Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) is an acquired neurological disease with complex global dysfunctions represented by pathological dysregulation of the nervous, immune and endocrine systems, with impaired cellular energy metabolism and ion transport. 
ME/CFS is primarily characterized by profound, debilitating fatigue. Other symptoms may include:[1, 32]
· Neurocognitive Impairments
· Sleep Disturbance
· Neurosensory, Perceptual and Motor Disturbances
· Flu-Like Symptoms
· Susceptibility to Viral Infections
· Gastro-Intestinal Disturbances
· Genitourinary Disorders
· Sensitivities to Food, Medications, Odors or Chemicals
· Cardiovascular: Light-Headedness/Dizziness, Postural Orthostatic Tachycardia, Orthostatic Intolerance, Neurally Mediated Hypotension
· Respiratory Problems
· Loss Of Thermostatic Stability (Subnormal Body Temperature, Sweating Episodes, Cold Extremities)
The dramatic decline in activity level and stamina is often severe enough to result in substantial occupational, educational, and social limitations that lead to defining ME/CFS as a major functional impairment. At least one quarter of those afflicted are either unemployed or on disability.
An intermittent pattern and relapse is common in ME/CFS as is an overall lower level of performance and activity than suffers were capable of prior to the illness. [3,4]
More than 4 million Americans suffer from ME/CFS and over 2.5% of the population aged 18-59 years meet the diagnostic criteria.[1,5] Only 20% have been properly diagnosed. Though more frequent in women aged 40-59 years, people of all ages, ethnicities, economic statuses, and both sexes may develop ME/CFS.[6,7]
International consensus criteria have defined the signs and symptoms of ME/CFS for diagnosis. A patient with MCS/CFS :
1. will meet the criteria for post-exertional neuroimmune exhaustion,
2. have at least one symptom from three neurological impairment categories,
3. have at least one symptom from three immune/gastro-intestinal/genitourinary impairment categories, and
4. have at least one symptom from energy metabolism/transport impairments.
As of the writing of this paper, two new biomarkers have been discovered for ME/CFS and confirmatory clinical tests have been developed.[8,9]
The “ATP profile” test confirms a ME/CFS diagnosis for patients who have insufficient energy due to mitochondrial cellular respiration dysfunction. The function of mitochondria in producing ATP (adenosine triphosphate) for energy and recycling ADP (adenosine diphosphate) to replenish the ATP supply is determined by the ATP profile. Patients who are not diagnosed with ME/CFS by the ATP profile may not have ME/CFS or may suffer from energy wastage due to other factors.
The serum chemokine and cytokine profile shows a distinct pathogen associated signature for the inflammatory serum chemokines IL-8, IP-10, MIP-a and MIP-1b, as well as the pro inflammatory cytokines IL-6, TNFa and IL-1b. Cytokine and chemokine patterns can be used diagnostically for ME/CFS in subgroups.
Other disorders may resemble ME/CFS and these include multiple sclerosis, mononucleosis, hypothyroidism, Lyme, and lupus, as well as sleep disorders, certain prescription medications, and major depressive disorders.
Tests which may be run to exclude other fatiguing conditions include urinalysis, total protein, glucose, c-reactive protein, phosphorus, electrolytes, complete blood count (CBC) with leukocyte differential, alkaline phosphatase (ALP), creatinine, blood urea nitrogen (BUN), albumin, globulin, calcium, alanine aminotransferase (ALT) or aspartate transaminase serum level (AST), thyroid function tests (tsh and free t4), ANA, and rheumatoid factor (if indicated), lyme serology (if indicated).
“Comorbid conditions that clinicians should be alert for include fibromyalgia, irritable bowel syndrome, multiple chemical sensitivity, Gulf War syndrome, temporomandibular joint disorder, and overactive bladder or interstitial cystitis.”
The pathogenesis of ME/CFS is uncertain and likely multi-factorial. Conditions that have been proposed to trigger the development of ME/CFS include viral infection, immune disorders, hypothalamic-pituitary adrenal (HPA) axis dysfunction, and toxic exposure.
