Chronic Fatigue Syndrome/CFS/Chronic Fatigue Immunodeficiency Syndrome/CFIDS/Myalgic Encephalomyelitis/ME/Systemic Exertion Intolerance Disease/SEID

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Definition[edit]

This is a multi-system disorder that is characterized by poor sleep and severe fatigue.

For further clarification see the CDC’s fact sheet entitled “What is ME/CFS?” available in full online at: https://www.cdc.gov/me-cfs/about/index.html.

Synonyms and similar conditions[edit]

The following is a list of both similar and somewhat similar related terms:

Febricula, Nervous exhaustion, Neurasthenia, DaCosta’s Syndrome, Effort Syndrome, Autonomic Imbalance Syndrome, Chronic brucellosis, Hypoglycemia, “Total Allergy” syndrome, Chronic candidiasis, Chronic Epstein Barr virus infection, Chronic Fatigue and Immune Dysfunction Syndrome (CFIDS). (*Bennett, 1993), low natural killer syndrome (LNKS).

Most of these terms shed a little light on the problem and are somewhat misleading at the same time. For example, there appears to be more candida in Fibromyalgics and CFS. The term total allergy syndrome conveys the universal nature of the negative reactions of some patients to seemingly everything in the environment. It is sometimes called Chronic Fatigue and Immune Disfunction Syndrome (CFIDS) or also Chronic Epstein-Barr Virus (CEBV), Myalgic Encephalomyelitis (M.E), but Myalgic Encephalitis is more akin to fibromyalgia because, myalgia means sore muscles, and pain seemingly of muscular origin is the principle symptom of fibromyalgia. Another name is yuppie flu, but demographic studies do not seem to support the idea that the condition is in any way specific to yuppies (Young Urban Professionals in Westernized Countries). CFIDS is a term with some merit because it highlights the established fact that there are a number of immunological abnormalities. CEBV is probably a bad term because studies have found that persons who are chronically fatigued do not have high levels of Epstein Barr virus antibodies compared to controls. (Buchwald, 1996)

Relevance to somatosensation and pain[edit]

This disorder is part of a continuum with fibromyalgia. Both involve poor sleep. In fibromyalgia, muscular pains are more prominent. They are co-morbidities. A majority of patients diagnosed with CFS will has some chronic pain.

Comments on the name[edit]

Like fibromyalgia, there are many names for chronic fatigue syndrome. In the 1800s these patients likely would have been diagnosed with neurasthenia. Given that asthenia means “weakness” and given that there is evidence for pivotal roles for the brain and the nervous system in this disorder; neurasthenia is as good or perhaps even a better name than CFS.

Myalgic encephalomyelitis is another less common name. In the opinion of the author it is a poor name because “myelitis” means inflammation of the spinal cord, and there is little evidence for this. In Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness, (National Academies Press, 2015, available in full online at: http://www.nationalacademies.org/hmd/~/media/Files/Report%20Files/2015/MECFS/MECFS_ReportBrief.pdf ) the authors advised dropping the term CFS and replacing it with “systemic exertion intolerance disease (SEID)”. The authors state that when they say “exertion”, they mean that it could be of any sort including physical, cognitive, or emotional. They further stipulate that this disorder can affect many aspects of the patient’s life and many of their organ systems. (Page 4)

In the opinion of the author of this wiki, it is best to leave the name as chronic fatigue syndrome, because further attempts to change it will add to the confusion.

Holmes definition (1988)[edit]

This was the first US working case definition of CFS. The criteria were that the patient has to have a minimum of eight out of 11 minor symptoms from the list consisting of: fever or chills, sore throat, lymph node pain, muscle weakness, muscle pain, post-exertional malaise, headaches of a new or different type, migratory arthralgia, neuro-psychiatric complaints, sleep disturbance, and a sudden onset of symptoms. Chronic Fatigue Syndrome: A working case definition. Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Strauss SE, Jones JF, Dubois RE, Cunningham-Rundles C, Pahwa S, Tosato G, Zegans LS, Purtilo DT, Brown N, Schooley RT, Brus I. Ann Intern Med. 1988;108:387–389. [PubMed] available in full online at: https://pdfs.semanticscholar.org/7b3c/37849406de739ed89abcd37629e866dc5c8b.pdf.

The feeling of fatigue[edit]

The neurobiological basis for the conscious is probably unknown based on the author’s 2020 search of the scholarly literature. Poor sleep is probably a major contributor. According to Boissoneault et al., cortico-cerebellar interactions may be involved in producing feelings of fatigue. They also found that functional interactions between globus pallidum and occipital structures contributed to experimental fatigue in healthy individuals. (Functional brain connectivity of remembered fatigue or happiness in healthy adults: Use of arterial spin labeling. Jeff Boissoneault 1, Landrew Sevel 1, Michael E Robinson 1, Roland Staud 2, J Clin Exp Neuropsychol. 2018 Apr;40(3):224-233, doi: 10.1080/13803395.2017.1329407. Epub 2017 May 29, DOI: 10.1080/13803395.2017.1329407, available in full online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051525/.

