Myalgic encephalomyelitis (ME) is an internationally recognised syndrome and is formally listed in the International Classification of Diseases by the World Health Organisation as a "disorder of the brain" (i.e. as a neurological condition).

There are many reports of the syndrome in the medical literature dating from 1934.

Chronic fatigue syndrome (CFS) is a term which was first introduced in 1988, into which ME has been subsumed.

Earlier reports describing ME contain clear reference to the unmistakable neurological features, whereas early reports of CFS do not, focusing instead on symptoms commonly found in glandular fever.

Case Definitions vary remarkably, and there is appalling confusion over terminology and about selection and definition of patients studied. In 1991 a group of UK doctors (mostly psychiatrists) produced a new case definition which specifically excluded all neurological signs but which specifically included all cases of medically unexplained fatigue which had been present for six months. This was a retrograde step, as it broadened the official case definition to include many psychiatric conditions, particularly those in which tiredness and sleep disturbance predominate. These psychiatrists (led by Professor Simon Wesley of Kings College Hospital, London and known as the Wesley School") claim that ME does not exist, and that it is entirely synonymous with CFS and that CFS is a functional somatic (i.e. psychiatric) syndrome. Wesley is an adviser on CFS / ME to the UK Government. Fatigue syndromes are formally classified in the ICY as psychiatric conditions. In the United States, case studies and patient selection criteria are much more rigorous than in the UK, with the result that papers on CFS are describing cases of ME.

The UK National Task Force on CFS / ME recommends that the term "CFS(ME)" be used to describe those who are more severely and chronically affected.

Unless lawyers are aware of this confusing background, they will be unable to look after the best interests of their clients, as is their duty.

Over 3000 reference papers (dating back to 1884) have been obtained.

A representative selection is listed here. Given that CFS / ME is a dysfunction at cell membrane level, it affects virtually all bodily systems to some degree, so it is not easy to divide these medical reference papers into discrete sections and / or medical disciplines. It is therefore imperative to be familiar with all sections listed.

Individual papers are cited below, being roughly divided into the following broad sections.


These date from 1955 – 1991, and include an historical summary from 1750 (published in 1991 in Reviews of Infectious Diseases).


These papers cover more than one aspect of CFS / ME and include for example evidence of impaired oxygen delivery to muscle; evidence of delayed recovery from fatiguing exerCFSe and lists of symptoms commonly found in CFS / ME (which number over 60).


Although there is as yet no single, specific, definitive test for CFS / ME (which is also the case in numerous other medical conditions), nevertheless there is an entirely consistent and reproducible pattern of abnormalities which have been observed worldwide. Such abnormalities particularly include immunological, neuroendocrinological, nuclear imaging and psychometric parameters. However, psychiatrists of the Wessely School persistently advise both Government and medical practitioners that no tests should be performed on CFS patients with the exception of psychiatric tests (which they claim are mandatory in all cases); these psychiatrists are funded largely by The Linbury Trust (Sainsbury), which in 1998 produced a "CFS Research Portfolio" (edited by Robin Fox, a former editor of the Lancet and published by The Royal Society of Medicine) which categorically states that searching for causes is not only futile but may prevent recovery.


One international CFS / ME expert writes that in his experience, CFS / ME "is one of the most disabling diseases that I care for, far exceeding HIV disease except for the terminal stages". Australian research describes CFS / ME patients as suffering more dysfunction than multiple sclerosis sufferers; the .sickness impact profile (SIP) is more extreme than in end-stage renal disease and heart disease, and only in terminally ill cancer patients has the overall SIP score been found to reach that found in CFS / ME. American research found that the quality of life in patients with CFS / ME is significantly, particularly and uniquely disrupted, and that the illness causes marked disruption and devastation. Scandinavian research has shown that patients with "non-visible" disability suffer more stigmatisation than those with visible disability.


This section provides evidence of the natural history of severe CFS / ME, showing that the prognosis is extremely poor for the severely ill subset, with no symptom improvement, and it shows symptom patterns in long‑duration CFS.


The syndrome is known to be related to a dysfunctional stress response, and there is evidence that precipitating factors include physical trauma (specifically a breakdown in the blood‑brain barrier) and critical life events. Other factors include infections; anaesthesia; immunisations and exposure to certain chemicals.


This section shows evidence for and implications of the endocrine disruption found in CFS / ME, especially that associated with hypothalamic‑pituitary adrenal axis dysfunction.


These papers show commonly found dysfunction in both the central nervous system and in the autonomic nervous system; they include papers on dysequilibrium and vertigo which are known components of severe CFS / ME.


Evidence of demyelination and cerebral oedema has been documented in the CFS / ME literature since 1988.


There is evidence that such problems include intermittent jelly‑like nystagmus; difficulty in accommodation / focusing / visual acuities; photosensitivity; photophobia; blurred vision; double vision; crusted eyes; dry eyes; itchiness; narrowed arterioles; retinal defects; fibrillar changes in vitreous; chorioretinal macular abnormalities and optic pallor (the latter is also observed in MS). Objective findings of the anterior segment suggest an organic aetiology.


Published evidence shows that enlargement of the spleen and liver is not unusual. Evidence shows infiltration of the splenic sinuses by atypical lymphoid cells, with reduction in white pulp, suggesting a chronic inflammatory process.


Hair loss in CFS / ME is documented in the literature. One author states "It is a rare woman with CFS who has not had hair loss, usually diffuse and non-scarring". Elsewhere, it is documented as occurring in 20% of patients.


Evidence reveals the known tropism of Coxsackie B viruses for muscle, brain, heart and pancreas, all of which are documented as being target organs in CFS / ME. There is also evidence of human herpes virus 6 (HHV6) reactivation playing a role in the pathogenesis of both CFS / ME and MS. HHV6 Variant A is more common in AIDS and CFS / ME, whilst Variant B is found in MS. HHV6 used to be called human B‑lymphotropic virus (HBLV); it was discovered in 1986.

