Guest blog by Maryann Spurgin, Ph.D.

Note: I wrote this proposal in the late Fall of 2015 and in early 2016 as a work proposal (Circulatory Impairment in Myalgic Encephalomyelitis: A Work Proposal —by Maryann Spurgin, Ph.D. January 16, 2016)

https://docs.google.com/document/d/1y_SoLHW8NaxBrI8bmBiY-ehBZfd3Ji7yttV50bG5qRY/mobilebasic?pli=1).

"An idea is always a generalization, and generalization is a property of thinking. 
To generalize means to think."

~ Georg Wilhelm Friedrich Hegel

“As the biggest library if it is in disorder is not as useful as a small but well-arranged one, so you may accumulate a vast amount of knowledge but it will be of far less value than a much smaller amount if you have not thought it over for yourself.”

~Arthur Schopenhauer

"Out-of-date theories are not in principle unscientific because they have been discarded."

~Thomas S. Kuhn, The Structure of Scientific Revolutions

"We see the world in terms of our theories."

~Thomas S. Kuhn

In mid January I began sending it to medical schools, and in late January/early February, I sent an earlier, longer version to some privately funded research teams, including to Ron Davis. Very recently, on May 27, 2016, I sent it to the research team at NIH at the following email addresses:

[email protected]
[email protected]

Although I did discuss it with several medical professors at medical schools who contacted me, were interested, but were unable to obtain funding, neither the privately funded teams nor the NIH contacted me or sent a return email. Some additional information has been added to this version that was not in the version circulated in April/May.

I wrote it as an abstract, a proposal to try to obtain a position on a research team to explain, elucidate and integrate into research, or see if researchers could integrate what knowledge I bring, the pathophysiology of the circulatory impairment in ME that I, as well as numerous researchers, think is so crucial to understanding why patients with ME relapse at the slightest exertion.

While it may have been unrealistic to believe that a work position would come out of this proposal, being too realistic and lacking ambition and imagination never advanced science. The field of ME research is currently bereft not only of creative thinking, but also of the ability to integrate published research onto theory, or to formulate working hypotheses. Apparently the proposal was good enough for some of its suggestions to have been adopted by research teams, although I was neither hired nor acknowledged.

An ominous problem of past research is that whether the quality of the research is good or bad, whether it relates to ME or to the CDC’s 1994 "fatiguing illness" govt. construct, the “Materials and Methods” sections of nearly all of the articles in this period cite the Fukuda Definition, which is too broad and thus findings cannot be replicated. I will be using "ME" in this proposal to distinguish it from the broader category of "fatigue" that has been so damaging in finding consistent research findings in the "CFS" Fukuda definition and Reeves/Oxford criteria. The findings I discuss here do not apply to the broader category of fatigue. 

Here is my proposal:

For many years, I have followed and collated research on Myalgic Encephalomyelitis (ME), in particular on the circulatory impairment of which Dr. A. Melvin Ramsay spoke and of which there are many recently discovered facets. Despite lack of research on circulatory impairment in ME in the 1950's, Dr. A. Melvin Ramsay astutely observed it clinically as one of the three essential components of ME, noting pale, cold skin as a sign.

Sixty years later, the research behind these observations is now extensive, although some of that research was published under the name "CFS"; yet it applies to patients with ME or those with ME who are misdiagnosed with "CFS," itself a govt construct that, as noted above, has impeded consistent findings. My view is that "CFS" is a government construct. There are people with everything from MS to fibromyalgia to depression to ME who are diagnosed with "CFS." So there are not two separate diseases, ME and "CFS"; rather, those diagnosed with "CFS" have something else in need of diagnosis, whether ME or another disease. Much of the research on ME was done under the name "CFS."

I have spent 22 years studying circulatory impairment in ME by reading published research on its many facets, beginning over 20 years ago with Dr. L.O. Simpson's work on impaired capillary blood flow [1], the haematological/ hemorheological flow problems that impede delivery of oxygen and nutrients to organs and tissues and impede removal of lactic acid, toxins and metabolic waste due to poorly deformable Red Blood Cells.

Much later, in the 1990's, Dr. David Bell's and the late Dr. David Streeten's joint work on low blood volume (hypovolemia) in ME was published [2, 3]. Dr. Streeten was a world-renowned endocrinologist whose area of specialization was blood pressure and orthostatic disorders.

