Chronic_fatigue_syndrome

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Chronic fatigue syndrome/ myalgic encephalomyelitis Classification & external resources
ICD-10	G93.3
ICD-9	780.71
DiseasesDB	1645
MedlinePlus	001244
eMedicine	med/3392  ped/2795
MeSH	D015673

Chronic fatigue syndrome (CFS) is one of several names given to a poorly understood, variably debilitating disorder of uncertain cause/causes. Based on a 1999 study of adults in the United States, CFS is thought to affect approximately 4 per 1,000 adults.Jason LA, Richman JA, Rademaker AW, Jordan KM, Plioplys AV, Taylor RR, McCready W, Huang CF, Plioplys S (1999). "A community-based study of chronic fatigue syndrome". Arch. Intern. Med. 159 (18): 2129-37. PMID 10527290.  For unknown reasons, CFS occurs more often in women, and adults in their 40s and 50s.Gallagher AM, Thomas JM, Hamilton WT, White PD. Incidence of fatigue symptoms and diagnoses presenting in UK primary care from 1990 to 2001. J R Soc Med 2004;97:571-5. PMID 15574853. The illness is estimated to be less prevalent in children and adolescents, but study results vary as to the degree.Jason LA, Jordan K, Miike T, Bell DS, Lapp C, Torres-Harding S, Rowe K, Gurwitt A, De Meirleir K, Van Hoof ELS (2006). "A Pediatric Case Definition for Myalgic Encephalomyelitis and Chronic Fatigue Syndrome". Journal of Chronic Fatigue Syndrome 13 (2-3): 1-44. doi:10.1300/J092v13n02_01. 

CFS often manifests with widespread myalgia and arthralgia, cognitive difficulties, chronic mental and physical exhaustion, often severe, and other characteristic symptoms in a previously healthy and active person. Despite promising avenues of research, there remains no assay or pathological finding which is widely accepted to be diagnostic of CFS. It remains a diagnosis of exclusion based largely on patient history and symptomatic criteria, although a number of tests can aid diagnosis.Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas MD, Lerner AM, Bested AC, Flor-Henry P, Joshi P, Powles ACP, Sherkey JA, van de Sande MI (2003). "Myalgic encephalomyalitis/chronic fatigue syndrome: Clinical working definition, diagnostic and treatment protocols". Journal of Chronic Fatigue Syndrome 11 (1): 7-36. doi:10.1300/J092v11n01_02.  Whereas there is agreement on the genuine threat to health, happiness, and productivity posed by CFS, various physicians\' groups, researchers, and patient activists champion very different nomenclature, diagnostic criteria, etiologic hypotheses, and treatments, resulting in controversy about nearly all aspects of the disorder. Even the term chronic fatigue syndrome is controversial because a large part of the patient community believes the name trivializes the illness. Jason LA, Taylor RR. (2001). Measuring Attributions About Chronic Fatigue Syndrome. J Chronic Fatigue Syndr 8 (3/4); 31-40 TXT formal Chronic fatigue syndrome is not the same as "chronic fatigue”. Fatigue is a common symptom in many illnesses, but CFS is a multi-systemic disease and is relatively rare by comparison.Ranjith G (2005). "Epidemiology of chronic fatigue syndrome.". Occup Med (Lond) 55 (1): 13-9. PMID 15699086.  Definitions (other than the 1991 UK Oxford criteria)Sharpe M, Archard L, Banatvala J, Borysiewicz L, Clare A, David A, Edwards R, Hawton K, Lambert H, Lane R (1991). "A report--chronic fatigue syndrome: guidelines for research.". J R Soc Med 84 (2): 118-21. PMID 1999813.  Synopsis by -476446699 at GPnotebook) require a number of features, the most common being severe mental and physical exhaustion which is "unrelieved by rest" (1994 Fukuda definition),Fukuda K, Straus S, Hickie I, Sharpe M, Dobbins J, Komaroff A (1994). "The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group.". Ann Intern Med 121 (12): 953-9. PMID 7978722.  case definition and may be worsened by even trivial exertion (a mandatory diagnostic criterion according to some systems). Most diagnostic criteria require that symptoms must be present for at least six months, and all state the symptoms must not be caused by other medical conditions. CFS patients may report many symptoms which are not included in all diagnostic criteria, including muscle weakness, cognitive dysfunction, hypersensitivity, orthostatic intolerance, digestive disturbances, depression, poor immune response, and cardiac and respiratory problems. It is unclear if these symptoms represent co-morbid conditions or are produced by an underlying etiology of CFS.Afari N, Buchwald D (2003). "Chronic fatigue syndrome: a review". Am J Psychiatr 160 (2): 221-36. PMID 12562565.  Some cases improve over time, and treatments (though none are universally accepted) bring a degree of improvement to many others, though full resolution may be only 5-10% according to the United States Centers for Disease Control and Prevention (CDC).