It is possible that reactivation of a composite viral load occurs as an epiphenomenon of an underlying immune system dysfunction, thus giving rise to the protean symptornatology.


There is substantial evidence that concurrent stress at the time of viral exposure leads to more severe disease. Stress is known to increase susceptibility to those diseases which are immune‑related, e.g.. infectious disease, cancer and autoimmune disorders.


The most commonly found immune abnormalities are very low natural killer (NK) cells, with decreased cytolytic activity, and an increased CD4 ‑ CD8 ratio; there is an increase in the CD8+ cytotoxic T cells bearing antigenic markers of activation on their cell surface; there are higher frequencies of low levels of various autoantibodies, especially anti­nuclear and anti‑smooth muscle antibodies; there are low levels of circulating immune complexes; there are increased levels of IgE and decreased levels of IgG3. Low levels of IgG3 have been reported since 1986 in patients with aching muscles. Overall, these abnormalities are consistent with evidence demonstrating chronic, low‑grade immune activation in CFS / ME.

Importantly, it has been convincingly demonstrated that changes in different immune parameters correlate with particular aspects of disease symptornatology and severity.


The relationship between viral infections and onset of allergic disease is well documented in the medical literature.

With specific relationship to CFS / ME, there is overwhelming published evidence that allergies, food intolerance and multiple chemical sensitivities (MCS) are very common; an increasing sensitivity and adverse reaction to many drugs / therapeutic substances is widely believed to be virtually pathognomonic of CFS / ME.

Cells cannot be attacked by the immune system unless they display on their surfaces complex glycoprotein molecules known as Class 11 MHC antigens; cells can be induced to do this by gamma‑interferon, which is an anti‑viral chemical produced by the immune system when under viral attack.

Allergies in CFS / ME are thought to be the result of this mechanism, which makes the body cells susceptible to on‑going attack by the immune system.

Because reference to allergies is so widespread throughout the CFS / ME literature, many of these references are to be found throughout these reference papers, mostly in the sections on General CFS / ME, Immunology and Neuroendocrinology

More and more patients are presenting themselves with "total allergy syndrome"; ‑this is recognised as part of CFS / ME; whilst some psychiatrists are notoriously dismissive about its existence, the literature (from highly reputable internationally acclaimed experts) clearly shows that it does exist, and that such patients do indeed develop abnormal immune parameters whilst under observation. A leading professor of clinical immunology has published papers confirming that these are patients with multiple sensitivities, and that their symptoms are not all in the mind.


It is well‑established that patients with CFS / ME and others with neuromuscular dysfunction can have problems with anaesthesia ‑‑‑ depolarising muscle relaxants have a known risk of causing potassium release from muscle, which can lead to cardiac arrest, and it is important to avoid histamine releasers. Muscle weakness increases the risk of respiratory failure.


References to vascular problems in CFS / ME have been in the medical literature from 1938. Such problems include vasomotor instability; impaired blood flow in the micro­circulation consistent with inflammatory processes; vasculopathy including Reynard’s disease and cutaneous vasculitis; vasculitis of the liver and cerebral hypo perfusion due to vasculitis.


Documented problems include myocarditis; chronic pericarditis; paroxysmal attacks of chest pain (Syndrome X); palpitations, with sinus tachycardia being particularly troublesome; shortness of breath (due to fatigue of the voluntary muscles of respiration); flattening and inversion of T waves; a lower stroke volume and cardiac output (indicating a defect in the higher cortical modulation of cardiovascular autonomic control). CFS / ME patients have higher heart rates and lower pulse pressure and have baseline differences from normals.


Evidence shows that CFS / ME patients have a significant decrease in vital capacity (VC). The incidence of bronchial hyper‑responsiveness is remarkably high. Compared with controls, CFS / ME patients showed a significant reduction in ail lung function parameters studied.


Irritable bowel syndrome (IBS) is so widespread and common a problem in CFS / ME that reference to it is to be found throughout various sections of the reference papers, in particular in the section on Quality of Life in CFS / ME.


The literature contains objective evidence of brain impairment in the majority of patients which is compatible with a chronic viral encephalitis. Patients have a particular pattern of hypo perfusion of the brainstem. Brain perfusion impairment in CFS / ME provides objective evidence of central nervous system dysfunction.


Neuropsychological testing reveals a pattern of cognitive impairment which is compatible with an organic brain lesion. Tests on CFS / ME patients revealed a performance which was sevenfold worse than that found in either the controls or in depressed patients. Results indicate that the memory deficit in CFS / ME is more severe than has been assumed by the CDC criteria. A pattern has emerged of brain behaviour which supports neurological compromise in CFS / ME.


There is a substantial body of literature which strongly refutes claims that patients are overly suggestible; it is quite specific that patients are not somatising, and it confirms that patients are not exhibiting "abnormal illness behaviour" and that the illness is not explained by inactivity or psychiatric disorder. Depressive symptoms are more likely to be a consequence rather than a cause of illness. Serious doubts are raised about the validity of the application of a psychiatric label. A conviction by patients of physical illness is understandable and legitimate.


Whilst there are considerable overlaps of symptornatology between CFS / ME and fibromyalgia, there are significant differences. Of foremost importance is the fact that the WHO recognises and specifies that they are two different syndromes. The literature recognises that up to 70% of those with CFS / ME also have concurrent fibromyalgia, and that this represents an additional burden of suffering amongst those with CFS / ME.


