1.htm

Greetings from Kumamoto, Japan where I happen to be killing time in an internet café during the evenings after the presentations from the 4th Japanese Fatigue Society Meetings. ...

I had the great good fortune of seeing a personal milestone passed with the recent conference in Oslo, Norway. I can remember twenty five years ago hearing someone say that in the future there would someday be medical conferences packed with health care providers studying how to diagnose and treat ME/CFS. I can remember being a little dubious. But now I can say that I have seen it come to pass.

The Oslo conference was two days; the first day for patients and support persons, and the second day was for health care providers. On that second day the conference center was packed with over 450 health care providers. We heard presentations on an outbreak of ME/CFS in Bergen, Norway, and numerous other review talks. It was extraordinary to see so many health care providers eager to learn about ME/CFS. A representative from their health department cancelled a number of appointments so that she could stay and hear the entire proceedings. I have a hard time remembering when that ever happened in the US. Congratulations to Ellen Piro and the Norwegian ME Association. ...

John: The success of the human spirit,
Case Reports

John is 85 years old, and showed up in the office for a follow-up check after twenty-five years. I saw him for a few visits in 1982, and he had been ill then for about twenty years. It had started with mononucleosis somewhere in the 60’s, and he never quite recovered. His course is a textbook of the natural history of the illness, good news and bad news. The timid and those persons assuming that ME/CFS/FM is a benign illness might elect not to read this section further, as John’s illness did not disappear. Some years ago the CDC published a paper saying that ME/CFS is not a progressive illness. They have not followed it long enough.

Like most persons with an acute infectious onset,
John was very ill for a couple of weeks and then seemed to get better.
He got up to around the 70% activity mark and was doing pretty well, and then crashed. For the next two years he was quite ill but slowly, very slowly began to improve. He endured hundreds of tests and even more comments about how he was probably “under some stress” or depressed. It was, after all, the 60’s, and physicians had not yet become familiar with ME/CFS. But even in his 40’s, John was a tough old bird, and he got along with his life as best as possible.

When I first saw him his activity was clearly reduced to about 40% of normal.
He had all the classic symptoms, but his spirits were good, and he had some support from family and friends. Eventually he got social security disability, and, while he was not pulling in the big bucks, he got by.

There were ups and downs.
The good times were characterized by a few days at a time of pretty good activity where he could get out, visit friends, read and study. As the years went by the degree and length of the good times slowly decreased. The degree and length of the bad times slowly increased. John was always dedicated to physical exercise, and he employed common sense. One of the most difficult days of his life was the day he could not get back to his house after a short walk. As the years progressed he used a wheelchair more and more. Yet when I tested his muscle strength on the examining table it was normal. The problem in ME/CFS is the inability to sustain activity.

John’s illness and its slowly progressive nature were not a surprise to me. But what caused me to sit back and listen in admiration was the strength of the human spirit. Despite the difficulties, the lack of recognition, and the physical symptoms, John not only maintained his dignity, he was able to find meaning and many moments of joy over the past 50 years. John is my teacher. New cars, money, social stature and daily comforts are insignificant when stacked up against the success of the human spirit. If and when I reach the tender age of 80, I hope I will be able to say I have accomplished as much as John. ...

Dorsal root ganglionitis: A personal history.

It has only been recently that I have become aware of Sophia’s story. It is a nightmare that has been written by Sophia’s mother concerning her daughter’s illness and death. The story is available on the Invest in ME website (www.investinme.org). Like many families struggling against this illness, Sophia’s mother was told by her physician that “I was keeping her ill and as long as I was looking after her she would never recover.” Sophia was forcibly removed from her home and put in a locked psychiatric ward. After prolonged difficulties Sophia passed away November 22, 2005.

The initial autopsy showed no cause of death, but further tests showed “unequivocal inflammatory changes affecting the special nerve cell collections (dorsal root ganglia) that are the gateways (or station) for all sensations going to the brain through the spinal cord. The changes of dorsal root ganglionitis seen in 75% of Sophia’s spinal cord were very similar to that seen during active infection by herpes viruses (such as shingles).”

It is hoped that Drs. Chaudhuri and O’Donovan will identify the cause of the spinal cord damage and publish their results. But will the medical community listen? Could it be that the ganglionitis was caused by a herpes group virus like ones being studied in the Stanford study? I pray that no one with severe ME is ever forcibly incarcerated in a mental hospital again, and I pray that Sophia may rest in peace.