Contents 1 Nomenclature 2 Signs and symptoms 2.1 Onset 2.1.1 Sudden onset cases 2.1.2 Gradual onset cases 2.2 Course 2.3 Activity levels 3 Proposed causes and pathophysiology 3.1 Neurological abnormalities 3.2 Psychiatric abnormalities 3.3 Stress and trauma 3.4 Oxidative stress 3.5 Immune dysfunction 3.5.1 RNase L deregulation 3.5.2 Hyperactive immunity 3.5.3 Allergies 3.5.4 Immunodeficiency 3.5.5 Other immunological findings 3.6 Psychoneuroimmunological interactions 3.7 Infectious etiology 3.8 Endocrine dysfunction 3.9 Gene expression 3.10 Genetic polymorphisms 3.11 Metabolic disorders 3.12 Toxic agents 3.13 Other findings 4 Diagnosis 4.1 CDC 1994 criteria 4.2 NICE (UK) 2007 criteria 4.3 Other systems 4.4 Issues with the definitions/criteria 4.5 Testing 4.6 Diagnostic controversies 5 Treatment 5.1 Behavioral interventions 5.1.1 Cognitive Behavioral Therapy (CBT) 5.1.1.1 Similar and related treatments 5.1.2 Graded Exercise Therapy (GE, GA, GET or Adaptive Pacing) 5.2 Medication 5.2.1 Antidepressants 5.2.2 Autonomic nervous system stimulants 5.2.3 Hormones 5.3 Other medical treatments 5.3.1 Allergy identification and treatment 5.4 Complementary and alternative medicine 5.4.1 Essential fatty acid treatments 5.4.2 Magnesium 5.4.3 Complementary and alternative medicine usage 6 Prognosis 6.1 Recovery 6.2 Deaths 7 Epidemiology 7.1 Disease associations 7.2 Co-morbidity 7.3 Social issues 8 History 8.1 The concept 8.2 WHO classification 8.3 Controversy 9 See also 10 References 11 External links

Nomenclature

It has been suggested that this section be split into a new article entitled ME/CFS nomenclatures. (Discuss)

The naming of chronic fatigue syndrome has been challenging, since consensus is lacking within the medical, research, and patient communities regarding the defining features of the syndrome. It may be considered by different authorities to be a central nervous system, metabolic, (post-)infectious, immune system or neuropsychiatric disorder.

There are a number of different terms which have been identified at various times with this disorder.

• Myalgic encephalomyelitis or ME translates to "inflammation of the brain and spinal cord with muscle pain" and first appeared as "benign myalgic encephalomyelitis" in a Lancet editorial by Sir Donald Acheson in 1956.(No authors listed) (1956). "A new clinical entity?". Lancet 270 (6926): 789–90. PMID 13320887.  In a 1959 review he referred to several older reports that appeared to describe a similar syndrome.Acheson E (1959). "The clinical syndrome variously called benign myalgic encephalomyelitis, Iceland disease and epidemic neuromyasthenia.". Am J Med 26 (4): 569-95. PMID 13637100.  The neurologist Lord Brain included ME in the 1962 sixth edition of his textbook of neurology, (1962) in Brain R: Diseases of the Nervous System, 6.  A 1978 British Medical Journal article stated the Royal Society of Medicine conference to discuss the illness during that year clearly agreed Myalgic Encephalomyelitis was a distinct name for the disease. The article also stated the previous word (benign) used with ME was rejected as unsatisfactory and misleading because the condition may be devastating to the patient.No authors listed. "Epidemic myalgic encephalomyelitis". Br Med J. 1 (6125): 1436-7. PMID 647324.  In 1988 both the UK Department of Health and Social Services and the British Medical Association officially recognized it as a legitimate and potentially distressing disorder.^{[citation needed]} Opponents of the term ME state that there is no objective evidence of inflammation. In some patients diagnosed with CFS (e.g. the case of Sophia Mirza), central nervous system inflammation has been documented. Many patients, and some research and medical professionals in the United Kingdom and Canada, use this term in preference to or in conjunction with CFS (ME/CFS or CFS/ME). The international association of researchers and clinicians is named IACFS/ME.
• Myalgic encephalopathy, similar to the above, with "pathy" referring to unspecified pathology rather than inflammation; this term has some support in the UK and US.
• Chronic Epstein-Barr virus (CEBV) or Chronic Mononucleosis; the term CEBV was introduced in 1985 by virologists Dr. Stephen StrausStraus S, Tosato G, Armstrong G, Lawley T, Preble O, Henle W, Davey R, Pearson G, Epstein J, Brus I (1985). "Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection.". Ann Intern Med 102 (1): 7-16. PMID 2578268.  and Dr. Jim JonesJones J, Ray C, Minnich L, Hicks M, Kibler R, Lucas D (1985). "Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: elevated anti-early antigen antibodies.". Ann Intern Med 102 (1): 1-7. PMID 2578266.  in the United States. The Epstein-Barr virus, a neurotropic virus that more commonly causes infectious mononucleosis, was thought by Straus and Jones to be the cause of CFS. Subsequent discovery of the closely related human herpesvirus 6 shifted the direction of biomedical studies, although a vastly expanded and substantial body of published research continues to show active viral infection or reinfection of CFS patients by these two viruses. These viruses are also found in healthy controls, lying dormant.
• Chronic fatigue syndrome (CFS) was proposed in 1988 by researchers from the U.S. Centers for Disease Control and Prevention (CDC) to replace the name chronic Epstein-Barr virus syndrome when they published an initial case definition for research of the illness after investigating the 1984 Lake Tahoe ME epidemic. CFS is used increasingly over other designations, particularly in the United States. Many patients and clinicians perceive the term as trivializing, Jason LA, Taylor RR. (2001). Measuring Attributions About Chronic Fatigue Syndrome. J Chronic Fatigue Syndr 8 (3/4); 31-40 TXT formal and as the 1994 Fukuda paper itself cedes, stigmatizing, which led to a movement in the United States to change the name and definition.Advocacy Archives: Name Change. The CFIDS Association of America. Retrieved on 2008-01-16. Eighty-five percent of respondents to a 1997 survey conducted by the Chronic Fatigue Immune Dysfunction Syndrome Association of America wanted the name changed. The CFS Coordinating Committee (CFSCC) of the U.S. Department of Health and Human Services formed a name change workgroup in 2000.Lavrich, Carol (September 29 2003), Name Change Workgroup, CFSCC, National Institutes of Health Building 31C, Conference Room 10, Bethesda, Maryland: US Department of Health and Human Services, Chronic Fatigue Syndrome Advisory Committee, <http://www.hhs.gov/advcomcfs/sept_meeting_min.html#carollavrich>. Retrieved on 29 December 2007 Terms were recommended which implied specific underlying etiologies or pathologic processes, but work was shelved in December 2003 when the successor CFS Advisory Committee (CFSAC) decided a name change would be too disruptive at that time.Bell D.S. et al (December 03 2003), Name Change, Hubert H. Humphrey Building, 200 Independence Avenue, SW, Room 800, Washington, DC 20201: US Department of Health and Human Services Chronic Fatigue Syndrome Advisory Committee (CFSAC)

