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Myalgic Encephalomyelitis: a multi-system disorder

Myalgic encephalomyelitis: a multi-system disorder

Myalgic encephalomyelitis, or ME, is classified as a neurological disorder by the World Health Organization, in the same category as ALS, multiple sclerosis, and Parkinson’s. However, the illness is a complex and multifactorial disorder with significant complications arising in the endocrine, cardiovascular, musculoskeletal, and digestive systems.

ME is similar in many ways to multiple sclerosis, and can best be swiftly understood by comparing and contrasting attributes of ME to those of MS. ME shares a relapsing-remitting pattern with MS, as well as similarity in signs, symptoms, and severity. This similarity has caused some physicians to label ME ‘atypical MS’.

ME can be debilitating, and despite the relapsing-remitting nature, full recovery is uncommon, occurring in 0-6% of the ME population according to several studies. People with severe ME have a quality of life similar to those with cancer and late-stage AIDS. Though many function at a higher level, worsening of symptoms can be both sudden and permanent.

ME is an illness that is more common in women. It can strike at any age, but the most common age of onset is between 25 and 35 years old.

Signs and Symptoms:

The Canadian Consensus Criteria, guided by an international cohort of experts in the diagnosis and treatment of the illness, has published the following diagnostic criteria.

Post-exertional malaise, or PEM, is the hallmark feature of the illness. After exertion, whether mental or physical, people with ME experience a ‘crash’, an acute worsening of symptoms that lasts between 24 and 48 hours. Studies show that people with ME have a paradoxical reaction to exercise, experiencing decreased oxygenation of muscles in comparison to baseline, abnormalities in muscles’ uptake of glucose, decreased cerebral blood flow, and a reduced heart rate at maximum workload. ME patients also experience greater confusion and disorientation after and during exercise, while exercise has a focusing effect on healthy individuals.

Despite this hard data, recommendations for ME have included an exercise regime in certain countries. Multiple studies have shown this to not only be unhelpful to people with ME, but actively detrimental. In a recent survey, nearly three-quarters of responders who underwent graded exercise therapy (GET) reported that their condition worsened thereafter. A significant proportion had not returned to their pre-regime level of wellness even years later. Therefore, graded exercise should be contraindicated in patients with ME.

Instead, pacing therapy, in which the patient is active when they are capable of activity, and encouraged to rest when they feel ill, shows benefits for most patients’ long-term health.

Sleep dysfunction is experienced by the majority of ME patients, especially at the start of this long-term illness. Sleep is often unrefreshing, occasionally with a disturbed or inverted rhythm.

Pain is experienced by most who suffer from ME, typically in the muscles and joints. Headaches that did not occur before onset are usually present, especially at the base of the skull.

Neurological and cognitive manifestations are another hallmark diagnostic feature. In order to be diagnosed with ME, patients should demonstrate at least two of the following: confusion, difficulty concentrating, aphasia, word retrieval difficulties, spatial instability, disorientation, photophobia and sensitivity to noise, and inability to focus vision. Marked weight changes are common, and blood sugar dysregulation, with hypoglycemic episodes, hyperglycemic episodes, or both, is common. Various endocrinological markers may indicate dysregulation, but not necessarily in a pattern recognizable to the practitioner.

Autonomic, neuroendocrine, and immune manifestations often coexist with the illness, and may be identified and diagnosed separately based on criteria entirely unrelated to the diagnosis of ME.

Autonomic disorders that are common co-diagnoses include POTS (postural orthostatic tachycardia syndrome), neurally mediated hypotension, delayed postural hypotension, palpitations, and dyspnea.

Neuroendocrine manifestations include loss of thermostatic regulation, feverishness with cold extremities, intolerance of heat and cold and marked weight change, as well as worsening of symptoms with physical or emotional stress.

Immune manifestations include recurrent flu-like symptoms, swollen lymph nodes, and general malaise, as well as food sensitivities and chemical sensitivities that did not exist before onset.

This is a summarized, and therefore incomplete picture of the diagnostic criteria. Please refer to Carruthers et al. for a more thorough grounding in diagnosis of myalgic encephalomyelitis.