Misdiagnosis is very common in complex and poorly understood illness and patients are often ignored or dismissed by medical practitioners without justification. This increases their suffering. The literature abounds with evidence that patients have often been given an inappropriate label (usually by psychiatrists), and that such labels abruptly disappear when medical science and knowledge discover an underlying organic aetiology. Examples are legion, and include diabetes, hypothyroidism, pernicious anaemia, peptic ulcer, multiple sclerosis and Parkinson's disease ‑‑ in the 1940s, psychiatrists claimed that the intention tremor was due to the inner conflict of the patient who wished to masturbate but who knew it was wrong, and that the intention tremor was a manifestation of such inner conflict; it was not until the discovery of the neurotransmitters and the role of dopamine that such views were abandoned. Unfortunately, some psychiatrists seem unable learn from past experience.

not now Killing Me Softly : FM/CFS & Suicide

On August 15, 1996, Dr. Jack Kevorkian reportedly assisted in the suicide of Judith Curren, 42, of Pembroke, Massachusetts. She suffered from chronic fatigue syndrome (CFS) and fibromyalgia (FM). Jan Murphy, another FM sufferer, also turned to Kevorkian for help; ABCNews.com later reported her assisted suicide in the summer of 1997.

A recently publicized investigation in the UK revealed that just last year, Julia Revill, age 58, hanged herself outside her family home after becoming frustrated at a lack of medical help for her Myalgic Encephalomyelitis (ME). ME is the name used abroad for chronic fatigue syndrome. She had shown some improvement after treatment at the UK's only ME hospital in Essex but had been refused funding by the local health authority for further treatment there, and her condition deteriorated.

The loss ofone of our ownalways hits hard. These and other reports sent shock waves through the FM/CFS community. Patients with fibromyalgia and chronic fatigue syndrome have an exquisite understanding of the pain-both physical pain and emotional anguish-associated with having a poorly understood, incurable disease. "When you start hearing there is no hope, no treatment, and no cure over and over, you lose your will to fight," wrote Jan Murphy in a eulogy read at her funeral. "What most people saw of me was a shell of what was going on inside."

The FM/CFS community is certainly not alone in addressing the problem of suicide. Each year, nearly 30,000 people in the United States take their own lives. It is the 11th leading cause of death in our country and accounts for more than 10% of all deaths in the US.

Suicide and FM/CFS

It is unclear whether there is an increased risk of suicide among FM/CFS patients, as compared to the general population. No specific data exist about the number of FM/CFS-related suicides. However, there is evidence that chronic pain and illness put patients at risk for suicide. According to the CFIDS Association of America, experts studying 80 suicide cases in the state of Washington suggested that physical illness-including cancer, heart disease and arthritis-contributed to half of those suicides. An illness like fibromyalgia or chronic fatigue syndrome, which is often doubted or neglected by the medical community, the public, and sometimes family and friends, can present unique problems. Patients with FM/CFS can become victims of isolation and despair.

Secondary depression is a well-known symptom of FM/CFS and is common with any type of chronic pain. Sufferers depend on a variety of sources of support, including pain management, psychological support, and financial support. When one of these essential needs remains unmet over a long period of time, it is possible for patients to begin to believe that their situation is hopeless.

In fact, a recent report published by Action for ME, a UK non-profit organization, revealed that 51% of survey respondents have felt suicidal as a result of their illness. Those with the most severe cases of the illness and who received delayed diagnosis and management were most likely to have considered suicide.

Responding to Suicidal Thoughts

Martha Ainsworth http://www.metanoia.org/ainsworth-bio.htm, founder and director of Metanoia, a non-profit organization dedicated to suicide prevention, describes the problem of suicide succinctly. She writes, “Suicide happens when pain exceeds resources for coping with pain.” There are many kinds of pain that may lead to suicide, and individuals vary greatly in their capacity to withstand pain. According to Ainsworth, you can survive suicidal feelings if you do either of two things: (1) find a way to reduce your pain, or (2) find a way to increase your coping resources. Both are possible.

It is important to realize that suicide is a permanent solution to a temporary problem. The Journal of the American Medical Association has reported that 95% of all suicides occur at the peak of a depressive episode. For many people who feel suicidal, there seems to be no other way out. But suicidal thoughts are typically a reflection of distorted thinking caused by severe depression or even by the neurological changes associated with FM/CFS itself. When we are depressed, we tend to see things through the very narrow perspective of the present moment. A week or a month later, things may look completely different.

Warning Signs of Suicide

Talking or joking about suicide or statements about being reunited with a deceased loved one

Making statements about hopelessness, helplessness, or worthlessness ("Life is useless" or "Everyone would be better off without me.”)

Preoccupation with death (recurrent death themes in music, literature, or drawings)

Appearing suddenly happier or calmer

Loss of interest in things one cares about

Unusual visiting or calling people one cares about (saying good-byes)

Giving possessions away, making arrangements, or settling one's affairs

Self-destructive or risk-taking behavior (alcohol/drug abuse, reckless driving, self-injury or mutilation).

Most people who once thought about killing themselves are now glad to be alive. They say they didn’t want to end their lives - they just wanted to stop the pain. According to Dr. William Collinge, Ph.D., author of several books including Recovering from Chronic Fatigue Syndrome, “If you can remind yourself that the suicidal thoughts or feelings are transitory and symptomatic of the illness, this will help you get through those times when you are in the bottom of the pits and can't see any way out. Also, talking about your feelings with a confidant or loved one can help immeasurably.”

Experts agree that talking about suicidal feelings is one of the most important things you can do. Talking to a caring and supportive friend or family member can be helpful, and there are a variety of helplines and support groups to whom people who are feeling suicidal can reach out. Severe depression, the primary cause of suicide, is highly treatable. If depression is recognized and treated, many suicides can be prevented.

Anyone who has suffered with fibromyalgia or chronic fatigue syndrome knows that it requires a huge adjustment, not only to the illness itself but to all the consequences it has on our lives. Chronic illness is likely to affect the way sufferers live, the way they see themselves, and how they relate to others. With the present state of world events, many people are feeling additional tension, anxiety, or sadness. But suffering with severe depression may be unnecessary. If you or someone you know is having thoughts of suicide, it’s essential that you know you don’t have to go it alone. Suicide is preventable, and there are a variety of resources that can provide the support you need.

