1 Consistent Abnormalities found in CFS patients

<div data-canvas-width="376.78587833333336">From: <a href="https://paradigmchange.me/me/abnormalities/">ME and CFS Medical Abnormalities | Myalgic Encephalomyelitis</a></div>

<div data-canvas-width="376.78587833333336">More than 1,000 peer-reviewed articles have been published demonstrating a wide variety of physiological abnormalities in patients with myalgic encephalomyelitis, chronic fatigue syndrome and ME/CFS. </div>

1) Neurological <a href="https://meaustralia.net/2018/05/23/brain-differences-shown-in-chronic-fatigue-syndrome-fukuda-study/">Brain differences shown in chronic fatigue syndrome (Fukuda) study – ME Australia</a>

<a href="http://med.stanford.edu/news/all-news/2014/10/study-finds-brain-abnormalities-in-chronic-fatigue-patients.html">Study finds brain abnormalities in chronic fatigue patients | News Center | Stanford Medicine</a>

There is less white matter in brains of cfs patients (in certain regions) as well as lesions on the outside (of those regions) and white matter abnormalities in the right hemisphere.

Less Grey Matter, From: <a href="https://link.springer.com/article/10.1007/s12035-017-0598-z">A Comparison of Neuroimaging Abnormalities in Multiple Sclerosis, Major Depression and Chronic Fatigue Syndrome (Myalgic Encephalomyelitis): is There a Common Cause? | SpringerLink</a>

In the first relatively large study consisting of 28 CFS patients and 28 healthy controls, these authors reported significant reductions in global GM volume in CFS and that the extent of such reductions correlated with the degree of physical disability [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR190">190</a>]. In the later study, these authors also reported a global reduction in GM volume which increased significantly, albeit slightly (approximately 6%), following a course of CBT [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR191">191</a>]. Finally, in their longitudinal MRI study, Shan and others have recently reported a progressive decrease in WM volumes in the left inferior fronto–occipital fasciculus in a cohort of 15 CFS participants (unchanged in 10 normal controls), with decreased regional WM volumes in adjacent regions and GM volume reduction in contralateral regions over a 6-year period; these regional WM and GM volumes once again correlated with illness severity

other conditions (may) include maladaptive stress response (see Seretonin downregulator medicine trials of Cortene <a class="thought-link" href="brain://api.thebrain.com/zBeZ4L6q6n0BlcEIzuFxfQ/jOoiG8XZ0UyB91S0Hl0aTA/CorteneCt38ASeretoninDownregulator">Cortene (CT38) (a Seretonin Downregulator)</a>)

From: <a href="https://link.springer.com/article/10.1007/s12035-017-0598-z">A Comparison of Neuroimaging Abnormalities in Multiple Sclerosis, Major Depression and Chronic Fatigue Syndrome (Myalgic Encephalomyelitis): is There a Common Cause? | SpringerLink</a>

There is copious evidence of abnormalities in resting-state functional network connectivity states, grey and white matter pathology and impaired cerebral perfusion in patients afforded a diagnosis of multiple sclerosis, major depression or chronic fatigue syndrome (CFS) (myalgic encephalomyelitis)

3) CFS patients show heart preloading problems

4) Although only two cytokines were found to be different (TGF-β higher and resistin lower) in ME/CFS patients compared with controls, 17 cytokines correlated with ME/CFS severity. Thirteen of these cytokines are proinflammatory and may contribute to many of the symptoms these patients experience for several years. Only CXCL9 (MIG) inversely correlated with fatigue duration.

5) from: <a href="https://www.newscientist.com/article/2121162-metabolic-switch-may-bring-on-chronic-fatigue-syndrome/">Metabolic switch may bring on chronic fatigue syndrome | New Scientist</a>

The levels of some amino acids in the blood of women with CFS was abnormally low – specifically for the types of amino acid that can be used by the body as an alternative fuel source.

These shortfalls were not seen in men with CFS, but that could be because men tend to extract amino acids for energy from their muscles, instead of their blood. And the team saw higher levels of an amino acid that’s a sign of such a process.

6) different gut bacteria, immune response, vitamin etc.
frequently have impaired NK and T cell functions and numbers, suggesting chronic immune activity may be exhausting and depleting them.

7) Researchers at the <a href="http://med.stanford.edu/">Stanford University School of Medicine</a> have linked chronic fatigue syndrome to variations in 17 immune-system signaling proteins, or cytokines, whose concentrations in the blood correlate with the disease’s severity. The findings provide evidence that inflammation is a powerful driver of this mysterious condition

8) Some people with ME/CFS have abnormalities in the HPA axis. Researchers are especially interested in some of the central-nervous-system chemicals and hormones controlled by the HPA axis:

9a) Neurotransmitter changes
Neurotransmitters are chemicals that communicate messages in your brain. Research has shown that some people with ME/CFS have abnormal levels of certain important neurotransmitters (serotonin and dopamine). Researchers are working to explain the role these abnormalities play in ME/CFS.

9b) Stress hormone deficiencies
Experts know levels of the stress hormone cortisol are low in ME/CFS patients, and they believe this could be what makes it hard to deal with stress -- either physical (such as infection or exertion) or mental.

From: 'The Hypocortisolism in Chronic Fatigue Syndrome (ME/CFS) – Artifact or Central Factor?' <a href="http://phoenixrising.me/research-2/the-pharmacogenomics-papers/the-hypocortisolism-in-chronic-fatigue-syndrome-mecfs-artifact-or-central-factor">http://phoenixrising.me/research-2/the-pharmacogenomics-papers/the-hypocortisolism-in-chronic-fatigue-syndrome-mecfs-artifact-or-central-factor</a>

A mild hypocortisolism (low cortisol levels) is one of the few more or less consistently observed abnormalities in CFS and has apparently played a major role in convincing the CDC to devote a good deal of research funding to examine the stress response in CFS.
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From: PhoenixRising user pemone on 'Anyone Trying Niagen?' <a href="http://forums.phoenixrising.me/index.php?threads/anyone-trying-niagen.30636/">http://forums.phoenixrising.me/index.php?threads/anyone-trying-niagen.30636/</a>
The disease we have seems to downregulate NAD+ production, which leads to all kinds of problems creating ATP. The Watson article is suggesting ways we can fix the NAD+ problem quickly and easily.