The third aspect of circulatory impairment is cardiac:

The late Dr. A. Martin Lerner pioneered it, with his hypothesis that the disease is a viral cardiomyopathy. He found on biopsies virally infected cardiac myocytes in the disease, published in the 1990's [4-6]. He argued that the disease is at its root a viral cardiomyopathy. 

Importantly, there was also NIH grant-funded research by Drs Benjamin Natelson and Arnold Peckerman on abnormal impedance cardiography and other cardiac abnormalities in ME patients [7]. These important studies influenced researcher/clinician Dr. Paul Cheney, who found and illuminated problems with cardiac diastolic dysfunction in the disease (diastolic problems not caused by volume depletion but by a pathology in the heart itself), following his own experience with heart failure and his subsequent heart transplant.

This extensive body of research shows that, without identifying the root cause of ME, disorders of microcirculation and macrocirculation are well established pathophysiological findings [8-11], and that combined circulation problems can conspire to create havoc in the heart and other organs of the body.

I have thought a lot about circulatory problems over many years, and how these impairments come together to create the intolerable symptomatology of ME that could lead someone to be so impaired as to not be able to swallow, and could lead the Institute of Medicine to declare that organ failure, even death, can occur from the slightest exertion and/or sensory overload.

This happens, I believe, when one or more or all of the following three conditions hold:

1. Metabolic demand exceeds the capacity for cardiac output. Studies have shown that if the level of exertion or metabolic demand on the heart exceeds the capacity of the heart to pump blood by even 1%, the organism dies. Rest and limiting demands on a heart whose output is reduced by disease is crucial to survival.
2. An impaired RBC/capillary delivery system is present (My own theory is that this impairment may be a defense mechanism to slow metabolic demand in order to protect the heart); And…
3. When low blood volume is present.

One of these impairments alone could cause havoc, but the three of these pathophysiologies together could lead to extreme multisystem involvement and death. In a patient who is already volume depleted, poor diastolic filling from still another, cardiac problem could be doubly dangerous, yet this is exactly what Dr. Cheney has found.

Although this research does not hypothesize a cause, and circulation problems are likely the result of some underlying (likely viral) cause, this particular aspect of the pathophysiology, I believe, is crucial to a biological understanding of ME, and to explaining why ME patients relapse and can die from exertion. Mitochondrial problems that are not primary mitochondrial disease but are an epiphenomenon of the (unknown) cause or causes likely also play a role, especially in cardiac and brain dysfunction (see the home page of my website that discusses mitochondrial epiphenomena and the references I provided on the site).

The ME Society of America is an organization that I created focused on compiling high-quality studies investigating the pathophysiology of ME. Although my website is now archived, the articles I chose to include still stand on strong scientific ground and help elucidate the pathophysiology of ME. I have given serious consideration as to which research articles are of high quality and are concerned with Myalgic Encephalomyelitis and not a broader category of fatigue.

Here is my now-archived site:
https://web.archive.org/web/20140213060809/http://www.cfids-cab.org/MESA/

My Ph.D is in philosophy and classics and I taught philosophy before becoming ill and for a short while after. Post graduation, I spent over 10 years studying philosophy of science, writing reviews on the science of ME and articles on medical politics. I got sick on March 2, 1982, at 10:00PM, and have had a front-row seat to the unfolding of this tragic debacle both in personal experience and in following research and advocacy, the scientific-political apparatus that has developed over the field of ME research and hung ominously over it in the past two decades.

There is a very wide gap between both the advocates and researcher-clinicians who were present at the beginning of the earlier outbreaks when Ramsay and Dowsett were around as well as at the beginning of the outbreaks in the U.S in the eighties and onward, and the researchers and advocates who are newly discovering the field today, who are shocked at what they mistakenly perceive as a lack of knowledge and research on the disease, as the below quote demonstrates: 

"CFS is one of the last major diseases we know nothing about"
–Ron Davis (famed Stanford geneticist) 

While this is a well-intentioned plea for more research, as a basic statement it is incorrect. I am often shocked when I read statements like this, as I am when newly ill advocates and the media portray ME as "mysterious." It is not. There is in fact a core of research, hard data, and also of valuable unpublished knowledge gathered by clinicians in great danger of being lost. (As I mentioned, since this proposal was sent out in January/early February, both Drs. Bell and Cheney were hired by the OMF co-founded by Davis).