. http://www.co-cure.org/ccpccd.pdf 041020
. "The Canadian Expert Consensus Panel has published a medical milestone, the first clinical case definition for the disease known as myalgic encephalomyelitis/chronic fatigue syndrome. This definition is clearly a vast improvement over the CDC's 1994 Fukuda criteria, which led to misunderstanding in both research and treatment modalities by making "fatigue" a compulsory symptom but by downplaying or making optional the disease's hallmark of post-exertional sickness and other cardinal ME/CFS symptoms. In sharp contrast to the Fukuda criteria, this new clinical case definition makes it compulsory that in order to be diagnosed with ME/CFS, a patient must become symptomatically ill after exercise and must also have neurological, neurocognitive, neuroendocrine, dysautonomic, and immune manifestations. In short, symptoms other than fatigue must be present for a patient to meet the criteria. This case definition, which incorporates some of the current research on dysautonomia, cardiac, and immune problems, was published in the Journal of Chronic Fatigue Syndrome, Vol. 11 (1) 2003."

It is summarized as follows:

1. POST-EXERTIONAL MALAISE AND FATIGUE: There is a loss of physical and mental stamina, rapid muscular and cognitive fatigability, post-exertional fatigue, malaise and/or pain, and a tendency for other symptoms to worsen. A pathologically slow recovery period (it takes more than 24 hours to recover). Symptoms exacerbated by stress of any kind. Patient must have a marked degree of new onset, unexplained, persistent, or recurrent physical and mental fatigue that substantially reduces activity level. [Editor’s note: The M.E. Society prefers to use “delayed recovery of muscle function,” weakness, and faintness rather than “fatigue.” Further, we disagree that the muscle dysfunction is “unexplained.” See our M.E. Definitional Framework and researchers’ medical explanations on this website.]

2. SLEEP DISORDER: Unrefreshing sleep or poor sleep quality; rhythm disturbance.

3. PAIN: Arthralgia and/or myalgia without clinical evidence of inflammatory responses of joint swelling or redness. Pain can be experienced in the muscles, joints, or neck and is sometimes migratory in nature. Often, there are significant headaches of new type, pattern, or severity. [Editor’s note: neuropathy pain is a common symptom and should be added here as well.]

4. NEUROLOGICAL/COGNITIVE MANIFESTATIONS: Two or more of the following difficulties should be present: confusion, impairment of concentration and short-term memory consolidation, difficulty with information processing, categorizing, and word retrieval, intermittent dyslexia, perceptual/sensory disturbances, disorientation, and ataxia. There may be overload phenomena: informational, cognitive, and sensory overload -- e.g., photophobia and hypersensitivity to noise -- and/or emotional overload which may lead to relapses and/or anxiety.


a. AUTONOMIC MANIFESTATIONS: Orthostatic Intolerance: e.g., neurally mediated hypotension (NMH), postural orthostatic tachycardia syndrome (POTS), delayed postural hypotension, vertigo, light-headedness, extreme pallor, intestinal or bladder disturbances with or without irritable bowel syndrome (IBS) or bladder dysfunction, palpitations with or without cardiac arrhythmia, vasomotor instability, and respiratory irregularities. [Editor’s note: low plasma and/or erythrocyte volume should be added as another explanation for orthostatic intolerance in this disease. We also hold that more cardiac symptoms should be listed such as left-side chest aches and resting tachycardias, which, in addition to low blood volume, have also been documented in the research. The full text of the case definition does suggest 24-hour Holter monitoring, and when tachycardias with T-wave inversions or flattenings are present that they not be labeled as nonspecific since they aid in the diagnosis of ME/CFS. See the above link to access the diagnostic part of the document.]

b. NEUROENDOCRINE MANIFESTATIONS: loss of thermostatic stability, heat/cold intolerance, anorexia or abnormal appetite, marked weight change, hypoglycemia, loss of adaptability and tolerance for stress, worsening of symptoms with stress and slow recovery, and emotional lability.

c. IMMUNE MANIFESTATIONS: tender lymph nodes, sore throat, flu-like symptoms, general malaise, development of new allergies or changes in status of old ones, and hypersensitivity to medications and/or chemicals.

6. The illness persists for at least 6 months. It usually has an acute onset, but onset also may be gradual. Preliminary diagnosis may be possible earlier. The disturbances generally form symptom clusters that are often unique to a particular patient. The manifestations may fluctuate and change over time. Symptoms exacerbate with exertion or stress.


This summary is paraphrased from Dr. Kenny van DeMeirleir's book Chronic Fatigue Syndrome: A Biological Approach, February 2002, CRC Press, pg. 275. A few edits and suggestions were added by the M.E. Society of America. As we have noted, the M.E. Society of America holds that this is the best case definition so far, although it is not perfect. Listing more cardiac and neurological symptoms (e.g., chest pain, left-side chest aches, tachycardia, and neuropathy pain), and emphasizing muscle weakness and faintness instead of “fatigue,” would have more accurately represented the symptomatology and vastly improved the criteria (please see our M.E. Definitional Framework on this website). Nevertheless, the Canadian Consensus Panel clinical case definition more accurately represents the experience and manifestations of the disease than other current case definitions.


Research Kills Theory That Chronic Fatigue Syndrome/ME is Psychosomatic


High Profile Sufferer: Up to 6,000 ME sufferers in Northern Ireland, like round-the-world yachtswoman and author Clare Francis, are now being recognised as suffering with the debilitating illness
Source: the Irish News (Belfast, Northern Ireland) via Co-Cure

By Anne Madden
Health Correspondent

"...A light flashed at the end of a tunnel of ignorance and enigma for thousands of ME sufferers at a conference in Belfast on Saturday, November 2, 2002.

World-renowned clinician Professor Kenny De Meirleir from Belgium discussed the findings of his research which demolishes the long-held theory that ME is psychosomatic.