ME/CFS is similar to many infections, including Epstein-Barr (EBV), human retroviruses, human herpesvirus 6, enteroviruses, rubella, Candida albicans, bornaviruses, and Mycoplasma. No one virus has been linked to every case of ME/CFS; however, ME/CFS may the result of post-viral infection from a variety of virus’.[1,10] Many studies have uncovered a flu-like sickness that precedes the onset of ME/CFS. It is believed that a virus may trigger and lead to chronic activation of the immune system and altered cytokine production. 
“An alteration in cytokine profile, a decreased function of natural killer (NK) cells, a presence of autoantibodies and a reduced responses of T cells to mitogens and other specific antigens have been reported” in ME/CFS.[11,12]
Various triggering events, such as traumatic injury or a viral infection, may lead to the chronic expression of cytokines and then to ME/CFS. Serum chemokine and cytokine profiles have identified a distinct pathogen associated signature for the inflammatory serum chemokines, as well as the pro inflammatory cytokines. High levels of pro-inflammatory cytokines may explain fatigue and flu-like symptoms.
Studies have reported immune cell phenotype changes and NK cell dysfunction as common manifestations of ME/CFS. Studies have shown that ME/CFS patients are more likely to have a history of co-occurring allergies than are healthy controls, though not all ME/CFS patients have allergies.
There may also be a disorder in the early activation of the immune system involving protein kinase C.
Hypothalamic-Pituitary Adrenal (HPA) Axis
Physical or emotional stress is frequently reported just prior to the onset of ME/CFS. ME/CFS patients produce lower levels of cortisol than do healthy controls which influences the immune system, behavior, and other body systems.  While the levels are lower, they are still within the normal range.
HPA axis is involved in the adaptive responses to stress. ME/CFS patients report exacerbation of symptoms after physical and psychological stress. One study showed that ME/CFS patients are capable of producing a sufficient cortisol response under some types of stress, but an overall subtle dysregulations of the HPA axis exists.
The HPA axis deregulation may exacerbate or perpetuate symptoms. Cortisol acts to suppress inflammation and cellular immune activation. Supplementary cortisol has been shown to temporarily alleviate fatigue.
Neurally Mediated Hypotension
Many patients with Myalgic Encephalomyelitis (Chronic Fatigue Syndrome) (ME/CFS) have neurally mediated hypotension when subjected to head-up tilt and disturbances of atonomic regulation of both blood pressure and pulse.[1,17]
A study performed by Michael Maes found that the functional symptoms of ME/CFS have a genuine organic cause in the activation of peripheral and central inflammatory and oxidative and nitrosative stress pathways and gut-derived inflammation.
All people with ME/CFS are physically impaired. The Center’s for Disease Control and Prevention cites that roughly half of people with ME/CFS partially recover, some returning to work and others growing progressively more disabled.[1,19] The sooner a patient is diagnosed and treated, the better the chances of recovery.[1,10]
Because ME/CFS is a multi-system illness, it is important to address more than one symptom at a time. Treatment options include pharmacologic, nutitional, and alternative therapies along with managing activity levels.
There is no specific drug for treating Myalgic Encephalomyelitis (Chronic Fatigue Syndrome).[1,19] Specific symptoms may be treated with pharmacologic medications.[1,19] However, there are guidelines which should be exercised.[1,19]
1. A greatly reduced dosage of ¼ to ½ of the normal dosage is recommended as patients with ME/CFS are often highly sensitive to pharmacologic interventions.
2. The least number of drugs possible should be used to avoid drug interaction. In some cases, a single drug may act on multiple symptoms.
3. Drugs should be aimed at correcting the cause of symptoms.
4. Patients should be monitored for side effects, particularly those which may cause cognitive problems.
5. Remember that one drug may not work for every ME/CFS patient.
Medscape provides a detailed chart with by symptom with suggested drugs and dosages. It can be downloaded online from http://images.medscape.com/pi/editorial/clinupdates/2008/17442/table1.pdf. It provides suggestions for symptoms ranging from sleep problems, anticonvulsants, cognitive stimulants, muscle relaxants, restless leg syndrome, orthostatic intolerance, and pain to antidepressants.
