ME/CFS Timeline

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Contents

Early History

The popular view of ME is that it arose in the middle of the 20th Century, with the Royal Free outbreak of 1955 being the earliest occurrence generally quoted. Despite this popular belief, similar infectious conditions which may or may not have the same causation have been reported far earlier than this.

In 1837, Charles Darwin wrote ""Of late anything which flurries me completely knocks me up afterwards, and brings on a violent palpitation of the heart." He suffered for forty years with malaise, vertigo, dizziness, severe GO symptoms, insomnia, and other symptoms that could have been ME.[1]

In 1855, Florence Nightingale caught a fever in the Crimea. Four days later an assistant surgeon, George Lawson, was also struck down with 'Crimea Fever'. They both suffered with many ME symptoms for decades after the initial infection. [2]

1930s

1934, Los Angeles Outbreak

The Los Angeles County General Hospital was the site of the first ever recorded outbreak of the condition. Initial thoughts at the time believed the illness might be linked to polio, but, as the patients' muscles, albeit weakened, did not waste, this was subsequently not deemed to be an accurate explanation of events. Around 200 members of staff contracted the condition and over 50% of them were still unable to work six months later. Their symptoms essentially composed of:

· Long-duration muscle pain, tenderness, weakness, as well as sensory symptoms

· Memory lapses, difficulty concentrating, sleep disturbance, emotional instability, and being unable to walk even small distances without suffering from fatigue (Macintyre, 1998).

See: Epidemiological study of an epidemic diagnosed as poliomyelitis occurring among the personnel of the Los Angeles County General Hospital during the summer of 1934. Public Health Bulletin No. 240, April 1938.

http://babel.hathitrust.org/cgi/pt?id=mdp.39015022082260;view=1up;seq=617

and http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751857/pdf/calwestmed00415-0071.pdf

1940s

1948-9 Akureyri outbreak

Iceland experienced an outbreak in 1948-9 of ME/CFS in a small town in the north of the island called Akureyri. The incident affected in excess of 1000 people. In a subsequent polio epidemic on the island in 1955, the same town was apparently unaffected. As a result, it has been argued that the virus that 'triggered' the ME/CFS outbreak resulted in a level of immunity to polio (Macintyre, 1998).

http://www.name-us.org/DefintionsPages/DefinitionsArticles/Acheson1959.pdf

1950s

1955, Royal Free Hospital Outbreak.

  • 292 members of staff come down with an infectious outbreak, that forces the hospital's closure between 25th July and 5th October.
  • The case, along with several others, went on to coin the term 'benign myalgic encephalomyelitis.' (ME)

http://www.ncbi.nlm.nih.gov/pubmed/13320887

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1962472/?tool=pmcentrez


1956, May 26: Acheson ED. "A New Clinical Entity?" in Volume 267, Issue 6926, pg 789-790, Lancet.

  • Although at the time this Editorial was anonymous, it was later conceded by Sir Donald Acheson that he had written it.

“In spite of perplexing variations in the clinical picture from case to case it soon became clear that a new clinical entity had appeared.”

“Relapses are frequent.”

“Among the more characteristic features are the severe muscular pains, often accompanied by exquisite tenderness. Most commonly they affect the neck, back or limbs but there may also be Bornholm-like chest and abdominal pains.”

“In nearly every patient there are symptoms or signs of disease of the central nervous system.”

“Hepatitis and splenomegaly may also turn out to be part of the picture.”

“The term ‘benign myalgic encephalomyelitis’ does describe some of the striking features by (1) symptoms and signs of damage to the brain and spinal cord; (2) protracted muscle pain with paresis and cramp; (3) emotional disturbances in convalescence; (4) normal cerebrospinal fluid; (5) involvement of the reticulo-endothelial system; (6) a protracted course with relapses in severe cases.”

“We believe that its characteristics are now sufficiently clear to differentiate it from poliomyelitis, epidemic myalgia, glandular fever, the forms of epidemic encephalitis already described, and, need it be said, hysteria.”

http://www.meactionuk.org.uk/Organic_evidence_for_Gibson.pdf (Page 9)


1957, October 19: The Medical Staff of the Royal Free Hospital. "An Outbreak of Encephalomyelitis in the Royal Free Hospital Group, London, in 1955" in the British Medical Journal.

"On July 13, 1955, a resident doctor and a ward sister on the staff of the Royal Free Hospital were admitted to the wards with an obscure illness. By July 25 more than 70 members of the staff were similarly affected, and it was plain that there was in the hospital an epidemic of a highly infectious character, producing amongst other things manifestations in the central nervous system..."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1962472/pdf/brmedj03125-0013.pdf


1959: Acheson ED. "The Clinical Syndrome Variously Called Benign Myalgic Encephalomyelitis, Iceland Disease and Epidemic Neuromyasthenia" in the American Journal of Medicine.

"In view of the dissimilarity of the clinical picture to any known bacterial infection, attention has naturally been focused on isolating a virus as the responsible agent."

“Pain in the muscles was an almost constant feature. In severe cases it was agonizing and unresponsive even to opiates” “Definite parasthesia occurred. Diplopia (was noted).”

“It would be manifestly erroneous to consider as hysteria the emotional instability associated with this illness. The disorder is not a manifestation of hysteria.”

“Other sensory disturbances consisted of loss of memory and difficulty in concentration.”

“It is concluded that the disease is recognizable in its epidemic form on clinical and epidemiological grounds and therefore may properly be considered a clinical entity.”

"The disease is probably due to infection by an unknown agent or group of related agents."

http://www.meresearch.org.uk/information/keypubs/Acheson_AmJMed.pdf

1960s

1969, WHO ICD-8: Benign myalgic encephalomyelitis (ME) Volume I: code 323: page 158 and in Volume II (the CodeIndex) on page 173.

  • ICD-8 was approved in 1965 and published in 1969

1970s

1970, January 3: McEvedy CP, Beard AW. "Concept of Benign Myalgic Encephalomyelitis" in the British Medical Journal.

"The reports of the 15 recorded outbreaks of benign myalgic encephalomyelitis have been reviewed and in one instance the original clinical data studied. We believe that a lot of these epidemics were psychosocial phenomena caused by one of two mechanisms, either mass hysteria on the part of the patients or altered medical perception of the community. We suggest that the name "myalgia nervosa" should be used for any future cases of functional disorder which present the same clinical picture."

and

"Can this formulation be applied to any or all of the other 14? After looking at the published reports on these epidemics (which we review below with our comments), and in one instance studying the original clinical data, our conclusion is that two mechanisms are at work, both psychosocial. We believe that between them they account for the phenomenon of benign myalgic encephalomyelitis."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1700895/pdf/brmedj02268-0023.pdf


1970, January 3: McEvedy CP, Beard AW. "Royal Free Epidemic of 1955: A Reconsideration" in the British Medical Journal.

"The hypothesis of an hysterical epidemic seems to us to fit well with these and other findings. The greater susceptibility of the segregated female would explain the failure of the epidemic to propagate beyond the institutional population or, within the institution, to affect significantly the males and the patients."

and

"The occurrence of a mass hysterical reaction shows not that the population is psychologically abnormal but merely that it is socially segregated and consists predominantly of young females."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1700894/pdf/brmedj02268-0019.pdf


1975, WHO ICD-9: Benign myalgic encephalomyelitis (ME) Volume II on page 182.


1977, May 21: Letter from AM Ramsay, EG Dowsett, JV Dadswell, WH Lyle, JG Parish. "Icelandic Disease (Benign Myalgic Encephalomyelitis or Royal Free Disease)" in the British Medical Journal.

"None of the names in common use is completely descriptive of this syndrome, which is not truly benign, is not always myalgic, and has no proven connection with hysteria or neurasthenia."

"The sufferers are usually parents of young children or members of the armed Forces or of the teaching, nursing, or medical professions."

"Last year a research group was formed to study the aetiology and epidemiology of this syndrome. Our investigations so far indicate that the illness may accompany the more common viral infections and that the unique fatigue pattern may be due to mitochondrial damage."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1607215/?page=1


1978, ME accepted as a nosological organic entity by the Royal Society of Medicine.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1994528/


1978, November: Parish JG. "Early Outbreaks of "Epidemic Neuromyasthenia' " in the Postgraduate Medical Journal.

Abstract:

"The literature of the outbreaks of 'epidemic neuromyasthenia' (ENM) from 1934 to 1955 has been selected to show that the disease affects other people besides young adult females in hospitals and nursing homes. There have been district epidemics, in which the male: female ratio was almost even and several male outbreaks affecting soldiers in barracks. Some outbreaks appear to have been triggered off by an epidemic of poliomyelitis, and the epidemiology of outbreaks in Iceland in 1948 and 1955 suggests that the normal cytopathological effects of poliomyelitis infection have been suppressed by the new disease. In the Durban epidemic (1955) a toxic metabolite was discovered in the urine of many patients and a markedly increased urinary excretion of creatine was noted in two New York State outbreaks. The results of the transmission of an agent from patients with ENM to monkeys suggest that the neurological disorder might be in the form of mild disseminated lesions scattered throughout the nervous system from the brain to peripheral nerves and associated with perivascular round cell infiltration without significant cellular damage. ENM infection was widespread in the North of England in 1955 and associated with lymphocyte abnormalities, which have persisted in some cases for several years. This suggests a continuous organic process."

From Conclusions:

"This review of the early outbreaks of ENM reveals the wide spectrum of the presentation of the illness from a mild systemic disturbance, which is similar to that of other enteroviral diseases, to a meningo-encephalomyelitis with ocular palsies and upper motor neurone signs. However, the systemic illness is distinguished in many patients by a prolonged convalescence portrayed by mental changes, particularly depression, autonomic disturbances, a profound tendency to fatigue easily and relapses of the original features of the illness. The neurological complications occur more frequently in confined outbreaks affecting large groups of persons living together. The neurological changes vary considerably in situation and severity from patient to patient and show a similar tendency to recur at the original site or in a different part of the nervous system. Several epidemics appear to have been triggered off by an outbreak of an infection with enteric organisms or poliovirus which then subsides. In some patients there is a direct involvement of muscles, which may feel swollen and tender and fatigue rapidly on sustained activities such as walking. The profound generalized and muscular fatigability is a striking feature of the disease..."

"Neither of the names commonly used for the disease is completely satisfactory. 'Epidemic neuro-myasthenia' describes the epidemic nature of the disease and the abnormal fatigability of the nervous system and muscles, but the term is liable to be confused with neurasthenia and does not take into account the encephalomyelopathy. 'Benign myalgic encephalomyelitis' does not define the mild systemic form of the disease, which occurs frequently in district epidemics with its characteristic fatigability. The chronic disability revealed by the follow-up of the Los Angeles cases does not justify the title 'benign'. However, until more is known about the underlying pathology of the disease it seems preferable to use the term 'epidemic neuromyasthenia' and qualify the more severe neurological cases with the description 'encephalomyelitic form.' "

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2425322/

1980s

1984-1985: Incline Village/Lake Tahoe outbreak. After receiving repeated requests from Drs. Daniel Peterson and Paul Cheney, who had seen over 150 cases of an unknown illness, the CDC sent two investigators, Jon Kaplan and Gary Holmes, to Incline Village, Nevada in September 1985. The investigators saw about ten patients. Kaplan left after one week. Holmes stayed on and collected blood samples from 15 patients, selected on the basis of their reported fatigue, and 30 controls before returning to Atlanta. (Hillary Johnson, Osler's Web. 1996, Crown Publishers, New York. pages 43-54)

Holmes later remarked, "It was beautiful [Lake Tahoe], and I must admit, that was the one reason I wanted to go." (Osler's Web, page 44)


1986: 20/20 ABC television report, "Is That What's Wrong With Me," on the Lake Tahoe illness.

http://www.youtube.com/watch?v=4xdtVan0xko&feature=player_embedded


1986, May 30: CDC Morbidity and Mortality Weekly Report, "Chronic Fatigue Possibly Related to Epstein-Barr Virus -- Nevada."

"From November 1984 through August 1985, approximately 90 patients evaluated for persistent fatigue were diagnosed as having chronic Epstein-Barr virus (CEBV) disease by a two-physician community internal medicine practice near Lake Tahoe, Nevada."

"Currently available data neither prove nor disprove the hypothesis that EBV activity is responsible for chronic illness, but it is clear that the diagnosis of CEBV using current clinical and laboratory criteria in an individual patient is unreliable. Further examinations of immune function in these patients, as well as studies for other possible etiologies, are needed to define this syndrome and provide a framework for epidemiologic and therapeutic studies."

"In the meantime, CEBV should be a diagnosis of exclusion. Physicians evaluating patients thought to have CEBV should continue to search for the more definable, and possibly treatable, conditions that may be responsible for their symptoms, such as endocrine and autoimmune diseases; malignancies; chronic heart, liver, kidney, and pulmonary disease; anxiety and depression; and chronic infectious diseases, such as CMV and tuberculosis... Once the syndrome is better defined, epidemiologic and therapeutic studies can be initiated."

http://www.cdc.gov/mmwr/preview/mmwrhtml/00000740.htm


1986, June 7: Los Angeles Times article by Robert Steinbrook, "160 Victims at Lake Tahoe : Chronic Flu-Like Illness a Medical Mystery Story."

"Schmidt is among 160 residents of Lake Tahoe's North Shore who have been diagnosed by two local physicians since the winter of 1985 as having a chronic flu-like illness in a medical puzzle that has assumed national proportions."

"Most of the victims are well-educated, previously healthy, about 40 years old and are more likely to be women than men. Their complaints also are similar: severe fatigue, recurrent colds and difficulties with memory and concentration. About half of them have enlarged lymph nodes in their neck and almost all have abnormal blood tests, suggesting that a common viral infection may be involved."

http://articles.latimes.com/1986-06-07/news/mn-9956_1_lake-tahoe


1987: Joan Irvine in California comes down with ME/CFS after receiving a blood transfusion. In 1992, she wrote letters to Dr. William Reeves, head of the CFS program at the CDC, and Dr. George Rutherford, chief of the infectious disease branch of the California Department of Health. Both men wrote letters advising Irvine against donating blood. Photocopies of the letters and Irvine's account of events can be found here: http://www.cfs-news.org/joan.htm Joan Irvine committed suicide in 1996.


1987, April 27: First CDC Definitional Meeting. The CDC hosted the First International Symposium on Immunology and Pathogenesis of Persistent Virus Infections in Atlanta, Georgia. After the main session, Dr. Carlos Lopez of the CDC invited a group of researchers and physicians to a meeting to discuss the Incline Village/Lake Tahoe illness. Three of the doctors attending, Bryron Hyde, J. Gordon Parish, and Alexis Shelokov, were familiar with outbreaks of Myalgic Encephalomyelitis. Finding no interest in, or knowledge of, ME at the meeting, these three doctors left early. (Osler's Web, pages 205-206)

http://www.imet.ie/imet_documents/BYRON_HYDE_little_red_book.pdf (Pages 22-23)


1987, July 16: Rolling Stone article by Hillary Johnson, "Journey Into Fear: The Growing Nightmare of Epstein-Barr Virus.” Part 2, August 13, 1987.


!987, July 28: New York Times article by Philip M. Boffey, "Fatigue 'Virus' Has Experts More Baffled And Skeptical Than Ever."

Quote:

The ailment, known as chronic Epstein-Barr virus infection, chronic mononucleosis or chronic fatigue syndrome, has stirred rising concern in public and medical circles over the last two years.

But whether patients have fallen into the grip of a new, worsening scourge or have merely succumbed to the latest health hysteria is confounding many medical researchers. And the more experts study patients who have the fatiguing ailment, the less important a culprit the Epstein-Barr virus seems...