The debilitating condition, which affects around 6,000 people in Northern Ireland and 240,000 across the UK, has a range of symptoms chiefly characterised by chronic tiredness.

For years ME (Myalgic Encephalomyelitis) or Chronic Fatigue Syndrome (CFS) has been mocked as the 'yuppie flu' suggesting that sufferers are all middle class neurotics. However, the results of Professor De Meirleir's £3 million research offer a powerful case for ME being a biological, not a psychological problem.

The professor, who is an advisor to the US and Canadian governments on ME, told the conference at Queen's University, Belfast that the difficulty of the disease is that it is not one but several conditions.

He described how there are three main sub-groups of the disease, from mild to severe, with a variety of symptoms. But the factor that is common to them all is a disordered immune system.

"Innate immunity dysfunction would be a more accurate name for CFS," he said. Professor De Meirleir described how there are a number of different mechanisms which trigger the condition, but he has no doubt that CFS is an immune disorder. "No two people have the same disorder," he said.

"In some people it is stress plus exposure to heavy metals. In other cases people may have had a long-standing stress plus a viral infection which wasn't treated properly."

The professor offered hope to many sufferers that if CFS is diagnosed in its early stages it can be treated with the right combination of therapies. However, the most severe cases who suffer for more than 10 years can suffer permanent damage to their immune system which greatly enhances their risk of cancer.

"The pathology of the disease is not a mystery anymore," he said.

"The Americans have now worked out the entire genome of CFS. Unsurprisingly, all the genes are related to the immune system. We can say for certain that CFS is an immune disorder.

However, he argued that genetic predisposition is a weak factor in the disease, although it is about twice as common in women as men. Exposure to heavy metals or organophosphates , contracting a lymphotropic virus such as Dengue fever or EBV and long-standing mental or physical stress can all be trigger factors. His research also reveals that 6.4 per cent of ME patients began suffering symptoms 40 to 72 hours after a blood transfusion..."

"It is time people with ME had their condition investigated just like people who present with other diseases such as cancer"



Novel Chronic Fatigue Syndrome (CFS) Theory Finally Produces Detailed Explanations for Many CFS Observations


By Dr. Martin L. Pall
Professor of Biochemistry and Basic Medical Sciences
Washington State University
Source: http://molecular.biosciences.wsu.edu/Faculty/pall.html

A novel theory of the cause of Chronic Fatigue Syndrome (CFS) has been published which is supported by diverse biochemical and physiological observations of CFS, while providing explanations for five of most difficult puzzles about this medical condition.

The theory has been published by Dr. Martin L. Pall (Professor of Biochemistry and Basic Medical Sciences, Washington State University) in several publications (1-4,9). The theory starts with the observation that infections that precede and may therefore induce CFS and related conditions act to induce excessive production of inflammatory cytokines that induce, in turn, the inducible nitric oxide synthase (iNOS). This enzyme, in turn, synthesizes excessive amounts of nitric oxide which reacts with another compound (superoxide) to produce the potent oxidant peroxynitrite.

Peroxynitrite acts via six known biochemical mechanisms to increase the levels of both nitric oxide and superoxide which react to produce more peroxynitrite. In this way, once peroxynitrite levels are elevated, they may act to continue the elevation, thus producing a self-sustaining vicious cycle (ref.1). It is this cycle, according to the theory, that maintains the chronic symptoms of CFS and it is this cycle, therefore, that must be interrupted to effectively treat this condition.

Twelve different observations on chronic fatigue syndrome and its symptoms provide support for this theory:
1. The levels of neopterin, a marker for the induction of the inducible nitric oxide synthase are reported to be elevated in CFS (1).
2. Mitochondria are reported to be dysfunctional in CFS and mitochondria are known to be attacked by peroxynitrite and also by nitric oxide (1).
3. Both cis-aconitate and succinate levels are reported to be elevated in CFS and the enzymes that metabolize these two compounds are known to be inactivated by peroxynitrite (1).
4. The four inflammatory cytokines implicated have been reported to be elevated in 10 different studies of CFS (1,2).
5. These same inflammatory cytokines have been reported to induce fatigue when injected into humans (1).
6. An animal (mouse) model of CFS has "fatigue" induced by a bacterial extract that can induce both the inflammatory cytokines and also the inducible nitric oxide synthase.
7. Polyunsaturated fatty acid pools are reported to be depleted in CFS and such polyunsaturated fatty acids are known to be oxidized by oxidants such as peroxynitrite.
8. Anecdotal evidence has suggested that antioxidants such as coenzyme Q10, flavonoids and glutathione precursors may be useful in CFS treatment, consistent with a role for an oxidant such as peroxynitrite.
9. Women are reported to produce more nitric oxide than men, possibly explaining the gender bias seen in CFS. A similar gender bias is seen in autoimmune diseases characterized by excessive peroxynitrite (e.g., lupus, rheumatoid arthritis).
10. Cases of CFS are associated with high levels of deleted mitochondria DNA, suggesting but not proving that mitochondrial dysfunction can produce the symptoms of CFS (1).
11. Biochemical similarities - depletion of glutamine and cystine pools - have been reported in CFS and several diseases characterized by elevated peroxynitrite levels, suggesting a similar biochemical basis for all of these conditions (1).
12. Because peroxynitrite is a potent oxidant, this theory predicts that oxidative stress will be elevated in CFS. There was no direct evidence for this when the theory was published, but three subsequent papers have reported substantial evidence for such oxidative stress in CFS (5-7A). These results, may therefore, be considered to confirm important predictions of the theory, although the authors were unaware of this theory when they initiated these studies.