Common abnormalities that can be shown by routine tests

From:

The mild abnormalities I always look for in CFS in the above tests are:

▪ Low or low normal white cell count – can be a sign of poor immune function which most commonly is secondary to nutritional deficiencies, such as low zinc, low magnesium, low B vitamins, low essential fatty acids.

▪ Low or low normal platelet count – can be a sign of toxic stress

▪ Low MCV (mean corpuscular volume) suggesting iron or copper deficiency. Low iron is suggestive of HYPOCHLORHYDRIA, in which case other mineral deficiencies are also likely.

▪ High MCV suggesting B12, folic acid or HYPOTHYROIDISM

▪ A high blood sugar or a low blood sugar suggests there may be a tendency to HYPOGLYCAEMIA (a pre-diabetic tendency). A normal blood sugar tells you very little! Normal ranges of blood glucose have been changed because so many people now have carbohydrate intolerance. A normal blood sugar should be between 4-6mmol/l. High blood sugar is now associated with toxic stress because chemicals cause insulin resistance.

▪ Low potassium. Potassium varies according to diet! Low potassium means there is a lack of vegetables in the diet. Bananas may be rich in potassium but they are high glycaemic index, so beware!

▪ High normal bilirubin – may be Gilbert’s syndrome suggesting poor ability to detoxify.

▪ High normal or abnormal liver enzymes – suggesting liver damage, usually from chemicals, or poor nutritional status.

▪ High urea or creatinine suggesting dehydration

▪ Low urea or creatinine suggesting low protein diet

▪ Low glomerular filtration rate suggesting poor kidney function – could be due to allergy or toxic damage but may indicated poor mitochondrial function.

▪ A TSH tells you very little about thyroid status! It is essential to see the actual level of thyroid hormones in the blood.

▪ Low levels of B12 can be due to HYPOCHLORHYDRIA or MALABSORPTION

▪ High uric acid can point to poor ANTIOXIDANT status. See GOUT.

▪ Raised cholesterol could mean low levels of vitamin D or hypothyroidism.

▪ Low levels of calcium likely to mean low levels of vitamin D.

<div data-canvas-width="376.78587833333336">From: Reviving the Broken Marionette: Treatments for CFS/ME and Fibromyalgia</div>

Immune dysfunction is an integral part of CFS/ME.6,7 In the United States the illness is sometimes called CFIDS, for chronic fatigue and immune dysfunction syndrome. Some patients get all the infections; others never even catch a cold. Swelling of lymph nodes and fever may be chronic or intermittent. Allergic symptoms may include food and chemical allergies and intolerances, chronic rhinitis and urticaria (hives). Bladder problems and IBS are common.

Most patients have neurological symptoms, which can include paresthesias (abnormal sensations), impaired coordination and balance, tremor, tinnitus, photophobia (sensitivity to light), hyperacuity (sensitivity to noise), vertigo, visual disturbances, nystagmus and epileptic seizures.

Depression and anxiety are often of neurological origin. Sleep disorders are very prevalent.

Cardiac and circulatory problems such as tachycardia and palpitations are common. The usual pattern is high pulse combined with a low blood pressure. Nearly all patients suffer from orthostatic hypotension.

Some cannot even sit up because of this. Other common symptoms include e.g. nausea, hair loss, dizziness, PMS, dyspnea, muscle tension, sexual problems, edema, hot and cold intolerance, night sweats, hypoglycemia, and rashes.

Etiology
There are dozens if not hundreds of different theories about the etiology of CFS/ME, though most of them are connected. It is now widely accepted that most if not all cases of CFS/ME have an infectious origin, but it is not clear whether this is a chronic infection or a postinfectious state (see CHAPTER 5 for more information). Most theories about the cause of symptoms (such as cardiomyopathy and hypercoagulation) do implicate an infectious agent.

Almost all theories also connect to poor circulation. Postulated causes include hypovolemia (low blood volume), orthostatic hypotension or other dysautonomic states, hypercoagulation, poor erythrocyte deformability and combinations of these. Reduced circulation to brain and other organs could explain virtually all symptoms. Blood perfusion in the brain, especially in the brainstem, has been shown to be impaired in CFS/ME.8

CFS/ME is not generally considered an autoimmune illness, but autoimmunity could still contribute to its symptoms. Several autoantibodies have been detected more commonly compared to healthy controls.

These include e.g. gangliosides, phospholipids and serotonin. 9 Antinuclear antibodies (ANA) are found in a subset of CFS/ME patients. In one study over 50% of CFS/ME patients had autoantibodies to muscarinic cholinergic receptors.10

Mitochondrial dysfunction has also been proposed and muscle biopsies have provided evidence of it.11 One theory proposes that CFS/ME is a channelopathy (an illness caused by abnormal ion channel function).12

Oxidative stress may also play a part.13 Several toxins have been associated with CFS/ME, including organophosphates and ciguatera toxin.14

From: <a href="https://www.nature.com/articles/d41586-017-08965-0">A reboot for chronic fatigue syndrome research</a>

Montoya and his colleagues revealed<a href="https://www.nature.com/articles/d41586-017-08965-0#ref-CR9">9</a> abnormalities in the levels of 17 immune-system proteins called cytokines in people with severe cases of the syndrome. What disrupts the inflammatory response, however, remains unknown. One possibility is that, as in some autoimmune disorders, T cells mistakenly become alarmed by one of the body’s own proteins, rather than by an invader, and B cells secrete self-reactive antibodies.