Some virus experts continue to believe that much of the chronic fatigue is psychosomatic. "A lot of illness that is now being associated with chronic Epstein-Barr virus infection is probably ordinary neuroses which are manifested nowadays as tiredness," said Dr. Eliot Kieff, head of infectious diseases at the Brigham and Women's Hospital.

"It's a disease mostly of younger adults who are having difficulties in what are ordinarily difficult phases of life, he added. These people are very unhappy, and it's often very difficult to sort out how much of their psychological problems come from their illness and how much is the cause of their illness. Most of them do not want to see a psychologist or a psychiatrist. They're looking for a physical cause of their illness and a relationship with their physician."

Dr. Komaroff, however, is convinced that the chronic fatigue syndrome is "a real, organic disease," although the Epstein-Barr virus may not be the prime cause. Such symptoms as swollen glands, fevers and sore throats "are hard to attribute to a psychological cause," he said, and most patients describe a sudden onset of disease, suggesting an infectious agent...

http://www.nytimes.com/1987/07/28/science/fatigue-virus-has-experts-more-baffled-and-skeptical-than-ever.html


1987, August 10: Nightline ABC television report on chronic fatigue and chronic Epstein-Barr virus syndrome (CEBV).

http://www.youtube.com/watch?v=CqpvRC_YurY&feature=player_embedded Part 1

http://www.youtube.com/watch?v=ta39YmPCUQ0&feature=player_embedded Part 2


1987, November 15: Caligiuri et al. "Phenotypic and Functional Deficiency of Natural Killer Cells in Patients with Chronic Fatigue Syndrome" in the Journal of Immunology.

"Natural killer (NK)3 cells are large granular lymphocytes that appear to play a significant role in the host's defense against viral infection. We performed an extensive phenotypic and functional characterization of NK cells on 41 patients with the chronic fatigue syndrome (CFS), or "chronic active Epstein-Barr virus infection" syndrome, and on 23 age- and sex-matched asymptomatic control subjects in an attempt to further characterize this illness. These studies demonstrated that a majority of patients with CFS have low numbers of NKH1+T3- lymphocytes, a population that represents the great majority of NK cells in normal individuals."

http://www.jimmunol.org/cgi/content/abstract/139/10/3306


1988, March 1: The Holmes Definition of Chronic Fatigue Syndrome. Holmes et al. "Chronic Fatigue Syndrome: A Working Case Definition" in the Annals of Internal Medicine.

A case of chronic fatigue syndrome is defined by, "New onset of persistent or relapsing, debilitating fatigue or easy fatigability in a person who has no previous history of similar symptoms, that does not resolve with bedrest, and that is severe enough to reduce or impair average daily activity below 50% of the patient's premorbid activity level for a period of at least 6 months."

"Other clinical conditions that may produce similar symptoms must be excluded by thorough evaluation, based on history, physical examination, and appropriate laboratory findings."

Eleven Symptom Criteria are listed: Mild fever, sore throat, painful lymph nodes, muscle discomfort or myalgia, prolonged (24 hours or greater) generalized fatigue after levels of exercise that would have been easily tolerated in the patient's premorbid state (post-exertional malaise), generalized headaches, migratory arthralgia without joint swelling or redness, neuropsychologic complaints (one or more of the following: photophobia, transient visual scotomata, forgetfulness, excessive irritability, confusion, difficulty thinking, inability to concentrate, depression), and sleep disturbance (hypersomnia or insomnia). "Description of the main symptom complex as initially developing over a few hours to a few days" is also listed as a symptom.

To fulfill a symptom criterion, a symptom must have begun at or after the time of onset of increased fatigability, and must have persisted or recurred over a period of at least 6 months.

Three Physical Criteria are listed: Low-grade fever, nonexudative pharyngitis, and palpable or tender anterior or posterior cervical or axillary lymph nodes.

A case of chronic fatigue syndrome must meet the fatigue criteria, and not be explainable by any other cliniical conditions which may produce similar symptoms. Six of the eleven Symptom Criteria must be met, and two of the three Physical Criteria. Or, a case may meet eight, or more, of the Symptom Criteria and none of the Physical Criteria.

"Specific laboratory tests or clinical measurements are not required to satisfy the definition of the chronic fatigue syndrome, but the recommended evaluation includes serial weight measurements (weight change of more than 10% in the absence of dieting suggests other diagnoses); serial morning and afternoon temperature measurements; complete blood count and differential; serum electrolytes; glucose; creatinine, blood urea nitrogen; calcium, phosphorus; total bilirubin, alkaline phosphatase, serum aspartate aminotransferase, serum alanine aminotransferase; creatine phosphokinase or aldolase; urinalysis; posteroanterior and lateral chest roentgenograms; detailed personal and family psychiatric history; erythrocyte sedimentation rate; antinuclear antibody; thyroid-stimulating hormone level; HIV antibody measurement; and intermediate-strength purified protein derivative (PPD) skin test with controls."

"If any of the results from these tests are abnormal, the physician should search for other conditions that may cause such a result. If no such conditions are detected by a reasonable evaluation, this criterion is satisfied."

http://www.cfids-me.org/holmes1988.html

Dr. Byron Hyde states in his 2006 "A Brief History of Myalgic Encephalomyelitis and an Irreverent History of Chronic Fatigue Syndrome," "To my knowledge he [Dr. Holmes] never continued to show any interest in this disease process and Pub Med and Google searches fail to reveal any subsequent scientific papers concerning ME or CFS." (Page 23)

Regarding the name, chronic fatigue syndrome:

"The curious name: The authors named the disease Chronic Fatigue Syndrome: Fatigue is a totally undefinable concept. Fatigue is impossible to measure or quantify. Fatigue is so non-specific that it can be a common element in any acute or chronic disease and many psychiatric diseases. Worse, it redirects the medical and public attention to the totally undefinable fatigue and away from the obvious Central Nervous System changes in these patients. Much worse, it makes fun of a serious illness since most people and most physicians tend to equate fatigue with laziness, work avoidance, something that a bit of effort will chase away. It has turned out to be a damning indictment to all M.E. patients." (A Brief History, pages 23-24)

Regarding the Holmes definition:

"It is my opinion that the CDC 1988 definition of CFS describes a non-existing chimera based upon inexperienced individuals who lack any historical knowledge of this disease process. The CDC definition is not a disease process. It is (a) a partial mix of infectious mononucleosis/glandular fever, (b) a mix of some of the least important aspects of M.E. and (c) what amounts to a possibly unintended psychiatric slant to an epidemic and endemic disease process of major importance." (A Brief History, page 23)

http://www.imet.ie/imet_documents/BYRON_HYDE_little_red_book.pdf


1988, March 5: David AS, Wessely S, Pelosi AJ. "Postviral Fatigue Syndrome: Time for a New Approach" in the British Medical Journal.

"We take issue with the notion that if it were not for immunological abnormalities 'it would have been easy to concur with McEvedy and Beard that the illness is entirely a manifestation of hysteria.' Present controversy rests on a false dualism and an outdated separation of mind and body, and the shortcomings of these approaches are emphasised by increasing knowledge of the biological abnormalities found in psychiatric disorders. Hysteria itself is an outmoded diagnosis and is being replaced by the concept of 'abnormal illness behaviour.' This takes account of the interaction between 'organic' illnesses and psychiatric symptoms and a more sensitive appreciation of how social factors govern the presentation and outcome of illness. It is a better description of the often fraught interplay between sufferers with the postviral fatigue syndrome and their doctors."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2545306/pdf/bmj00275-0042.pdf


1988, May: Straus SE, Dale JK, Wright R, Metcalfe DD. "Allergy and the Chronic Fatigue Syndrome" in the Journal of Allergy and Clinical Immunology.

"The demography of this syndrome reflects an excessive risk for educated adult white women. This may reflect either a bias toward the cohort of sufferers who can best afford a sophisticated medical evaluation or some unique constitutional frailty of such individuals. Most patients with this syndrome report excellent prior health. Some had engaged in competitive sports or at least aggressively maintained physical conditioning. A less casual appraisal, however, often uncovers histories of unachievable ambition, poor coping skills, and somatic complaints…It is difficult and at times unpleasant to address the demands of such patients or to test hypotheses as to the etiology of their woes.”

http://www.ncbi.nlm.nih.gov/pubmed/2836490


1988, December 29: Straus SE et al. "Acyclovir Treatment of the Chronic Fatigue Syndrome" in the New England Journal of Medicine.

"Three patients had acyclovir-induced nephrotoxicity and were withdrawn from the study. Of the 24 patients who completed the trial, similar numbers improved with acyclovir therapy and with placebo (11 and 10, respectively). Neither acyclovir treatment nor clinical improvement correlated with alterations in laboratory findings, including titers of antibody to Epstein–Barr virus or levels of circulating immune complexes or of leukocyte 2′,5′-oligoadenylate synthetase. Subjective improvement correlated with various measures of mood."

"We conclude that acyclovir, as used in this study, does not ameliorate the chronic fatigue syndrome. We believe that the clinical improvement observed in most patients reflected either spontaneous remission of the syndrome or a placebo effect."

http://www.nejm.org/doi/full/10.1056/NEJM198812293192602

1990s

1990, June: Klimas et al. "Immunologic Abnormalities in Chronic Fatigue Syndrome" in the Journal of Clinical Microbiology.

"The chronic fatigue syndrome (CFS), formerly known as chronic Esptein-Barr virus syndrome, is a clinical state of some complexity and uncertain etiology. In order to characterize in a comprehensive manner the status of laboratory markers associated with cellular immune function in patients with this syndrome, 30 patients with clinically defined CFS were studied. All of the subjects were found to have multiple abnormalities in these markers. The most consistent immunological abnormality detected among these patients, when compared with normal controls, was low natural killer (NK) cell cytotoxicity.... The pattern of immune marker abnormalities observed was compatible with a chronic viral reactivation syndrome."

"In summary, the results of the present study, in which a number of the attributes of immunologic function were determined in a single cohort of patients, as well as the combined results of a number of studies in the literature that was reviewed, suggest that CFS is a form of acquired immunodeficiency."

http://jcm.asm.org/cgi/reprint/28/6/1403


1990, July: Dowsett EG, Ramsay AM, McCartney RA, Bell EJ. "Myalgic Encephalomyelitis--A Persistent Enteroviral Infection?" in the Postgraduate Medical Journal.

"Myalgic encephalomyelitis is a common disability but frequently misinterpreted. Amongst 6,000 patients referred for general microbiological diagnosis between 1975 and 1987, 420 cases were recognized. Coxsackie B neutralization tests, in 205 of these, demonstrated significant titres in 103/205 (50%), while of 124 additionally investigated for enteroviral IgM, 38/124 (31%) were positive. This illness is distinguished from a variety of other post-viral states by an unique clinical and epidemiological pattern characteristic of enteroviral infection. Prompt recognition and advice to avoid over-exertion is mandatory. Routine diagnosis, specific therapy and prevention, await further technical advances."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2429637/pdf/postmedj00163-0031.pdf


1990, November 12: Newsweek cover story, "Chronic Fatigue Syndrome."

http://www.newsweek.com/1990/11/11/chronic-fatigue-syndrome.html


1990, December 4: New York Times article by Lawrence Altman, "Chronic Fatigue Syndrome Finally Gets Some Respect."

"After years of dismissing chronic fatigue syndrome as yuppie hypochondria and little more than a figment of the imagination, doctors in growing numbers are coming to believe that it is a distinct condition and one that may reflect an overcharged immune system."

"But just what agent may be switching the immune system into overdrive is still an enigma. Scientists around the world who are seeking to solve the mystery say infectious organisms and chemicals are their prime suspects. But before they can clinch the case they are trying first to develop a reliable test to distinguish the syndrome from the many other conditions with which it is easily confused."

"Marking the seriousness with which the illness is now taken, the Federal epidemiological agency, the Centers for Disease Control in Atlanta, has started an investigation that officials say is more comprehensive than those the agency initially carried out for AIDS."

"Although the new research is providing some tantalizing clues, experts like Dr. Stephen E. Straus, chief of medical virology at the National Institutes of Allergy and Infectious Diseases in Bethesda, Md., cautioned that the clues could join a list of leads that evaporated after more extensive research."

"Chronic fatigue syndrome began receiving widespread attention in the mid-1980's after reports of about 100 cases in the Lake Tahoe area of California. Questions immediately arose as to whether the ill-defined mix of symptoms amounted to a discrete disease at all, and if so, whether it was a new condition or was merely an old malady like the neurasthenia of the 1860's, since known by other names, including Icelandic disease."

"Now that some of the dust has settled, chronic fatigue syndrome appears to be the same as what is called low natural killer cell syndrome in Japan and myalgic encephalomyelitis in England. In the United States, chronic fatigue syndrome has also been called Epstein-Barr virus syndrome, chronic mononucleosis and yuppie flu..."

http://www.nytimes.com/1990/12/04/science/chronic-fatigue-syndrome-finally-gets-some-respect.html


1991, February: The Oxford Definition of Chronic Fatigue Syndrome. Sharpe et al. "A Report - Chronic Fatigue Syndrome: Guidelines for Research." in the Journal of the Royal Society of Medicine.

"Due to contradictory findings of previous research into fatigue, the authors of the Oxford definition attempt to construct a new criteria. They believed that the contradictory findings were a result of "investigators trained in different disciplines, using different criteria to define the condition." This group believed that previous studies into diseases such as epidemic neuromyasthenial, idiopathic chronic fatigue and myalgia syndrome, benign myalgic encephalomyelitis, chronic infectious mononucleosis, Royal Free disease, postviral fatigue syndrome, fibrositis-fibromyalgia, and chronic fatigue syndrome, where in fact all referring to a similar group of patients."

A case of chronic fatigue syndrome is defined by the presence of: "A syndrome characterized by fatigue as the principal symptom. A syndrome of definite onset that is not lifelong. The fatigue is severe, disabling, and affects physical and mental functioning. The symptom of fatigue should have been present for a minimum of 6 months during which it was present for more than 50% of the time. Other symptoms may be present, particularly myalgia, mood and sleep disturbance."

Other medical conditions that may account for the symptom of fatigue are considered exclusions.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1293107/pdf/jrsocmed00127-0072.pdf

From Dr. Byron Hyde's "A Brief History of Myalgic Encephalomyelitis and an Irreverent History of Chronic Fatigue Syndrome," 2006:

"In effect the Oxford definitions are not only bad since they are in effect a copy and a variation of the CDC definition and the authors in general do not appear to understand the definitions of Myalgic Encephalomyelitis but in addition they are onerous because they further lead the way with the psychiatric-sation of physical medicine in general and the psychiatrization of M.E. in particular or the technical confusion implicit in the CDC diagnostic criteria."

http://www.imet.ie/imet_documents/BYRON_HYDE_little_red_book.pdf (Page 27)

From Jason et al. "The Development of a Revised Canadian Myalgic Encephalomyelitis Chronic Fatigue Syndrome Case Definition," 2010:

"These criteria [the Oxford] were not frequently used by investigators, as they were considered considerably broader than the Holmes et al. (1988) criteria and a few years later, international consensus developed a new CFS case definition (Fukuda et al., 1994)."

http://www.scipub.org/fulltext/ajbb/ajbb62120-135.pdf


1991, April: DeFreitas et al. "Retroviral Sequences Related to Human T-Lymphotropic Virus Type II in Patients with Chronic Fatigue Immune Dysfunction Syndrome" in the Proceedings of the National Academy of Sciences.