[Author’s comment: The finding of involvement of the occipital lobe is somewhat unexpected given the typical understating that this lobe is mostly involved in vision.]

Demographics[edit]

There are various estimates of its prevalence of CFS in the US. Broderick et al. claim that it affects 4 million Americans. The CDC states: “About 90 percent of people with ME/CFS have not been diagnosed.” (https://www.cdc.gov/me-cfs/about/index.html)

“According to the CDC, more than one million Americans have ME/CFS. At least one-quarter of individuals with ME/CFS are bedbound or housebound at some point in the illness and most never regain their pre-disease level of functioning. ME/CFS strikes people of all ages and racial, ethnic, and socioeconomic groups, and is two to four times more common in women than men.” (The National Institute of Neurological Disorders and Stroke (NINDS) Common Data Elements (CDE), Overall Working Group Summary https://www.commondataelements.ninds.nih.gov/Doc/MECFS/MECFS_Overall_Working_Group_Summary.pdf)

The Institute of Medicine (IOM) 2015 report, an estimated 836,000 to 2.5 million Americans suffer from ME/CFS, but most of them have not been diagnosed.” (https://www.cdc.gov/me-cfs/.)

The female-to-male ratio is 4:1. (Chronic fatigue syndrome: a review. N. Afari, D. Buchwald. Am J Psychiatry, 2 (2003), pp. 221-236) CFS can occur in children.

It seems likely that many people who are diagnosed with severe insomnia would also qualify for CFS. There is considerable data on the prevalence of insomnia, but less on the prevalence in society of severe insomnia. The WHO definition of insomnia is already quite severe because it calls for 3 difficult nights a week.

Insomnia is common in women, older adults, people with medical disabilities, chronic pain patients and people with mental health problems especially people who have anxiety disorders who are worriers with a chain of worries that keep them from getting to sleep at night. (Prevalence of chronic insomnia in adult patients and its correlation with medical comorbidities. Swapna Bhaskar,1 D. Hemavathy,2 and Shankar Prasad3, J Family Med Prim Care. 2016 Oct-Dec; 5(4): 780–784, doi: 10.4103/2249-4863.201153.)

Fatigue rating scale[edit]

These are handy simple scales that typically allow the patient to rate their fatigue on a horizontal bar that is divided from 0-10. Zero is defined as “feeling energetic with no fatigue” 2 is mild, 5 is moderate, 8-10 is severe with 10 representing “worst possible fatigue”.

Key symptoms[edit]

According to Ferré, these are:

  • generalized fatigue lasting over 6 months,
  • fatigue worsening after exercise (98%),
  • non-restorative sleep (94%), (waking tired even with a reasonable number of hours of sleep)
  • recurrent headache (90%)
  • concentration and/or memory problems (85%),
  • musculoskeletal pain (75%),
  • swollen lymph nodes and or psychiatric disorders (65%).

(Chronic fatigue syndrome and sleep disorders: Clinical associations and diagnostic difficulties, A. Ferré, Neurologia, Vol. 33. Num. 6. pages 351-418 (July - August 2018) DOI: 10.1016/j.nrleng.2015.11.020 available in full online at: https://www.elsevier.es/en-revista-neurologia-english-edition--495-articulo-chronic-fatigue-syndrome-sleep-disorders-S2173580818300038 made available under a Creative Commons license (https://creativecommons.org/licenses/by-nc-nd/4.0/) which does not include commercial use.)

[Author’s comment: The most noteworthy aspects of this list are the near universal presence of fatigue that worsens with exercise (98%) and the 94% with non-restorative sleep. These facts arouse the suspicion that it may be mainly a sleep disorder. Even the concentration and memory problems could be explained by sleep deprivation. The main symptom is fatigue, and it is common knowledge that people generally feel fatigued as a result of a poor night of sleep.]

International consensus criteria for ME[edit]

In 2011 a group of experts published international consensus criteria for ME in the Journal of Internal Medicine. (Myalgic encephalomyelitis: International Consensus Criteria. B.M. Carruthers, M.I. Van de Sande, K.L. De Meirleir, N.G. Klimas, G. Broderick, T. Mitchell, et al. J Intern Med, 4 (2011), pp. 327-338, available in full online at: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2796.2011.02428.x. The introduction to this paper states: “Myalgic encephalomyelitis (ME), also referred to in the literature as chronic fatigue syndrome (CFS), is a complex disease involving profound dysregulation of the central nervous system (CNS) [1-3] and immune system [4-8], dysfunction of cellular energy metabolism and ion transport [9-11] and cardiovascular abnormalities [12-14].” Their criteria are quite complicated. They are found in table 1 of the paper which is entitled “Myalgic encephalomyelitis: international consensus criteria”.