Differential Diagnosis:


Reactions to exercise can help differentiate depression and ME. Depressive patients who exercise will experience a lift in mood and well-being, whereas the effect of exercise on ME patients is a ‘crash’ and worsening of all symptoms. Symptoms such as joint and muscle pain, cognitive impairment, and immunological disturbances can also help differentiate depressive disorders from ME. While both depression and ME can be identified as a systemic inflammatory disorder, many other illnesses fit this description as well, including cancer and MS. Raised inflammatory markers alone should not be diagnostic for major depressive disorder.

Some laboratory data for depressive disorders and ME are directly contradictory. Recently, elevated VEGF has been identified as a novel marker for depression. Low VEGF is more common in ME, which supports the finding of decreased exercise capacity. Both interleukin 6 and interleukin 10 are also high in depressive patients, but low in ME patients.

As a disorder with a poorly-understood etiology first experienced predominantly by young women, ME can be characterized as depression by practitioners with little knowledge of ME or its diagnostic criteria. While it is not out of the question that a patient be depressive and also have ME, in the same way that a patient can be depressive and also have ALS, it is important that the physician be aware that:
  • ME is not caused by depression
  • ME is not a form of depression
  • People with ME are not more likely to be depressed than other patient subsets with chronic illness
Finally, it is worth noting that ME patients are particularly sensitive to certain classes of drugs, including serotonin reuptake inhibitors. If depression is comorbid with ME, the smallest available dosage may have to be cut in half or into quarters to be appropriate for an ME patient. Serotonin syndrome may be possible at subclinical dosages.


Patients with somatoform disorder will have a long history of complaints, whereas patients with ME will discuss most if not all of their complaints as having a specific time of onset, typically in their late 20s or early 30s.

Patients with somatoform disorder will not have any abnormal lab findings. Patients with ME will have multiple lab findings that show ill health. Please see ‘Laboratory Testing’ below.


Fibromyalgia has many similarities to ME. However, ME typically begins with a large stressor such as an acute viral or bacterial illness, whereas fibromyalgia is often triggered by a physical trauma. ME, unlike fibromyalgia, has cardiac and endocrine disruption, whereas pain is the predominant feature in fibromyalgia.


Multiple sclerosis is perhaps the illness most like ME. ME and MS share fatigue, exercise intolerance, a relapsing-remitting pattern with a chronic course, GI dysfunction, postural hypotension, cardiac dysfunction, and exacerbation by physical and emotional stress as features. Nearly all lab findings are identical in ME and MS. However, the following lab values will differ:
  • CD69 expression tends to be elevated in MS, but depressed in ME
  • Anti-muscarinic, anti-mu-opioid, anti-5-HTA, and Anti-D2 receptor antibodies are often found in ME, but not in MS

Laboratory Testing:

There are several tests that can help the physician in his or her identification of ME.

  • MRI – Findings on MRI should show punctate white-matter lesions, particularly on the frontal and subcortical regions.
  • PET Scans – can reveal decreased glucose metabolism and hypoperfusion or hypometabolism in the brain stem
  • SPECT Scans – can reveal areas of decreased cerebral blood flow

  • Neuropsychological Testing – Can reveal decreased processing speed and other signs of cognitive dysfunction
  • Autonomic Panel – Tilt Table Tests, Valsalva maneuver and other autonomic tests can help identify common comorbid ANS dysfunction
  • 24 Hour Holter Monitor – As the GP, ask the cardiologist to particularly look for repetitive oscillating T-wave inversions and T-wave flats. This may not be reported, but is diagnostic in ME.
  • Sleep studies – sleep studies should demonstrate reduced REM sleep and inverted diurnal rhythms

  • ACTH Stimulation Test – the gold standard to identify primary adrenal insufficiency
  • Insulin Tolerance Test – this test can help determine whether the patient produces stress hormones at healthy levels in response to an endocrine challenge.
  • Methacholine Challenge Test – while unspecific, this test can help determine whether dyspnea is caused by anxiety-related issues or physical impairment