Research indicates that malabsorption and deficiencies in a variety of vitamins, minerals, amino acids, and other nutrients may play a role in ME/CFS.[19,20,21,46]. Basic guidelines for nutritional treatment include:
1. Test for nutritional deficiencies, particularly in vitamins B, D, C, E, magnesium, sodium, zinc, essential fatty acids, folic acid, tryptophan, carnitine, and CoQ10.
2. Be aware that borderline results of nutrients may be exacerbating or mimicking ME/CFS symptoms.
3. Maintaining a well balanced diet and taking a multi-vitamin are recommended.
4. Be sure that all supplements taken are noted in the patient file and monitor for negative drug interactions.
5. Avoid foods and chemicals for which sensitivity exists.
Nutrition therapy with certain agents that down-regulate the nitric oxide and peroxynitrite (NO/ONOO-) cycle of biochemistry has also been recommended. The following agents have been predicted to be useful to down-regulate the NO/ONOO- cycle and reduce symptoms in clinical trials:
Alternative therapies have been shown to decrease symptoms and increase function in some people with ME/CFS. Massage, healing touch, hydrotherapy, and acupuncture for example, can help to reduce pain, relieve fatigue, and improve balance. Suggestions for alternative therapies:
1. Research the therapy to ensure it is safe and effective.
2. Keep an open mind to alternative therapies.
3. Keep exercise and movement therapy within tolerance.
Symptoms generally worsen after exertion.[1,26]. The key to avoiding a fatigue “crash” is managing activity.[1,24,25] Excessive physical or mental exercise is counter productive and may lead to a relapse.[27,28] Suggestions for managing activity level[1,24,25,27,2829,30,31]:
1. Avoid extreme exercise.
2. Avoid mentally stressful work and encounters.
3. Aim for balance and moderation by pacing to manage energy and avoid the push/crash cycle. View available energy like a reserve which goes bankrupt when it runs out.
4. Experiment to find the optimal amount of exertion which won’t cause a relapse.
Some patients are too ill to exert themselves at all. Severe patients may be bed bound and should not be encouraged to push themselves beyond their capabilities.
1. Centers for Disease Control and Prevention. Chronic Fatigue Syndrome. 2008, November 18. Retrieved January 21, 2009, from FirstGov -- The U.S. Government's Official Web Portal Department of Health and Human Services “Safer Healthier People” Centers for Disease Control and Prevention. Web site: http://www.cdc.gov/cfs/
2. Nisenbaum R, Jones JF, Unger ER, Reyes M, Reeves WC. A population based study of the clinical course of chronic fatigue syndrome. Health Qual Life Outcomes. 2003;1:49.
3. Buchwald D, Pearlman T, Umali J, Schmaling K, Katon W. Functional status in patients with chronic fatigue syndrome. Am J Med. 1996;101:364-370.
4. Christodoulou C, DeLuca J, Lange G, et al. Relation between neuropsychological impairment and functional disability in patients with chronic fatigue syndrome. J Neurol Neurosurg Psychiatr. 1998;64:431-434.
5. Reeves WC, Jones JF, Maloney E, et al. Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Popul Health Metr. 2007;5:5.
6. Reyes M, Nisenbaum R, Hoaglin DC, et al. Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Intern Med. 2003;163:1530-1536.
7. Jones JF, Nisenbaum R, Solomon L, Reyes M, Reeves WC. Chronic fatigue syndrome and other fatiguing illnesses in adolescents: a population based study. J Adolesc Health. 2004;35:34-40.
8. Myhill S, Booth NE, McLauren-Howard, J. Chronic Fatigue Syndrome and Mitochondrial Dysfunction. Int J Clin Exp Med (2009) 2, 1-16.
9. Lombardi VC, Redelman D, White DC, Fremont M, DeMerirleir K, Peterson D, and Mikovits JA. Serum cytokine and chemokine profiles of individuals with myalgic encephalomyelitis (ME) reveal distinct pathogen associated signatures. September 2008:43(3):245.
11. Lorusso L, Mikhaylova SV, Capelli E, Ferrari D, Ngonga GK, Ricevuti G. Immunological aspects of chronic fatigue syndrome. Autoimmun Rev. 2009 Feb;8(4):287-91. Epub 2008 Sep 16.
12. Barker E, Fujimura SF, Fadem MB, Landay AL, Levy JA. Immunologic abnormalities associated with chronic fatigue syndrome. Clin Infect Dis. 1994 Jan;18 Suppl 1:S136-41.