All patients must meet their criteria for “postexertional neuroimmune exhaustion” which is criteria (A), “and 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).”

Proposed new diagnostic criteria from the Institute of Medicine[edit]

These can be found in the article entitled: Redefining an Illness. Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome; Board on the Health of Select Populations; Institute of Medicine. National Academies Press (US); 2015 Feb 10, by the National Academy of Sciences, available in full online at: https://www.ncbi.nlm.nih.gov/books/NBK274235/.)

For their proposed criteria to diagnosis ME/CFS see: https://www.ncbi.nlm.nih.gov/books/NBK284892/box/box_S_1/?report=objectonly

Diagnosis requires that the patient have the following three symptoms:

1) six months or more of substantial impairment in the ability to function at pre-illness levels for occupation, education, social and personal activity, as well as having undue fatigue that is not relieved by rest.

2) Post-exertional malaise, and

3) unrefreshing sleep.

In addition, the patient must have either:

4) cognitive impairment

5) orthostatic intolerance

or both 4) and 5).

Possible distinction between CFS and ME[edit]

While these terms have been used interchangeably, Twisk distinguishes between the two. Twisk argues that the distinctive features of ME are: “muscle weakness and easy muscle fatigability, cognitive impairment, circulatory deficits, a marked variability of the symptoms in presence and severity, but above all, post-exertional “malaise”: a (delayed) prolonged aggravation of symptoms after a minor exertion.

Twisk also claims that CFS stands in contrast to ME and CFS primarily involves “unexplained chronic fatigue “accompanied by four out of a list of 8 symptoms, e.g., headaches.” They point to the need for objective tests to reduce confusion. They note that some of the “characteristic symptoms, e.g., post-exertional “malaise” and muscle weakness, can be assessed objectively using well-accepted methods, e.g., cardiopulmonary exercise tests and cognitive tests. (Accurate diagnosis of myalgic encephalomyelitis and chronic fatigue syndrome based upon objective test methods for characteristic symptoms. Frank NM Twisk, World J Methodol. 2015 Jun 26; 5(2): 68–87.Published online 2015 Jun 26. doi: 10.5662/wjm.v5.i2.68, available in full online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4482824/, PMCID: PMC4482824, PMID: 26140274.)

Author’s opinion: CFS is similar to and on a continuum with fibromyalgia[edit]

Based on the clinical experience of the author, most fibromyalgia patients have most of the symptoms listed in the Holmes definition except for fevers and chills sore throats and lymph node pain. There are definite similarities between chronic fatigue syndrome and fibromyalgia, including muscle pain and sleep difficulties. A surprising number of patients with chronic fatigue syndrome have muscle pains. According to A. Ferré it is 75%.

In the opinion of the author, fibromyalgia and CFS are part of a continuum. In patients in which muscle pain is the most prominent symptom, fibromyalgia is the most likely diagnosis and in patient in which fatigue is the most prominent symptom, CFS is the most likely diagnosis. Patients can qualify for both at the same time.

It is not unusual for to find that patients that have been referred to an insomnia clinic for severe insomnia, turn out to have muscle pains that had not been the focus of attention. It is likely that some of them have fibromyalgia.

Neural correlates of fatigue in chronic fatigue syndrome[edit]

A small study was done by Cook et al. to image the neural correlates of a mentally fatiguing cognitive task in chronic fatigue syndrome. (Functional neuroimaging correlates of mental fatigue induced by cognition among chronic fatigue syndrome patients and controls. Cook DB1, O'Connor PJ, Lange G, Steffener J. Neuroimage. 2007 May 15;36(1):108-22.) They challenged the patients with a fatiguing cognitive task. The fatiguing task was significantly positively related to cerebellar, temporal, cingulate and frontal regions. There was a significant negative relationship to the left posterior parietal cortex.