An accidental finding has lent support to this idea. In 2008, Øystein Fluge, an oncologist at Haukeland University Hospital in Bergen, Norway, treated a lymphoma patient with rituximab, an antibody therapy that kills B cells. The patient told him that the drug resolved their ME/CFS. Fluge and his colleagues then conducted a placebo-controlled trial with 30 people who had the condition (and not cancer), and found that rituximab improved their symptoms<a href="https://www.nature.com/articles/d41586-017-08965-0#ref-CR10">10</a>. As word spread, Fluge was flooded with hundreds of e-mails from people asking to take part in his trials, and doctors around the world fielded desperate requests for the experimental therapy.

Yet any hopes that Fluge dared to have were dashed last October, as he assessed data from an as-yet unpublished 151-person clinical trial and found that rituximab proved no better than the placebo. Fluge says the finer details of the trial might yet reveal whether a small subset of participants benefited. Like many others, he suspects that ME/CFS might turn out to be several diseases, with different causes and underlying mechanisms. Therefore, what helps some people might not help others. This effect might not be discernible until researchers can tease out how patients differ from one another. Still, the trial’s overall failure suggests that autoimmunity is not the main cause of ME/CFS, says Derya Unutmaz, an immunologist at the Jackson Laboratory for Genomic Medicine in Farmington, Connecticut. Rather, he speculates that inflammation seen in ME/CFS might result from a problem on the regulatory side of a person’s immune system, which normally reins in the T-cell response to innocuous viruses, mould particles or other non-threatening stimuli. “Rituximab’s failure is very disappointing for patients, but the fact that such a trial was done is a very important thing in the field,” Unutmaz adds. “By ruling this out, we can focus on other directions.” This is the kind of scientific response that patient advocates have been fighting for since the 1990s.

From: <a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122982">Abnormalities of AMPK Activation and Glucose Uptake in Cultured Skeletal Muscle Cells from Individuals with Chronic Fatigue Syndrome</a>

We found four main differences in cultured skeletal muscle cells from subjects with CFS; increased myogenin expression in the basal state, impaired activation of AMPK, impaired stimulation of glucose uptake and diminished release of IL6. The retention of these differences in cultured muscle cells from CFS subjects points to a genetic/epigenetic mechanism, and provides a system to identify novel therapeutic targets.

From: <a href="https://www.meassociation.org.uk/2017/11/new-scientist-blood-cells-in-chronic-fatigue-syndrome-are-drained-of-energy-04-november-2017/">New Scientist: Blood cells in chronic fatigue syndrome are drained of energy | 04 November 2017 | ME Association</a>

Across almost all measures of energy capacity, the cells from people with CFS were weaker compared with their healthy counterparts. If other cells are equally compromised, it could explain why people with the condition are often bed- or wheelchair-bound for months, and struggle with even modest physical exertion.

“The CFS cells couldn’t produce as much energy as the control cells,” says Tomas. “At baseline, they didn’t perform as well, but the maximum they could reach under any conditions was so much lower than the controls.”

Tomas and her colleagues measured the efficiency of mitochondria, the energy-generating powerhouses in cells. The mitochondria are the dominant source of energy for all of our cells. The team found that mitochondria in CFS cells can’t produce energy properly.

“We’ve shown definitively that it’s a fault in mitochondria,” says Tomas. “It points directly to a physiological, not psychological disorder.”

Tomas measured the oxygen consumption of cells in comfortable and stressed conditions, to see how well they could raise their game with glucose in short supply, a situation forcing the cells to consume more oxygen to compensate. Even at baseline, control cells consumed twice as much oxygen as the CFS cells. The disparity widened dramatically when the cells were stressed.

Metabolically exhausted

In another test that artificially pushed cells to their maximum capacity starting from baseline, CFS cells could only increase their mitochondrial output by 47 per cent, roughly half the 98 per cent increase achieved by control cells.

The implication is that cells from CFS patients can’t raise their output to meet the energy demands of routine physical tasks.

“These exciting results confirm what others have postulated but not been able to prove, namely that cells of patients with CFS are easily metabolically exhausted when put under any form of stress,” says Stephen Holgate of Southampton General Hospital. “In many ways, this is how patients describe their whole-body experience with CFS.”

“This is a major step forwards, supporting previous studies, which demonstrated that mitochondrial function can be impaired in this illness,” says Karl Morten of the University of Oxford. “A major question now is whether the situation in these white blood cells reflects whole-body mitochondrial dysfunction in patients,” he says.

To that end, Tomas is currently taking samples of muscle cells and testing them in the same way as the blood cells. “It would be good if we could get this repeated in muscle cells,” she says. “It’s important the patient population know we are looking into this. Patients sometimes think no one cares, but we do have interest, and want to find out what’s going on.”

<div data-canvas-width="376.78587833333336">From: <a href="https://paradigmchange.me/me/abnormalities/">ME and CFS Medical Abnormalities | Myalgic Encephalomyelitis</a></div>

To read the citations and a brief description of each article, please click on the topic links below.

The full abstract for each article can be easily found by typing the PMID number into the <a href="https://www.ncbi.nlm.nih.gov/pubmed/" target="_blank" rel="noopener noreferrer">PubMed</a> search engine.

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<a href="https://paradigmchange.me/me/abnormalities-brain/" target="_blank" rel="noopener noreferrer">Brain Abnormalities</a>

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Exertion & Energy

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General Issues

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Rusin A, Seymour C, Mothersill C. Chronic fatigue and immune deficiency syndrome (CFIDS), cellular metabolism, and ionizing radiation: a review of contemporary scientific literature and suggested directions for future research. Int J Radiat Biol. 2018 Mar;94(3):212-228. PMID: 29297728

This study investigated biochemical pathways known to be involved in radiation response and in CFIDS to determine if there might be common underlying mechanisms leading to symptoms experienced by those accidentally or deliberately exposed to radiation and those suffering from CFIDS. Evidence for involvement of the alpha-synuclein, cytochrome c oxidase, αB-crystallin, RNase L, and lactate dehydrogenase/STAT1 pathways is strong and suggests a common underlying mechanism involving mitochondrial dysfunction mediated by ROS and disruption of ATP production. The downstream effect of this is compromised energy production.