Second Meeting, <http://www.hhs.gov/advcomcfs/dec_meeting_min.html#name_change>. Retrieved on 16 January 2008

• Chronic fatigue immune dysfunction syndrome (CFIDS); many patients and advocacy groups in the USA use the term CFIDS, in an attempt to reduce the psychiatric stigma attached to "chronic fatigue," as well as the public perception of CFS as a psychiatric syndrome. The term also calls attention to the immune dysfunction in patients which research suggests is an integral part of the illness.Buchwald D, Cheney P, Peterson D, Henry B, Wormsley S, Geiger A, Ablashi D, Salahuddin S, Saxinger C, Biddle R (1992). "A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection.". Ann Intern Med 116 (2): 103-13. PMID 1309285. 
• Post-viral fatigue syndrome (PVFS); this is a related disorder. According to ME researcher, Dr. Melvin Ramsay, "The crucial differentiation between ME and other forms of post-viral fatigue syndrome lies in the striking variability of the symptoms not only in the course of a day but often within the hour.Ramsay MA (1986), "Postviral Fatigue Syndrome. The saga of Royal Free disease", Londen, ISBN 0-906923-96-4
• Low Natural Killer Syndrome (LNKS); this term reflected research on patients showing diminished in-vitro natural killer cell activity in a small 1987 study in Japan.edited by Straus, Stephen E. (1994). Chronic Fatigue Syndrome. New York, Basel, Hong Kong: Marcel Dekker Inc., 227. ISBN 0824791878. Aoki T, Usuda Y, Miyakoshi H, Tamura K, Herberman RB. (1987). "Low natural killer syndrome: clinical and immunologic features". Nat Immun Cell Growth Regul. 6 (3): 116-28. PMID 2442602.  A case definition for CFS in JapanKitani T, Kuratsune H, Yamaguchi K. (Nov 1992). "Diagnostic criteria for chronic fatigue syndrome by the CFS Study Group in Japan". Nippon Rinsho. 50 (11): 2600-5. PMID 1287236.  was adopted in 1991 based on the CDC 1988 criteria, an updated diagnostic guideline is planned.Hashimoto N. et al (Jun 2007). "History of chronic fatigue syndrome". Nippon Rinsho. 65 (6): 975-82. PMID 17561685. 
• Yuppie Flu; this was a factually inaccurate term first published in a November 1990 Newsweek cover story and never official medical terminology. It reflects a stereotypical assumption that CFS mainly affects the affluent ("yuppies"), and implies that it is a form of burnout.Cowley, Geoffrey, with Mary Hager and Nadine Joseph (1990-11-12), "Chronic Fatigue Syndrome", Newsweek: Cover Story CFS, however, affects people of all races, genders, and social standings, and is not a form of flu. The phrase is considered offensive by patients and clinicians.Compact Oxford English Dictionary, Oxford University Press[1]Packhard, Randall M. (2004). Emerging Illnesses and Society: Negotiating the Public Health Agenda. Johns Hopkins University Press, p. 156. ISBN 0-801-879-426Anon. "New Therapy For Chronic Fatigue Syndrome To Be Tested At Stanford" Medical News Today[2]
• Uncommonly used terms include Akureyri Disease, Iceland disease (in Iceland),Blattner R (1956). "Benign myalgic encephalomyelitis (Akureyri disease, Iceland disease)". J. Pediatr. 49 (4): 504-6. PMID 13358047.  Royal Free disease (after the location of an outbreak), atypical poliomyelitis, epidemic neuromyasthenia, epidemic vasculitis, raphe nucleus encephalopathy, and Tapanui flu (after the New Zealand town Tapanui where the first doctor in the country to investigate the disease, Dr Peter Snow, lived).