Abstract:

"Chronic fatigue immune dysfunction syndrome (CFIDS) is a recently recognized illness characterized by debilitating fatigue as well as immunological and neurological abnormalities [Straus, S. E. (1988) J. Inf. Dis. 157, 405412]. Once thought to be caused by Epstein-Barr virus, it is now thought to have a different but unknown etiology. We evaluated 30 adult and pediatric CFIDS patients from six eastern states for the presence of human T-lymphotropic virus (HTLV) types I and II by Western immunoblotting, polymerase chain reaction, and in situ hybridization of blood samples. The majority of patients were positive for HTLV antibodies by Western blotting and for HTLV-II gag sequences by polymerase chain reaction and in situ hybridization. Twenty nonexposure healthy controls were negative in all assays. These data support an association between an HTLV-ll-like virus and CFIDS."

Discussion:

"We have presented evidence for HTLV-II-like infection of blood cells from CFIDS patients and, to a lesser extent, from some people who closely associate with them. More than 50% of samples from 31 patients contained antibodies to at least two viral gene products by Western blot analysis. Since serologic assays using HTLV-I-derived antigens cannot distinguish between HTLV-I- and -II-specific antibodies, the positive Western blots may be directed toward either virus..."

"Although our data support an association between an HTLV-like agent and CFIDS, we cannot, as yet, define the agent's role in the disease process. Rather than an etiologic agent, it may be a benign secondary infection to which immunologically compromised patients are susceptible. Alternatively, it may be one of two viruses that, when coinfecting the same hematopoetic cells, induce immune dysfunction. In any case, biological characterization of this agent and its role in the pathogenesis of CFIDS awaits its isolation."

http://www.pnas.org/content/88/7/2922.full.pdf


1992, WHO ICD-10: Benign myalgic encephalomyelitis (ME) & Chronic Fatigue Syndrome' (CFS) G93.3 Disorders of the Nervous System. First time CFS listed by the WHO.


1992: Dr. Hugh Fudenberg, Professor and Chairman, Department of Basic and Clinical Immunology and Microbiology, Medical University of South Carolina, states that there is “a greater death rate [for ME/CFS] than normals in the same age range.” (Byron Hyde, Editor, The Clinical and Scientific Basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. 1992, The Nightingale Research Foundation, Ottawa. page 664.)


1992, January 15: Buchwald et al. "A Chronic Illness Characterized by Fatigue, Neurologic and Immunologic Disorders, and Active Human Herpesvirus Type 6 Infection" in the Annals of Internal Medicine.

The study finds, "Neurologic symptoms, MRI findings, and lymphocyte phenotyping studies suggest that the patients may have been experiencing a chronic, immunologically mediated inflammatory process of the central nervous system. The active replication of HHV-6 most likely represents reactivation of latent infection, perhaps due to immunologic dysfunction."

http://www.annals.org/content/116/2/103.abstract


1992, January 15: Boston Globe article by Richard Knox, "Chronic Fatigue is Linked to Virus."

"The study focused on the original cluster of chronic fatigue patients in the Lake Tahoe region of northern California and Nevada that first brought the disorder to public and scientific attention in 1985. Reflecting the medical establishment's skepticism toward the syndrome, the report was rejected by medical journals until enough data accumulated to show undeniable evidence of viral, immune-system and brain effects."

"Nearly four of five Lake Tahoe patients had evidence of brain inflammation as revealed by magnetic resonance imaging scans, compared with only one in five healthy comparison subjects. Similarly, 70 percent of the chronic fatigue patients had evidence of active infection by human herpes virus-6, versus 20 percent of the control subjects."

"The syndrome is marked by profound fatigue, usually developing suddenly after a flu-like illness, that lasts more than six months and usually for years. A high proportion of the Lake Tahoe patients also suffered from muscle aches, headaches, difficulty concentrating, recurrent sore throats, sleeping problems, depression, joint pain and other symptoms..."

http://pqasb.pqarchiver.com/boston/access/61700719.html?FMT=ABS&date=Jan%2015,%201992


1992, January 15: New York Times article by Lawrence Altman, "Study Detects Chronic Fatigue Abnormality."

http://www.nytimes.com/1992/01/15/us/study-detects-chronic-fatigue-abnormality.html


1992, August 15: Reeves et al. Letter to the Annals of Internal Medicine regarding Buchwald et al.:

"To the Editors: Buchwald and colleagues conclude that the chronic fatigue observed in their patients may reflect an immunologically mediated inflammatory process of the central nervous system and may be associated with human herpesvirus 6 (HHV-6). The authors, however, failed to consider organic causes of chronic fatigue for analysis as a separate category and referred to neurologic symptoms without specifying diagnostic criteria. The study also lacked appropriate controls; this was not a cohort study with matched controls, as stated in the abstract, but a case series with variously selected nonmatched controls..."

The letter ends, "We conclude that the disease Buchwald and co-workers described is not chronic fatigue syndrome or any other clinical entity, and that they showed no association with active HHV-6 replication."

http://www.annals.org/content/117/4/343.extract


1993, March 19: CDC Morbidity and Mortality Weekly Report, "Inability of Retroviral Tests to Identify Persons with Chronic Fatigue Syndrome, 1992."

"Chronic fatigue syndrome (CFS) is characterized by prolonged, debilitating fatigue (1)[Holmes, 1988]. Although the cause of CFS unknown, CDC and researchers in other organizations have been investigating whether infection with a previously unidentified retrovirus might be an etiologic factor. Based on reports suggesting that retroviral infection with a human T-lymphotropic virus type 2 (HTLV-II)-like retrovirus or a spumavirus might be associated with CFS (2,3)[DeFreitas, 1991; Palca J. On the track of an elusive disease. Science 1991;254:1726-8], some research and commercial laboratories developed assays to test specimens from persons with CFS. Even though the hypothesized association between infection with retroviruses and CFS has not been confirmed, these tests are used commonly to evaluate patients with CFS. This report summarizes the findings of a controlled, blinded study conducted in 1992 to determine whether three retroviral tests can distinguish serologically between patients with CFS (i.e., case-patients) and healthy controls."

"None of the three assays could differentiate between case-patients and controls in either the combined study population or any of the individual study populations. Both the original PCR assay from laboratory A and the cell-culture assay from laboratory B were positive for 59% and nearly 50%, respectively, of the case-patients and controls. The modified assay from laboratory A was negative for nearly all the case-patients (90%) and controls (96%)."

"The study described in this report is the first controlled, blinded trial to examine the ability of these retroviral tests (i.e., PCR assay, PCR modified assay, and culture for foamy cell cytopathic effect) to distinguish CFS case-patients from controls. The findings from this study do not support the hypothesized association between infection with retroviruses and CFS and are consistent with findings from other studies assessing evidence of retroviral infection."

"Although previously unidentified retroviral agents might be etiologic factors or cofactors for CFS, no scientific basis exists for the use of retroviral testing to confirm the diagnosis of CFS. Diagnostic testing of patients with suspected CFS should be done solely to exclude other diagnoses."

http://www.cdc.gov/mmwr/preview/mmwrhtml/00019881.htm


1993, September 27: Second CDC Definitional Meeting. The Division of Viral and Rickettsial Diseases hosted a two-day meeting in Atlanta to discuss revising the Holmes definition. Members of the government panel included Stephen Straus of the NIH, psychiatrist Susan Abbey of the University of Toronto, and William Reeves of the CDC. Dr. Byron Hyde attended the meeting. His objection to the inclusion of Susan Abbey was ignored. Requests by patient advocates that doctors with experience treating CFS patients be included on the panel were dismissed.

"They were trying to frame this illness in a medical-social-cultural context." Miami immunologist Nancy Klimas recalled. "But there was no data." (Hillary Johnson, Osler's Web. 1996, Crown Publishers, New York. pages 637-638)


1994: Heneine et al. "Lack of Evidence for Infection With Known Human and Animal Retroviruses in Patients With Chronic Fatigue Syndrome" in Clinical Infectious Diseases.

Abstract:

"We investigated 21 patients with chronic fatigue syndrome who were identified through the surveillance system of the Centers for Disease Control and Prevention (CDC) in Atlanta for the presence of several human and animal retroviruses. In addition, we evaluated 21 CDC employee controls matched with the patients for age (±5 years), gender, and race. The viruses tested included human T-lymphotropic viruses types I and II; human spuma retrovirus; simian T-lymphotropic virus type I; simian retroviruses types 1, 2, and 3; bovine leukemia virus; feline leukemia virus; and gibbon ape leukemia virus. Samples of peripheral blood lymphocytes and leukocytes from patients and controls were analyzed in a blinded fashion for retroviral sequences; polymerase chain reaction (PCR) amplification assays and Southern blot hybridization to 32P-labeled internal oligoprobes were used. All PCR assays were optimized for maximal sensitivity on respective infected cell lines or plasmids, and sensitivity controls were included in each experiment. All samples from patients and controls were negative for the tested retroviral sequences. Our data indicate that none of these retroviruses plays an etiologic role or is a cofactor in the chronic fatigue syndrome illnesses of our study population."

http://www.cdc.gov/cfs/publications/studies_of_causes/lack_of_evidence.html


1994, December 15: The Fukuda Definition of Chronic Fatigue Syndrome. Fukuda et al. including the International Chronic Fatigue Syndrome Study Group. "The Chronic Fatigue Syndrome: A Comprehensive Approach to Its Definition and Study" in the Annals of Internal Medicine.

A case of the chronic fatigue syndrome is defined by the presence of "persistent or relapsing chronic fatigue that is of new or definite onset that is not the result of ongoing exertion and is not substantially alleviated by rest. The fatigue must result in substantial reduction in previous levels of occupational, educational, social, or personal activities."

Four of eight other symptoms, "sore throat; tender cervical or axillary lymph nodes; muscle pain, multijoint pain without joint swelling or redness; headaches of a new type, pattern, or severity; unrefreshing sleep; and postexertional malaise lasting more than 24 hours." also are required to meet the case definition. Symptoms must persist or reoccur over six consecutive months.

Other medical conditions, which could explain the symptom of fatigue, are listed as exclusions.

The use of medical tests to help diagnose chronic fatigue syndrome is proscribed:

"The use of tests to diagnose the chronic fatigue syndrome (rather than to exclude other diagnostic possibilities) should be done only in the setting of protocol-based research. The fact that such tests are investigational and do not aid in diagnosis or management should be explained to the patient."

"In clinical practice, no additional tests, including laboratory tests and neuroimaging studies, can be recommended for the specific purpose of diagnosing the chronic fatigue syndrome. Tests should be directed toward confirming or excluding other etiologic possibilities. Examples of specific tests that do not confirm or exclude the diagnosis of the chronic fatigue syndrome include serologic tests for Epstein-Barr virus, retroviruses, human herpesvirus 6, enteroviruses, and Candida albicans; tests of immunologic function, including cell population and function studies; and imaging studies, including magnetic resonance imaging scans and radionuclide scans (such as single-photon emission computed tomography and positron emission tomography) of the head."

Issues that were of importance when creating the definition:

"The central issue in chronic fatigue syndrome research is whether the chronic fatigue syndrome or any subset of it is a pathologically discrete entity, as opposed to a debilitating but nonspecific condition shared by many different entities. Resolution of this issue depends on whether clinical, epidemiologic, and pathophysiologic features convincingly distinguish the chronic fatigue syndrome from other illnesses."

and

"The extent to which the features of the chronic fatigue syndrome are generic features of chronic fatigue and deconditioning due to physical inactivity common to a diverse group of illnesses must also be established."

http://www.annals.org/content/121/12/953.full

From Jason et al. 2010 "The Development of a Revised Canadian Myalgic Encephalomyelitis Chronic Fatigue Syndrome Case Definition" in the American Journal of Biochemistry and Biotechnology:

"The Fukuda et al. (1994) case definition uses polythetic [having many, but not all properties in common] criteria, that is, a set of symptoms in which not all need to be present to make a diagnosis. The use of polythetic criteria derived by expert committees (as is the case with CFS) may not be methodologically sound (Jason and Choi, 2008) [See paper for full reference]. For example, use of polythetic criteria may result in the comparison of two different groups of patients within the same diagnostic category or similar groups in different diagnostic categories. Because the Fukuda et al. (1994) criteria only require four symptoms out of a possible eight, critical CFS symptoms such as post-exertional malaise and memory and concentration problems are not required of all patients and this might further complicate identification of comparable samples."

http://www.scipub.org/fulltext/ajbb/ajbb62120-135.pdf


1996: Osler's Web: Inside the Labyrinth of the Chronic Fatigue Syndrome Epidemic by Hillary Johnson is published by Crown Publishers, New York.


1996: Primetime Live television show segment on CFS. Topics covered include the Incline Village/Lake Tahoe outbreak in the 1980's, the CDC's response, Dr. Paul Cheney, Dr. Daniel Peterson, Dr. David Bell, Elaine DeFreitas, Hillary Johnson, and Osler's Web.

http://vimeo.com/13048135


1999: The Social Security Administration issues Ruling SSR 99-2p, a policy interpretation clarifying how CFS can be deemed a "medical impairment" under SSA regulations. The ruling provides examples of medical signs and laboratory findings associated with CFS that can help secure disability payments.

http://www.ssa.gov/OP_Home/rulings/di/01/SSR99-02-di-01.html


1999: Jason et al. "A Community-Based Study of Chronic Fatigue Syndrome" in the Archives of Internal Medicine.

The study finds a prevalence rate for CFS of 422 per 100,000.

http://archinte.ama-assn.org/cgi/content/full/159/18/2129


1999, July 22: Letter of Apology from CDC director Dr. Jeffery Kopland to the New Jersey Chronic Fatigue Syndrome Association.

"I personally apologize for the breach of trust that occurred regarding the CDC's chronic fatigue syndrome (CFS) resources. We are making unprecedented, agency-wide changes and improvements to prevent this type of incident from happening again (please see enclosure). I am also reinvigorating our efforts to increase our knowledge about CFS and its effects on the lives of those persons who must meet its health challenge on a daily basis."

From the enclosure, "CDC Response to Chronic Fatigue Syndrome:"

"In August 1998, in response to allegations that funds had been misspent, the Director of CDC requested the Department of Health and Human Services Office of the Inspector General (OIG) to audit costs charged to the Chronic Fatigue Syndrome (CFS) Program. The audit and resulting internal report, "Audit of Costs Charged to the Chronic Fatigue Syndrome Program at the Centers for Disease Control and Prevention," concluded that CDC mismanaged CFS resources and provided misleading information to Congress. Resources intended for CFS were actually used for measles, polio and other disease areas."

"This was a breach of the CDC's solemn trust and is in direct conflict with its core values."

http://www.njcfsa.org/ (Archive)

2000 - 2005

2001, October: Taylor RR, Jason LA. "Sexual Abuse, Physical Abuse, Chronic Fatigue, and Chronic Fatigue Syndrome: A Community-Based Study" in the Journal of Nervous and Mental Disease.

From the Abstract:

"Using a randomly selected community-based sample, this investigation examined whether histories of childhood sexual, physical, and death threat abuse predicted adulthood outcomes of specific medical and psychiatric conditions involving chronic fatigue. This study also tested prior suggestions that most individuals with chronic fatigue syndrome report a past history of interpersonal abuse. Multinomial logistic regression was used to examine the relationship between abuse history and chronic fatigue group outcomes while controlling for the effects of sociodemographics. Compared with healthy controls, childhood sexual abuse was significantly more likely to be associated with outcomes of idiopathic chronic fatigue, chronic fatigue explained by a psychiatric condition, and chronic fatigue explained by a medical condition. None of the abuse history types were significant predictors of chronic fatigue syndrome. A closer examination of individuals in the chronic fatigue syndrome group revealed that significantly fewer individuals with CFS reported abuse as compared with those who did not."

http://journals.lww.com/jonmd/Abstract/2001/10000/Sexual_Abuse,_Physical_Abuse,_Chronic_Fatigue,_and.8.aspx


2002, May: Fitzpatrick M. "Myalgic Encephalomyelitis: The Dangers of Cartesian Fundamentalism" in the British Journal of General Practice.