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Hatziagelaki E, Adamaki M, Tsilioni I, Dimitriadis G, Theoharides TC. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Metabolic Disease or Disturbed Homeostasis? J Pharmacol Exp Ther. 2018 Aug 3. PMID: 30076265

The ME/CFS phenotype has been associated with abnormalities in energy metabolism, mostly with mitochondrial dysfunction, resulting in reduced oxidative metabolism. The authors propose that stimulation of hypothalamic mast cells activates microglia leading to focal inflammation in the brain and disturbed homeostasis.

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Nagy-Szakal D, Barupal DK, Lee B, Che X, Williams BL, Kahn EJR, Ukaigwe JE, Bateman L, Klimas NG, Komaroff AL, Levine S, Montoya JG, Peterson DL, Levin B, Hornig M, Fiehn O, Lipkin WI. Insights into myalgic encephalomyelitis/chronic fatigue syndrome phenotypes through comprehensive metabolomics. Sci Rep. 2018 Jul 3;8(1):10056. PMID: 29968805

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Lacourt TE, Vichaya EG, Chiu GS, Dantzer R, Heijnen CJ. The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure. Front Behav Neurosci. 2018 Apr 26;12:78. PMID: 29755330

The authors propose a model of an imbalance in energy availability and energy expenditure as a consequence of low-grade inflammation and discuss how chronic low-grade inflammation can lead to reduced cellular-energy availability. They then present evidence for these metabolic pathways in models of persistent fatigue, focusing on chronic fatigue syndrome and cancer-related fatigue.

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de Vega WC, Erdman L, Vernon SD, Goldenberg A, McGowan PO. Integration of DNA methylation & health scores identifies subtypes in myalgic encephalomyelitis/chronic fatigue syndrome. Epigenomics. 2018 May;10(5):539-557. PMID: 29692205

DNA methylome profiles in immune cells were integrated with symptomatology from 70 women with ME/CFS using similarity network fusion to identify subtypes. The researchers concluded that ME/CFS subtypes are associated with specific DNA methylation differences and health symptomatology.

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Tomas C, Newton J. Metabolic abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a mini-review. Biochem Soc Trans. 2018 Jun 19;46(3):547-553. PMID: 29666214

This mini-review offers a brief summary of current research into the identification of metabolic abnormalities in CFS/ME which may represent potential biomarkers for the disease. The progress of research into key areas including immune dysregulation, mitochondrial dysfunction, 5′-adenosine monophosphate-activated protein kinase activation, skeletal muscle cell acidosis, and metabolomics are presented here.

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Monro JA, Puri BK. A Molecular Neurobiological Approach to Understanding the Aetiology of Chronic Fatigue Syndrome (Myalgic Encephalomyelitis or Systemic Exertion Intolerance Disease) with Treatment Implications. Mol Neurobiol. 2018 Sep;55(9):7377-7388. PMID: 29411266

Evidence demonstrating a biological aetiology for CFS/ME/SEID is adduced from a study of the history of the disease and a consideration of the role of the following in this disease: nitric oxide and peroxynitrite, oxidative and nitrosative stress, the blood-brain barrier and intestinal permeability, cytokines and infections, metabolism, structural and chemical brain changes, neurophysiological changes and calcium ion mobilisation.

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Komaroff AL, Takahashi R, Yamamura T, Sawamura M. Neurologic Abnormalities in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Review. Brain Nerve. 2018 Jan;70(1):41-54. PMID: 29348374

Recent studies of neuroimaging as well as analysis of blood markers, energy metabolism and mitochondrial function have revealed many objective biological abnormalities in ME/CFS. Specifically, it is suspected that the symptoms of ME/CFS may be triggered by immune activation – either inside or outside the brain – through release of inflammatory cytokines. In this review, we summarize potentially important recent findings on ME/CFS, focusing on objective evidence.

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Kuratsune H. Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Brain Nerve. 2018 Jan;70(1):11-18. PMID: 29348370

We present here the Japanese clinical diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome(ME/CFS) that were proposed in 2016 by the Japanese Ministry of Health, Labour and Welfare study group. The clinical diagnosis criteria of ME/CFS were created to be used by healthcare agencies in charge of primary care practice. We also explain the current prognosis in ME/CFS and medical treatments used in major medical institutions in Japan.

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de Vega WC, McGowan PO. The epigenetic landscape of myalgic encephalomyelitis/chronic fatigue syndrome: deciphering complex phenotypes. Epigenomics. 2017 Nov;9(11):1337-1340. PMID: 29043854

Mechanistic research is needed to understand how epigenetic modifications affect functional changes in ME/CFS, and whether or not such adverse epigenetic changes can be reversed or treated. An important step in the right direction is to identify and validate biomarkers for objective diagnosis. Two main approaches are needed: deep phenotyping of the disease and co-morbid conditions, focusing more on patients than case/(healthy) control comparisons, and integration of phenotype and biological data that includes epigenetic profiles.

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Komaroff AL. Inflammation correlates with symptoms in chronic fatigue syndrome. Proc Natl Acad Sci U S A. 2017 Aug 22;114(34):8914-8916. PMID: 28811366

This is an overview article on the state of ME/CFS research, written by a Harvard physician who has been studying the illness for more than 30 years.

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Jain V, Arunkumar A, Kingdon C, Lacerda E, Nacul L. Prevalence of and risk factors for severe cognitive and sleep symptoms in ME/CFS and MS. BMC Neurol. 2017 Jun 20;17(1):117. PMID: 28633629

Cognitive and sleep symptoms are more common in ME/CFS patients than in MS patients and healthy controls, providing further support for existing evidence of central nervous system abnormalities in ME/CFS. Findings suggest that people with ME/CFS who are smokers, or have a low income, are more likely to report severe cognitive and sleep symptoms.