Signs and symptoms

Onset

Sudden onset cases

The majority of CFS cases start suddenly, usually accompanied by a "flu-like illness"Sairenji T, Nagata K (2007). "Viral infections in chronic fatigue syndrome.". Nippon Rinsho 65 (6): 991-6. PMID 17561687. Evengård B, Jonzon E, Sandberg A, Theorell T, Lindh G (2003). "Differences between patients with chronic fatigue syndrome and with chronic fatigue at an infectious disease clinic in Stockholm, Sweden.". Psychiatry Clin Neurosci 57 (4): 361-8. PMID 12839515. Evengård B, Schacterle RS, Komaroff AL (1999). "Chronic fatigue syndrome: new insights and old ignorance.". J Intern Med 246 (5): 455-69. PMID 10583715.  which is more likely to occur in winter,Jason LA, Taylor RR, Carrico AW (2001). "A community-based study of seasonal variation in the onset of chronic fatigue syndrome and idiopathic chronic fatigue.". Chronobiol Int 18 (2): 315-9. PMID 11379670. Zhang QW, Natelson BH, Ottenweller JE, Servatius RJ, Nelson JJ, De Luca J, Tiersky L, Lange G (2000). "Chronic fatigue syndrome beginning suddenly occurs seasonally over the year.". Chronobiol Int 17 (1): 95-9. PMID 10672437.  while a significant proportion of cases begin within several months of severe adverse stress.Hatcher S, House A (2003). "Life events, difficulties and dilemmas in the onset of chronic fatigue syndrome: a case-control study.". Psychol Med 33 (7): 1185-92. PMID 14580073. Theorell T, Blomkvist V, Lindh G, Evengard B. "Critical life events, infections, and symptoms during the year preceding chronic fatigue syndrome (CFS): an examination of CFS patients and subjects with a nonspecific life crisis.". Psychosom Med. 61 (3): 304-10. PMID 10367610. Salit IE (1997). "Precipitating factors for the chronic fatigue syndrome.". J Psychiatr Res 31 (1): 59-65. PMID 9201648.  Many people report getting a case of a flu-like or other respiratory infection such as bronchitis, from which they seem never to fully recover and which evolves into CFS. The diagnosis of Post Viral Fatigue Syndrome is sometimes given in the early stage of the illness. One study reported CFS occurred in some patients following a vaccination or a blood transfusion.De Becker P, McGregor N, De Meirleir K (2002). "Possible Triggers and Mode of Onset of Chronic Fatigue Syndrome". Journal of Chronic Fatigue Syndrome 10 (2): 2-18. doi:10.1300/J092v10n02_02.  The accurate prevalence and exact roles of infection and stress in the development of CFS however are currently unknown.

Gradual onset cases

Other cases have a gradual onset, sometimes spread over years. Patients with Lyme disease may, despite a standard course of treatment, "evolve" clinically from the symptoms of acute Lyme to those similar to CFS.Donta S (2002). "Late and chronic Lyme disease.". Med Clin North Am 86 (2): 341-9, vii. PMID 11982305.  This has become an area of great controversy.

Course

It can be inferred from the 2003 Canadian clinical working definition of ME/CFS that there are 8 categories of symptoms:

• Fatigue: Unexplained, persistent, or recurrent physical and mental fatigue/exhaustion that substantially reduces activity levels and is not relieved (or not completely relieved) by rest.

• Post-exertional malaise: An inappropriate loss of physical and mental stamina, rapid muscular and cognitive fatigability, post exertional malaise and/or fatigue and/or pain and a tendency for other associated symptoms to worsen with a pathologically slow recovery period of usually 24 hours or longer. According to the authors of the Canadian clinical working definition of ME/CFS, the malaise that follows exertion is often reported to be similar to the generalized pain, discomfort and fatigue associated with the acute phase of influenza. Although common in CFS, this may not be the most severe symptom in the individual case, where other symptoms (such as headaches, neurocognitive difficulties, pain and sleep disturbances) can dominate.