  • Pathogenic Testing – the dysregulation of the immune system in ME may mean a variety of infectious organisms not found in the general population that need to be addressed with antibiotic therapy. This may include Lyme, Borrelia, Tularemia, Parvovirus, Chlamydia pneumoniae, and Mycoplasma. Enteroviruses are common.
  • IgA, IgG subclass, IgM and IgE - Low IgA and IgG subclasses are common in myalgic encephalomyelitis. IgM and/or IgE may be elevated to compensate.
  • T3/T4 ratios can reveal thyroid dysfunction.
  • Liver enzymes can help point to infectious states.
  • B-Vitamins are often dysregulated in ME, particularly B12 and folic acid.
  • VEGF (vascular endothelial growth factor) is often dysregulated in ME patients. This may partially explain patients’ atypical response to exercise.
  • Food and allergy testing is employed in order to identify new food sensitivities the patient may have developed at onset.


There is no cure for ME. However, there are palliative treatments that are currently in use. In general, each symptom can be addressed individually. It is worth noting that orthostasis has been identified as the factor that most significantly effects quality of life in ME patients. It is worth the practitioner’s time to identify the cause of the orthostasis and do his or her best to address this issue independent of other symptoms and concerns.

However, there are some novel treatments for ME on the horizon.


Since B-cell dysregulation may be part of the etiology of ME, rituximab and other drugs that affect B-cell function are currently being tested as medications for ME. Phase-three drug trials are underway and the results look very promising, with a small but significant percentage of test subjects experiencing complete remission. Rituximab has also been used in cancer and MS.


While it is almost certainly the case that there is no one infectious organism responsible for ME, but an overall immune dysregulation, antibiotic therapy and other antimicrobial therapies can be a vital part of treatment for ME patients who have acquired infections as a part of this dysregulation. Longer-term and stronger antibiotics than you would typically prescribe may be necessary to address the problem, and a broad range of diagnostic tests should be applied. Look especially for pathogens only elevated in elderly or immunocompromised patient subgroups.


Anti-virals such as Valtrex, Famvir, or Valcyte may be appropriate interventions for ME patients who test positive for Coxsackie, Epstein-Barr, or Parvovirus.


Low-dose naltrexone (LDN), Imunovir, and Nexavir are all immunomodulators that have been used to address Th-2-dominant immune states in ME.


GcMAF is an emerging injectable that encourages macrophage activation. In cases where infection is a major contributor to symptoms, GcMAF may be considered as a treatment option. Its availability is limited, and research on its use is promising but scarce.


One of the more consistent findings in ME is dysregulation of B-12 and folic acid. Many patients have gut dysbiosis, food intolerances, and other digestive disturbances that may make it difficult to absorb B-vitamins. In that case, sublingual or injectable B-12 should be considered.


ME is an oxidative disorder, and as such, discomfort may be partially alleviated by anti-inflammatories such as DHEA, flavonoid complexes, and Vitamins A, D, E, and C. CoQ-10 and other citric-acid cycle intermediates have also been shown to increase energy levels in ME patients.

Recent Research in ME:

For many years, the etiology of ME has challenged the medical and research community. However, several recent studies have shown remarkable promise in advancing our understanding of this illness.


Mady Hornig and her team at Columbia University discovered a pattern of upregulated inflammatory and anti-inflammatory markers in early ME (first three years after onset) all of which were inverted in late ME (over three years after onset). Long-term patients’ immune markers were lower even than those of controls.

Dysregulated immune markers included IL-12p40, IL-12p70, IFN-gamma, TNF-alpha, and GM-CSF (CSF2). The marked involvement of interferon-gamma points to an initial infective trigger, as it is the product of activated T-cells, natural killer cells, and macrophages.

Hornig’s study, besides pointing to a future blood test for ME, is the first to identify a two-stage illness, with an acute phase and a chronic phase.


Chris Armstrong and his team discovered a pattern of dysregulated glycolysis in ME by analyzing blood and urine metabolites in a cohort of ME patients. Byproducts of glycolysis were reduced in the urine, whereas glucose in the blood was significantly elevated in comparison to controls. Other energy-producing reactions’ metabolites were elevated, which may indicate compensatory energy metabolic mechanisms in people with ME.