CFS puzzles explained by the elevated nitric oxide/peroxynitrite theory:
There are five different puzzles of CFS that are explained by this theory. The first of these, the chronic nature of CFS, is explained by the self-sustaining vicious cycle that is central to this theory. The second is how infection and other stress which often precede CFS may produce CFS. This theory predicts that each of these can lead into this mechanism by inducing excessive nitric oxide. Infection is not the only stress that may be involved in this way - both physical trauma and severe psychological trauma can produce excessive nitric oxide synthesis (2). In addition, tissue hypoxia may induce this cycle by increasing levels of superoxide (the other precursor of peroxynitrite) (2).

A third puzzle about CFS is how it leads to the many biochemical/physiological correlates reported to occur in CFS. This is discussed with the list of 12 such correlates described above.

A fourth puzzle about CFS is how the diverse symptoms of this condition may be generated. It turns out that a variety of factors, including nitric oxide, superoxide, oxidative stress and mitochondrial/energy metabolism dysfunction may have important roles (2). For example, nitric oxide is known to stimulate the nociceptors that initiate the perception of pain, and therefore excessive nitric oxide may cause the multi-organ pain associated with CFS (2).

Nitric oxide has a central role in learning and memory and so its elevation may also provide a partial explanation for the cognitive dysfunction characteristic of CFS (2). Other symptoms explained by this theory include orthostatic intolerance, immune dysfunction, fatigue and post-exertional malaise (2). The immune dysfunction reported in CFS may allow for opportunistic infections to develop, such as mycoplasma or HHV6 infections, which may exacerbate the basic CFS mechanism by increasing inflammatory cytokine synthesis.

What about multiple chemical sensitivity, posttraumatic stress disorder and fibromyalgia?

A fifth puzzle regarding CFS is its variable symptoms and, most importantly, its association with three other conditions of equally puzzling etiology, multiple chemical sensitivity (MCS), posttraumatic stress disorder (PTSD) and fibromylagia (FM). The theory explains the variable symptoms, from one case to another, in part, by a somewhat variable tissue distribution of the elevated nitric oxide/peroxynitrite.

A common etiology (cause) for CFS with MCS, PTSD and FM has been suggested by others (discussed in refs 4,9). A common causal mechanism for these four conditions is suggested not only by the association among these different conditions (many people are afflicted by more than one) but also by the overlapping symptoms typically found in these four conditions (see refs. 4 and 9 for discussion). These overlaps raise the question about whether MCS, FM and PTSD may be caused by excessive nitric oxide and peroxynitrite. Each of these four conditions is reported to be often preceded by and possibly induced by exposure to a relatively short-term stress that can induce excessive nitric oxide synthesis.

Pall and Satterlee (4) present a substantial case for an excessive nitric oxide/peroxynitrite cause for multiple chemical sensitivity (MCS), including the following:

- Organic solvents and pesticides whose exposure is reported to precede and presumably induce multiple chemical sensitivity, are also reported to induce excessive nitric oxide synthesis. Such chemicals are also reported to induce increased synthesis of inflammatory cytokines which induce, in turn, the inducible nitric oxide synthase (leading to increased synthesis of nitric oxide).

- Neopterin, a marker of induction of the inducible nitric oxide synthase, is reported to be elevated in MCS.

- Markers of oxidative stress are reported to be elevated in MCS, as predicted if excessive peroxynitrite is involved.

- In animal models of MCS, there is convincing evidence for an essential role for both excessive NMDA activity (where such activity is known to induce excessive nitric oxide) and for excessive nitric oxide synthesis itself. If one blocks the excessive nitric oxide synthesis in these animal models, the characteristic biological response is also blocked. This and other evidence shows that nitric oxide has an essential role (4).

Somewhat similar evidence is available suggesting an elevated nitric oxide/peroxynitrite mechanism for both PTSD and FM (9). PTSD is thought to be induced by excessive NMDA stimulation, which, as discussed above, is known to produce excessive nitric oxide and peroxynitrite (9). Two inflammatory cytokines known to induce increased synthesis of nitric oxide have been reported to be elevated in PTSD. PTSD animal model studies have reported an essential role for both excessive NMDA stimulation and nitric oxide synthesis in producing the characteristic biological response.

Interestingly, a recent study of FM implicates elevated nitric oxide and also elevated NMDA stimulation (8), and such NMDA stimulation is known to increase nitric oxide synthesis. As in the other conditions discussed here, there is a pattern of evidence from studies of FM patients, consistent with the proposed nitric oxide/peroxynitrite mechanism (9).

The theory that elevated nitric oxide/peroxynitrite is responsible for the etiology of CFS, MCS, PTSD and FM appears to be the only mechanism to be proposed that explains the multiple overlaps among these four conditions. While the pattern of evidence supporting it cannot be considered definitive, the many types of evidence providing support for this view must be considered to be highly suggestive.

What does this proposed mechanism suggest about CFS treatment? As discussed in ref 1, there are a number of agents that may be useful in the treatment of CFS, based primarily on anecdotal evidence, that are expected to lower the consequences of the proposed nitric oxide/peroxynitrite mechanism. Possibly the most intriguing such mechanism relates to the widespread use of vitamin B12 injections in treatment of CFS (3). Two forms of vitamin B12 are being used here, hydroxocobalamin, which is a nitric oxide scavenger and cyanocobalamin, which is converted to hydroxocobalamin by Pall human cells (3).

These observations suggest that the nitric oxide/peroxynitrite proposed mechanism for CFS makes useful predictions for effective treatment. It is hoped that this proposed mechanism may allow us to optimize the use of these and other agents for treatment of CFS and related conditions.

from: http://www.chronicfatiguesupport.com/library/showarticle.cfm/ID/4393/


Chronic fatigue syndrome researchers offer physical evidence

24 Aug 2004

A University of Alberta study has verified that there is physical evidence for those who suffer from chronic fatigue syndrome (CFS), giving new weight to the often stigmatized and misdiagnosed disorder. Research just published in the "International Journal of Psychophysiology" determined that, using independent criteria, CFS can be distinguished from depression--two disorders that share many of the same symptoms

CFS is an often debilitating disorder, characterized by a constellation of symptoms including fever, sore throat, headache, muscle weakness, myalgias, post-external malaise, sleep and cognitive disturbances. The level of disability varies for people with CFS, but some individuals find they are unable to return to work or function normally on a day-to-day basis. Unfortunately, many of these symptoms are subjective in nature and are difficult to quantify or confirm, says Hannah Pazderka-Robinson, the lead author on the study. Not only does the stigma attached with the disorder play an emotional toll on the patient, but it has implications for insurance claims as well.