How did it come about whereby advocates, clinicians and researchers failed to produce a second generation -– rather this second generation is made up of people who have come across ME either through recent illness or serendipity?

A main factor in this disjoint is the malign triad of the Wessely School in the UK, Reeves and others at the CDC, Fauci, the late Straus and others at the NIH who followed and continue to follow the psychiatric model [12], gained power, and sucked all of the oxygen out of biomedical research into ME. Exposing this noxious apparatus is a crucial step in clearing the air so that genuine ME research can be conducted. Others, like Berkeley journalist David Tuller, are working on this problem by debunking the PACE trial.

A second step is recognition and a thorough study of the biomedical research and even transmission of some unpublished knowledge that we long-term observers have accumulated, and integrating it into theory and forming hypotheses.

The Psychiatric Cartel's influence has resulted in a circumstance where there are no clear intellectual inheritors to the foremost researcher-clinicians who have studied it the longest, the late Drs. Ramsay, Dowsett, Drs. Cheney, Bell, the late Streeten, the late Dr. Lerner, and Drs. Simpson, Natelson, Peckerman, Cheney etc.

(Note again: after this proposal was sent out in January/February, the Open Medicine Foundation did hire Drs. Bell and Cheney. I was told by David Tuller that he forwarded my proposal to Ron Davis and to his wife, Janet, on Feb 5, 2016. I was not contacted by either.)

KNOWLEDGE of research could, if it were widely known, form a core from which researchers today could work.

There was a period of innovation in the late 80’s and onward during the Clinton administration and even in the 2000's by independent researchers that supplied many findings important to understanding the pathophysiology and biological medical explanations of M.E. that slowed to a trickle once the Psychiatric Cartel become fully established. Results on mitochondrial dysfunction, NK cell cytotoxicity, bone marrow abnormalities, reduced grey matter in the brain, abnormal sympathetic control, and the part that I have studied most intensely, loss of blood volume, abnormal capillary nutrient delivery, viral infection of the heart muscle, diastolic dysfunction in the heart-- these studies present medical explanations for ME with data that fit the theory that circulatory problems combine with other problems to cause severity and death.

Given the problems of case definition described above, how can one assess the quality of the research? One can identify good research by relying on both historical knowledge and how well the hypotheses fit the raw data and explain the symptomatology, and deaths. If the leading biomedical cause of death in ME is heart failure, if the disease is deemed by researchers to be "as disabling as those with congestive heart failure," shouldn't that be a clue that some type of cardiac insufficiency is key?

In my own experience of having severe ME, the circulatory problems ring true....yet the researcher-clinicians who have worked on this are (or were prior to this proposal) ignored. How can this be? Even patients and advocates prefer to focus on immune abnormalities and just about anything other than this.

Does "Immune System" disease sounds more serious than cardiac insufficiency? Not to me. I believe from experience that ME is caused by a virus that does wreck havoc on the immune system and on every other system of the body; the mitochondrial problems may play another key role. I have responded well to immune modulators myself, such as interferon in treating my own case, and to substances that improve mitochondrial function. But I also believe that the circulatory problems comprise a large part of what make it so debilitating and deadly. Treating the circulation problems alone (e.g., with fish or flax oil) without addressing the underlying cause could actually lead to eventual worsening of the disease by leading to over exertion and eventual relapse.

When confronted with a disease as complex as ME, one must always keep an open mind. Some of the treatments from which I have benefited might sound unconventional, like low-dose oral interferon alpha at 1 IU per pound of body weight, or drinking 2 gallons of water a day (with electrolyte repletion of course) for circulation, or using Hawthorn and magnesium for diastolic heart failure, but conventional thinking never advanced science.

No one knows the cause, although all of us who suffer from it will tell you that it is caused by a virus or viruses. But many aspects of the pathophysiology are well explained. The original researcher-clinicians amassed a critical intuition and knowledge of the pathophysiology of ME. This knowledge could, if it is applied, form a vital core from which any further research projects could spring. The alternative would be a lengthy process akin to the rediscovery of Mendel.

I see a pathophysiological hypotheses of the core group of biomedical researchers (Drs. Ramsay, Dowsett, Streeten, Bell, Cheney, Lerner, etc ). As Dr. Bell is retired, Dr. Streeten and Dr. Lerner have passed away, and Dr. Cheney focuses on clinical practice (once again, Bell and Cheney were consulted and placed on committees at OMF after this proposal was circulated), there is a huge threat that knowledge regarding ME, both published and unpublished, could be lost to researchers new to the field.