"The diagnosis of benign myalgic encephalomyelitis emerged in response to an epidemic of muscle pain and fatigue at the Royal Free Hospital in London in 1955. Though the term implies inflammation of the brain and spinal cord, no such pathology has ever been identified. In the early 1980s the term, abbreviated to ME came to be applied to sporadic, but increasingly numerous, cases of profound and prolonged fatigue, associated with muscle pain and malaise, and a wide range of other symptoms. Medical opinion shifted towards the term chronic fatigue syndrome, which emphasised the predominant symptom without making any assumptions about the cause of the condition or its pathology. A 1996 report by an earlier working group of the Royal Colleges of Physicians, Psychiatrists and General Practitioners [Chronic Fatigue Syndrome, 1996] explicitly rejected the term ME on the grounds that it erroneously endorses the existence of a specific pathological process for which in the context there is no evidence."

"Organisations such as Action for ME and the ME Association, which are supported by some sufferers and their families and carers, repudiated the 1996 report. Their campaigning efforts pushed the Department of Health into setting up the working group that produced the new report. Many ME activists feel that the term fatigue, a familiar synonym for tiredness, fails to reflect the profundity of their symptoms. They also cling to the conviction that their symptoms are the result of some infectious agent or immunological disorder and thus favour a label which implies such an aetiology (though exhaustive researches have failed to confirm this). No doubt, like generations of doctors, some enjoy the legitimacy conferred by a polysyllabic Latinate term, even though perhaps because it mystifies rather than clarifies the underlying condition."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1314314/pdf/12014557.pdf


2003, January: The Canadian Consensus Definition of ME/CFS. Carruthers et al. "Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols" in the Journal of Chronic Fatigue Syndrome.

Abstract:

"Recent years have brought growing recognition of the need for clinical criteria for myalgic encephalomyelitis (ME), which is also called chronic fatigue syndrome (CFS). An Expert Subcommittee of Health Canada established the Terms of Reference, and selected an Expert Medical Consensus Panel representing treating physicians, teaching faculty and researchers. A Consensus Workshop was held on March 30 to April 1, 2001 to culminate the review process and establish consensus for a clinical working case definition, diagnostic protocols and treatment protocols. We present a systematic clinical working case definition that encourages a diagnosis based on characteristic patterns of symptom clusters, which reflect specific areas of pathogenesis. Diagnostic and treatment protocols, and a short overview of research are given to facilitate a comprehensive and integrated approach to this illness. Throughout this paper, “myalgic encephalomyelitis” and “chronic fatigue syndrome” are used interchangeably and this illness is referred to as “ME/CFS.”

http://www.co-cure.org/ccpccd.pdf

From Jason et al. "The Development of a Revised Canadian Myalgic Encephalomyelitis Chronic Fatigue Syndrome Case Definition" 2010:

"A clinical case definition for ME/CFS that is called the Canadian criteria also specified the these two core symptoms [post-exertional malaise and impaired memory and concentration] as well as several other symptoms (Carruthers et al., 2003). The acronym ME/CFS refers to Myalgic Encephalomyelitis and Chronic Fatigue Syndrome, according to the Canadian Case Definition. The patient community has felt that the term chronic fatigue syndrome trivializes the seriousness of this illness, as the illness is typified by many severe symptoms in addition to fatigue and fatigue is generally regarded as a common symptom experienced by many otherwise healthy individuals in the general population. The term Myalgic Encephalomyelitis had been used prior to the use of the term chronic fatigue syndrome (Acheson, 1959)."

"The Canadian clinical case definition specifies that post-exertional malaise must occur with a loss of physical or mental stamina, rapid muscle or cognitive fatigability, usually taking 24 hours or longer to recover. In addition, there need to be two or more neurological/cognitive manifestations (e.g., confusion, impairment of concentration and short term-memory). There also needs to be unrefreshing sleep or poor sleep quantity or rhythm disturbance, as well as a significant degree of arthralgia and/or myalgia (there are a small number of patients with no pain or sleep dysfunction and a diagnosis can only be given when these individuals have a classical case with an infectious illness onset). Finally, there needs to be at least one symptom from two of the following categories: autonomic manifestations (neurally mediated hypotension, light headedness), neuroendocrine manifestations (e.g., recurrent feelings of feverishness and cold extremities) and immune manifestations (e.g., recurrent sore throats)."

"Jason et al. (2004) compared persons meeting the Canadian clinical case definition (Carruthers et al., 2003), the Fukuda et al. criteria and people experiencing chronic fatigue explained by psychiatric reasons. The Canadian criteria, in contrast to the Fukuda et al. criteria, selected cases with less psychiatric comorbidity, more physical functional impairment, more fatigue/weakness and neuropsychiatric and neurology symptoms. Moreover, those meeting the Canadian criteria were more symptomatically different from the psychiatrically-caused chronic fatigue group than those meeting the Fukuda et al. (1994) criteria."

http://www.scipub.org/fulltext/ajbb/ajbb62120-135.pdf


2003, July 14: Reyes et al. "Prevalence and Incidence of Chronic Fatigue Syndrome in Wichita, Kansas" in the Archives of Internal Medicine.

The study finds a prevalence rate for CFS of 235 per 100,000.

http://archinte.ama-assn.org/cgi/content/full/163/13/1530


2003, December 31: Revision of the Fukuda Definition of Chronic Fatigue Syndrome. Reeves et al. including the International Chronic Fatigue Syndrome Study Group. "Identification of Ambiguities in the 1994 Chronic Fatigue Syndrome Research Case Definition and Recommendations for Resolution." in BMC Health Services Research.

"Ambiguities in the [1994 Fukuda] CFS research definition that contribute to inconsistent case identification were identified. Recommendations for use of the definition, standardization of classification instruments and study design issues are presented that are intended to improve the precision of case ascertainment. The International CFS Study Group also identified ambiguities associated with exclusionary and comorbid conditions and reviewed the standardized, internationally applicable instruments used to measure symptoms, fatigue intensity and associated disability."

The use of "instruments" (questionnaires) to select research subjects is recommended:

"Several instruments that measure fatigue have been used in studies of CFS. The instruments have considerable overlap and each has advantages and disadvantages. We recommend that research studies of CFS consider using the more extensive Checklist Individual Strength, but shorter instruments such as the Chalder and Krupp scales are also appropriate. The Checklist Individual Strength (CIS) is a 20-item inventory with 4 subscales: fatigue severity, concentration, reduced motivation and, physical activity. The fatigue severity subscale measures both general and physical fatigue and a score above 36 represents severe fatigue. The CIS focuses on fatigue over the preceding two weeks. Considerable normative data have been collected with reference to both CFS and post cancer patients and it has been used in epidemiological studies."

"These symptoms are non-specific and variable in both nature and severity over time. They were selected on the basis of consensus clinical opinion and were not identified empirically. We recommend that research studies use the SPHERE [a questionnaire] (discussed below) to query subjects (cases and controls) about the occurrence, duration, and severity of the 8 case defining symptoms and other potentially accompanying symptoms."

The use of medical imaging is not recommended:

"Impaired short-term memory or concentration severe enough to cause substantial reduction in previous levels of occupational, educational, social, or personal activities is a case defining symptom and is reported by most persons with CFS. The deficit appears to be global but non-specific deficit most notably in the areas of attention and information processing. Newly emerging technology (e.g., functional neuroimaging) may complement and eventually replace traditional neurocognitive function tests. However, the Group did not recommend specific imaging measurements at this time."

A diagnosis of major depressive order is no longer an exclusion for research:

"The 1994 case definition stated that any past or current diagnosis of major depressive disorder with psychotic or melancholic features, anorexia nervosa, or bulimia permanently excluded a subject from the classification of CFS. Because these illnesses may resolve with little or no likelihood of recurrence and only active disease or disease requiring prophylactic medication would contribute to confusion with evaluation of CFS symptoms, we now recommend that if these conditions have been resolved for more than 5 years before the onset of the current chronically fatiguing illness, they should not be considered exclusionary."

http://www.biomedcentral.com/1472-6963/3/25


2004, October 7: Press Release for the American Association for Chronic Fatigue Syndrome (AACFS) Seventh International Conference on Chronic Fatigue Syndrome, Fibromyalgia and Related Disorders October 8-10, 2004 Madison, Wisconsin.

Quote:

CDC researcher Dr. William Reeves, Chief of the CFS research program, reported that $US 9.1 billion of earnings and wages are lost annually in the US alone due to disability caused by CFS.

CFS patients are more sick and have greater consequent disability than patients with chronic obstructive lung disease, cardiac disease, osteoarthritis and depression yet fewer than 16% of CFS sufferers in the general population are diagnosed and treated for CFS.

A CDC collaborative study with Australian researchers found that the strongest predictor of the development of post-infectious (chronic) fatigue syndrome is the severity of the acute illness at onset. Psychological factors played no role in the development of CFS following infection.

http://www.mesite.dk/News.11.htm


2005: Whittemore Peterson Institute for Neuro-Immune Disease founded.

From Annette Whittemore, "The Whittemore Peterson Institute: Building Bridges through Private and Public Sector Collaboration" in Molecular Interventions, June 2010:

"In early 2005, Dr. Peterson and I began working to describe this institute’s future clinical practice. Meanwhile, my husband discussed with John Lilley, then president of the University of Nevada–Reno, the School of Medicine’s desire for a new medical research building. Our Governor and good friend, Kenny Guinn, agreed to place this project in his state budget. Legislative leaders who understood the potential benefits to both patients and future medical education in this state also began to offer their support. This new research facility was to house three significant interest groups: researchers from the University of Nevada’s Medical School; the Nevada Cancer Institute; and the Center for Neuroimmune Disease (now called the WPI). That winter, I gathered scientific information for a presentation to the 2005 state legislature, arguing the need for such a medical center. University representatives and Nevada Cancer Institute scientists did the same. Passionate pleas were made by several patient advocates in addition to our testimony. By the end of the legislative session, ten million dollars has been allocated to support a new research and medical office building. The main portion of the building was built from bond money which was based on the indirect costs of the researchers’ grants. My husband and I committed to give or raise an additional $5 million towards WPI’s portion of the building, and soon the construction began, bringing reality to a dream."

http://molinterv.aspetjournals.org/content/10/3/120.full


2005, December: Jones et al. "Orthostatic Instability in a Population-Based Study of Chronic Fatigue Syndrome" in the American Journal of Medicine.

Conclusions:

"Orthostatic instability was similar in persons with chronic fatigue syndrome and nonfatigued controls subjects recruited from the general Wichita population. Delayed responses to head-up tilt tests were common and may reflect hydration status. These findings suggest reappraisal of primary dysautonomia as a factor in the pathogenesis of chronic fatigue syndrome."

http://www.amjmed.com/article/PIIS0002934305004468/fulltext

From the Discussion of Major Features of ME/CFS, Autonomic Manifestations section of the Canadian Consensus Criteria:

Orthostatic intolerance is commonly seen in ME/CFS patients and includes: Neurally mediated hypotension (NMH), Postural orthostatic tachycardia syndrome (POTS) and delayed postural hypotension.

http://www.co-cure.org/ccpccd.pdf (Pages 18-19)


2005, December 15: The Empiric Definition of Chronic Fatigue Syndrome. Reeves et al. "Chronic Fatigue Syndrome – A Clinically Empirical Approach to Its Definition and Study" in BMC Medicine.

"The primary objective of this study was to implement recommendations of the International CFS Study Group [Reeves, 2003] and define CFS on the basis of scores from standardized and validated instruments [questionnaires] that assess the major dimensions of the illness as specified by the 1994 CFS case definition [Fukuda, 1994]. Functional impairment, fatigue and an accompanying symptom complex characterize CFS. We defined functional impairment as scores ≤ 70 on the physical function or ≤ 50 on the role physical or ≤ 75 on the social function or ≤ 66 on the role emotional subscales of the SF-36. We defined severe fatigue as scores ≥ 13 on the general fatigue or ≥ 10 on the reduced activity subscales of the MFI. Finally, we defined the accompanying symptom complex as reporting the occurrence of ≥ 4 of 8 symptoms and scoring ≥ 25 on the Symptom Inventory Case Definition subscale. One could debate our choice of specific subscales from the SF-36 and MFI and the specific cut-off values we chose on the SF-36, MFI and Symptom Inventory. However, these instruments have been validated, have been used extensively in studies of CFS and other illnesses, and are known to be reproducible. In contrast, most studies of CFS merely note that they used the 1994 case definition and they do not generally specify how disability, fatigue and symptom occurrence were elucidated. Thus, it is difficult to assess the validity of their diagnostic criteria and essentially impossible to compare results between studies critically."

http://www.biomedcentral.com/1741-7015/3/19/

From Jason et al. 2010 "The Development of a Revised Canadian Myalgic Encephalomyelitis Chronic Fatigue Syndrome Case Definition" in the American Journal of Biochemistry and Biotechnology:

"However, using these new empiric criteria, the estimated prevalence rates of CFS have increased to 2.54% [Reeves et al., 2007], rates that are about ten times higher than prior CDC estimates [Reyes et al., 2003] and prevalence estimates of other investigators [Jason et al., 1999] using the Fukuda et al. criteria. It is possible that the increase in CFS prevalence in the United States is due to a broadening of the Fukuda et al. case definition in an attempt to operationalize the criteria. Further, the empiric case definition has potential for inclusion of cases with primary psychiatric conditions. In support of this thesis, Jason et al. [2008] found that 38% of those with a diagnosis of a Major Depressive Disorder were misclassified as having CFS using the new CDC empiric case definition."

http://www.scipub.org/fulltext/ajbb/ajbb62120-135.pdf

2006 - 2009

2006: Jason et al. "Causes of Death Among Patients With Chronic Fatigue Syndrome" in Health Care for Women International.

"Chronic fatigue syndrome (CFS) is a debilitating illness affecting thousands of individuals. At the present time, there are few studies that have investigated causes of death for those with this syndrome. The authors analyzed a memorial list tabulated by the National CFIDS Foundation of 166 deceased individuals who had had CFS. There were approximately three times more women than men on the list. The three most prevalent causes of death were heart failure, suicide, and cancer, which accounted for 59.6% of all deaths. The mean age of those who died from cancer and suicide was 47.8 and 39.3 years, respectively, which is considerably younger than those who died from cancer and suicide in the general population."

http://www.theoneclickgroup.co.uk/documents/ME-CFS_docs/Causes%20of%20Death%20-%20CFS%20Patients.pdf


2006: Nater UM, Wagner D, Solomon L, Jones JF, Unger ER, Papanicolaou DA, Reeves WC, Heim C. "Coping Styles in People with Chronic Fatigue Syndrome Identified from the General Population of Wichita, KS" in the Journal of Psychosomatic Research.

The study used the empiric criteria for CFS.

Abstract:

"Objective: Studies of primary and tertiary care patients suggest that maladaptive coping styles contribute to the pathogenesis and maintenance of chronic fatigue syndrome (CFS). We assessed coping styles in persons with unexplained fatigue and nonfatigued controls in a population-based study."

"Methods: We enrolled 43 subjects meeting the 1994 Research Case Definition of CFS, matching them with 61 subjects with chronic unexplained fatigue who did not meet criteria for CFS [we term them insufficient symptoms or fatigue (ISF)] and 60 non-ill (NI) controls. Coping styles and clinical features of CFS were assessed using standard rating scales."

"Results: Subjects with CFS and ISF reported significantly more escape-avoiding behavior than NI controls. There were no differences between the CFS and ISF subjects. Among participants with CFS, escape-avoiding behavior was associated with fatigue severity, pain, and disability."