"There are a number of medical professionals who don't believe that CFS exists in the first place," said Pazderka-Robinson. "The problem is, both CFS and depression are characterized by very similar profiles. Imagine a patient who approaches a doctor and tells him they feel depressed and tired all the time.

"Since depression shows a high co-morbidity with CFS, some CFS patients are often given antidepressants--that don't work or work poorly, since they do not address the underlying condition. Again, when these medications don't work, physicians sometimes jump to the conclusion that there isn't really anything, physically, wrong. Obviously, both misdiagnosis and the tendency for doctors to treat these patients as if they're not really sick can be extremely distressing. It can also undermine the patient's trust in the doctor and make them less likely to seek treatment if the condition worsens."

The most significant part of the research was to provide independent verification for CFS sufferers that these patients are different than normal controls and they're not "just depressed," said Pazderka-Robinson.

Numerous psychological investigations have attempted to differentiate these groups, with limited success. The U of A study was the first of its kind to use electrodermal activity--electrodes were placed on each hand--to investigate the differences among CFS, depression patients and healthy controls. Using tone and light stimuli, the results showed that CFS can be discriminated from those with major depression by recordings of skin temperatures and electrodermal activity.

Moreover, the profile of CFS patients is clearly different from normal controls, suggesting there is a clear biological basis to the condition.

Pazderka-Robinson completed this study with researchers from the University Centre for Neuroscience at the University of Alberta and from Alberta Hospital.

. Myalgic = muscle pain

Encephalo = brain

Myel = central nervous system

Itis = inflammation

myalgic encephalomyelitis / m_e


- c_f_s / chronic_fatigue_syndrome

- cfids / chronic fatigue immune dysfunction syndrome

- nds /
neuroendocrineimmune dysfuction syndrome

- pvfs /
post-viral immune dysfunction syndrome

- fn / florence nightingale disease


About Myalgic Encephalomyelitis and Fibromyalgia

"Classified by the World Health Organization as a disease of the nervous system. ME is the subject of research by the Centers for Disease Control in the US and top researchers around the world"

Fibromyalgia Syndrome
Fibro = joint

Myalgia = muscle pain

"...Classified by the World Health Organization as a disease of the musculoskeletal system. Thought by many researchers to be a condition the same as, or related to ME.

What causes ME/CFS and FM?

The cause has not yet been identified. On-going research suggest that an infectious agent (possibly a virus) or other triggers invade brain and muscle cells, causing the immune system in some people to become chronically overactive.

Who, When and How Long?

ME and FM can be contracted by anyone at any age. A small minority of people recover completely, some experience a series of relapses and remissions, while in others the symptoms may persist for many years. An early and accurate diagnosis with immediate and appropriate treatment measures greatly enhances the chances for recovery.

The type, severity, and frequency of symptoms of ME and FM vary from one individual to another and often from day to day..."



"...myalgic encephalomyelitis (M.E.), [is] a multi-system disease adversely affecting the heart, brain, neuroendocrine, immune, and circulatory systems...Many different viruses, bacteria, or toxins may be involved in the etiology of the disease in combination with genetic factors. Studying research-based subsets is the key to scientific progress in this area of investigation. In a number of publications, Dr. A. Melvin Ramsay outlined a definitional framework that described abnormal muscle metabolism, circulatory impairment, and cerebral involvement. There is, however, a more current, research-updated criteria compiled by the Canadian Consensus Panel for ME/CFS, which includes neuroendocrine, immune, and cardiocirculatory symptoms as well as abnormal muscle metabolism, circulatory impairment, and cerebral/neurological involvement...Unfortunately, in 1988, what was historically known both as myalgic encephalomyelitis and as the well-documented epidemic neuromyasthenia was renamed “Chronic Fatigue Syndrome” by employees at the Centers for Disease Control (CDC), who imposed the misleading “fatigue” term onto patients and researchers. In 1994, more damage was done when the CDC broadened the definition for CFS to include many diverse, unrelated diseases, for which “CFS” became an umbrella term. Currently, a government-appointed name-change workgroup has proposed a new umbrella term, Neuroendocrineimmune Dysfunction Syndrome (NDS), under which Ramsay, Canadian, and other selection criteria subsets would be placed.

Ramsay's preliminary observations and identification of the essential features were well grounded, but in the years since Ramsay published, there has been a great deal of research that has increased our understanding of this disease. For example, mounting research indicates that orthostatic intolerance, in some cases involving a virally induced dysfunction of the autonomic nervous system, low plasma and/or erythrocyte volume, or left-ventricular failure upon postural stress according to new research, should be added as a separate and important feature of M.E. that occurs when the degree of illness is moderate or severe. The Canadian Clinical Case Definition lists neurally mediated hypotension, postural orthostatic tachycardia syndrome, cardiac arrhythmia, and neuroendocrine immune manifestations. While it also lists fatigue as a symptom, a more accurate use of language would be to use “muscle weakness and painor “delayed muscle recovery after exerciseas opposed to the vague and inaccurate term “fatigue” for muscle problems. We urge researchers and patients to eliminate the label of fatigue and focus instead on a neuroendocrine immune, cardiocirculatory model. In addition to what the Canadian Consensus Panel described, some research has shown respiratory chain deficits and damage to the mitochondrial DNA, and, when the degree of illness is severe, acquired myopathic changes in some subsets.