Immune abnormalities in chronic fatigue syndrome[edit]

Natural killer cells[edit]

An open source article by Eaton-Fitch et al. states: “Compromised natural killer (NK) cell cytotoxic function is a well-documented and consistent feature of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). (A systematic review of natural killer cells profile and cytotoxic function in myalgic encephalomyelitis/chronic fatigue syndrome. Eaton-Fitch N, du Preez S, Cabanas H, Staines D, Marshall-Gradisnik S.Syst Rev. 2019 Nov 14;8(1):279. doi: 10.1186/s13643-019-1202-6.PMID: 31727160, available in full online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857215/. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/))

They further explain the role of NK cells in the body:

“Decreased NK cell activity is considered the most consistent immunological observation in ME/CFS patients [1, 7, 15–19]. Several studies have reported significantly decreased NK cell function in ME/CFS patients compared with healthy controls (HC) [1, 2, 14, 19–28]. These studies have demonstrated variations in NK cell phenotype and regulatory receptors, significantly reduced cytolytic proteins, impaired mitogen-activated protein kinases (MAPK) phosphorylation, increased expression of degranulation markers and impaired calcium (Ca2+) mobilisation.

NK cells are large granular lymphocytes of the innate immune system with natural cytotoxicity against tumour cells and virus-infected cells independent of prior sensitisation and in a non-MHC restricted manner [29]. NK cells have a protective role in various inflammatory conditions through immune cell activation, cytokine production and direct cytotoxicity [29]. In human peripheral blood, NK cell sub-populations are defined by their expression of cell-surface molecules, namely CD56 and CD16, which can distinguish cells into the following subsets: CD56BrightCD16−, CD56BrightCD16Dim-, CD56DimCD16−, CD56DimCD16Bright, CD56−CD16Bright [30]. CD56DimCD16Bright NK cells represent at least 90% of all peripheral NK cells and display significantly higher cytolytic capacity against infected or malignant target cells as this sub-population contains more cytolytic proteins and form more conjugates with target cells [31, 32]. CD56Bright NK cells are potent cytokine producers. The major cytokines produced include interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α), granulocyte-macrophage colony-stimulating factor, interleukin (IL)-10 and IL-13 [30].” (Eaton-Fitch et al. 2019)

In Japan chronic fatigue syndrome (CFS) this is sometimes called low natural killer syndrome (LNKS). Dr. Tadao Aoki has treated these patients with injections of 1 mg/day of Shiitake extract. There is a claim that in these patients natural killer activity gradually returned to normal.

In 1987, Dr. Aoki and Dr. Ronald Herberman reported on 23 Japanese LNKS patients. ages 14-77. The majority were under 40 and had presented LNKS symptoms of long-standing duration, They claimed that treatment with lentinan for 6 months or more brought the NK activity to within normal range (Sourced from Barbara Feick Gregory's Chronic Fatigue Syndrome Website available online at:http://barbfeick.com/cfs/treatment/nutritional/shiitake.htm.)

Summary of immune abnormalities in CFS by Komaroff and others[edit]

Komaroff summarized some of the known immune system abnormalities in CFS (Inflammation correlates with symptoms in chronic fatigue syndrome, Anthony L. Komaroffa,1Proc Natl Acad Sci U S A. 2017 Aug 22; 114(34): 8914–8916. doi: 10.1073/pnas.1712475114 available in full online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576849/.):

  • impairment of natural killer cell function,
  • activated CD8+ cytotoxic T cells are increased, (For the Wikipedia article which explains the function of these cells see:

https://en.wikipedia.org/wiki/Cytotoxic_T_cell)

  • antibodies against β2, M3 and M4 receptors are increased (Komaroff cites: Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome, Madlen Loebela, Patricia Grabowskia, Harald Heideckeb, Sandra Bauera, Leif G.Hanitscha, Kirsten Wittkea, Christian Meiselac, Petra ReinkedeHans-Dieter Volkae, Øystein Flugef, Olav Mellafg, Carmen Scheibenbogen Brain, Behavior, and Immunity Volume 52, February 2016, Pages 32-39, available in full online at:

https://www.sciencedirect.com/science/article/pii/S0889159115300209?via%3Dihub.)

  • various proinflammatory cytokines are increased.

Broderick et al. demonstrated a profound imbalance in the regulation of immune function. They found that Th1 and Th7 responses were highly attenuated. There was high Th2 marker expression. They found indirect evidence for diminished NK cell responsiveness to IL-12 and LTα stimulus. They argued that their analysis identified important subnetworks such as IL-2:IFNγ:TNFα. They also proposed that this could be targeted to try to restore normal immune function. (A Formal Analysis of Cytokine Networks in Chronic Fatigue Syndrome. Gordon Broderick,a,1 Jim Fuite,b Andrea Kreitz,c Suzanne D Vernon,d Nancy Klimas,e and Mary Ann Fletcherf. Brain Behav Immun. 2010 Oct; 24(7): 1209–1217, available in full online at: http://isiarticles.com/bundles/Article/pre/pdf/33162.pdf.)