• Sleep dysfunction: "Unrefreshing" sleep/rest, poor sleep quantity, insomnia or rhythm disturbances. A study found that most CFS patients have clinically significant sleep abnormalities that are potentially treatable.Krupp LB, Jandorf L, Coyle PK, Mendelson WB (1993). "Sleep disturbance in chronic fatigue syndrome.". J Psychosom Res 37 (4): 325-31. PMID 8510058.  Several studies suggest that while CFS patients may experience altered sleep architecture (such as reduced sleep efficiency, a reduction of deep sleep, prolonged sleep initiation, and alpha-wave intrusion during deep sleep) and mildly disordered breathing, overall sleep dysfunction does not seem to be a critical or causative factor in CFS.Reeves WC, Heim C, Maloney EM, Youngblood LS, Unger ER, Decker MJ, Jones JF, Rye DB (2006). "Sleep characteristics of persons with chronic fatigue syndrome and non-fatigued controls: results from a population-based study.". BMC Neurol 6: 41. PMID 17109739. Watson NF, Kapur V, Arguelles LM, Goldberg J, Schmidt DF, Armitage R, Buchwald D (2003). "Comparison of subjective and objective measures of insomnia in monozygotic twins discordant for chronic fatigue syndrome.". Sleep 26 (3): 324-8. PMID 12749553. Van Hoof E, De Becker P, Lapp C, Cluydts R, De Meirleir K (2007). "Defining the occurrence and influence of alpha-delta sleep in chronic fatigue syndrome.". Am J Med Sci 333 (2): 78-84. PMID 17301585. Ball N, Buchwald DS, Schmidt D, Goldberg J, Ashton S, Armitage R (2004). "Monozygotic twins discordant for chronic fatigue syndrome: objective measures of sleep.". J Psychosom Res 56 (2): 207-12. PMID 15016580.  Sleep may present with vivid disturbing dreams, and exhaustion can worsen sleep dysfunction."Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Clinical Case Definition and Guidelines for Medical Practitioners - An Overview of the Canadian Consensus Document"; authored by Carruthers and van de Sande; published in 2005, ISBN 0-9739335-0-X, [3]

• Pain: Pain is often widespread and migratory in nature, including a significant degree of muscle pain and/or joint pain (without joint swelling or redness, and may be transitory). Other symptoms include headaches (particularly of a new type, severity, or duration), lymph node pain, sore throats, and abdominal pain (often as a symptom of irritable bowel syndrome). Patients also report bone, eye and testicular pain, nerve pain and painful skin sensitivity. Chest pain has been attributed variously to microvascular disease or cardiomyopathy by researchers, and many patients also report painful tachycardia. A systematic review assessing the studies of chronic pain in CFS found that although the exact prevalence is unknown, it is strongly disabling in patients, but unrelated to depression.Meeus M, Nijs J, Meirleir KD (2007). "Chronic musculoskeletal pain in patients with the chronic fatigue syndrome: A systematic review.". Eur J Pain 11 (4): 377-386. PMID 16843021. 

• Neurological/cognitive manifestations: Common occurrences include confusion, forgetfulness, mental fatigue/brain fog, impairment of concentration and short-term memory consolidation, disorientation, difficulty with information processing, categorizing and word retrieval, and perceptual and sensory disturbances (e.g. spatial instability and disorientation and inability to focus vision), ataxia (unsteady and clumsy motion of the limbs or torso), muscle weakness and "twitches". There may also be cognitive or sensory overload (e.g. photophobia and hypersensitivity to noise and/or emotional overload, which may lead to "crash" periods and/or anxiety). A review of research relating to the neuropsychological functioning in CFS was published in 2001 and found that slowed processing speed, impaired working memory and poor learning of information are the most prominent features of cognitive dysfunctioning in patients with CFS, which couldn\'t be accounted solely by the severity of the depression and anxiety.Michiels V, Cluydts R (2001). "Neuropsychological functioning in chronic fatigue syndrome: a review.". Acta Psychiatr Scand 103 (2): 84-93. PMID 11167310. 

• Autonomic manifestations: Common occurrences include orthostatic intolerance, neurally mediated hypotension (NMH), postural orthostatic tachycardia syndrome (POTS), delayed postural hypotension, lightheadedness, extreme pallor, nausea and irritable bowel syndrome, urinary frequency and bladder dysfunction, palpitations with or without cardiac arrhythmias, and exertional dyspnea (perceived difficulty breathing or pain on breathing).

• Neuroendocrine manifestations: Common occurrences include poor temperature control or loss of thermostatic stability, subnormal body temperature and marked daily fluctuation, sweating episodes, recurrent feelings of feverishness and cold extremities, intolerance of extremes of heat and cold, digestive disturbancesBurnet RB, Chatterton BE (2004). "Gastric emptying is slow in chronic fatigue syndrome.". BMC Gastroenterol 4: 32. PMID 15619332.  and/or marked weight change - anorexia or abnormal appetite, loss of adaptability and worsening of symptoms with stress.