"Conclusions: We demonstrate significantly higher reporting of maladaptive coping in a population-based sample of people with CFS and other unexplained fatiguing illnesses defined by reproducible standardized clinical empirical means in comparison to NI controls."

http://www.cfids-cab.org/cfs-inform/Cfsliving/nater.etal06.pdf


2006, April 21: New York Times article, "Genetics and Stress Are Found Linked To Fatigue Disorder."

Quote:

Chronic fatigue syndrome appears to result from something in people's genetic makeup that reduces their ability to deal with physical and psychological stress, researchers reported Thursday.

"'The results are groundbreaking," said Dr. William Reeves of the federal Centre for Disease Control and Prevention in Atlanta.

Dr. Reeves said the study demonstrated that people with chronic fatigue syndrome were unable to deal with everyday challenges and adversity, including injuries, illnesses, divorce and stressful jobs. [Dr. Reeves was referring to research on CFS defined using the empiric criteria.]

The research is described in a collection of 14 articles published in this month's issue of Pharmacogenomics, a scientific journal.

http://query.nytimes.com/gst/fullpage.html?res=9F01E2DF153FF932A15757C0A9609C8B63


2006, May: Dr. Byron Hyde in "A Brief History of Myalgic Encephalomyelitis and an Irreverent History of Chronic Fatigue Syndrome."

Regarding the situation in England: "Essentially, if you cannot first prove a disease by careful examination and scientific reproducible testing and upon this, search for adequate treatments, if we cannot do this English physicians essentially are simply sending all chronically ill Britons and British medicine back to the dark ages." (Page 28)

Regarding the 1994 Fukuda definition: "It was totally unusable. It removed patients as being ill with CFS with multiple disease conditions associated with M.E. It took the psychiatric approach of not permitting the intensive investigation of patients who essentially had an unknown complex disease process. The definition failed to address the findings that we already knew from the Lake Tahoe epidemic mentioned in this history or in any of the previous epidemics. This definition was a waste of good money." (Page 29)

Regarding the 2003 Canadian Consensus Criteria: "This is the first definition constructed by specialists who have spent collectively over 100 years studying ME and CFS. It is the first definition and introduction to ME and CFS that makes a bit of sense, but like I in the first years of study, I confused ME and CFS as being the same. As I have explained, they are not." (Page 30)

http://www.imet.ie/imet_documents/BYRON_HYDE_little_red_book.pdf


2006, September 1: Hickie et al. including the Dubbo Infection Outcomes Study Group. "Post-Infective and Chronic Fatigue Syndromes Precipitated by Viral and Non-Viral Pathogens: Prospective Cohort Study" in the British Medical Journal.

From the Abstract:

"Results: Prolonged illness characterised by disabling fatigue, musculoskeletal pain, neurocognitive difficulties, and mood disturbance was evident in 29 (12%) of 253 participants at six months, of whom 28 (11%) met the diagnostic criteria for chronic fatigue syndrome. This post-infective fatigue syndrome phenotype was stereotyped and occurred at a similar incidence after each infection. The syndrome was predicted largely by the severity of the acute illness rather than by demographic, psychological, or microbiological factors."

"Conclusions: A relatively uniform post-infective fatigue syndrome persists in a significant minority of patients for six months or more after clinical infection with several different viral and non-viral micro-organisms. Post-infective fatigue syndrome is a valid illness model for investigating one pathophysiological pathway to chronic fatigue syndrome."

http://www.bmj.com/cgi/rapidpdf/bmj.38933.585764.AE?ijkey=yO3kKdtbDa0h2kH&keytype=ref


2006, November: Heim C, Wagner D, Maloney E, Papanicolaou DA, Solomon L, Jones JF, Unger ER, Reeves WC. "Early Adverse Experience and Risk for Chronic Fatigue Syndrome" in Archives of General Psychiatry.

The study used the empiric criteria for CFS. The conclusions:

"This study provides evidence of increased levels of multiple types of childhood trauma in a population-based sample of clinically confirmed CFS cases compared with nonfatigued controls. Our results suggest that childhood trauma is an important risk factor for CFS. This risk was in part associated with altered emotional state. Studies scrutinizing the psychological and neurobiological mechanisms that translate childhood adversity into CFS risk may provide direct targets for the early prevention of CFS."

http://archpsyc.ama-assn.org/cgi/content/full/63/11/1258


2006, November 16: Reeves WC, Heim C, Maloney EM, Youngblood LS, Unger ER, Decker MJ, Jones JF, Rye DB. "Sleep Characteristics of Persons with Chronic Fatigue Syndrome and Non-Fatigued Controls: Results from a Population-Based Study" in BMC Neurology'."

The study used the empiric criteria for CFS.

Conclusion:

"Although disordered breathing during sleep may be associated with CFS, this study generally did not provide evidence that altered sleep architecture is a critical factor in CFS. Future studies should further scrutinize the relationship between subjective sleep quality relative to objective polysomnographic measures."

http://www.biomedcentral.com/1471-2377/6/41

From the Discussion of Major Features of ME/CFS, Sleep Dysfunction section of the Canadian Consensus Criteria:

"Sleep and other diurnal rhythm disturbances may include early, middle or late insomnia, with reversed or irregularly irregular insomnia, hypersomnia, abnormal diurnal variation of energy levels, including reversed or chaotic diurnal rest and sleep rhythms. This results in lack of tolerance for shift work/activity or time zone shifts when travelling. Loss of the deeper phases of sleep is especially characteristic, with frequent awakenings, and loss of restorative feelings in the morning. Restless leg syndrome and periodic limb movement disorder often accompany sleep disturbance. A very small percentage of ME/CFS patients do not have sleep dysfunction, but do not fit any other disease criteria."

http://www.co-cure.org/ccpccd.pdf (Page 16)


'2007. February 4: CFS ME/CFS Name Change Committee ' http://www.mecfsforums.com/wiki/Name_Change_Committee_2/4/2007


2007, June 8: Reeves et al. "Prevalence of Chronic Fatigue Syndrome in Metropolitan, Urban, and Rural Georgia." in Population Health Metrics.

The study, using the empiric criteria for CFS, finds a prevalence rate for CFS of 2540 per 100,000.

http://www.pophealthmetrics.com/content/5/1/5


2007, July 17: New York Times article by David Tuller, "Chronic Fatigue No Longer Seen as 'Yuppie Flu'."

Quote:

But the syndrome is now finally gaining some official respect. The Centers for Disease Control and Prevention, which in 1999 acknowledged that it had diverted millions of dollars allocated by Congress for chronic fatigue syndrome research to other programs, has released studies that linked the condition to genetic mutations and abnormalities in gene expression involved in key physiological processes. The centers have also sponsored a $6 million public awareness campaign about the illness. And last month, the C.D.C. released survey data suggesting that the prevalence of the syndrome is far higher than previously thought, although these findings have stirred controversy among patients and scientists. Some scientists and many patients remain highly critical of the C.D.C.’s record on chronic fatigue syndrome, or C.F.S. But nearly everyone now agrees that the syndrome is real.

“People with C.F.S. are as sick and as functionally impaired as someone with AIDS, with breast cancer, with chronic obstructive pulmonary disease,” said Dr. William Reeves, the lead expert on the illness at the C.D.C., who helped expose the centers’ misuse of chronic fatigue financing...

Last month, however, the disease control centers reported that a randomized telephone survey in Georgia, using a less restrictive methodology to identify cases, found that about 1 in 40 adults ages 18 to 59 met the diagnostic criteria — an estimate 6 to 10 times higher than previously reported rates.

However, many patients and researchers fear that the expanded prevalence rate could complicate the search for consistent findings across patient cohorts. These critics say the new figures are greatly inflated and include many people who are likely to be suffering not from chronic fatigue syndrome but from psychiatric illnesses.

http://www.nytimes.com/2007/07/17/science/17fatigue.html

http://www.nytimes.com/ref/health/healthguide/esn-chronicfatigue-ess.html (May 30, 2008 update)


2007, November 17: Jones JF. "An Extended Concept of Altered Self: Chronic Fatigue and Post-Infection Syndromes" in Psychoneuroendocrinology.

"Or if altered activation in higher cortical regions was preferentially present or combined with changes in lower areas, would cognitive-behavioral therapy (CBT), a ‘‘top-down’’ therapy, or combined therapy be more effective for these ‘‘adaptive,’’ ‘‘learned,’’ or conditioned responses? It is of interest that CBT remains an effective therapy for CFS without specific understanding of its mode of action (Whiting et al., 2001; Deary et al., 2007). At any level of therapy the ultimate goal is directed intervention in chronic illness states in order to break the ‘‘circle’’ of chronic sickness behavior due to altered self with return to a functional self state capable of responding to current and future challenges."

Concluding Remarks:

"Chronic illnesses, such as CFS and PIFs, in the absence of evidence of standard mechanisms of pathogenesis, require new concepts of illness origin. In illnesses that follow infection, symptoms that were initiated as the consequence of innate and/or adaptive immune system responses may be perpetuated by ongoing alterations in a normally positive dynamic self construct. Approaching such alterations by studying the function of the brain using a ‘‘top-down’’ paradigm may offer clues to the generation of the illness and sites for targeted therapy. The extended altered self model might also apply to the study of other stress-associated and somatic illnesses, but this essay is designed to generate discussion and not to describe in detail all possible avenues of investigation of the topics at hand."

Acknowledgments:

"Drs. Helen Mayberg, William C. Reeves, Beth Unger, Myron Levin, and Urs Nater provided valuable insight into the conception and completion of this work. In addition, Dr. Mayberg gave permission to alter and to use Figure 1. Dr. Reeves also assisted with the graphic preparation of the figure, and Drs. Unger, Levin, and Nater provided editorial advice. Dr. Andrew Twaddle provided valuable insights into the sociological origins of ‘‘sickness behavior.’’

http://www.cfids-cab.org/rc/Jones-4.pdf


2008-2009: Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences, Course Bulletin.

William Reeves is listed as a Clinical Assistant Professor.

http://www.med.emory.edu/education/omesa/bulletin/ClinicalScience/PsychBehavioral.html


2008, February 13: Email exchange between Kristin Loomis, Executive Director of the HHV-6 Foundation, and William Reeves of the CDC.

From Kristin Loomis to William Reeves, February 13, 2008:

Quote:

Dr. Reeves,

I am writing to invite you to participate in a mini-conference we are organizing on "Viruses in CFS" on June 22-23rd in Baltimore, Maryland, just after the 6th International Conference on HHV-6 & 7. We would also be honored if you would serve on the advisory committee....

From William Reeves to Kristin Loomis, May 2, 2008:

Quote:

1) What precisely is the objective of my attendance at the meeting? What do you want me to do?

2) I do not understand the confusion regarding my response to Dr. Ablashi. Responsibility for CFS research at CDC has been assigned to my Branch. Responsibility for laboratory work on herpes group viruses has been assigned to Dr. Schmid's Branch (in a different Center). My laboratory team does not have expertise in herpes group viruses, we do not have reagents appropriate to working with this group of viruses nor do we have some of the specialized equipment used to work with this type of virus. This in no way precludes CDC studying the role of herpesviruses in CFS....

Dr. Schmid's comment to Dr. Ablashi that he does not study CFS likely reflects the fact that his work on herpesgroup viruses is driven by CDC priorities (and resource allocation) in other areas such as STD's mental retardation, bioterrorism, and vaccine preventable diseases.

http://listserv.nodak.edu/cgi-bin/wa.exe?A2=ind0905a&L=co-cure&T=0&F&S&P=7987


2008, October 21: Jason et al. "Evaluating the Centers for Disease Control’s Empirical Chronic Fatigue Syndrome Case Definition" in the Journal of Disability Policy Studies.

"The Centers for Disease Control and Prevention (CDC) recently developed an empirical case definition that specifies criteria and instruments to diagnose chronic fatigue syndrome (CFS) in order to bring more methodological rigor to the current CFS case definition. The present study investigated this new definition with 27 participants with a diagnosis of CFS and 37 participants with a diagnosis of a Major Depressive Disorder. Participants completed questionnaires measuring disability, fatigue, and symptoms. Findings indicated that 38% of those with a diagnosis of a Major Depressive Disorder were misclassified as having CFS using the new CDC definition. Given the CDC’s stature and respect in the scientific world, this new definition might be widely used by investigators and clinicians. This might result in the erroneous inclusion of people with primary psychiatric conditions in CFS samples, with detrimental consequences for the interpretation of epidemiologic, etiologic, and treatment efficacy findings for people with CFS."

http://www.cfids-cab.org/MESA/Jason-10.pdf


2009, January: Heim C, Nater UM, Maloney E, Boneva R, Jones JF, Reeves WC. "Childhood Trauma and Risk for Chronic Fatigue Syndrome" in the Archives of General Psychiatry.

The study used the empiric criteria for CFS.

"Subjects were diagnosed with CFS if they met criteria of the 1994 case definition as applied following recommendations of the International Chronic Fatigue Syndrome Study Group regarding measurement of the major illness domains. Subjects completed a series of rating scales to assess symptoms of CFS and functioning, including the 36-Item Short Form Health Survey, the Multidimensional Fatigue Inventory, and the CDC Symptom Inventory."

From the Comment section:

"Our results confirm childhood trauma as an important risk factor of CFS. [Heim, 2006] In addition, neuroendocrine dysfunction manifested by decreased salivary cortisol awakening response was associated with childhood trauma in CFS, likely reflecting a biological correlate of vulnerability due to early developmental insults. The associations observed in this study are particularly important because we evaluated persons with CFS and well control subjects identified from the Georgia population rather than clinical settings. Thus, the results can be generalized to the population of persons with CFS."

"In conclusion, our results lend further support for the hypothesis that CFS represents a disorder of adaptation that is promoted by early environmental insults, leading to failure to compensate in response to challenge. Hypocortisolism might potentially be a biological substrate of such vulnerability induced by early-life stress. Longitudinal studies are needed to provide information on the causal relationship between childhood trauma, hypocortisolism, and CFS and to systematically evaluate developmental trajectories as well as mediators and moderators of this relationship. Such studies have the potential to elucidate the pathophysiology, identify subtypes, and devise strategies for preventing and treating CFS. Our findings emphasize the need to revise prevailing dichotomous approaches that differentiate between psychological and biological contributors to CFS."

http://archpsyc.ama-assn.org/cgi/content/full/66/1/72


2009, May 27-28: CFS Advisory Committee Meeting Minutes.

Quote:

Reeves: "We are in the process of planning a cognitive behavioral therapy (CBT) and graded exercise (GET) trial as part of the provider registry population in Macon. We're going to do that in collaboration with the providers in Macon, with Mercer Medical School, with the U.K. group, and with Mayo Clinic."

http://www.hhs.gov/advcomcfs/meetings/minutes/cfsac052709min.pdf


2009, October 5: Aslakson E, Vollmer-Conna U, Reeves WC, White PD. "Replication of an Empirical Approach to Delineate the Heterogeneity of Chronic Unexplained Fatigue" in Population Health Metrics."

The study used the empiric criteria for CFS.

From the Abstract:

"Results: We identified five classes in the best fit analysis. Participants in Class 1 (25%) were polysymptomatic, with sleep problems and depressed mood. Class 2 (24%) was also polysymptomatic, with insomnia and depression, but participants were also obese with associated metabolic strain. Class 3 (20%) had more selective symptoms but was equally obese with metabolic strain. Class 4 (20%) and Class 5 (11%) consisted of nonfatigued, less symptomatic individuals, Class 4 being older and Class 5 younger. The classes were generally validated by independent variables. People with CFS fell equally into Classes 1 and 2. Similarities to the Wichita findings included the same four main defining variables of obesity, sleep problems, depression, and the multiplicity of symptoms. Four out of five classes were similar across both studies."