According to Lorusso et al. in CFS there have been reports of:

  • decreased function of natural killer (NK) cells,
  • presence of autoantibodies and reduced responses of T cells to mitogens as well as other specific antigens,
  • abnormal activation of the T lymphocyte subsets,
  • decreased antibody-dependent cell-mediated cytotoxicity,
  • increased CD8+ cytotoxic T lymphocytes and CD38 and HLA-DR activation markers,
  • decrease in CD11b expression associated with an increased expression of CD28+ T subsets. (Immunological aspects of chronic fatigue syndrome.” Lorusso L1, Mikhaylova SV, Capelli E, Ferrari D, Ngonga GK, Ricevuti G. Autoimmun Rev. 2009 Feb;8(4):287-91.)

Lorusso et al. argued that the observation of high levels of pro-inflammatory cytokines could explain some symptoms such as fatigue.

For a review article about natural killer cells which helps clarify the clinical significance of a deficiency see: Natural Killer Cells: Development, Maturation, and Clinical Utilization, Alex M. Abel1,2, Chao Yang1,2, Monica S. Thakar1,3 and Subramaniam Malarkannan1,2,3,4,5* Front. Immunol., 13 August 2018 available in full online at: https://www.frontiersin.org/articles/10.3389/fimmu.2018.01869/full, doi: https://doi.org/10.3389/fimmu.2018.01869 and made available through a Creative Commons Attribution License (CC BY) which includes commercial use (https://creativecommons.org/licenses/by/4.0/).

For the Wikipedia article on natural killer cells see: https://en.wikipedia.org/wiki/Natural_killer_cell.

Sleep deprivation and immunity[edit]

A study by De Lorenzo demonstrated that 72 hours of paradoxical sleep deprivation caused a decrease in NK and NKT counts as well as their cytotoxic activity against B16F10 melanoma cells in vitro. De Lorenzo et al. argue that this is mediated by glucocorticoid-induced increased expression of β2-AR. (Sleep-deprivation reduces NK cell number and function mediated by β-adrenergic signalling. De Lorenzo BH1, de Oliveira Marchioro L2, Greco CR2, Suchecki D2. Psychoneuroendocrinology. 2015 Jul;57:134-43.) (Sleep labs are able to test patients for paradoxical i.e. REM sleep deprivation.) Some studies in man have reported REM sleep deprivation in CFS. (See for example Sleep structure and sleepiness in chronic fatigue syndrome with or without coexisting fibromyalgia. Togo F, Natelson BH, Cherniack N, FitzGibbons J, Garcon C, Rapoport DM. Arthritis Res Ther. 2008;10:R56, available in full online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2483445/.)

A study by Fondell et al. found that a shortening of sleep is associated with higher T cell and lower natural killer cell activities. (Short natural sleep is associated with higher T cell and lower NK cell activities. Fondell E1, Axelsson J, Franck K, Ploner A, Lekander M, Bälter K, Gaines H. Brain Behav Immun. 2011 Oct;25(7):1367-75. doi:10.1016/j.bbi.2011.04.004.

Sleep disorders as the likely cause of CFS[edit]

Is CFS a pseudo-mystery?[edit]

Based on the front-line clinical experience of the author, there is an exceedingly close relationship between severe insomnia and severe life-changing chronic fatigue. It can be damaging to a patient to tell them that they have a mystery disorder when they don’t. Precious time can be lost in getting the patient to treatment. It is now well established that cognitive behavioural therapy for insomnia is quite effective in many people.

The percentage of people with CFS and severe sleep problems may be even higher than reported. The author has observed that there is a small number of people who deny having a sleep problem because they say they sleep for a normal number of hours such as 7-8 for an adult. However, when asked if they ever wake up feeling restored. The answer is often “no”. Technically they may not qualify as has having insomnia under the WHO definition. (The ICD-10 definition of the WHO says as criteria 1: “Difficulty in getting off to sleep and the maintenance of sleep and unsatisfactory sleep quality”. What if a person gets to sleep and stays asleep for the whole night but wakes highly unrefreshed? It seems they wound not qualify has having insomnia according to this definition. Either the definition should be broadened, or a new category should be recognized. It could be called “dys-somnia”.) Further questioning of these patients may reveal that they are extremely light sleepers or that they have an undiagnosed sleep disorder such as sleep apnea. To resolved this problem it is very important to take a detailed sleep history, (For a detailed sleep questionnaire developed by the author of this Encyclopedia, which can be done at home by the patient see: https://www.torontotouchclinic.ca/wp-content/uploads/2020/05/Sleep-Questionaire-long-form3.pdf. For health care workers who would like to be able to have the form done online in a private secure manner contact The Toronto Touch Clinic at: torontotouchclinic@gmail.com.

Light sleep and non-restorative sleep[edit]

Ferré found that 94 % of CFS patients have non-restorative sleep. [The author of this wiki tests for non-restorative sleep with the following questions: Even if you have a full night of sleep, do you wake up feeling restored in the morning? How many times a month do you wake up in the morning feeling restored and energized and ready to take on the challenges of the day?]