Learning the prior research is crucial in the inductive step of forming hypotheses that will be scientifically useful once investigated.

I have a strong appreciation for the thoughts and inferences that Dr. Cheney accumulated over the course of treating severe ME for so long, but that have never found their way into a published study. 

In addition to the valuable core of research by Drs. Peckerman, Natelson, Lerner, Bell, Streeten and a few others that actually was published, some of this unpublished but well-known research can help form a guide for any new undertaking in ME research. To give one example, I have a 6-hour talk by Dr. Cheney on diastolic dysfunction in ME that is one of the most fascinating things I've ever observed on the disease: only the first three hours are on Youtube [13]. After he presented these talks in Dallas, Dr. Cheney discovered that a two-hour echocardiogram is required to diagnose diastolic dysfunction in ME. Actual diastolic heart failure is also routinely missed by cardiologists.

I wrote and circulated this proposal to research teams in late January/early February of 2016 because I was interested in obtaining a position on a research team to explain, elucidate and integrate into research the pathophysiology of the circulatory impairment in ME that I and numerous researchers think is so crucial to understanding why patients have such problems with exercise and relapse at the slightest exertion, why ME patients cannot tolerate light or sound, why the slightest thought or sound even can make them so sick. I was not appointed as a consultant, although some research teams used several of the ideas in my proposal. I later circulated it on the internet in April and May 2016, and then to NIH. I believe that integrating all aspects of circulatory impairment in ME is important to understanding ME, although by no means exclusive.

I believe that discussions of heart problems are key, including diastolic dysfunction and reduced cardiac output found by Dr. Cheney and others who have worked on heart problems in ME. I sought to integrate cardiac findings with other circulatory findings, such as low blood volume that was found by Drs. Bell and Streeten, resulting in systemic volume depletion and cardiac volume depletion (with cardiac depletion from two sources, the heart's diastolic filling problem that Cheney shows to be a cardiac problem in ME independent of generalized volume depletion, and whatever is causing general volume depletion in ME, which Dr. Streeten believed was a problem with the kidneys' inability to retain salt). The ultimate cause of these problems remains unknown, although viral onslaught is likely.

Finally, uncovering how and why these problems co exist with the micro circulatory problems found by Dr. Simpson: abnormal/impaired delivery of blood & oxygen to tissues and organs and impaired removal of toxins and metabolic waste due to impaired capillary blood flow from prolonged RBC abnormalities in ME is key to this discussion (again, my theory is that this may be a protective mechanism to reduce exertion and hence reduce metabolic demand on the heart).

I offer some preliminary lab tests.

Recommended Lab Tests for Circulatory Impairment:

1. Urinary mineral toxicology test, looking for extreme excess sodium excretion in urine (this would indicate an inability to retain salt). I discovered the usefulness this test for ME myself, which had I ordered in my case years ago to search for mineral toxicology. I discovered its usefulness for ME quite by accident.

The philosopher of science Thomas S. Kuhn stated that data will be missed and overlooked unless and until there is a theory that makes a space for it. In fact, Kuhn went so far as to say that the data will be invisible to us without a theory. Nothing in my own experience has made this ring true so much as the mineral toxicology test that I ordered over 20 years ago. The idea was to look for heavy metals. The test came up negative, or "normal," or so I had thought. I did not even notice at the time that an abnormal amount of sodium (in the thousands beyond the normal range) was present. It was only after Peter Rowe's work on NMH and his recommendations of drinking water and taking salt tablets, and after my discussions with Dr. Streeten on poor kidney retention of salt as part of the problem in volume depletion, that I even NOTICED the abnormality on that test that indicated an inability to retain salt. It was not until many years later that orthostatic problems, sodium depletion, volume depletion began to be discussed in ME, and that was when I noticed the abnormality on that test.

2. (CBC), looking for: a. Low blood sodium (another indicator of poor sodium retention). b. Low sed rate: very low in ME. Relates to the RBC pathology found by Dr. Simpson [1].

3. SPECT scan of the brain: shows cerebral hypoperfusion (Dr. Byron Hyde).

4. Nuclear Medicine: test for low blood volume (Dr. David Streeten).

5. 24-hour holter monitor EKG: T wave flattenings and/or inversions [6].