"Conclusion: These data support the hypothesis that chronic medically unexplained fatigue is heterogeneous and can be delineated into discrete endophenotypes that can be replicated. The data do not support the current perception that CFS represents a unique homogeneous disease and suggests broader criteria may be more explanatory. This replication suggests that delineation of endophenotypes of CFS and associated ill health may be necessary in order to better understand etiology and provide more patient-focused treatments."

http://www.pophealthmetrics.com/content/7/1/17


2009, October 8: Lombardi VC, Ruscetti FW, Gupta JD, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK,Petrow-Sadowski C, Gold B, Dean M, Silverman RH, Mikovits JA. "Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome" in Science.

"Chronic fatigue syndrome (CFS) is a debilitating disease of unknown etiology that is estimated to affect 17 million people worldwide. Studying peripheral blood mononuclear cells (PBMCs) from CFS patients, we identified DNA from a human gammaretrovirus, xenotropic murine leukemia virus-related virus (XMRV), in 68 of 101 patients (67%) compared to 8 of 218 (3.7%) healthy controls. Cell culture experiments revealed that patient-derived XMRV is infectious and that both cell-associated and cell-free transmission of the virus are possible. Secondary viral infections were established in uninfected primary lymphocytes and indicator cell lines following exposure to activated PBMCs, B cells, T cells, or plasma derived from CFS patients. These findings raise the possibility that XMRV may be a contributing factor in the pathogenesis of CFS."

From Supporting Online Materials and Methods: http://www.sciencemag.org/cgi/data/1179052/DC1/1

"Patient samples. Banked samples were selected for this study from patients fulfilling the 1994 CDC Fukuda Criteria for Chronic Fatigue Syndrome (S1) [Fukuda, 1994] and the 2003 Canadian Consensus Criteria for Chronic Fatigue Syndrome/myalgic encephalomyelitis (CFS/ME) [sic] and presenting with severe disability. Samples were selected from several regions of the United States where outbreaks of CFS had been documented (S2) [DeFreitas, 1991]. These are patients that have been seen in private medical practices, and their diagnosis of CFS is based upon prolonged disabling fatigue and the presence of cognitive deficits and reproducible immunological abnormalities. These included but were not limited to perturbations of the 2-5A synthetase/RNase L antiviral pathway, low natural killer cell cytotoxicity (as measured by standard diagnostic assays), and elevated cytokines particularly interleukin-6 and interleukin-8. In addition to these immunological abnormalities, the patients characteristically demonstrated impaired exercise performance with extremely low VO2 max measured on stress testing. The patients had been seen over a prolonged period of time and multiple longitudinal observations of the clinical and laboratory abnormalities had been documented."

http://www.cfids-cab.org/MESA/Lombardi.pdf


2009, October 9: Los Angeles Times article by Thomas Maugh, "Virus Discovery Called Breakthrough in Fight Against Chronic Fatigue Syndrome."

Quote:

Dr. William C. Reeves, who heads chronic fatigue syndrome research at the Centers for Disease Control and Prevention, cautioned against racing to conclusions based on the findings, even though he characterized them as promising.

"It is almost unheard of to find an association of this magnitude in any study of an infectious agent and a well-defined disease, much less an [ill-defined] illness like chronic fatigue syndrome," he said in an e-mail. It is extremely difficult to prove causation with a ubiquitous virus like XMRV, and it "is even more difficult in the case of CFS, which represents a clinically and epidemiologically complex illness," Reeves said.

http://www.latimes.com/news/nationworld/nation/la-sci-fatigue9-2009oct09,0,3368993.story


2009, October 12: New York Times article by Denise Grady, "Is a Virus the Cause of Fatigue Syndrome?"

Quote:

The study [Lombardi et al.] received a mixed review from Dr. William C. Reeves, who directs public health research on the syndrome at the Centers for Disease Control and Prevention. He called the research exciting but preliminary, and said he was surprised that a prestigious journal like Science had published it, because the researchers did not state the ages or sex of the patients and controls, or describe the duration of the illness or how it came on.

“If I don’t know the nature of the cases and controls, I can’t interpret the findings,” Dr. Reeves said.

“We and others are looking at our own specimens and trying to confirm it,” he said, adding, “If we validate it, great. My expectation is that we will not.”

He noted that there had been false starts before, including a study in the 1990s linking the syndrome to another retrovirus, which could not be confirmed by later research...

Dr. William Schaffner, an infectious disease expert at Vanderbilt University, said that the notion of a lingering viral infection was plausible. He said that although some patients claiming to have the syndrome seemed more likely to have a psychological problem, others seemed to have a physical illness.

“There is a group who are young, healthy, active and engaged, and all of a sudden they are laid low by something,” Dr. Schaffner said. “Everyone tells the physicians these are people who are functional and productive, and this is totally out of character. They are frustrated and often quite disheartened. You feel that medical science hasn’t caught up with their illness yet....”

The National Cancer Institute is taking XMRV seriously, said Dr. Stuart Le Grice, head of its Center of Excellence in HIV/AIDS and Cancer Virology.

He said health officials became especially concerned last spring when several research teams looking at prostate cancer reported finding XMRV in 3 percent to 4 percent of blood samples from healthy people in control groups. That could translate into 10 million American being infected with a newly discovered, poorly understood retrovirus that has already been linked to two diseases.

“Any virus at that level is obviously cause for concern,” Dr. Le Grice said, adding that it was important to find out if the virus was associated with any more diseases, and how closely.

He said that just carrying the virus did not necessarily mean a person was at high risk for disease, noting that people may harbor other viruses that will never harm them. The immune system probably keeps the viruses in check.

But he asked: “If it is a problem, how well can we diagnose it and how well can we treat it?”

Even though antiretroviral drugs have already been developed to treat H.I.V. infection, he said this virus was different and might need its own line of drugs.

He said more studies were needed to find out how common the virus is and how it is being transmitted. It is not known whether people can catch the disease from mice, or can infect one another. Retroviruses are often spread by blood and bodily fluids.

“How significant a risk is this to blood banks?” Dr. Le Grice asked. “Do we need to consider large-scale screening in blood banks?”

http://www.nytimes.com/2009/10/13/health/13fatigue.html?_r=2


2009, October 20: New York Times editorial by Hillary Johnson, "A Case of Chronic Denial."

Quote:

Earlier this month, a study published in the journal Science answered a question that medical scientists had been asking since 2006, when they learned of a novel virus found in prostate tumors called xenotropic murine leukemia virus-related virus, or XMRV: Was it a human infection?

XMRV is a gammaretrovirus, one of a family of viruses long-studied in animals but not known to infect people. In animals, these retroviruses can cause horrendous neurological problems, immune deficiency, lymphoma and leukemia. The new study provided overwhelming evidence that XMRV is a human gammaretrovirus — the third human retrovirus (after H.I.V. and human lymphotropic viruses, which cause leukemia and lymphoma). Infection is permanent and, yes, it can spread from person to person (though it is not yet known how the virus is transmitted).

That would have been news enough, but there was more. XMRV had been discovered in people suffering from chronic fatigue syndrome, a malady whose very existence has been a subject of debate for 25 years. For sufferers of this disease, the news has offered enormous hope. Being seriously ill for years, even decades, is nightmarish enough, but patients are also the targets of ridicule and hostility that stem from the perception that it is all in their heads. In the study, 67 percent of the 101 patients with the disease were found to have XMRV in their cells. If further study finds that XMRV actually causes their condition, it may open the door to useful treatments. At least, it will be time to jettison the stigmatizing name chronic fatigue syndrome...

Congress has appropriated money for research on chronic fatigue syndrome, too, though in far smaller amounts, but the C.D.C. has seemed unwilling to spend it productively. A decade ago, investigations by the inspector general for the Department of Health and Human Services and what was then called the General Accounting Office revealed that for years government scientists had been funneling millions meant for research on this disease into other pet projects...

Now, Judy Mikovits, the retrovirus expert at the Whittemore Peterson Institute, in Reno, Nev., who led the recent study, has revisited the cold case. Not surprisingly, the institute is private, created by the parents of a woman who suffers from chronic fatigue syndrome. But Dr. Mikovits collaborated with scientists at the National Cancer Institute and the Cleveland Clinic.

When she began her work on this disease in 2006, Dr. Mikovits, a 22-year veteran of the National Cancer Institute, knew little about chronic fatigue syndrome. But she was intrigued that an unusually high number of patients being followed by a Nevada doctor were suffering rare lymphomas and leukemias; at least one had died. And she was also impressed that the doctor, Dan Peterson, had built an extraordinary repository of more than 8,000 chronic fatigue syndrome tissue samples going back as far as 1984.

“My hypothesis was, ‘This is a retrovirus,’ and I was going to use that repository to find it,” Dr. Mikovits told me.

What she found was live, or replicating, XMRV in both frozen and fresh blood and plasma, as well as saliva. She has found the virus in samples going back to 1984 and in nearly all the patients who developed cancer. She expects the positivity rate will be close to 100 percent in the disease.

“It’s amazing to me that anyone could look at these patients and not see that this is an infectious disease that has ruined lives,” Dr. Mikovits said. She has also given the disease a properly scientific new name: X-associated neuroimmune disease.

For patients who have been abandoned to quackish theories and harsh ideologies about their illness for 25 years, the dismantling of “chronic fatigue syndrome” can’t come soon enough.

http://www.nytimes.com/2009/10/21/opinion/21johnson.html

2010

2010: Revised Canadian Consensus Definition. Jason et al. "The Development of a Revised Canadian Myalgic Encephalomyelitis Chronic Fatigue Syndrome Case Definition" in the American Journal of Biochemistry and Biotechnology.

Abstract:

"Problem statement: Several investigators have indicated that case definitions for Chronic Fatigue Syndrome (CFS) are characterized by vaguely worded criteria that lack operational definitions and guidelines. The most widely used CFS case definition is the Fukuda et al. criteria, which uses polythetic criteria (i.e., patients are only required to have four out of a possible eight symptoms). Yet two of these eight symptoms (post-exertional malaise and memory/concentration problems) are an essential feature of this illness and the Fukuda et al. criteria do not require that these symptoms be present among all patients. Significant methodological problems could occur if investigators in different settings recruit samples with different percentages of these core symptoms. In contrast, the Canadian clinical case definition does require specific ME/CFS symptoms such as post-exertional malaise and memory/concentration problems. The provision of operationally explicit, objective criteria on specific key symptoms might reduce criterion variance as a source of unreliability. In addition, the use of structured interview schedules will ensure that symptoms are assessed in a consistent way across settings. Conclusion/Recommendations: In this article, we specified explicit rules for determining whether critical symptoms meet ME/CFS criteria using a revised Canadian case definition and a questionnaire has been developed to assess core symptoms. It is hoped that these developments will lead to increased reliability of this revised Canadian case definition as well as more frequent use of these criteria by investigators."

http://thescipub.com/issue-ajbb/6/2

http://niceguidelines.files.wordpress.com/2011/07/revised-canadian-myalgic-encephalomyelitis-chronic-fatigue-syndrome-case-definition.pdf


2010, April: Jason et al. "Sensitivity and Specificity of the CDC Empirical Chronic Fatigue Syndrome Case Definition." in Psychology.

"When using all three criteria for fatigue, symptoms and disability, the sensitivity was at an unacceptably low level of .65. The sensitivity and specificity outcomes for the Reeves et al. criteria [the empiric criteria] suggest that these recommended scales [questionnaires] and cutoff points would not be considered a good diagnostic tool for selecting CFS cases from the general population."

http://www.scirp.org/journal/Home.aspx?IssueID=251&JournalID=148


2010, May 7: National Expert Panel on New and Emerging Infections. Meeting of Subgroup on Xenotropic Murine Leukaemia Virus-Related Virus (XMRV). Summary of Discussion, Skipton House, Department of Health. Final July 14, 2010. Corrected August 4, 2010.

Current Detection Methods:

"XMRV shares DNA sequence homology with endogenous retroviruses existing in the mouse genome. This can lead to false positive results in laboratories that also work on mice. The possibility of contamination is compounded by the fact that many laboratories use MuLV plasmids as vectors for several areas of work. This could potentially lead to false positive tests for XMRV, owing to murine DNA being detected rather than human DNA. This issue makes sample sharing between laboratories for corroboration of findings difficult (as contaminated tissue would always generate false positives). Members considered it essential that any future investigative work in the UK should be done using samples that have been obtained within the UK under strict sampling protocols, preferably using fresh tissue samples."

XMRV and Chronic Fatigue Syndrome (CFS):

"A potential association between CFS and XMRV infection was first made by Lombardi et al in October 2009, a research group from the Whittemore Peterson Institute in the USA. This Institute was set up to specifically research the pathophysiology of diseases such as CFS. However, three studies have been published in which the researchers failed to replicate Lombardi’s findings. Members considered that these 'negative' studies were valid and, together with their knowledge of the results of two further studies awaiting publication (CDC study – Switzer et al 2010, Retrovirology in press; Boston study – Huber et al, in preparation) that failed to demonstrate any association of XMRV with CFS, provided good evidence of a lack of association with CFS."

"Though retroviruses are known to induce oncogenesis, XMRV is known to behave quite differently and distinctly from other retroviruses, and a biological mechanism by which XMRV could induce syndromes such as CFS has not been proposed."

http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@ab/documents/digitalasset/dh_118427.pdf


2010, July: Nater UM, Jones JF, Lina JS, Maloneya E, Reeves WC, Heim C. "Personality Features and Personality Disorders in Chronic Fatigue Syndrome: A Population-Based Study" in Psychotherapy and Psychosomatics.

The study used the empiric criteria for CFS.

Results:

"Twenty-nine percent of the CFS cases had at least 1 personality disorder, compared to 28% of the ISF [Insufficient Symptoms and Fatigue] cases and 7% of the well controls. The prevalence of paranoid, schizoid, avoidant, obsessive-compulsive and depressive personality disorders were significantly higher in CFS and ISF compared to the well controls. The CFS cases had significantly higher scores on neuroticism, and significantly lower scores on extraversion than those with ISF or the well controls. Personality features were correlated with selected composite characteristics of fatigue."

Conclusions:

"Our results suggest that CFS is associated with an increased prevalence of maladaptive personality features and personality disorders. This might be associated with being noncompliant with treatment suggestions, displaying unhealthy behavioral strategies and lacking a stable social environment. Since maladaptive personality is not specific to CFS, it might be associated with illness per se rather than with a specific condition."

http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowAbstract&ArtikelNr=319312&Ausgabe=254424&ProduktNr=223864


2010, July 1: Switzer WM, Jia H, Hohn O, Zheng HQ, Tang S, Shankar A, Bannert N, Simmons G, Hendry RM, Falkenberg VR, Reeves WC, Heneine W. "Absence of Evidence of Xenotropic Murine Leukemia Virus-related Virus Infection in Persons with Chronic Fatigue Syndrome and Healthy Controls in the United States." in Retrovirology.

The study used the empiric criteria for CFS.

Abstract:

Background: "XMRV, a xenotropic murine leukemia virus (MuLV)-related virus, was recently identified by PCR testing in 67% of persons with chronic fatigue syndrome (CFS) and in 3.7% of healthy persons from the United States. To investigate the association of XMRV with CFS we tested blood specimens from 51 persons with CFS and 56 healthy persons from the US for evidence of XMRV infection by using serologic and molecular assays. Blinded PCR and serologic testing were performed at the US Centers for Disease Control and Prevention (CDC) and at two additional laboratories."