• Immune manifestations: Common occurrences include tender lymph nodes, recurrent sore throat, recurrent flu-like symptoms, general malaise, new sensitivities to food and/or medications and/or chemicals (which may complicate treatment). At least one study has confirmed that most CFS patients reduce or cease alcohol intake, mostly due to personal experience of worsening symptomsWoolley J, Allen R, Wessely S (2004). "Alcohol use in chronic fatigue syndrome.". J Psychosom Res 56 (2): 203-6. PMID 15016579.  (although the cause of this is unknown and may not be strictly "immunological" as implied by the symptom list).

Activity levels

Patients report critical reductions in levels of physical activityMcCully KK, Sisto SA, Natelson BH (1996). "Use of exercise for treatment of chronic fatigue syndrome.". Sports Med 21 (1): 35-48. PMID 8771284.  and are as impaired as persons whose fatigue can be explained by another medical or a psychiatric condition.Solomon L, Nisenbaum R, Reyes M, Papanicolaou DA, Reeves WC (2003). "Functional status of persons with chronic fatigue syndrome in the Wichita, Kansas, population.". Health Qual Life Outcomes 1 (1): 48. PMID 14577835.  According to the CDC, studies show that the disability in CFS patients is comparable to some well-known, very severe medical conditions, such as; multiple sclerosis, AIDS, lupus, rheumatoid arthritis, heart disease, end-stage renal disease, chronic obstructive pulmonary disease (COPD) and similar chronic conditions.[4] Press Conference: The Chronic Fatigue and Immune Dysfunction Syndrome Association of America and The Centers For Disease Control and Prevention Press Conference at The National Press Club to Launch a Chronic Fatigue Syndrome Awareness Campaign - November 3 2006, 10 a.m. ET[5] The Centers For Disease Control and Prevention (website): Chronic Fatigue Syndrome > For Healthcare Professionals > Symptoms > Clinical Course The severity of symptoms and disability is the same in both genders,Ho-Yen DO, McNamara I (1991). "General practitioners\' experience of the chronic fatigue syndrome". Br J Gen Pract 41 (349): 324-6. PMID 1777276.  and chronic pain is strongly disabling in CFS patients, but despite a common diagnosis the functional capacity of CFS patients varies greatly.Vanness JM, Snell CR, Strayer DR, Dempsey L 4th, Stevens SR (2003). "Subclassifying chronic fatigue syndrome through exercise testing.". Med Sci Sports Exerc 35 (6): 908-13. PMID 12783037.  While some patients are able to lead a relatively normal life, others are totally bed-bound and unable to care for themselves. A systematic review found that in a synthesis of studies, 42% of patients were employed, 54% were unemployed, 64% reported CFS-related work limitations, 55% were on disability benefits or temporary sick leave, and 19% worked full-time.Ross SD, Estok RP, Frame D, Stone LR, Ludensky V, Levine CB (2004). "Disability and chronic fatigue syndrome: a focus on function.". Arch Intern Med 164 (10): 1098-107. PMID 15159267. 

Proposed causes and pathophysiology

It has been suggested that this section be split into a new article. (Discuss)

The cause of CFS is unknown, although a large number of causes have been proposed. In a basic overview of CFS for health professionals, the CDC states that "After more than 3,000 research studies, there is now abundant scientific evidence that CFS is a real physiological illness."CDC - CFS Basic Overview (PDF file, 31 KB) The cause of CFS may be different for different patients, but if so, the various causes may result in a common clinical outcome.