Julie Newton and her team discovered that muscle cells of patients with ME had increased myogenin expression but decreased IL-6 secretion in comparison to controls and, when an electrical pulse was sent through the tissue to simulate exercise, muscle cells of ME patients demonstrated impaired AMPK activation and impaired uptake of glucose. Cells responded normally to insulin.


Myalgic encephalomyelitis is a multi-factorial neurological disease that causes significant impairment in the nervous, endocrine, musculoskeletal, digestive, and cardiac systems of the body. Primary symptoms include post-exertional ‘crashes’, cognitive impairment, unrefreshing and disordered sleep, and multiple other autonomic and endocrine disorders.

Treatment is primarily focused on abating the symptoms of the illness, but several novel immunotherapies are on the horizon that may help your patient today or in the future. The most important thing is to treat your patient with understanding and respect for the strength and fortitude they demonstrate by living every day with an illness that is not well-understood by medical professionals and perhaps even by those closest to them. Most are not expecting a cure but basic palliative care, understanding, and coordination with the specialist or specialists they need. If you can provide that, they will be more than happy with your care.

References and Resources:

Armstrong, C. W., McGregor, N. R., Lewis, D. P., Butt, H. L., & Gooley, P. R. (2015, May 30). Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome patients. Metabolomics. doi:10.1007/s11306-015-0816-5

Brown, A. E., Jones, D. E., Walker, M., & Newton, J. L. (2015, April 2). Abnormalities of AMPK activation and glucose uptake in cultured skeletal muscle cells from individuals with Chronic Fatigue Syndrome. PLoS ONE, 10(4). doi:10.1371/journal.pone.0122982

Carruthers, B. M., van de Sande, M.I., DeMeirlier, K. L., Klimas, N. G., Broderick, G., Mitchell, T. (2011). Myalgic Encephalomyelitis: International Consensus Criteria. Journal of Internal Medicine, 11(1), 327-338. doi: 10.1111/j.1365-2796.2011.02428.x

Carruthers, B. M., & van de Sande, M. I. (2005). Myalgic encephalomyelitis/Chronic fatigue syndrome: a clinical case definition and guidelines for medical practitioners; an overview of the Canadian Consensus document. Vancouver, Canada: Carruthers & van de Sande. Retrieved from http://sacfs.asn.au/download/consensus_overview_me_cfs.pdf

Carvalho, A. F., Köhler, C. A., McIntyre, R. S., Knöchel, C., Brunoni, A. R., Thase, M. E., & Quevedo, J. (2015, December). Peripheral vascular endothelial growth factor as a novel depression biomarker: A meta-analysis. Psychoneuroendocrinology, 62, 18-26. doi: http://dx.doi.org/10.1016/j.psyneuen.2015.07.002

Chronic Fatigue Syndrome A Roadmap for Testing and Treatment. (2014, July 25). In ME/CFS Roadmap. Retrieved August 4, 2015, from https://sites.google.com/site/cfstestingandtreatmentroadmap/

Costigan A, Elliott C, McDonald C, Newton JL. Orthostatic symptoms predict functional capacity in chronic fatigue syndrome: implications for management. QJM. 2010 Aug;103(8):589-95. doi: 10.1093/qjmed/hcq094. Epub 2010 Jun 9. PubMed PMID: 20534655.

Falk Hvidberg, M., Brinth, L. S., Olesen, A. V., Petersen, K. D., & Ehlers, L. (2015). The Health-Related Quality of Life for Patients with Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS). PLoS ONE, 10(7), e0132421. http://doi.org/10.1371/journal.pone.0132421

Hornig, M., Montoya, J. G., Klimas, N. G., Levine, S., Felsenstein, D., Bateman, L., & Peterson, D. L. (2015, February 27). Distinct plasma immune signatures in ME/CFS are present early in the course of illness. Biomarkers, 1(1), 1-10. doi:10.1126/sciadv.1400121