Q&As: Epinephrine and ..Propranolol.

... But I think there are a couple of general and specific connections between epinephrine and CFS symptoms, which play out in the literature on propranolol. Propranolol's effect on POTS is well-documented, but the drug probably also boosts immune functioning, reduces inflammation in certain circumstances, regulates sense and pain perception, eases digestion (particularly of carbs), and increases the threshold for exertion. Epinephrine's negative effect in these areas could fuel a self-reinforcing cycle, like Pall's NO/ONOO cycle. Moreover, anecdotal risk factors for CFS, like long-term exercise and type A personality, probably involve increased epinephrine.

Lastly, it's also curious to think about propranolol in terms of all the obtuse research that favors psychological treatment. This is because epinephrine can be consciously controlled to a small degree by, for instance, self-awareness and breathing slowly. However, if the long-term benefits of psychological treatments ultimately lie in teaching patients to control epinephrine release, then propranolol would be much more effective.

Answer:
A very interesting set of questions. First of all, adrenalin (epinephrine and/or norepinephrine) is very involved in the illness, particularly the frazzled subtype. It can be measured after simple standing, and when it is over 600 it is considered abnormal (Hyper-adrenergic). It is my observation that treating patients with this type with any medication (coffee, stimulants, midodrine) which increases adrenalin, they get worse.

Secondly, I don’t think beta blockers such as propranolol do very much good. The hyperadrenergic response is a response – it is trying to improve a sad state of affairs, and when it is blocked, patients don’t seem to feel much better. Their chest pain goes away, though. CT scans of the adrenals show that they are small, thus the name “adrenal fatigue”, probably because they have been squeezed for so long.

2008-04-06 Newsletter
http://www.davidsbell.com/PrintLynNewsV5N2.htm

.. Many of you have written to the e-mail address attached to the website, and I apologize for having neglected it for the past year. I read some letters and feel so overwhelmed that I cannot write back, so I have not even gone to the mailbox recently. I also get so angry when I read the nightmare stories many of you have experienced. All you did wrong was to get sick. Then the medical industrial complex made your life miserable.

The medical industrial complex includes the drug companies who are not interested unless they make a big profit, the health insurance companies who will use any excuse to deny patients medications or testing, and the disability industry who survive only because they take your money and deny benefits if you get sick. All of this is done under the guise of “modern evidence-based medicine”. But evidence-based medicine only works in illnesses like hypertension where you have enormous funding.

I think I have become an old codger.
Cynical, disappointed .. Enough of that.
In my office I have a sign for ME/CFS patients
“Whining will be allowed for ten minutes only”. ...

Also I would like to thank a generous sponsor who kindly is sending me to the upcoming HHV6 conference. It is my hope that the next issue will be devoted to describing the science behind the ME/CFS – HHV6 link. ...

Mitochondrial disease: Clinical Notes

In the past week I have seen two patients who had an exercise lactate test which showed an elevation of blood lactate after mild exercise. They were told by their physician that they had “mitochondrial disease”. They were advised to take some vitamins, maybe some CoQ10, and have a nice day. Like nearly everything else, the term mitochondrial disease left these patients feeling bewildered and somewhat lost. While I agree that ME/CFS is a mitochondrial disease, this term needs clarification because ME/CFS is a mitochondrial disease like no other.

Until recently, when a child was diagnosed as having a mitochondrial disease, it was a disaster, even a death sentence, for it meant that there were major abnormalities in the mitochondrial or nuclear DNA that regulated energy production. Without energy (ATP) it is impossible to survive. These diseases are called MELAS, Kearns-Sayre, Leber hereditary optic neuropathy and so on.

Nearly three hundred mitochondrial illnesses have been identified from genetic mutations. It is a specialized area of pediatrics, where it is possible to measure severe abnormalities in the mitochondria on muscle biopsy testing. This is what most clinicians think of when the words mitochondrial disease are mentioned, but these illnesses do not, in general, apply to ME/CFS. Many patients with ME/CFS have had muscle biopsies and most of the mitochondrial tests on these biopsies are relatively normal. We will return to why this is in a bit.