Neurological abnormalities

Researchers have found evidence that CFS may involve distinct neurological abnormalities. MRI and SPECT scans show abnormalities within the brain.Schwartz RB, Garada BM, Komaroff AL, et al (1994). "Detection of intracranial abnormalities in patients with chronic fatigue syndrome: comparison of MR imaging and SPECT". AJR. American journal of roentgenology 162 (4): 935–41. PMID 8141020.  Studies have shown that CFS patients have abnormalities in blood flow to the brainAbu-Judeh HH, Levine S, Kumar M, et al (1998). "Comparison of SPET brain perfusion and 18F-FDG brain metabolism in patients with chronic fatigue syndrome". Nuclear medicine communications 19 (11): 1065–71. PMID 9861623.  possibly indicative of viral causeSchwartz RB, Komaroff AL, Garada BM, et al (1994). "SPECT imaging of the brain: comparison of findings in patients with chronic fatigue syndrome, AIDS dementia complex, and major unipolar depression". AJR. American journal of roentgenology 162 (4): 943–51. PMID 8141022.  and similar but not identical compared to patients with clinical depression.MacHale SM, Lawŕie SM, Cavanagh JT, et al (2000). "Cerebral perfusion in chronic fatigue syndrome and depression". The British Journal of Psychiatry : the journal of mental science 176: 550–6. PMID 10974961. Fischler B, D\'Haenen H, Cluydts R, et al (1996). "Comparison of 99m Tc HMPAO SPECT scan between chronic fatigue syndrome, major depression and healthy controls: an exploratory study of clinical correlates of regional cerebral blood flow". Neuropsychobiology 34 (4): 175–83. PMID 9121617.  A number of studies have shown that CFS patients have abnormal levels of neurotransmitters including increased serotoninDemitrack MA, Gold PW, Dale JK, Krahn DD, Kling MA, Straus SE (1992). "Plasma and cerebrospinal fluid monoamine metabolism in patients with chronic fatigue syndrome: preliminary findings". Biol. Psychiatry 32 (12): 1065–77. PMID 1282370. Badawy AA, Morgan CJ, Llewelyn MB, Albuquerque SR, Farmer A (2005). "Heterogeneity of serum tryptophan concentration and availability to the brain in patients with the chronic fatigue syndrome". J. Psychopharmacol. (Oxford) 19 (4): 385–91. doi:10.1177/0269881105053293. PMID 15982993.  (the opposite of what is found in primary depression).Cleare AJ, Bearn J, Allain T, et al (1995). "Contrasting neuroendocrine responses in depression and chronic fatigue syndrome". Journal of affective disorders 34 (4): 283–9. PMID 8550954.  Reduced brain serotonin receptor sensitivity or number,Cleare AJ, Messa C, Rabiner EA, Grasby PM (2005). "Brain 5-HT1A receptor binding in chronic fatigue syndrome measured using positron emission tomography and [11C]WAY-100635". Biol. Psychiatry 57 (3): 239–46. doi:10.1016/j.biopsych.2004.10.031. PMID 15691524.  and high auto antibodies to serotonin have also been found.Klein R, Berg PA (1995). "High incidence of antibodies to 5-hydroxytryptamine, gangliosides and phospholipids in patients with chronic fatigue and fibromyalgia syndrome and their relatives: evidence for a clinical entity of both disorders". Eur. J. Med. Res. 1 (1): 21–6. PMID 9392689.  Recent studies found altered gene expression in the brain’s serotonin and sympathetic nervous system pathways,Goertzel BN, Pennachin C, de Souza Coelho L, Gurbaxani B, Maloney EM, Jones JF (2006). "Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome". Pharmacogenomics 7 (3): 475–83. doi:10.2217/14622416.7.3.475. PMID 16610957.  with altered responses of the HPA axis to serotonin.Dinan TG, Majeed T, Lavelle E, Scott LV, Berti C, Behan P (1997). "Blunted serotonin-mediated activation of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome". Psychoneuroendocrinology 22 (4): 261–7. PMID 9226729.  Other reported neurotransmitter irregularities include glutamate,Kuratsune H, Yamaguti K, Lindh G, et al (2002). "Brain regions involved in fatigue sensation: reduced acetylcarnitine uptake into the brain". Neuroimage 17 (3): 1256–65. PMID 12414265.  acetylcholine sensitivity associated increased cutaneous microcirculation,Spence VA, Khan F, Kennedy G, Abbot NC, Belch JJ (2004). "Acetylcholine mediated vasodilatation in the microcirculation of patients with chronic fatigue syndrome". Prostaglandins Leukot. Essent. Fatty Acids 70 (4): 403–7. doi:10.1016/j.plefa.2003.12.016. PMID 15041034.  and autoantibodies to cholinergic receptors associated with central pain.Tanaka S, Kuratsune H, Hidaka Y, et al (2003). "Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome". Int. J. Mol. Med. 12 (2): 225–30. PMID 12851722.  Beta-endorphin, a natural pain killer, has been found to be low in CFS patients, the opposite of what is found in primary depression.Conti F, Pittoni V, Sacerdote P, Priori R, Meroni PL, Valesini G (1998). "Decreased immunoreactive beta-endorphin in mononuclear leucocytes from patients with chronic fatigue syndrome". Clin. Exp. Rheumatol. 16 (6): 729–32. PMID 9844768. Panerai AE, Vecchiet J, Panzeri P, et al (2002). "Peripheral blood mononuclear cell beta-endorphin concentration is decreased in chronic fatigue syndrome and fibromyalgia but not in depression: preliminary report". The Clinical journal of pain 18 (4): 270–3. PMID 12131069. 