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Mensah FKF, Bansal AS, Ford B, Cambridge G. Chronic fatigue syndrome and the immune system: Where are we now? Neurophysiol Clin. 2017 Apr;47(2):131-138. PMID: 28410877

In this review, the authors discuss the potential of different components of the immune system to be involved in the pathogenesis of ME/CFS.

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Glassford JA. The Neuroinflammatory Etiopathology of Myalgic Encephalomyelitis/Chronic Fatigue Syndome (ME/CFS). Front Physiol. 2017 Feb 17;8:88. PMID: 28261110r

The symptomatology of ME/CFS appears to emanate from a variety of sources of chronic neurological disturbance and associated distortions, and chronicity, in noxious sensory signaling and neuroimmune activation. This article incorporates a summary review and discussion of biomedical research considered relevant to this essential conception perspective.

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McManimen SL, Devendorf AR, Brown AA, Moore BC, Moore JH, Jason LA. Mortality in Patients with Myalgic Encephalomyelitis and Chronic Fatigue Syndrome. Fatigue. 2016;4(4):195-207. PMID: 28070451

This study sought to determine if patients with ME or CFS are reportedly dying earlier than the overall population from the same cause. The findings suggest patients in this sample are at a significantly increased risk of earlier all-cause and cardiovascular-related mortality, and they had a directionally lower mean age of death for suicide and cancer compared to the overall U.S. population.

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Jason LA, Zinn ML, Zinn MA. Myalgic Encephalomyelitis: Symptoms and Biomarkers. Curr Neuropharmacol. 2015;13(5):701-34. PMID: 26411464

The authors summarize advances in the physiological and neurological approaches to understanding, diagnosing, and treating ME.

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Fischer DB, William AH, Strauss AC, Unger ER, Jason L, Marshall GD Jr, Dimitrakoff JD. Chronic Fatigue Syndrome: The Current Status and Future Potentials of Emerging Biomarkers. Fatigue. 2014 Jun 1;2(2):93-109. PMID: 24932428

The authors review potential CFS biomarkers related to neurological and immunological components of the illness.

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Bansal AS, Bradley AS, Bishop KN, Kiani-Alikhan S, Ford B. Chronic fatigue syndrome, the immune system and viral infection. Brain Behav Immun. 2011 Jul 2. PMID: 21756995

The authors review what is known about the immune system in CFS. Slightly increased parameters of inflammation and pro-inflammatory cytokines such as interleukin (IL) 1, IL6 and tumour necrosis factor (TNF) α are likely present. Additionally, impaired natural killer cell function appears evident. Alterations in T cell numbers have been described by some and not others. While the prevalence of positive serology for the common herpes viruses appears no different from healthy controls, there is some evidence of viral persistence and inadequate containment of viral replication. The ability of certain herpes viruses to impair the development of T cell memory may explain this viral persistence and the continuation of symptoms.

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May M, Emond A, Crawley E. Phenotypes of chronic fatigue syndrome in children and young people. Arch Dis Child. 2010 Apr;95(4):245-9. PMID: 19843509

Exploratory factor analysis was performed on symptoms present at assessment in 333 children and young people with CFS/ME. Three phenotypes were identified using factor analysis: Factor 1, muscoloskeletal, had loadings on muscle and joint pain and hypersensitivity to touch, and was associated with worse fatigue, physical function and pain. Factor 2, migraine, loaded on noise and light hypersensitivity, headaches, nausea, abdominal pain and dizziness and was most strongly associated with physical function and pain. Factor 3, sore throat, had loadings on sore throat and tender lymph nodes and was not associated with fatigue or pain.

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Carlo-Stella N, Cuccia M. Demographic and clinical aspects of an Italian patient population with chronic fatigue syndrome. Reumatismo. 2009 Oct-Dec;61(4):285-9. PMID: 20143004

Besides persistent fatigue, a clinical syndrome of CFS with infectious, neurological and rheumatological characteristics is outlined from the data in Italy.

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Bassi N, Amital D, Amital H, Doria A, Shoenfeld Y. Chronic fatigue syndrome: characteristics and possible causes for its pathogenesis. Isr Med Assoc J. 2008 Jan;10(1):79-82. PMID: 18300582

Several mechanisms have been suggested to play a role in CFS, such as excessive oxidative stress following exertion, immune imbalance characterized by decreased natural killer cell and macrophage activity, immunoglobulin G subclass deficiencies (IgG1, IgG3) and decreased serum concentrations of complement component. Autoantibodies were also suggested as a possible factor in the pathogenesis of CFS. Recent studies indicate that anti-serotonin, anti-microtubule-associated protein 2 and anti-muscarinic cholinergic receptor 1 may play a role in the pathogenesis of CFS. It has been demonstrated that impairment in vasoactive neuropeptide metabolism may explain the symptoms of CFS.

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Hooper M. Myalgic encephalomyelitis: a review with emphasis on key findings in biomedical research. J Clin Pathol. 2007 May;60(5):466-71. PMID: 16935967

A review of research findings in CFS, termed a “chronic multiple-symptom, multiorgan, multisystem illness.”

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Klimas NG, Koneru AO. Chronic fatigue syndrome: inflammation, immune function, and neuroendocrine interactions. Curr Rheumatol Rep. 2007 Dec;9(6):482-7. PMID: 18177602

Studies of CFS patients show a variety of dysfunctions, including mitochondrial dysfunction and immune dysfunction.

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Miike T. Childhood chronic fatigue syndrome. Nihon Rinsho. 2007 Jun;65(6):1099-104. PMID: 17561704

For children and adolescents with CFS, four major symptoms are important: sleep disorders, easy fatigability, disturbed learning and memorization and immunological problems.

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Kuratsune H. Overview of chronic fatigue syndrome focusing on prevalence and diagnostic criteria. Nihon Rinsho. 2007 Jun;65(6):983-90. PMID: 17561686

Recent studies reveal that CFS can be understood to be a special condition based on the abnormality of neuroendocrine-immunologic system caused by the psycho-social stress and some genetic components. Under these conditions, a reactivation of various kinds of herpes virus infections and/or chronic infections might occur as a result of immune dysfunction, causing the abnormal production of several cytokines. A distinctive feature of CFS is thought to be the secondary brain dysfunction caused by the abnormal production of several cytokines.