6. Tilt Table Test for Orthostatic Hypotension [3] (non-severe patients only; this test will cause damage in severe ME).

 7. CPET: Two Day Exercise Test: shows abnormalities and worsened perfusion on second day (non-severe patients only, test will cause damage in severe ME) [14].

These tests comprise only a small sample of the tests that can be done for circulatory impairment, and while they are not diagnostic, a clinical history and the presence of these abnormalities could be helpful.

Maryann Spurgin, PhD.

References:

1. Simpson L. Myalgic Encephalomyelitis (ME): A Haemorheological Disorder Manifested as Impaired Capillary Blood Flow. The Journal of Orthomolecular Medicine. 1997; 12.

2. Streeten DH, Bell DS. Circulating blood volume in CFS. J of CFS. 1998;4(1):3-11.

3. Streeten DH, Thomas D, Bell DS. The roles of orthostatic hypotension, orthostatic tachycardia, and subnormal erythrocyte volume in the pathogenesis of the chronic fatigue syndrome. Am J Med Sci. 2000 Jul;320(1):1-8. PubMed PMID: 10910366.

4. Dworkin HJ, Lawrie C, Bohdiewicz P, Lerner AM. Abnormal left ventricular myocardial dynamics in eleven patients with chronic fatigue syndrome. Clin Nucl Med. 1994 Aug;19(8):675-7. PubMed PMID: 7955743.

5. Lerner AM, Goldstein J, et al. Cardiac Involvement in Patients with Chronic Fatigue Syndrome as Documented With Holter and Biopsy Data in Birmingham, Michigan, 1991-1993. Infectious Diseases in Clinical Practice 1997:6:327-333

6. Lerner AM, Lawrie C, Dworkin HS. Repetitively negative changing T waves at 24-h electrocardiographic monitors in patients with the chronic fatigue syndrome. Left ventricular dysfunction in a cohort. Chest. 1993 Nov;104(5):1417-21. PubMed PMID: 8222798.

7. Peckerman A, LaManca JJ, Dahl KA, Chemitiganti R, Qureishi B, Natelson BH. Abnormal impedance cardiography predicts symptom severity in chronic fatigue syndrome. Am J Med Sci. 2003 Aug;326(2):55-60. PubMed PMID: 12920435

8.  Biswal B, Kunwar P, Natelson BH. Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling. J Neurol Sci. 2011 Feb 15;301(1-2):9-11. doi: 10.1016/j.jns.2010.11.018. Epub 2010 Dec 16. PubMed PMID:  21167506; PubMed Central PMCID: PMC3139492.

9. Hollingsworth KG, Hodgson T, Macgowan GA, Blamire AM, Newton JL. Impaired cardiac function in chronic fatigue syndrome measured using magnetic resonance cardiac tagging. J Intern Med. 2012 Mar;271(3):264-70. Doi:  10.1111/j.1365-2796.2011.02429.x. Epub 2011 Aug 15. PubMed PMID: 21793948; PubMed Central PMCID: PMC3627316.

10. Yoshiuchi K, Farkas J, Natelson BH. Patients with chronic fatigue syndrome have reduced absolute cortical blood flow. Clin Physiol Funct Imaging. 2006 Mar;26(2):83-6. PubMed PMID: 16494597.

11. Khan F, Spence V, Kennedy G, Belch JJ. Prolonged acetylcholine-induced vasodilatation in the peripheral microcirculation of patients with chronic fatigue syndrome. Clin Physiol Funct Imaging. 2003 Sep;23(5):282-5. PubMed PMID:12950326.

12. Frustrating survey of chronic fatigue. Lancet. 1996 Oct 12;348(9033):971.PubMed PMID: 8855845.
“ Psychiatry has won the day for now. A decade hence, when an organic cause for at least some cases.”[c]

13.  Cheney, P. URL: https://www.youtube.com/watch?v=8x2yJaiB_sI. LV Diastolic Dysfunction in CFS. Accessed: May 17, 2016.

14. Keller BA, Pryor JL, Giloteaux L. Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO₂peak indicates functional impairment. J Transl Med. 2014 Apr 23;12:104. Doi: 10.1186/1479-5876-12-104. PubMed PMID: 24755065; PubMed Central PMCID: PMC 4004422.