What are mitochondria?
Think of mitochondria as the power factories of the cell.
Nearly every cell in the body has them, usually around 500 or so in every cell. They take in oxygen and glucose and put out carbon dioxide and energy (ATP). There are two hundred different steps in this process and we will quiz you after this article. Actually all you need to know is ATP, the prime energy storage chemical (battery) of the body, and oxidative phosphorylation (ox-phos) the complex electron transport chains that do the major work. Because the mechanism of energy production is essential to nearly every cell, a defect will have symptoms in every organ system. Sound familiar?

Oxidative metabolism, the ability to utilize oxygen to produce energy, is quite efficient, and it is fascinating to look at the theories of how they came to be part of our cells. However, when the energy demand is excessive, the cells revert to a more primitive, and less efficient, form of energy production, anaerobic metabolism (metabolism without oxygen). For an interesting study on the anaerobic threshold in ME/CFS, see the literature review article that follows.

When to suspect mitochondrial disease.
In a recent review article (Haas 2007) there is a list of symptoms that suggest looking for mitochondrial disease. Among these symptoms are neurologic symptoms such as ataxia, myoclonus, and encephalopathy, exercise intolerance, sensitivity to general anesthesia, and constipation. A score sheet has been developed to help in when to suspect mitochondrial disease and most ME/CFS patients would fall into the positive range. For lots of information on mitochondria please go to www.mitosoc.org, but remember that they are talking about “conventional” mitochondrial disorders, not ME/CFS.

There is another form of mitochondrial disease, or secondary mitochondrial disease. In secondary mitochondrial disease the primary problem is not with the mitochondria, but some other problem messes up mitochondrial function. There are many illnesses where the primary defect ends up causing problems with the generation of energy in mitochondria. For example, thyroid hormone is needed for successful oxidative phosphorylation.

With hypothyroidism (low thyroid) energy production is impaired and fatigue, weakness, temperature regulatory problems, and difficulty concentrating result. This is one of the reasons that when you start to describe fatigue to your primary care physician, he or she begins to write out a script to test for thyroid hormone.

So what is the problem?
Why has ME/CFS not been diagnosed, studied and classified as other mitochondrial diseases? There are several reasons:

a) Mitochondrial disease is thought of by clinicians as a fatal disease of infancy, not one that occurs later in life.

b) Mitochondrial disease is usually thought of as a fixed, structural disease, and ME/CFS is a relapsing, remitting illness with some persons even becoming entirely well.

c) Mitochondrial diseases are hard to diagnose, requiring muscle biopsies and detailed ox-phos testing

d) Ox-phos testing is often normal in ME/CFS, and this has been the critical piece that has diverted attention from mitochondria.

e) Physicians are used to thinking of organ-specific diseases (liver, kidney, etc) and mitochondria are in all cells.

f) Few physicians have taken ME/CFS seriously until recently, and research in this area has been scant.

Test Relevancies.
Of the above reasons, only reason “d” is important to us here.
In 1990 I did a muscle biopsy study on ten ME/CFS patients with Dr. June Aprille. All ten persons had relatively normal ox-phos studies. Although we did not publish this finding, it is consistent with the few published studies that have been done. How can you have mitochondrial disease when the mechanism tests normal? I think that the answer to this paradox is just around the corner.

Hypothesis:
If you have a patient with emphysema who is sitting in an armchair, he or she is not out of breath. You can measure the damage in tests, but to make symptoms, you have to “stress” the system – make the patient run up and down stairs. If a person with G-6-PD deficiency is sitting quietly, the blood looks normal. But feed this person fava beans and abnormalities quickly become obvious.

Persons with ME/CFS keep themselves at a balance point.
They rest for two hours, then do a half hour of activity, then rest, then do more and so on. The worse the illness, the less overall activity is possible. If a ME/CFS patient does absolutely nothing for a few days, they usually feel pretty good. But go to the shopping mall for eight hours and the crash occurs. Here is the problem: in the patients studied for mitochondrial disease, they have been resting up (staying above the balance point) and a muscle biopsy done at that moment will probably not show much. But have a ME/CFS patient exercise, and then study mitochondrial function. My hunch is that the ox-phos reactions will be seriously impaired, but this has not been systematically and methodically done. For me, this hypothesis is generated by the VanNess, Snell, and Stevens study described in the next section.

There are lots of studies that implicate mitochondrial problems;

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