13. Mihaylova I, DeRuyter M, Rummens JL, Bosmans E, Maes M. Decreased expression of CD69 in chronic fatigue syndrome in relation to inflammatory markers: evidence for a severe disorder in the early activation of T lymphocytes and natural killer cells. Neuro Endocrinol Lett. 2007 Aug;28(4):477-83.
14. Van Den Eede F, Moorkens G, Van Houdenhove B, Cosyns P, Claes SJ. Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. Neuropsychobiology. 2007;55(2):112-20. Epub 2007 Jun 27.
15. Cleare AJ. The HPA axis and the genesis of chronic fatigue syndrome. Trends Endocrinol Metab. 2004 Mar;15(2):55-9.
16. Gaab J, Hüster D, Peisen R, Engert V, Heitz V, Schad T, Schürmeyer TH, Ehlert U. Hypothalamic-pituitary-adrenal axis reactivity in chronic fatigue syndrome and health under psychological, physiological, and pharmacological stimulation. Psychosom Med. 2002 Nov-Dec;64(6):951-62.
17. Davis SD, Kator SF, Wonnett JA, Pappas BL, Sall JL. Neurally mediated hypotension in fatigued Gulf War veterans: a preliminary report. Am J Med Sci. 2000 Feb;319(2):89-95.
18. Maes M. Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms. Curr Opin Psychiatry. 2009 Jan;22(1):75-83.
19. Harmon, M. Bateman L, Lapp C, McCleary KK. Chronic Fatigue Syndrome: From Diagnosis to Management CME/CE. Medscape. October 9, 2008.
20. Reeves WC, Jones JF, Maloney E, et al. Prevalence of chronic fatigue syndrome in metropolitan, urban, and rural Georgia. Popul Health Metr. 2007;5:5.
21. Reyes M, Nisenbaum R, Hoaglin DC, et al. Prevalence and incidence of chronic fatigue syndrome in Wichita, Kansas. Arch Intern Med. 2003;163:1530-1536.
22. Werbach MR. Nutritional strategies for treating chronic fatigue syndrome. Altern Med Rev. 2000;5:93-108.
23. Pall ML. Explaining “Unexplained Illnesses”: Disease Paradigm for Chronic Fatigue Syndrome, Multiple Chemical Sensitivity, Fibromyalgia, Post-Traumatic Stress Disorder, Gulf War Syndrome and Others. Hawthorn Medical Press. 2007.
24. Rimes KA, Chalder T. Treatments for chronic fatigue syndrome. Occup Med. 2005;55:32-39.
25. Whiting P, Bagnall A, Sowden A, Cornell J, Mulrow C, Ramirez G. Interventions for the treatment and management of chronic fatigue syndrome. JAMA. 2001;286:1360-1368.
26. Komaroff AL, Buchwald D. Symptoms and signs of chronic fatigue syndrome. Rev Infect Dis. 1991;13(suppl 1)S8-S11.
27. Bailey SP. Chronic fatigue syndrome. In: ACSM's Guidelines for Exercise Testing and Prescription. Philadelphia, Pa: Lippincott Williams & Wilkins; 2003:186-191.
28. McCully KK, Sisto SA, Natelson BH. Use of exercise for treatment of chronic fatigue syndrome. Sports Med. 1996;21:35-48.
29. Lloyd AR. To exercise or not to exercise in chronic fatigue syndrome? No longer a question. Med J Aust. 2004;180:437-438.
30. Wallman, KE, Morton AR, Goodman C, Grove
31. R, Guilfoyle AM. Randomized controlled trial of graded exercise in chronic fatigue syndrome. Med J Aust. 2004;180:444-448.Taylor RR, Friedberg F, Jason LA. A Clinician's Guide to Controversial Illnesses: Chronic Fatigue Syndrome, Fibromyalgia and Multiple Chemical Sensitivities. Sarasota, Fl: Professional Resource Press; 2001:63-86.
32. Caruthers, et al. Myalgic Encephalomyelitis: International Consensus Criteria. J Intern Med. 2011. doi: 10.1111/j.1365-2796.2011.02428.x
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