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Janal MN, Ciccone DS, Natelson BH. Sub-typing CFS patients on the basis of ‘minor’ symptoms. Biol Psychol. 2006 Aug;73(2):124-31. PMID: 16473456

The authors did an analysis of a population of CFS patients and came up with musculoskeletal, infectious and neurological subtypes.

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Gurbaxani BM, Jones JF, Goertzel BN, Maloney EM. Linear data mining the Wichita clinical matrix suggests sleep and allostatic load involvement in chronic fatigue syndrome. Pharmacogenomics. 2006 Apr;7(3):455-65. PMID: 16610955

The authors provide basic data about a group of CFS sufferers in Wichita, Kansas.

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Jason LA, Taylor RR, Kennedy CL, Jordan K, Huang CF, Torres-Harding S, Song S, Johnson D. A factor analysis of chronic fatigue symptoms in a community-based sample. Soc Psychiatry Psychiatr Epidemiol. 2002 Apr;37(4):183-9. PMID: 12027245

Individuals with chronic fatigue have symptoms that can be differentiated into theoretically distinct factors, including: Lack of Energy, Physical Exertion, Cognitive Functioning, and Fatigue and Rest.

<a href="https://paradigmchange.me/me/abnormalities-related/" target="_blank" rel="noopener noreferrer">Related Conditions</a>

Uhde M, Indart A, Fallon BA, Wormser GP, Marques AR, Vernon SD, Alaedini A. C-Reactive Protein Response in Patients With Post-Treatment Lyme Disease Symptoms Versus Those With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Clin Infect Dis. 2018 May 8. PMID: 29741589

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Maness C, Saini P, Bliwise DL, Olvera V, Rye DB, Trotti LM. Systemic exertion intolerance disease/chronic fatigue syndrome is common in sleep centre patients with hypersomnolence: A retrospective pilot study. J Sleep Res. 2018 Apr 6:e12689. PMID: 29624767

The authors sought to determine the frequency and correlates of systemic exertion intolerance disease in a hypersomnolent population. One-hundred and eighty-seven hypersomnolent patients completed questionnaires regarding sleepiness and fatigue; questionnaires and clinical records were used to assess for systemic exertion intolerance disease. Twenty-one percent met systemic exertion intolerance disease criteria, and the frequency of systemic exertion intolerance disease was not different across sleep diagnoses.

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Natelson BH, Vu D, Coplan JD, Mao X, Blate M, Kang G, Soto E, Kapusuz T, Shungu DC. Elevations of Ventricular Lactate Levels Occur in Both Chronic Fatigue Syndrome and Fibromyalgia. Fatigue. 2017;5(1):15-20. PMID: 29308330

While patients with CFS, fibromyalgia (FM) and comorbid CFS and FM can be differentiated from healthy subjects based on measures of CFS lactate, this neuroimaging outcome measure is not a viable biomarker for differentiating CFS from FM or from patients in whom symptoms of the two disorders overlap.

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Higgins JNP, Pickard JD, Lever AML. Chronic fatigue syndrome and idiopathic intracranial hypertension: Different manifestations of the same disorder of intracranial pressure? Med Hypotheses. 2017 Aug;105:6-9. PMID: 28735654

The authors hypothesise that idiopathic intracranial hypertension (IIH), IIH without papilloedema (IIHWOP), lesser forms of IIH and an undetermined proportion of chronic fatigue cases are all manifestations of the same disorder of intracranial pressure across a spectrum of disease severity, in which this subset of chronic fatigue syndrome would represent the most common and least severe and IIH the least common and most extreme.

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McManimen SL, Jason LA. Post-Exertional Malaise in Patients with ME and CFS with Comorbid Fibromyalgia. SRL Neurol Neurosurg. 2017;3(1):22-27. Epub 2017 Mar 10. PMID: 28603794

The purpose of this study was to determine if the PEM differences seen between patients with and without comorbid fibromyalgia (FM) exist for the Muscle or General PEM factors. The secondary diagnosis of FM in addition to ME and CFS appears to amplify the PEM symptomatology and worsen patients’ physical functioning.

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Castro-Marrero J, Faro M, Aliste L, Sáez-Francàs N, Calvo N, Martínez-Martínez A, de Sevilla TF, Alegre J. Comorbidity in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A Nationwide Population-Based Cohort Study. Psychosomatics. 2017 Sep – Oct;58(5):533-543. PMID: 28596045

A total of 1757 Spanish CFS/ME patients completed surveys were collected. Over 80% presented comorbidities. The researchers identified 5 CFS/ME clusters: group 1-fibromyalgia, myofascial pain, multiple chemical hypersensitivity, sicca syndrome, epicondylitis, and thyroiditis; group 2-alterations of ligaments and subcutaneous tissue, hypovitaminosis D, psychopathology, ligamentous hyperlaxity, and endometriosis. These 2 subgroups comprised mainly older women, with low educational level, unemployment, high levels of fatigue, and poor quality of life; group 3-with hardly any comorbidities, comprising mainly younger women, university students or those already employed, with lower levels of fatigue, and better quality of life; group 4-poorly defined comorbidities; and group 5-hypercholesterolemia.

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Hakim A, De Wandele I, O’Callaghan C, Pocinki A, Rowe P. Chronic fatigue in Ehlers-Danlos syndrome-Hypermobile type. Am J Med Genet C Semin Med Genet. 2017 Mar;175(1):175-180. PMID: 28186393

There is overlap in the symptoms and findings of Ehlers-Danlos syndrome (EDS) and chronic fatigue syndrome. A proportion of those with CFS likely have EDS that has not been identified.