Jackson et al. stated: “Non-restorative sleep despite sufficient or extended total sleep time is one of the major clinical diagnostic criteria; however, the underlying cause of this symptom is unknown.” (Sleep Abnormalities in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A Review, Melinda L. Jackson, Ph.D. and Dorothy Bruck, Ph.D. J Clin Sleep Med. 2012 Dec 15; 8(6): 719–728, available in full online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501671/.)

There is a clinical definition for light sleep and a sleep stage definition. The one of interest here is the clinical one which a feeling of being half-awake, combined with a sense that not sleeping deeply is preventing one from getting refreshed. The sleep stage definition is largely based on the EEG. It refers to stage 3 (old stage 3 and 4) sleep which is dominated by delta waves.

In the experience of the author this can be a common and sometime serious issue. It is pitifully under-researched. The main proponent has been the leading fibromyalgia expert, Dr. Harvey Moldofsky, who has been a mentor to the author of this Encyclopedia. Light sleep is related to the non-restorative sleep pattern. Based on clinical experience of approximately 50 cases, slight sleep is primarily a reaction to personal danger or danger to a loved one. It is probably very common in soldiers on the front lines. It is a major issue for young mothers who sleep with one eye open (or to be more precise, with one ear open) to watch out for their babies. Sometimes sleep is ruined after a few pregnancies, and the author has patients who became chronic long-term light sleepers after the birth of their babies. Some patients develop it when they move into a neighbourhood that they consider to be dangerous, Early detection of this problem is important.

There are no proven effective drug treatments for light sleep. More study is needed but as of 202. The most logical idea for treatment is to provide psychological treatment aimed at uncovering and all major sources of feelings of personal physical insecurity; the based on the individual patient’s list, to place them on a program that is aimed to rebuild this. This could range from moving to a safer neighbourhood, doing imagery rehearsal therapy for any nightmares that are augmenting feelings of physical endangerment. One patient who developed light sleep when she heard there were break-ins in her neighbourhood, made good progress when she started to go more into the neighbourhood and meet her neighbours. Prior they were unknowns and this may have involved a fear of the unknown, When, she found most were nice people she started to sleep better. One reasonable approach is to try to motivate the patient by saying: “Try to gradually rebuild your sense of personal physical security by getting yourself in to a safer mind set. In other words: Get to safe.”

Dr. Moldofsky was concerned about fibromyalgia patients who were what he called “tired mothers”. Based on several dozen cases, the author of this Encyclopedia confirms Moldofsky’s observation that tired mothers are a risk group. My theory is that the brains of animals and man evolved to listen in their sleep for sounds of danger. According to the theory, the brain has a sound danger analyzer. It is necessary for survival. It is essential for mothers. If they cannot wake to the first signs of danger to their baby, it may die at the hands of predator, Some mothers with a baby that has a respiratory problem seem to sleep lightly so that they can listen to each breath and jump into action at the first sign of a sigh, cough or gasp.

For a list of a large number of the known sleep abnormalities in CFS see Table 1 entitled “Summary of literature investigating sleep, measured polysomnographically, in CFS/ME patients compared to healthy controls, using standard diagnostic criteria” in Sleep Abnormalities in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A Review, Melinda L. Jackson, Ph.D. and Dorothy Bruck, Ph.D., J Clin Sleep Med. 2012 Dec 15; 8(6): 719–728, doi: 10.5664/jcsm.2276 available in full online at: http://jcsm.aasm.org/ViewAbstract.aspx?pid=28736. (For further information about non-restorative sleep see: Nonrestorative Sleep: Have We Finally Found It? Dieter Riemann, PhD, Sleep. 2010 Apr 1; 33(4): 417–418, doi: 10.1093/sleep/33.4.417, available in full online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849777/.)

Frequency of sleep disorders and sub-types of sleep disorders in CFS[edit]

Almost all patients with CFS appear to have sleep disorders. For example, a study by Gotts et al. of 343 patients with CFS found that 30.3% had a primary sleep disorder that explained their diagnosis. (Are there sleep-specific phenotypes in patients with chronic fatigue syndrome? A cross-sectional polysomnography analysis. Zoe M Gotts1, Vincent Deary1, Julia Newton2, Donna Van der Dussen3, Pierre De Roy3, Jason G Ellis1, Patient-centred medicine Research, BMJ Open, Volume 3, Issue 6, available in full online at: https://bmjopen.bmj.com/content/3/6/e002999. This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non-commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.) Furthermore, “hierarchical cluster analysis on the remaining 239 patients resulted in four sleep phenotypes being identified at saturation.” 89.1 percent of the remaining patients met the criteria for at least one objective sleep problem. In other words, almost all patients had sleep problems. Gotts et al. sub-classified the 239 into four groups:

Group 1

  • sleep onset latencies,
  • longer Rapid Eye Movement (REM) latencies
  • reduced percentages of both stage 2 and REM

Group 2

  • frequent arousals

Group 3

  • longer Total Sleep Time,
  • shorter REM Latencies,
  • higher percentage of REM and
  • lower percentage of wake time

Group 4

  • shortest Total Sleep Time
  • highest percentage of wake time and wake after sleep onset

[Author’s comments: The overall impression created by this study is that many sleep disorders (and perhaps any serious disruption of sleep) can result in the severe fatigue that we now call chronic fatigue syndrome.

The division into four groups seems somewhat arbitrary. The author’s impression is that the most common sleep disorder of all is insomnia, and that severe insomnia may be proven one day to be the main cause of CFS, but more study is needed.

Practice point: Given all the facts, it is wise for all patients suspected of having CFS to undergo a detailed assessment of their sleep beginning was the author’s sleep questionnaire.]

For a review of sleep issues in CFS see: Chronic fatigue syndrome and sleep disorders: Clinical associations and diagnostic difficulties. A. Ferré, Neurología (English Edition) Volume 33, Issue 6, July–August 2018, Pages 385-394, available in full online at: https://www.sciencedirect.com/science/article/pii/S2173580818300038.Made available under a Creative Commons license (https://creativecommons.org/licenses/by-nc-nd/4.0/) which does not include commercial use.

EEG studies[edit]

A study by Wu et al. using BEAM found that energy values of δ, θ, and α1 waves were significantly increased in patients as compared to controls. There was an increase of δ, θ, and α1energy values especially in the right frontal and left occipital regions. They also found that there was lower correlation in the patient group. They interpreted this as meaning that there was some evidence of reduced EEG complexity in CFS patients. (Electroencephalogram characteristics in patients with chronic fatigue syndrome, Tong Wu,1 Xianghua Qi,1 Yuan Su,2 Jing Teng,1 and Xiangqing Xu1Neuropsychiatr Dis Treat. 2016; 12: 241–249, doi: 10.2147/NDT.S92911 available in full online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4734796/.)

A study by of the EEG in sleep in patients with CFS found “In persons with CFS, delta power was diminished during slow wave sleep, but elevated during both stage 1 and REM. Alpha power was reduced during stage 2, slow wave, and REM sleep. Those with CFS also had significantly lower theta, sigma, and beta spectral power during stage 2, Slow Wave Sleep, and REM.” (Electroencephalographic correlates of Chronic Fatigue Syndrome, Michael J Decker, 1 Humyra Tabassum,1 Jin-Mann S Lin,1 and William C Reeves1 Behav Brain Funct. 2009; 5: 43. https://creativecommons.org/licenses/by/2.0/)

Sleep deprivation and immunity[edit]

A study by De Lorenzo demonstrated that 72 hours of paradoxical sleep deprivation caused a decrease in NK and NKT counts as well as their cytotoxic activity against B16F10 melanoma cells in vitro. De Lorenzo et al. argue that this is mediated by glucocorticoid-induced increased expression of β2-AR. (Sleep-deprivation reduces NK cell number and function mediated by β-adrenergic signalling. De Lorenzo BH1, de Oliveira Marchioro L2, Greco CR2, Suchecki D2. Psychoneuroendocrinology. 2015 Jul;57:134-43.) (Sleep labs are able to test patients for paradoxical i.e. REM sleep deprivation.) Some studies in man have reported REM sleep deprivation in CFS. (See for example Sleep structure and sleepiness in chronic fatigue syndrome with or without coexisting fibromyalgia. Togo F, Natelson BH, Cherniack N, FitzGibbons J, Garcon C, Rapoport DM. Arthritis Res Ther. 2008;10:R56, available in full online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2483445/.)

A study by Fondell et al. found that a shortening of sleep is associated with higher T cell and lower natural killer cell activities. (Short natural sleep is associated with higher T cell and lower NK cell activities. Fondell E1, Axelsson J, Franck K, Ploner A, Lekander M, Bälter K, Gaines H. Brain Behav Immun. 2011 Oct;25(7):1367-75. doi:10.1016/j.bbi.2011.04.004.