Results: "Archived blood specimens were tested from persons with CFS defined by the 1994 international research case definition and matched healthy controls from Wichita, Kansas and metropolitan, urban, and rural Georgia populations. Serologic testing at CDC utilized a Western blot (WB) assay that showed excellent sensitivity to MuLV and XMRV polyclonal or monoclonal antibodies, and no reactivity on sera from 121 US blood donors or 26 HTLV-and HIV-infected sera. Plasma from 51 CFS cases and plasma from 53 controls were all WB negative. Additional blinded screening of the 51 cases and 53 controls at the Robert Koch Institute using an ELISA employing recombinant Gag and Env XMRV proteins identified weak seroreactivity in one CFS case and a healthy control, which was not confirmed by immunofluorescence. PCR testing at CDC employed a gag and a pol nested PCR assay with a detection threshold of 10 copies in 1 ug of human DNA. DNA specimens from 50 CFS patients and 56 controls and 41 US blood donors were all PCR-negative. Blinded testing by a second nested gag PCR assay at the Blood Systems Research Institute was also negative for DNA specimens from the 50 CFS cases and 56 controls."

Conclusions: "We did not find any evidence of infection with XMRV in our U.S. study population of CFS patients or healthy controls by using multiple molecular and serologic assays. These data do not support an association of XMRV with CFS."

Discussion:

"CFS is a diagnosis of exclusion based on self-reported symptoms and requires careful medical and psychiatric evaluations to rule out conditions with similar clinical presentation. Our study and the negative reports from the UK and the Netherlands evaluated patients for exclusionary conditions and defined CFS according to criteria of the 1994 International CFS Research Case Definition [23] [Fukuda, 1994] or the earlier Oxford case definition [24] [Sharpe, 1991]. The Lombardi et al. study specifies that samples were selected from patients fulfilling the 1994 international CFS case definition [23] [Fukuda, 1994] and the 2003 Canadian Consensus Criteria for CFS/ME [sic] [25] [Carruthers, 2003]. Lombardi et al. did not specify if patients were evaluated for exclusionary conditions, or if the study subjects met both definitions, or which patients met either CFS definition. The 1994 International CFS case definition and the Canadian Consensus Criteria are different and do not necessarily identify similar groups of ill persons. Most notably, the Canadian Criteria include multiple abnormal physical findings such as spatial instability, ataxia, muscle weakness and fasciculation, restless leg syndrome, and tender lymphadenopathy. The physical findings in persons meeting the Canadian definition may signal the presence of a neurologic condition considered exclusionary for CFS and thus the XMRV positive persons in the Lombardi et al. study may represent a clinical subset of patients [11] [Lombardi, 2009]."

http://www.retrovirology.com/content/7/1/57


2010, July 1: Dr. Suzanne Vernon, Scientific Director of the CFIDS Association of America, statement, "Blood From a Stone."

Regarding the Switzer et al. study in Retrovirology:

"What about the CFS cases and controls? First, I would like to make a request of all authors of scientific papers – please provide a table that describes the subject and sample cohort! Combing back and forth in a paper to figure out who is who and what is what is frustrating! From what I can decipher, the samples were drawn from 18 people identified through a Georgia registry who met criteria described in the paper that is different from 1994 international CFS criteria. Eleven CFS cases and matched controls were identified from the Wichita studies, although it is not clear if these samples came from the longitudinal studies or the clinical study, and 22 CFS cases and controls from the Georgia community-based study. There is little indication that these three cohorts are comparable in regard to CFS definition, as each cohort was selected using different definition. The authors strenuously object to application of the Canadian case definition in other studies, stating that, “physical findings in persons meeting the Canadian definition may signal the presence of a neurological condition considered exclusionary for CFS.” Yet the physical findings listed are those commonly experienced by CFS patients, and one (tender lymphadenopathy) is a case-defining symptom of the 1994 criteria."

"Further, the samples from these three study cohorts were collected using different types of tubes, each of which has a distinct way of being processed. As if this weren’t bad enough, none of the blood tubes used were of the same type used in the Lombardi study. (They used tubes containing sodium heparin that are intended for use with virus isolation). The blood tubes from the 18 Georgia registry patients are designed to collect whole blood and preserve nucleic acid; it is not clear where the plasma came from for these subjects since plasma cannot be obtained using these blood tube types. So the explanation for not finding XMRV in these samples is simple – this was a study designed to not detect XMRV using a hodge-podge sample set."

http://www.cfids.org/xmrv/070110study.asp


2010, July 14: New York Times article by David Tuller, "Delay in Release of Study on Chronic Fatigue Syndrome Prompts an Outcry."

Quote:

Researchers at the National Institutes of Health and the Food and Drug Administration, citing a need to re-evaluate their data, have delayed publication of a new study believed to provide evidence of a link between chronic fatigue syndrome and a little-known retrovirus.

The study, already peer-reviewed, was supposed to appear in the prestigious Proceedings of the National Academy of Sciences. The delay has sparked an outcry on blogs and social networking sites among chronic fatigue patients, who are desperate for answers about their debilitating illness and fear that important scientific data are being suppressed.

“A cabal of top government administrators” with a habit of “heavy-handed, anti-science manipulation of peer-reviewed science” ordered the delay, Hillary Johnson, author of a book about the history of chronic fatigue syndrome, alleged on her Web site, OslersWeb.

Federal officials said publication was delayed because the findings contradicted those of the Centers for Disease Control and Prevention, which conducted its own study on chronic fatigue and the retrovirus, known as XMRV. The C.D.C. study, which found no connection, was initially also held up for reassessment because of the discrepancies, but was eventually published on July 1 in the journal Retrovirology.

A spokeswoman for the National Institutes of Health declined to comment in detail, but provided a statement from Dr. Harvey Alter, an author of the still-unpublished study and an N.I.H. infectious-disease expert. He said, “My colleagues and I are conducting additional experiments to ensure that the data are accurate and complete,” adding, “Our goal is not speed, but scientific accuracy....”

Since the report last year in Science, however, three other published studies, like the new C.D.C. paper, have raised doubts by failing to replicate the findings. The contradictory findings have been attributed to factors like how chronic fatigue cases have been selected and the difficulty in identifying XMRV infection because of a lack of standardized testing protocols.

The Science study was conducted by the Whittemore Peterson Institute for Neuro-Immune Disease, a research center at the University of Nevada, Reno, along with the National Cancer Institute and the Cleveland Clinic. Annette Whittemore, founder and president of the institute, faulted C.D.C. researchers for historically focusing on stress and other psychological factors as major causes of chronic fatigue syndrome, rather than possible infection.

“They’ve been working on chronic fatigue syndrome since the mid-80s, and yet we still don’t have any answers from the C.D.C.,” said Ms. Whittemore, whose daughter has the illness.

Stephan Monroe, director of the C.D.C.’s division of high-consequence pathogens and pathology, said the agency believed that infectious agents could be one of many possible triggers for the disease but that no pathogen had yet emerged as a “primary cause.”

He said he was not surprised by the current uproar among patients. “This is a very well-informed and highly connected patient and advocacy population, and whenever there’s any new information, it’s circulated widely,” he said.

http://www.nytimes.com/2010/07/14/health/14fatigue.html


2010, August 10: Hillary Johnson interview by Teri Arranga of Voice America. "Osler's Web, Unraveling Chronic Fatigue Syndrome, and More with Hillary Johnson."

http://www.voiceamerica.com/voiceamerica/vepisode.aspx?aid=47948 (Audio)


2010, August 23: Lo S, Pripuzova N, Li B, Komaroff AL, Hung G, Wang R, Alter HJ. "Detection of MLV-Related Virus Gene Sequences in Blood of Patients with Chronic Fatigue Syndrome and Healthy Blood Donors" in Proceedings of the National Academy of Sciences.

"Chronic fatigue syndrome (CFS) is a serious systemic illness of unknown cause. A recent study identified DNA from a xenotropic murine leukemia virus-related virus (XMRV) in peripheral blood mononuclear cells (PBMCs) from 68 of 101 patients (67%) by nested PCR, as compared with 8 of 218 (3.7%) healthy controls. However, four subsequent reports failed to detect any murine leukemia virus (MLV)-related virus gene sequences in blood of CFS patients."

"We examined 41 PBMC-derived DNA samples from 37 patients meeting accepted diagnostic criteria for CFS and found MLV-like virus gag gene sequences in 32 of 37 (86.5%) compared with only 3 of 44 (6.8%) healthy volunteer blood donors. No evidence of mouse DNA contamination was detected in the PCR assay system or the clinical samples. Seven of 8 gag-positive patients tested again positive in a sample obtained nearly 15 y later."

"In contrast to the reported findings of near-genetic identity of all XMRVs, we identified a genetically diverse group of MLV-related viruses. The gag and env sequences from CFS patients were more closely related to those of polytropic mouse endogenous retroviruses than to those of XMRVs and were even less closely related to those of ecotropic MLVs. Further studies are needed to determine whether the same strong association with MLV-related viruses is found in other groups of patients with CFS, whether these viruses play a causative role in the development of CFS, and whether they represent a threat to the blood supply."

"Why Have Other Studies Come to Different Conclusions? Although we find evidence of a broader group of MLV-related viruses, rather than just XMRV, in patients with CFS and healthy blood donors, our results clearly support the central argument by Lombardi et al. (3) that MLV-related viruses are associated with CFS and are present in some blood donors."

"However, four recent studies have failed to confirm the PCR results reported by Lombardi (7–10). There are various possible explanations for this disparity. As stated in the reports, there could be a difference in the prevalence of these infectious agents in CFS patient populations in different geographic areas. This argument is somewhat less plausible since the publication of a recent negative study with subjects from the United States (10). Nevertheless, the heterogeneity in gag gene sequences that we observed suggests that geographic differences in different MLV-related viruses may be considerable and could affect both the sensitivity and the specificity of molecular amplification using standard primer sets."

"Indeed, it is possible that the PCR primers used in various studies may have different sensitivity in detecting the diverse group of MLV-related virus gag gene sequences that we found in the clinical samples..."

"Further Considerations. The finding of XMRV or MLV sequences in persons with CFS or other diseases does not constitute definitive proof of viral infection. However, in the study of Lombardi et al. (3) and studies reviewed subsequently by Silverman et al. (22) the evidence for XMRV infection in humans not only involved detection of viral nucleic acids using PCR, but also reported the detection of viral antigens, detection of anti-viral antibodies, the ability to culture the virus in a prostate cancer cell line, the detection of gamma retrovirus particles by electron microscopy, and transmission of infection to macaques."

"In sum, none of the four studies that have failed to confirm the PCR evidence reported by Lombardi et al. (3), nor our own study, has attempted to fully replicate that study. It remains to be shown that the association that we have found, using the methods that we have described, can be generalized to a larger group of patients with CFS. Indeed, we suspect that the association will be lower in CFS cases identified through community-based surveys, as contrasted to cases seen at academic medical centers."

"Even if subsequent studies confirm an association between MLV-like viruses and CFS, that will not establish a causal role for these viruses in the pathogenesis of this illness. For example, such a high frequency of infections with MLV-related viruses in patients with CFS could reflect an increased susceptibility to viral infections due to an underlying CFS-related immune dysfunction, rather than a primary role for these viruses in the pathogenesis of CFS. Finally, the finding of MLV-related virus gag gene sequences in nearly 7% of healthy volunteer blood donors in our study and of XMRV in 3.7% of healthy controls in the study of Lombardi et al. (3) raises additional issues. The possibility that these agents might be blood-transmitted and pathogenic in blood recipients warrants extensive research investigations of appropriately linked donor–recipient cohorts."

From Materials and Methods:

Samples from CFS Patients and Healthy Controls. Initially, we tested 41 whole-blood samples that had been obtained for culture isolation of mycoplasmal agents in the mid-1990s. We maintained whole-blood, PBMC, and plasma samples from CFS patients in frozen storage at −80 °C. Of the 41 patient samples, 29 were collected from 25 patients by one of us (A.L.K.) at the Chronic Fatigue Research Center, Brigham and Women’s Hospital (Boston, MA). Four of the CFS patients also had blood obtained on a second occasion ∼2 y later.

Most of the patients were from the New England area; none were related, and virtually none had any regular social contact. Each of the 25 patients was systematically evaluated with a standardized history (supplemented by a patient questionnaire), physical examination, and battery of laboratory tests. Each met the 1988 CDC criteria for CFS, and 21 also met the 1994 CDC criteria. The average age of the patients at the time of venepuncture was 44.4 y; 4 were male and 21 were female.

All of the patients signed informed consent documents approved by the Institutional Review Board of Brigham and Women’s Hospital. A new set of blood samples was obtained in 2010 from 8 of the original 25 patients followed in the academic medical center. The blood samples were processed for PCR study without first being frozen. The other 12 samples from CFS patients were sent by individual clinicians taking care of patients in the mid-1990s who were given the diagnosis of CFS.

We do not have details regarding the methodology by which the referring clinicians established the diagnosis of CFS. The samples had also been sent in the mid-1990s and stored at −80 °C. Frozen PBMC samples from 44 normal blood donors from the Washington, DC, area were collected in 2003–2006 and stored at the Department of Transfusion Medicine, Clinical Center, National Institutes of Health. All patient and control samples were coded and tested in parallel.

http://www.pnas.org/content/early/2010/08/16/1006901107.full.pdf+html


2010, August 23: New York Times article by David Tuller, "Study Links Chronic Fatigue to Virus Class."

Quote:

When the journal Science published an attention-grabbing study last fall linking chronic fatigue syndrome to a recently discovered retrovirus, many experts remained skeptical — especially after four other studies found no such association.

Now a second research team has reported a link between the fatigue syndrome and the same class of virus, a category known as MLV-related viruses. In a paper published Monday by The Proceedings of the National Academy of Sciences, scientists found gene sequences from several MLV-related viruses in blood cells from 32 out of 37 chronic-fatigue patients but only 3 of 44 healthy ones.

The researchers did not find XMRV, the specific retrovirus identified in patients last fall. But by confirming the presence of a cluster of genetically similar viruses, the new study represents a significant advance, experts and advocates say...

People with a diagnosis of chronic fatigue syndrome are used to hearing scientists, doctors, employers, friends and family members dismiss the condition as psychosomatic or related to stress or trauma, despite evidence that it is often touched off by an acute viral illness. Many were ecstatic at news that the second study was being published.

“We’re really hoping this will blow the lid off,” said Mary Schweitzer, a historian who has written and spoken about having the illness. “Patients are hopeful that now the disease itself might be treated seriously, that they’ll be treated seriously, and that there might be some solution...”

Moreover, it remains unclear why only two research teams found evidence of retroviruses. One reason could be that different groups used varying testing and detecting methods; federal health officials have organized an effort to standardize the process.

The studies also used different methods of sampling chronic fatigue patients. Many experts and researchers argue that the C.D.C.’s strategy leads to overdiagnosis because it fails to fully distinguish the disease from psychiatric disorders like depression.

Officials with the agency say their methods are sound. William M. Switzer, a microbiologist who was the lead author of the agency’s paper, said of the new research, “These are very intriguing findings that need to be confirmed.”

The findings are sure to raise concerns about the safety of the blood supply. AABB, formerly known as the American Association of Blood Banks, recommended in June that people with the illness be discouraged from donating, pending further study.

“The possibility that these agents might be blood-transmitted and pathogenic in blood recipients warrants extensive research investigations,” Dr. Alter and his co-authors wrote in the new study...

http://www.nytimes.com/2010/08/24/health/research/24fatigue.html


2010, September: Mikovits JA, Lombardi VC, Pfost MA, Hagen KS, Ruscetti FW. "Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome" in Virulence.