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Bakken IJ, Tveito K, Aaberg KM, Ghaderi S, Gunnes N, Trogstad L, Magnus P, Stoltenberg C, Håberg SE. Comorbidities treated in primary care in children with chronic fatigue syndrome / myalgic encephalomyelitis: A nationwide registry linkage study from Norway. BMC Fam Pract. 2016 Sep 2;17(1):128. PMID: 27590471

The authors studied primary care diagnoses for Norwegian children with CFS/ME, with children with another hospital diagnosis (type 1 diabetes mellitus [T1DM]) and the general child population as comparison groups. This large nationwide registry linkage study confirms that the clinical picture in CFS/ME is complex. Children with CFS/ME were frequently diagnosed with infections, supporting the hypothesis that infections may be involved in the causal pathway. The long time span often observed from the first diagnosis of weakness / general tiredness to the diagnosis of CFS/ME might indicate that the treatment of these patients is sometimes not optimal.

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Lau CI, Lin CC, Chen WH, Wang HC, Kao CH. Increased risk of chronic fatigue syndrome in patients with migraine: A retrospective cohort study. J Psychosom Res. 2015 Dec;79(6):514-8. PMID: 26505533

The current study demonstrated an increased risk of CFS in patients with migraines. Proposed mechanisms in previous studies such as mitochondrial dysfunction and central sensitization may underlie the shared pathophysiology of these seemingly distinct but potentially overlapping disorders.

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Yang TY, Kuo HT, Chen HJ, Chen CS, Lin WM, Tsai SY, Kuo CN, Kao CH. Increased Risk of Chronic Fatigue Syndrome Following Atopy: A Population-Based Study. Medicine (Baltimore). 2015 Jul;94(29):e1211. PMID: 26200644

Atopy is associated with CFS, particularly in patients with numerous atopic syndromes.

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Gaber TA, Oo WW, Ringrose H. Multiple Sclerosis/Chronic Fatigue Syndrome overlap: When two common disorders collide. NeuroRehabilitation. 2014;35(3):529-34. PMID: 25238862

MS and CFS/ME are two common conditions with increased prevalence in middle aged females. The study results suggest that the two conditions may co-exist.

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Morris G, Maes M. Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics. BMC Med. 2013 Sep 17;11:205. PMID: 24229326

Mitochondrial dysfunctions, including lowered levels of ATP, decreased phosphocreatine synthesis and impaired oxidative phosphorylation, are heavily involved in the pathophysiology of both MS and ME/CFS. The findings produced by neuroimaging techniques are quite similar in both illnesses and show decreased cerebral blood flow, atrophy, gray matter reduction, white matter hyperintensities, increased cerebral lactate and choline signaling and lowered acetyl-aspartate levels.

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Morris G, Anderson G, Galecki P, Berk M, Maes M. A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and sickness behavior. BMC Med. 2013 Mar 8;11(1):64. PMID: 23497361

Differences and similarities between sickness behavior (an adaptive response induced by proinflammatory cytokines) and ME/CFS are discussed. The article concludes that these are two different conditions.

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Abbi B, Natelson BH. Is chronic fatigue syndrome the same illness as fibromyalgia: evaluating the ‘single syndrome’ hypothesis. QJM. 2013 Jan;106(1):3-9. PMID: 22927538

This review presents data showing differences between CFS and FM across a number of parameters.

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Castro-Marrero J, Cordero MD, Sáez-Francas N, Jimenez-Gutierrez C, Aguilar-Montilla FJ, Aliste L, Alegre-Martin J. Could mitochondrial dysfunction be a differentiating marker between chronic fatigue syndrome and fibromyalgia? Antioxid Redox Signal. 2013 Nov 20;19(15):1855-60. PMID: 23600892

The researchers looked at the possible association between mitochondrial biogenesis and oxidative stress in patients with CFS vs. patients with fibromyalgia (FM) and healthy controls. Compared to controls, both CFS and FM patients had decreased levels of Coenzyme Q10, decreased ATP levels, and increased levels of lipid peroxidation.  Several measures (mitochondrial citrate synthase activity, mitochondrial DNA content and expression levels of peroxisome proliferator-activated receptor gamma-coactivator 1-alpha and transcription factor A, mitochondrial by immunoblotting) were significantly lower in FM patients than either CFS patients or controls.

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Smylie AL, Broderick G, Fernandes H, Razdan S, Barnes Z, Collado F, Sol C, Fletcher MA, Klimas N. A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome. BMC Immunol. 2013 Jun 25;14:29. PMID: 23800166

Common to both Gulf War Illness and CFS, IL-10 and IL-23 expression contributed in an illness and time-dependent manner, accompanied in male subjects by NK and Th1 markers IL-12, IL-15, IL-2 and IFNγ. In female GWI and CFS subjects IL-10 was again identified as a delineator but this time in the context of IL-17 and Th2 markers IL-4 and IL-5. Exercise response also differed between sexes: male GWI subjects presented characteristic cytokine signatures at rest but not at peak effort whereas the opposite was true for female subjects.

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Itoh Y, Shigemori T, Igarashi T, Fukunaga Y. Fibromyalgia And Chronic Fatigue Syndrome In Children. Pediatr Int. 2011 Nov 24. PMID: 22115414

In a group of children, ANA titers were higher and the prevalence of anti-Sa was far more frequent in CFS patients than in FM cases. The authors conclude that CFS and FM are different from each other at least in childhood from the immunological aspects, although a few patients were suffering from both conditions.

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Schutzer SE, Angel TE, Liu T, Schepmoes AA, Clauss TR, Adkins JN, Camp DG, Holland BK, Bergquist J, Coyle PK, Smith RD, Fallon BA, Natelson BH. Distinct cerebrospinal fluid proteomes differentiate post-treatment lyme disease from chronic fatigue syndrome. PLoS One. 2011 Feb 23;6(2):e17287. PMID: 21383843

Analysis of cerebral spinal fluids accurately distinguished CFS, Chronic Lyme and healthy subjects, and thus has potential as a biomarker.