ME/CFS Illness Management Survey Results “No decisions about me without me”. (2015, May). ME Association. Retrieved from http://www.meassociation.org.uk/wp-...No-decisions-about-me-without-me-30.05.15.pdf

Meyer T, Stanske B, Kochen MM, Cordes A, Yüksel I, Wachter R, Lüers C, Scherer M, Binder L, Pieske B, Herrmann-Lingen C. Serum levels of interleukin-6 and interleukin-10 in relation to depression scores in patients with cardiovascular risk factors. Behav Med. 2011 Jul;37(3):105-12. doi: 10.1080/08964289.2011.609192. PubMed PMID: 21895428.

Morris, G., & Maes, M. (2013). Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics. BMC Medicine, 11, 205. doi:10.1186/1741-7015-11-205

Peterson, D, E. W. Brenu, G. Gottschalk, et al., “Cytokines in the Cerebrospinal Fluids of Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis,” Mediators of Inflammation, vol. 2015, Article ID 929720, 4 pages, 2015. doi:10.1155/2015/929720

Twisk, F. N. M. (2014). The status of and future research into Myalgic Encephalomyelitis and Chronic Fatigue Syndrome: the need of accurate diagnosis, objective assessment, and acknowledging biological and clinical subgroups. Frontiers in Physiology, 5, 109. doi:10.3389/fphys.2014.00109



  • Needless to say, please feel free to use this and hand it physically to anyone you want. Please do not re-post it elsewhere without attribution. If you do post it elsewhere, please link back to this page. If you do post it, please post it in its entirety rather than in bits and bobs, or simply link to the page.
  • I owe a lot of what is here to Hip's CFS Roadmap and the Canadian Consensus Criteria. I sincerely thank both parties.
  • The document is attached as a pdf file.
  • If anyone with design background wants to make this more of a booklet or pamphlet, I would love to see something like that! I'm also interested in making a one- or two-page version for those docs who even have a shorter attention span.
  • Looking for:
    • The source that states that severe ME is similar in QOF to late-stage AIDS and cancer
    • The source that states that PWME are no more likely to be depressed than other groups with chronic illnesses
    • I know I have seen both of these, and in reputable sources, I just need some help re-locating them. Thanks for any help anyone can give!
  • Finally, do remember that this is a ridiculously complex illness, and I could not fit every aspect of said illness into this small a space. However, if you feel as though I have left out something vital or worse, gotten something wrong, please do not hesitate to correct me.


You could add the CPET under testing or challenge tests, though if you left it out on purpose I'd understand why. There was also the buspirone/prolactin challenge test (http://www.ncbi.nlm.nih.gov/pubmed/1586780). It wasn't widely validated, but it was later correlated with abnormal SPECT scans (http://informahealthcare.com/doi/abs/10.1300/J092v04n03_04). Most patients probably don't have access to this or SPECT scanning though so I'm not sure how much good it does to include it. It is interesting in the context of the serotonin problems that you mentioned in the document.

I'm happy to see that you mentioned coxsackie, though I would change it to enterovirus as echoviruses are a problem as well. The antivirals listed don't have any effect however on enterovirus or parvo B19, so perhaps you could reword that part.
Thanks, Halcyon! I definitely should mention enterovirus and I should mention CPET by name. As far as the buspirone/prolactin test, I haven't heard of it before, and am interested in it for scholarly reasons. Thanks for pointing that out!
Ooooh, I looked at that study - how interesting! I could briefly mention it during the ME vs depression section.
"Chronic Fatigue Syndrome Found Worse Than Diabetes, Multiple Sclerosis, Cancer, etc."
Just a day ago. :)
Thanks ahmo! That's awesome. :)

Welll.... not awesome... you know what I mean! ;)
This is awesome, but you've gotta link the references at the bottom to corresponding bits in the text. I'd rather not go hunting through hundreds of pages of annoying scientific articles just to find a quote discrediting GET.
Brilliant! Am so glad this article is not linked to the bogus diagnosis of chronic fatigue as fatigue is a symptom, not an illness! Well done and thank you so much for posting!

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