Dysautonomia

Dysautonomia is the disruption of the function of the autonomic nervous system (ANS). The ANS controls many aspects of homeostasis. The dysautonomia that evidences itself in CFS shows up mostly in problems of orthostatic intolerance - the inability to stand up without feeling dizzy, faint, nauseated, etc.Goldstein DS, Robertson D, Esler M, Straus SE, Eisenhofer G (2002). "Dysautonomias: clinical disorders of the autonomic nervous system". Ann. Intern. Med. 137 (9): 753–63. PMID 12416949.  Research into the orthostatic intolerance found in CFS indicates it is very similar to that found in postural orthostatic tachycardia syndrome (POTS)Galland BC, Jackson PM, Sayers RM, Taylor BJ (2008). "A matched case control study of orthostatic intolerance in children/adolescents with chronic fatigue syndrome". Pediatr. Res. 63 (2): 196–202. doi:10.1203/PDR.0b013e31815ed612. PMID 18091356.  and hypocapnia.Natelson BH, Intriligator R, Cherniack NS, Chandler HK, Stewart JM (2007). "Hypocapnia is a biological marker for orthostatic intolerance in some patients with chronic fatigue syndrome". Dyn Med 6: 2. doi:10.1186/1476-5918-6-2. PMID 17263876.  POTS and CFS patients exhibit reduced blood flows to the heart upon standing that result in reduced blood flow to the brain. The reduced blood flows to the heart are believed to originate in blood pooling in the lower body upon standing. Many CFS patients report symptoms of orthostatic intolerance and low or lowered blood pressure.Newton JL, Okonkwo O, Sutcliffe K, Seth A, Shin J, Jones DE (2007). "Symptoms of autonomic dysfunction in chronic fatigue syndrome". QJM 100 (8): 519-26. doi:10.1093/qjmed/hcm057. PMID 17617647.  Tanaka H (2007). "[Autonomic function and child chronic fatigue syndrome]" (in Japanese). Nippon Rinsho 65 (6): 1105–12. PMID 17561705.  Stewart JM, Gewitz MH, Weldon A, Arlievsky N, Li K, Munoz J (1999). "Orthostatic intolerance in adolescent chronic fatigue syndrome". Pediatrics 103 (1): 116–21. PMID 9917448. 

Inner-ear disorders

Main article: balance disorder

Problems such as Meniere\'s, also tumor in the inner ear, Godefroy WP, Hastan D, van der Mey AG (2007). "Translabyrinthine surgery for disabling vertigo in vestibular schwannoma patients". Clin Otolaryngol 32 (3): 167–72. doi:10.1111/j.1365-2273.2007.01427.x. PMID 17550503. or Benign Paroxysmal Positional Vertigo (BPPV) can cause dizziness, vertigo, and fatigue. Tinnitus is also quite common.Byron M. Hyde (1992). The Clinical and scientific basis of myalgic encephalomyelitis/chronic fatigue syndrome. Ogdensburg, N.Y: Nightingale Research Foundation. ISBN 0-9695662-0-4.  Antibodies associated with hearing loss have been found in CFS and FMS patients with inner ear disordersHeller U, Becker EW, Zenner HP, Berg PA (1998). "[Incidence and clinical relevance of antibodies to phospholipids, serotonin and ganglioside in patients with sudden deafness and progressive inner ear hearing loss]" (in German). HNO 46 (6): 583-6. PMID 9677490. 

Orthostatic hypotension

Syndromes of orthostatic intolerance, in particular neurally mediated hypotension (NMH) and postural orthostatic tachycardia syndrome (POTS), have been shown to be associated with chronic fatigue syndrome.Tolan R, Stewart J. "Chronic Fatigue Syndrome", eMedicine, August 17 2006, retrieved November 9 2006. Rowe, PC. "General Information Brochure on Orthostatic Intolerance and its Treatment", Chronic Fatigue Clinic, Johns Hopkins Children\'s Center, February 2003, retrieved November 9 2006. These conditions, which reduce blood flow to the brain after periods of standing, can be diagnosed with a tilt table test. A clinical trial of fludrocortisone, a drug sometimes used to treat low blood pressure, showed little or no benefit for people with CFS.Rowe P, Calkins H, DeBusk K, McKenzie R, Anand R, Sharma G, Cuccherini B, Soto N, Hohman P, Snader S, Lucas K, Wolff M, Straus S (2001). "Fludrocortisone acetate to treat neurally mediated hypotension in chronic fatigue syndrome: a randomized controlled trial". JAMA 285 (1): 52-9. PMID 11150109. 

Psychiatric abnormalities

Depression

There is some overlap in symptoms between depression and CFS, and sometimes cases of CFS are mistakenly attributed to clinical depression. There are, however, many clinical differences between the two.Stein E (2001), "How to differentiate CFS from Psychiatric Disorder", Presented at The Alison Hunter Memorial Foundation Third International Clinical and Scientific Conference, Sydney, Australia

Clinical depression often responds well to physical exercise, whereas CFS is characterised by exercise intolerance but with a willingness to be active. (See section on post-exertion symptom exacerbation.) Comorbid depression occurs in 10-15% of CFS patients and should be treated as usual, except that the patient’s energy level, cognitive dysfunction and drug sensitivity must be taken into account. Comorbid depression may be a pre-existing condition, or the result of living with CFS.

Stress and trauma

The majority of people who experience stress/trauma do not develop CFS, but these factors (including infection) increase the likelihood of acquiring CFS within one yearSalit IE (1997). "Precipitating factors for the chronic fatigue syndrome.". J Psychiatr Res 31 (1): 59-65. PMID 9201648. Theorell T, Blomkvist V, Lindh G, Evengard B. "Critical life events, infections, and symptoms during the year preceding chronic fatigue syndrome (CFS): an examination of CFS patients and subjects wit