"In October 2009, we reported the first direct isolation of infectious xenotropic murine leukemia virus-related virus (XMRV). In that study, we used a combination of biological amplification and molecular enhancement techniques to detect XMRV in more than 75% of 101 patients with chronic fatigue syndrome (CFS). Since our report, controversy arose after the publication of several studies that failed to detect XMRV infection in their CFS patient populations. In this addenda, we further detail the multiple detection methods we used in order to observe XMRV infection in our CFS cohort. Our results indicate that PCR from DNA of unstimulated peripheral blood mononuclear cells is the least sensitive method for detection of XMRV in subjects’ blood. We advocate the use of more than one type of assay in order to determine the frequency of XMRV infection in patient cohorts in future studies of the relevance of XMRV to human disease."

"Patient selection poses a challenge to any study of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In our October 2009 paper, samples banked from 2006 to 2008 were selected for our study from severely disabled patients who fulfilled the 1994 CDC Fukuda Criteria for chronic fatigue syndrome [1] as well as the 2003 Canadian Consensus Criteria (CCC) for ME/CFS. [2] The CCC requires post-exertional malaise, which many clinicians feel is the sine qua non of ME/CFS. Furthermore the CCC further requires that patients exhibit post exetional fatigue, unrefreshing sleep, pain and neurological/cognitive manifestations, rather than these being optional symptoms. [3] Many clinicians interested in CFS are switching to the Canadian criteria because they feel it is more descriptive of the clinical entity being defined. The Fukuda criteria have the advantage of a longer period of usage and existence of many publications that have added modifications. Suffice it to say that the clinician author of the Science paper elected to use both criteria, thus bypassing the argument of which criteria were better. Moreover, the emphasis in the Science paper was directed toward the virology, not the clinical description of ME/CFS."

"Samples that are negative for XMRV by one of our PCR assays are sometimes positive by other assays. For example, in Figure 1A of the Science paper, patient 1118 was negative by single round PCR on DNA from unstimulated PBMCs, but positive in other assays (Science Figs. 2A and D, 4A and S5). Of the 34 patients whose PBMCs were negative for XMRV by DNA or cDNA PCR, 17 were positive for infectious virus when co-cultured with the LNCaP indicator cell line, as XMRV gag and env PCR products were detected in the cell line following their infection with XMRV from the patient PBMCs (Table 2). Both gag and env products obtained from either single-round or nested PCR were sequenced and shown to be 99% identical to XMRV VP62."

"Subsequent to our October 2009 publication, two papers from the United Kingdom [4,5] and a paper from the Netherlands [6] have appeared in which the authors report the lack of detection of XMRV PCR products from DNA of unstimulated PBMCs, using patient populations selected by only the Fukuda criteria or the Oxford criteria rather than both Fukuda and CCC criteria. We regret that these authors did not request positive control samples of our patients who exhibit XMRV PCR products even when assayed by the least sensitive detection method, namely PCR of DNA from unstimulated PBMCs. Given that only 7% of our 101 patients’ PBMCs exhibit products upon DNA PCR (Table 3 and 4), and that a number of patients were included in the UK studies who do not fulfill the CCC criteria, very few, if any, of the samples would be expected to be positive by DNA PCR. We also note that both studies followed different methods than ours for blood collection, DNA quantities and isolation and PCR, possible sources of the disparate results. The XMRV detection results of the 101 patients are listed in Table 4."

http://www.landesbioscience.com/journals/virulence/article/12486

2011

2011, January 3: New York Times article by David Tuller, "Exhausted by Illness, and Doubts."

Quote:

Since the first cases in the United States were identified in the 1980s, scientists have been divided over that question. Some have suspected that one or more viral infections are likely to play a central role.

But many other researchers — not to mention relatives, friends, employers, doctors and insurers of the million or more Americans estimated to suffer from the illness — have dismissed it as stress-related, psychosomatic or simply imaginary.

Now recent back-to-back announcements have highlighted both the volatility of the issue and the ambiguity of the science, and have alternately heartened and dismayed patients.

On Dec. 14, an advisory panel suggested that the Food and Drug Administration ban blood donations by people with a history of C.F.S., as the illness is often called. The goal was to prevent the possible spread of viruses that two high-profile studies had linked to the condition.

But then, on Dec. 20, the journal Retrovirology published four papers suggesting that key findings in those studies could have resulted from laboratory contamination.

The F.D.A. is not required to accept the opinion of its advisory panel. Yet patients still hailed the recommendation as a sign that their illness was being taken seriously.

“When an F.D.A. panel suggests that patients with C.F.S. not donate blood, that’s going to impact the way doctors think about it,” said Mary Schweitzer, a former history professor at Villanova, who has frequently written about living with the illness. Dr. Schweitzer said she has been unable to work for 16 years because of the syndrome, which was diagnosed after she suffered from a series of flulike illnesses.

The studies that concerned the F.D.A. had reported that people with the syndrome, which is also called myalgic encephalomyelitis or myalgic encephalopathy in Europe, showed higher rates of infection with the virus XMRV or others from the same category, known as MLV-related viruses. (These viruses are all relatives of mouse leukemia viruses, some of which can infect species other than mice; their role in human disease, if any, remains poorly understood.)

But several other research teams in the last year have found no connection between chronic fatigue syndrome and these viruses, although none tried to replicate the exact methods used by researchers who reported an association.

The new papers in Retrovirology reported that contamination of tissue samples or other laboratory items with mouse DNA or viral genetic material could lead to false positive results for XMRV, and by extension other MLV-related viruses, specifically when using polymerase chain reaction technology. The technique rapidly produces millions of copies of genetic segments, so even minute traces of genetic contamination can skew results.

“Our conclusion is quite simple: XMRV is not the cause of chronic fatigue syndrome,” said the senior author of one of the studies, Greg Towers, a professor of virology at University College London, in a statement released by Wellcome Trust Sanger Institute, the British research center that co-sponsored it.

Other scientists and advocates for patients have sharply criticized such certainty as unwarranted, noting that the Retrovirology papers themselves expressed their findings in more cautious terms. The critics agree that contamination can be a serious issue when using polymerase chain reaction technology. But the new papers, said Eric Gordon, a doctor in Santa Rosa, Calif., who treats many patients with the illness, do not evaluate other strategies besides P.C.R., as the technique is known, for detecting the MLV-related viruses, like testing for an immune response and culturing the viruses in cell lines.

“The articles make the point that P.C.R. doesn’t work that well for these viruses, and then they act like that disproves the whole idea,” said Dr. Gordon...

In a statement responding to the new papers in Retrovirology, Judy A. Mikovits, director of research at Whittemore Peterson and the senior author of the Science study, said her team took extensive steps to rule out P.C.R. contamination and also focused on other approaches to finding XMRV. “Nothing that has been published to date refutes our data,” she said.

Even some specialists stumbled over the meaning of the new findings. Vincent Racaniello, a professor of microbiology at Columbia not involved in the research, apologized on his Virology Blog for having stated that it was likely to spell “the beginning of the end” for the proposed connection between the viruses and chronic fatigue syndrome.

After reviewing the issue more thoroughly, he wrote, he realized that the new studies “show that identification of XMRV can be fraught with contamination problems, but they do not imply that previously published studies are compromised.” He added, “If I had difficulties interpreting these papers, how would nonscientists fare?”

Federal agencies have come down on different sides of the issue. In a paper published in The Proceedings of the National Academy of Sciences in August, researchers from the National Institutes of Health and the F.D.A. found a link between the fatigue syndrome and MLV-related viruses (although not specifically XMRV). In contrast, a study from the Centers for Disease Control and Prevention was among those not reporting a link...

http://www.nytimes.com/2011/01/04/health/04fatigue.html?_r=1


2011, August 22: The International Consensus Criteria for ME Caruthers et al. "Myalgic encephalomyelitis: International Consensus Criteria" in Journal of Internal Medicine.

Abstract:

The label ‘chronic fatigue syndrome’ (CFS) has persisted for many years because of the lack of knowledge of the aetiological agents and the disease process. In view of more recent research and clinical experience that strongly point to widespread inflammation and multisystemic neuropathology, it is more appropriate and correct to use the term ‘myalgic encephalomyelitis’ (ME) because it indicates an underlying pathophysiology. It is also consistent with the neurological classification of ME in the World Health Organization’s International Classification of Diseases (ICD G93.3).

Consequently, an International Consensus Panel consisting of clinicians, researchers, teaching faculty and an independent patient advocate was formed with the purpose of developing criteria based on current knowledge. Thirteen countries and a wide range of specialties were represented. Collectively, members have approximately 400 years of both clinical and teaching experience, authored hundreds of peer-reviewed publications, diagnosed or treated approximately 50 000 patients with ME, and several members coauthored previous criteria. The expertise and experience of the panel members as well as PubMed and other medical sources were utilized in a progression of suggestions/drafts/reviews/revisions. The authors, free of any sponsoring organization, achieved 100% consensus through a Delphi-type process.

The scope of this paper is limited to criteria of ME and their application. Accordingly, the criteria reflect the complex symptomatology. Operational notes enhance clarity and specificity by providing guidance in the expression and interpretation of symptoms. Clinical and research application guidelines promote optimal recognition of ME by primary physicians and other healthcare providers, improve the consistency of diagnoses in adult and paediatric patients internationally and facilitate clearer identification of patients for research studies.


From Table 1:

Myalgic encephalomyelitis is an acquired neurological disease with complex global dysfunctions. Pathological dysregulation of the nervous, immune and endocrine systems, with impaired cellular energy metabolism and ion transport are prominent features. Although signs and symptoms are dynamically interactive and causally connected, the criteria are grouped by regions of pathophysiology to provide general focus.

A patient will meet the criteria for postexertional neuroimmune exhaustion (A), at least one symptom from three neurological impairment categories (B), at least one symptom from three immune/gastro-intestinal/genitourinary impairment categories (C), and at least one symptom from energy metabolism/transport impairments (D).


A. Postexertional neuroimmune exhaustion (PENE pen’-e): Compulsory

This cardinal feature is a pathological inability to produce sufficient energy on demand with prominent symptoms primarily in the neuroimmune regions. Characteristics are as follows:

1. Marked, rapid physical and/or cognitive fatigability in response to exertion, which may be minimal such as activities of daily living or simple mental tasks, can be debilitating and cause a relapse.

2. Postexertional symptom exacerbation:e.g.acute flu-like symptoms, pain and worsening of other symptoms.

3. Postexertional exhaustion may occur immediately after activity or be delayed by hours or days.

4. Recovery period is prolonged, usually taking 24 h or longer. A relapse can last days, weeks or longer.

5. Low threshold of physical and mental fatigability (lack of stamina) results in a substantial reduction in pre-illness activity level.

Operational notes:For a diagnosis of ME, symptom severity must result in a significant reduction of a patient’s premorbid activity level.Mild(an approximate 50% reduction in pre-illness activity level),moderate(mostly housebound),severe(mostly bedridden) orvery severe(totally bedridden and need help with basic functions). There may be marked fluctuation of symptom severity and hierarchy from day to day or hour to hour. Consider activity, context and interactive effects.Recovery time: e.g. Regardless of a patient’s recovery time from reading for ½ hour, it will take much longer to recover from grocery shopping for ½ hour and even longer if repeated the next day – if able. Those who rest before an activity or have adjusted their activity level to their limited energy may have shorter recovery periods than those who do not pace their activities adequately.Impact: e.g. An outstanding athlete could have a 50% reduction in his/her pre-illness activity level and is still more active than a sedentary person.


B. Neurological impairments

At least one symptom from three of the following four symptom categories

1. Neurocognitive impairments

a. Difficulty processing information: slowed thought, impaired concentration e.g. confusion, disorientation, cognitive overload, difficulty with making decisions, slowed speech, acquired or exertional dyslexia

b. Short-term memory loss:e.g. difficulty remembering what one wanted to say, what one was saying, retrieving words, recalling information, poor working memory

2. Pain

a. Headaches:e.g. chronic, generalized headaches often involve aching of the eyes, behind the eyes or back of the head that may be associated with cervical muscle tension; migraine; tension headaches

b. Significant pain can be experienced in muscles, muscle-tendon junctions, joints, abdomen or chest. It is noninflammatory in nature and often migrates. e.g. generalized hyperalgesia, widespread pain (may meet fibromyalgia criteria), myofascial or radiating pain

3. Sleep disturbance

a. Disturbed sleep patterns:e.g. insomnia, prolonged sleep including naps, sleeping most of the day and being awake most of the night, frequent awakenings, awaking much earlier than before illness onset, vivid dreams/nightmares

b. Unrefreshed sleep:e.g. awaken feeling exhausted regardless of duration of sleep, day-time sleepiness

4. Neurosensory, perceptual and motor disturbances

a. Neurosensory and perceptual:e.g. inability to focus vision, sensitivity to light, noise, vibration, odour, taste and touch; impaired depth perception

b. Motor:e.g. muscle weakness, twitching, poor coordination, feeling unsteady on feet, ataxia

Notes: Neurocognitive impairments, reported or observed, become more pronounced with fatigue.Overload phenomenamay be evident when two tasks are performed simultaneously. Abnormal accommodation responsesof the pupils are common.Sleep disturbancesare typically expressed by prolonged sleep, sometimes extreme, in the acute phase and often evolve into marked sleep reversal in the chronic stage.Motor disturbancesmay not be evident in mild or moderate cases but abnormal tandem gait and positive Romberg test may be observed in severe cases.


C. Immune, gastro-intestinal and genitourinary Impairments

At least one symptom from three of the following five symptom categories

1. Flu-like symptoms may be recurrent or chronic and typically activate or worsen with exertion.e.g. sore throat, sinusitis, cervical and/or axillary lymph nodes may enlarge or be tender on palpitation

2. Susceptibility to viral infections with prolonged recovery periods

3. Gastro-intestinal tract:e.g. nausea, abdominal pain, bloating, irritable bowel syndrome

4. Genitourinary: e.g. urinary urgency or frequency, nocturia

5. Sensitivities to food, medications, odours or chemicals

Notes:Sore throat, tender lymph nodes, and flu-like symptoms obviously are not specific to ME but their activation in reaction to exertion is abnormal. The throat may feel sore, dry and scratchy. Faucial injection and crimson crescents may be seen in the tonsillar fossae, which are an indication of immune activation.


D. Energy production/transportation impairments

At least one symptom

1. Cardiovascular:e.g. inability to tolerate an upright position - orthostatic intolerance, neurally mediated hypotension, postural orthostatic tachycardia syndrome, palpitations with or without cardiac arrhythmias, light-headedness/dizziness

2. Respiratory:e.g. air hunger, laboured breathing, fatigue of chest wall muscles

3. Loss of thermostatic stability:e.g. subnormal body temperature, marked diurnal fluctuations; sweating episodes, recurrent feelings of feverishness with or without low grade fever, cold extremities

4. Intolerance of extremes of temperature

Notes:Orthostatic intolerance may be delayed by several minutes. Patients who have orthostatic intolerance may exhibit mottling of extremities, extreme pallor or Raynaud’s Phenomenon. In the chronic phase, moons of finger nails may recede.


Paediatric considerations

Symptoms may progress more slowly in children than in teenagers or adults. In addition to postexertional neuroimmune exhaustion, the most prominent symptoms tend to be neurological: headaches, cognitive impairments, and sleep disturbances.

1. Headaches: Severe or chronic headaches are often debilitating. Migraine may be accompanied by a rapid drop in temperature, shaking, vomiting, diarrhoea and severe weakness.

2. Neurocognitive impairments: Difficulty focusing eyes and reading are common. Children may become dyslexic, which may only be evident when fatigued. Slow processing of information makes it difficult to follow auditory instructions or take notes. All cognitive impairments worsen with physical or mental exertion. Young people will not be able to maintain a full school programme.

3. Pain may seem erratic and migrate quickly. Joint hypermobility is common.

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2011.02428.x/full

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