M.E. generally begins in childhood or early adulthood with an acute infection (although slow onset is also possible) resulting in immune dysregulation, and there is some evidence that mitochondrial dysfunction plays a role in the ensuing pathophysiology of M.E. and of other neurological diseases. Infections and/or environmental toxins, alone or in combination with genetic factors, may play a role in the etiology of the disease. Although we still do not have a universally accepted final theory as to why the body reacts in this way, research points to a cascade of events involving an abnormal neuroendocrine immune, cardiocirculatory response with immune system dysregulation (inflammation, low CD8’s [Klimas], and autoimmunity); post-exertional hypercoagulation and/or abnormal erythrocyte morphology with chronic and/or progressive post-exertional tissue hypoxia-ischemia; dysautonomia and neuroendocrine involvement such as elevated epinephrine, abnormal neural orthostatic responses to epinephrine, and low plasma and/or erythrocyte volume; and cardiomyopathy. Viral cardiomyopathy, viral encephalitis, and virally induced dysfunction of the autonomic nervous system may all contribute to the multi-system picture in a prominent subset of this disease, according to hypotheses for which researchers have presented evidence.

Others have argued that the muscle and neuroendocrine dysfunction may follow from inadequate oxygen delivery to tissues, either from coagulopathy, blood viscosity, and deposits of fibrin; or blood with high values of red cells with altered margins – or both. When the capacity of cells to take up and release oxygen is impaired, the body shifts to anaerobic metabolism, wherein incomplete metabolism of glycogen leads to the formation of lactic acid, which further impairs oxygen delivery. Brain, nerves, heart, skeletal muscles, and endocrine glands have higher requirements for oxygen and nutrient substrates, require more energy, and react to deficiencies with more serious consequences.

The mitochondria and respiratory chain are adversely affected by tissue hypoxia-ischemia; they are also adversely affected by elevated nitric oxide, another common finding in the disease. Some infectious agents also adversely affect the mitochondria. Mitochondrial metabolism is the principle source of energy intermediates as well as of free radicals. Acquired mitochondrial defects could be responsible for the neuronal degeneration. Mitochondrial respiratory chain dysfunction has been reported in association with primary mitochondrial DNA abnormalities. But defects in oxidative phosphorylation and increased free radical production have also been observed in diseases that are not due to inherited mitochondrial abnormalities. In these cases, the mitochondrial failure is likely to be an epiphenomenon that precipitates a secondary cascade of events. As in other conditions in which the respiratory chain is compromised, M.E. is a multi-system disease affecting many organ systems of the body. The end result of the above-described cascade may be a crisis in the cells of the skeletal muscles, heart, brain, kidney, endocrine, and other systems. Accumulated damage to the mitochondrial DNA over many years could lead to similar problems as in inherited mitochondrial diseases.

In her recent paper (Jan 01), "The Late Effects of ME," the well-known English ME specialist Dr. Betty Dowsett wrote: ".....FINAL STAGE (1,2) After a variable interval, a multi-system syndrome may develop, involving permanent damage to skeletal or cardiac muscle and to other "end organs" such as the liver, pancreas, endocrine glands and lymphoid tissues, signifying the further development of a lengthy chronic, mainly neurological condition with evidence of metabolic dysfunction in the brain stem. Yet, stabilization, albeit at a low level, can still be achieved by appropriate management and support. The death rate of 10% occurs almost entirely from end-organ damage within this group (mainly from cardiac or pancreatic failure)."..."




Complied by Jodi Bassett, 2004 http://www.ahummingbirdsguide.com/
- a hummingbird's guide to me/cfids - *information on living with severe myalgic encephalomyelitis /cfids


"...Many CFIDS patients have compared their cognitive difficulties to being "in a fog". In many ways, the CFIDS brain is functioning as though it is asleep, even though the patient is awake. Careful evaluation of data taken from hundreds of CFIDS patients showed patients had abnormal increases in slow wave activity compared to healthy controls and patients with other diseases. Essentially CFIDS patients are utilizing non-functional waveforms such as Delta and Theta to do functional tasks in a compensatory way. This slow wave activity is consistent with a metabolic encephalopathy (brain injury).

Research has shown that the brain activity of the CFIDS patient speeds up when the eyes are closed and it slows down when the eyes are open, which is the opposite of a normal response. This may be one reason that conventional EEG results for CFIDS patient are often evaluated as "normal", since they are typically done in an eyes-closed position. CFIDS patients display unique functional brain abnormalities only when you compare the data of patients/controls while being cognitively challenged with the eyes open..."
- from:


"...Many people with CFIDS experience brain fogthe sensation of being lost in a waking trance, hearing but not comprehending, talking but not making sense....The brain has four main states of alertness, each corresponding to a brain wave. High-frequency beta waves are present during active, waking moments, while alpha waves are associated with daydreaming or reflective states. Low-frequency theta and delta waves are usually present during rest or sleep.

People with CFIDS (PWCs) often show markedly different patterns than normal, Preston says. Preston has discovered that people with CFIDS produce predominantly slow-wave activity. While most people show beta (fast) wave activity when performing cognitive tasks, CFIDS patients try to perform them with theta and delta states instead.

Their intelligence remains intact, but the ability to access it is unpredictable and unreliable. The brain reverses the order in which it is supposed to perform; when the eyes are open, the brain slows down, and when they are closed, the brain speeds up.

It’s like trying to work when your brain says ‘sleep,’ Preston says. “It’s no wonder that people have so many disabling symptoms and trouble concentrating.”

The brain wave patterns of PWCs resemble those of people with closed head injuries and hepatic encephalophathy. Preston says the predominance of slow-wave activity can be correlated with symptoms such as sleep disturbance, short-term memory problems, low blood pressure, reduced energy, cognitive difficulties, headaches, nausea, heart arrhythmias and more..."


skyburst777 looking_for_a_cure_for_me 050607
skyburst777 _memorial_ 050607


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