Economic impact in the U.S.[edit]

“Using ME/CFS prevalence data of 0.42 and indirect costs estimates from Reynolds et al. (2004), the direct and indirect cost of ME/CFS to society was estimated to be $18,677,912,000 for the community sample and $23,972,300,000 for the tertiary sample. These findings indicate that whether or not individuals are recruited from a community or tertiary sample, ME/CFS imposes substantial economic costs.” (The Economic impact of ME/CFS: Individual and societal costs, Leonard A Jason, 1 Mary C Benton,2 Lisa Valentine,3 Abra Johnson,1 andSusan Torres-Harding4, Dyn Med. ; 7: 6. 2008, available in full online at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2324078/, doi: 10.1186/1476-5918-7-6. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)

Further information[edit]

NINDS CDE, Overall Working Group Summary. https://www.commondataelements.ninds.nih.gov/sites/nindscde/files/Doc/MECFS/MECFS_CDE_Overview_v5.pdf) The National Institute of Neurological Disorders and Stroke is a part of the U.S. National Institutes of Health and so it is a branch of the US government. “All NINDS-prepared information is in the public domain and may be freely copied.” (http://www.lb7.uscourts.gov/documents/13-1265.pdf)

Where are the diseases of yesteryear? DaCosta's syndrome, soldiers heart, the effort syndrome, neurocirculatory asthenia--and the mitral valve prolapse syndrome. Wooley CF.Circulation 1976 May;53(5):749-51, available in full online at: https://www.ahajournals.org/doi/pdf/10.1161/01.CIR.53.5.749

For CDC information see: https://www.cdc.gov/me-cfs/

For a review paper see: ME/CFS: A Primer for Clinical Practitioners, Lucinda Bateman, B.S., M.D.; Alison C. Bested, M.D. F.R.C.P.C.; Todd Davenport, D.P.T., O.C.S.; Kenneth J. Friedman, Ph.D.; Alan Gurwitt, M.D.; Leonard A. Jason, Ph.D.; Charles W. Lapp, M.D.; Staci R. Stevens, M.A.; Rosemary A. Underhill, M.B., B.S.; Rosamund Vallings, M.B., B.S. available in full online at: http://iacfsme.org/portals/0/pdf/Primer_Post_2014_conference.pdf

Examining case definition criteria for chronic fatigue syndrome and myalgic encephalomyelitis. Leonard A. Jason, Ph.D.,1 Madison Sunnquist, B.S., Abigail Brown, M.A., Meredyth Evans, M.A., Suzanne D. Vernon, Ph.D., Jacob Furst, Ph.D., andValerie Simonis, B.S. Author information ► Copyright and License information ►

The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. Ann Intern Med. 1994 Dec 15; 121(12):953-9.

Examining case definition criteria for chronic fatigue syndrome and myalgic encephalomyelitis. Leonard A. Jason, Ph.D.,1 Madison Sunnquist, B.S., Abigail Brown, M.A., Meredyth Evans, M.A.,Suzanne D. Vernon, Ph.D., Jacob Furst, Ph.D., and Valerie Simonis, B.S. Fatigue. 2014 Jan 1; 2(1): 40–56 available in full online at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3912876/.

Myalgic Encephalomyelitis/chronic fatigue syndrome: Clinical working case definition, diagnostic and treatments protocols. Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG, Lerner AM, Bested AC, Flor-Henry P, Joshi P, Powles ACP, Sherkey JA, van de

Pain quality in fibromyalgia[edit]

A study using a Portuguese version of the McGill Pain Questionnaire found that fibromyalgia patients (as compared to that in patients with osteoarthritis, and low back pain) “reported, comparatively, more intense pain through their choice of pain descriptors, both sensory and affective; they also chose a higher number of words from these classes than patients in the other groups”. (Pain evaluation of patients with fibromyalgia, osteoarthritis, and low back pain. Marques AP1, Rhoden L, de Oliveira Siqueira J, João SM Rev Hosp Clin Fac Med Sao Paulo. 2001 Jan-Feb;56(1):5-10, available in full online at: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0041-87812001000100002&lng=en&nrm=iso&tlng=en.) (Categorization of postoperative pain descriptors in the sensitive, affective and evaluative dimensions of painful experiences. Pereira LV, Sousa FA. Rev Lat Am Enfermagem. 2007 Jul-Aug;15(4):563-7 available in full online at: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0104-11692007000400007&lng=en&nrm=iso&tlng=en.)

They found that four descriptors were used exclusively by patients with fibromyalgia and not osteoarthritis patients. These were "vicious", "wretched", "blinding", and "exhausting". FM patients were much more likely to use the word “miserable” in describing their pain. Two of these terms, i.e. “vicious” and “wretched” involve evaluative judgments and by inference, evaluative judgement processing. In English, he word vicious connotes the idea of an evil agent evil intent, and word “wretched” connotes” an evaluation of one’s own condition as being very bad.

This author considers the descriptor of miserable, wretched, and vicious to be terms that involve an evaluative judgement and therefore to qualify as evaluative.