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Nickel JC, Tripp DA, Pontari M, Moldwin R, Mayer R, Carr LK, Doggweiler R, Yang CC, Mishra N, Nordling J. Interstitial cystitis/painful bladder syndrome and associated medical conditions with an emphasis on irritable bowel syndrome, fibromyalgia and chronic fatigue syndrome. J Urol. 2010 Oct;184(4):1358-63. PMID: 20719340

CFS and interstitial cystitis/painful bladder syndrome are related.

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Baraniuk JN, Zheng Y. Relationships among rhinitis, fibromyalgia, and chronic fatigue. Allergy Asthma Proc. 2010 May-Jun;31(3):169-78. PMID: 20615318

There is a high prevalence of idiopathic nonallergic rhinopathy in CFS. CFS also has significant overlap with systemic hyperalgesia (fibromyalgia), autonomic dysfunction (irritable bowel syndrome and migraine headaches), sensory hypersensitivity (dyspnea; congestion; rhinorrhea; and appreciation of visceral nociception in the esophagus, gastrointestinal tract, bladder, and other organs), and central nervous system maladaptations (central sensitization) recorded by functional magnetic resonance imaging (fMRI). Neurological dysfunction may account for the overlap of CFS with idiopathic nonallergic rhinopathy.

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Meeus M, Mistiaen W, Lambrecht L, Nijs J. Immunological similarities between cancer and chronic fatigue syndrome: the common link to fatigue? Anticancer Res. 2009 Nov;29(11):4717-26. PMID: 20032425

CFS patients display a number of immunological abnormalities also seen in cancer, including abnormalities of ribonuclease (RNase) L, hyperactivation of nuclear factor kappa beta (NF-kappa B), high oxidative stress and natural killer cell malfunction.

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Ciccone DS, Weissman L, Natelson BH. Chronic fatigue syndrome in male Gulf war veterans and civilians: a further test of the single syndrome hypothesis. J Health Psychol. 2008 May;13(4):529-36. PMID: 18420761

CFS was more likely to present in a sudden flu-like manner in civilians than Gulf War veterans. Comorbid fibromyalgia was more prevalent in civilians.

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Bennett B, Goldstein D, Friedlander M, Hickie I, Lloyd A. The experience of cancer-related fatigue and chronic fatigue syndrome: a qualitative and comparative study. J Pain Symptom Manage. 2007 Aug;34(2):126-35. PMID: 17544246

Qualitatively, cancer related fatigue appears closely related to CFS.

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Ferré Ybarz L, Cardona Dahl V, Cadahía García A, Ruiz E, Vázquez A, Fernández de Sevilla T, Alegre Martín J. Prevalence of atopy in chronic fatigue syndrome. Allergol Immunopathol (Madr). 2005 Jan-Feb;33(1):42-7. PMID: 15777523

Atopy was not more prevalent in patients with CFS than in healthy controls, although the CFS group tended to report more respiratory symptoms and drug allergies.

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Sinaii N, Cleary SD, Ballweg ML, Nieman LK, Stratton P. High rates of autoimmune and endocrine disorders, fibromyalgia, chronic fatigue syndrome and atopic diseases among women with endometriosis: a survey analysis. Hum Reprod. 2002 Oct;17(10):2715-24. PMID: 12351553

A survey showed that about 4.6% of endometriosis sufferers also reported having CFS.

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Aaron LA, Herrell R, Ashton S, Belcourt M, Schmaling K, Goldberg J, Buchwald D. Comorbid clinical conditions in chronic fatigue: a co-twin control study. J Gen Intern Med. 2001 Jan;16(1):24-31. PMID: 11251747

Compared to their nonfatigued co-twins, CFS twins had higher rates of fibromyalgia and irritable bowel syndrome. The strongest associations were observed between chronic fatigue and fibromyalgia, irritable bowel syndrome, chronic pelvic pain, multiple chemical sensitivities, and temporomandibular disorder.

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White KP, Speechley M, Harth M, Ostbye T. Co-existence of chronic fatigue syndrome with fibromyalgia syndrome in the general population. A controlled study. Scand J Rheumatol. 2000;29(1):44-51. PMID: 10722257

There is significant clinical overlap between CFS and FMS.

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Evengard B, Nilsson CG, Lindh G, Lindquist L, Eneroth P, Fredrikson S, Terenius L, Henriksson KG. Chronic fatigue syndrome differs from fibromyalgia. No evidence for elevated substance P levels in cerebrospinal fluid of patients with chronic fatigue syndrome. Pain. 1998 Nov;78(2):153-5. PMID: 9839828

Unlike fibromyalgia patients, CFS patients have normal levels of Substance P in their cerebrospinal fluid.

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De Lorenzo F, Hargreaves J, Kakkar VV. Phosphate diabetes in patients with chronic fatigue syndrome. Postgrad Med J. 1998 Apr;74(870):229-32. PMID: 9683977

The authors report a relationship between chronic fatigue syndrome and phosphate diabetes.

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Baraniuk JN, Clauw DJ, Gaumond E. Rhinitis symptoms in chronic fatigue syndrome. Ann Allergy Asthma Immunol. 1998 Oct;81(4):359-65. PMID: 9809501

In a CFS population, 24% had no significant rhinitis complaints, 30% had positive skin tests suggesting the potential for allergic rhinitis complaints, and 46% had nonallergic rhinitis.

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Gomborone JE, Gorard DA, Dewsnap PA, Libby GW, Farthing MJ. Prevalence of irritable bowel syndrome in chronic fatigue. J R Coll Physicians Lond. 1996 Nov-Dec;30(6):512-3. PMID: 8961203

63% of people belonging to a group for chronic fatigue sufferers fulfilled a diagnosis of irritable bowel syndrome (recurrent abdominal pain and at least three Manning criteria). This greatly exceeds estimates of irritable bowel syndrome prevalence of up to 22% in the general population.

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Auger PL, Gourdeau P, Miller JD. Clinical experience with patients suffering from a chronic fatigue-like syndrome and repeated upper respiratory infections in relation to airborne molds. Am J Ind Med. 1994 Jan;25(1):41-2. PMID: 8116649

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